CHEMOTHERAPY

60. INTRODUCTION AND GENERAL COSIDERATIONS

Chemotherapy: It is study of drugs which selectively inhibit or destroy specific agents
of diseases like bacteria, viruses, fungi and parasites including neoplastic cells.
Paul Ehrlich first coined the term chemotherapy in 1913 to describe drugs which attack
invading organisms without harming the host (magic bullet).
Chemotherapeutic agents are one of the most frequently used as misused class of drugs.
 TERMS AND CONCEPTS

Chemotherapeutic agents: Drugs or substances which are used to interfere with the
functioning of any type of foreign cells. These include all antibacterial, antifungal, antiviral,
antiprotozoal, anthelmintic and antineoplastic drugs.

Antibiotics: Antibiotics are agents (chemical) which are produced by various species of
microorganisms (e.g. bacteria, fungi and actinomycetes) and are used to kill or suppress
growth of other microorganisms or foreign cells. Synthetic agents are not antibiotics, but it is
antimicrobials or antibacterials.
Antimicrobials: All chemical substances, whether natural, synthetic or semi-synthetic which
are used to kill or suppress the growth of microorganisms.

Selective toxicity
Selective toxicity is the ability of an antimicrobial agent to kill an invading microorganism
without harming the cells of its host.
A drug that disrupts a microbial function not found in eukaryotic animal cells often has a
greater selective toxicity and a higher therapeutic index.

Bacteriostatic activity: It is the ability of an antibacterial agent to inhibit the growth and
multiplication of bacteria. The inhibited growth in time results in the death of organism
and/or the removal of organism by the host's defence cells.

Bactericidal activity: It is the ability of an antibacterial agent to cause death of bacteria.

The distinction between static and cidal actions is narrow for certain drugs as some
bacteriostatic (e.g. erythromycin and nitrofurantoin) becomes bactericidal at higher
concentrations.
Some bactericidal drugs (e.g. streptomycin) are only bacteriostatic under certain
circumstances.
It is also possible for an antimicrobial agent to be static for one organism and cidal for
another. e.g. chloramphenicol is bacteriostatic against Gram negative rods and bactericidal
for pneumococci.

Antimicrobial (Antibacterial) spectrum: It is the range of pathogenic organisms (e.g.

bacteria) against which an antimicrobial agent is active.
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They are often classified as broad spectrum or narrow spectrum.
The broad spectrum antimicrobials are active against a wide variety of orgasms (e.g. both
gram-positive and gram-negative bacteria), while narrow range antimicrobials are active
against a few class/type of organisms (e.g. gram negative or gram positive bacteria).
Extended spectrum is the term applied to antimicrobials those are effective against gram-
positive bacteria and also against a significant number of gram-negative bacteria (e.g.
ampicillin + sulbactam).

Potency
It is the antimicrobial activity per milligram (microgram) of a chemotherapeutic agent.
Potency is usually expressed on the basis of minimum inhibitory concentration (MIC),
minimum bacterial concentration (MBC) or minimum antibiotic concentration (MAC). All
these indices are determined in vitro.

Minimum inhibitory concentration (MIC): It is the lowest concentration of an

antimicrobial drug that prevents visible growth of bacteria when grown against sequentially
diminishing drug concentrations in vitro.
The MIC is the most commonly used standard by which activity of a particular antimicrobial
agent is judged, but the reported MIC for a particular bacterial species is not always constant.
The MIC of bacteria may differ with a subsequent infection by the same bacteria and also
may change during the course of infections.

MIC90: It is the MIC necessary to inhibit 90 percent of the organism tested.

Minimum bactericidal concentration (MBC): It is the lowest concentration of an

antimicrobial drug that kills the bacteria. The MBC is also determined in vitro in a fashion
similar to the MIC.

Minimum antibiotic concentration (MAC): It is the concentration of an antimicrobial drug

that reduces the growth of an organism in vitro by a factor of 10 (e.g. one log).
The MAC may be one-quarter or one-tenth of the MIC depending on the drug and the
organism.

Post-antibiotic effect (PAE): It is the persistence of the antimicrobial effect for a longer
period (few hours) after brief exposure to or in absence of detectable concentration of an
antimicrobial drug.
PAE varies with each drug and each organism. e.g. aminoglycosides are given at 12 to 24
hours intervals, although their half-lives are much shorter.

Biphasic (Eagle) effect: It is a phenomenon in which low doses of an antibacterial in vitro

against certain bacteria (e.g. staphylococci and streptococci) produce lysis whereas high
doses do not.

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Chemotherapeutic index: The ratio of toxic dosage level to the therapeutic dosage level is
termed the chemotherapeutic index. The higher this number safer is the drug.

 Properties of an Ideal Antimicrobial Agent

An ideal antimicrobial agent (AMA) should possess following characteristics.
1) It should have a powerful action against microorganisms.
2) It should have selective toxicity i.e. acts specifically on invading organisms without
any toxicity to host.
3) It should not be inactivated rapidly by tissue enzymes or GIT microflora.
4) It should have good oral bioavailability and penetrate efficiently to various body
tissues and fluids.
5) It should have long elimination half-life and not rapidly excreted by kidneys bile.
6) It should not favour bacterial resistance.
7) It should not interfere with host immune mechanisms.
8) It should be non-allergenic.
9) It should not show adverse drug interactions with other antimicrobial drugs.
10) It should have no/short withdrawal time in food-producing animals.
11) It should have a long shelf-life.
12) It should be easily available and cheap.

 CLASSIFICATION OF ANTIMICROBIAL DRUGS

The antimicrobial drugs can be classified in several ways based on mechanism of

action, chemical structure, type of organism/therapeutic use, spectrum of activity, type of
action and Sources.
A. Based on mechanism of action:
[Link] that inhibit cell wall synthesis
e.g. Penicillins, cephalosporins, monobactams, carbapenems,
cycloserine,bacitracin,vancomycin and clotrimazole.
[Link] that inhibit cytoplasmic membrane function
e.g. Polymyxins,amphotericin-B and nystatin.
[Link] that inhibit protein synthesis
e.g. Chloramphenicol and macrolides (50S), tetracyclines and aminoglycosides (30S).
[Link] that affect nucleic acid metabolism and synthesis
e.g. Fluoroquinolones,rifampicin,idoxuridine and acyclovir.
[Link] that interfere with intermediary metabolism
e.g. Sulphonamides and trimethoprim.

B. Based on chemical structure:

[Link]: e.g. Sulphadimidine,sulphadiazine and sulphanilamide.

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[Link]: e.g. Trimethoprim,ormethoprim and baquiloprim.
[Link]: e.g. Nalidixic acid,enrofloxacin, moxifloxacin & ciprofloxacin.
[Link]-lactam antibiotics: e.g. Penicillins, cephalosporins, monobactams & carbapenems.
[Link]: e.g. Streptomycin, gentamicin,amikacin and tobramycin.
[Link]: [Link],tetracycline,doxycycline and minocycline.
[Link] antibiotics: e.g. Erythromycin and azithromycin.
[Link] antibiotics: e.g. Polymixin-B,colistin and bacitracin.
[Link] derivatives: e.g. Nitrofurantoin and furazolidone.
[Link]: e.g. Metronidazole and tinidazole.
[Link] antibiotics: e.g. Nystatin and amphotericin-B.
[Link] derivatives: e.g. Ketoconazole,fluconazole and clotrimazole
C. Based on type of organism affected/therapeutic uses:
[Link]: e.g. Penicillins,aminoglycosides,tetracyclines & chloramphenicol.
[Link]: e.g. Amphotericin-B,griseofulvin and ketoconazole.
[Link]: e.g. Idoxuridine,vidaravine,zidovudine and ribavirin.
[Link]: e.g. Metronidazole,quinapyramine and diminazine.
[Link]: e.g. Albendazole,levamisole,niclosamide and praziquantel.
[Link]: e.g. Deltamethrin, cypermethrin, lindane &amitraz.
D. Based on spectrum of activity:
[Link] spectrum antimicrobials: e.g. Penicillin-G, streptomycin,erythromycin &
vancomycin.
[Link]-spectrum antimicrobials: e.g. Tetracycline,chloramphenicol,cephalexin,
gentamicin & ampicillin.
E. Based on type of action:
[Link]: e.g. Sulphonamides,chloramphenicol,erythromycin,trimethoprim&
clindamycin.
2. Bactericidal: e.g. Penicillin-G,cephalexin,streptomycin,vancomycin,bacitracin&
potentiated sulphonamides.
F. Based on Sources:
1. Natural and semi-synthetic:
a) Fungi: e.g. Penicillin-G, griseofulvin and cephalexin.
b) Actinomycetes: e.g. Streptomycin, tetracycline, erythromycin & chloramphenicol.
c) Bacteria: e.g. Polymyxin-B, colistin & bacitracin.
2. Synthetic:
e.g. Sulphonamides,trimethoprim, fluoroquinolones,nitrofurans and nitroimidazoles.

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 FACTORS AFFECTING CHOICE OF AN ANTIMICROBIAL AGENT

Choice of an antimicrobial agent depends mainly on three factors:

1. Organisms related factors
2. Drug related factors
3. Host related factors

1. Organisms related factors

Target organism:
• Identification of causative organism can be made from historical data and
experience or by cultural method.
• A rapid identification by Gram-stain.
Sensitivity pattern:
• It is important to select right antimicrobial drug.
• This is useful when there is wide variation in the susceptibility of different bacterial
species to antimicrobial agent.
• Disc diffusion test/bacterial sensitivity testing is the most commonly used method to
determine susceptibility to antimicrobials.
2. Drug related factors
Spectrum of activity:
• When target organism is known then a narrow spectrum drug that selectivity
affect the concerned organism is preferred.
• If serious life-threatening infections, causative organism is not known then to cover
all likely organisms with a broad spectrum drug may be used.

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• Polymicrobial/mix infection requires a broad-spectrum antimicrobial agent or
combination of two or more agents.
Type of activity required:
• A bactericidal drug may be preferred over bacteriostatic drug in the treatment of life-
threatening infections, endocarditis, infections at less accessible sites and in impaired
host defence status.
• As bacteriostatic drugs should be used only when host immunity is strong and
systems are functioning normally.

Pharmacokinetic profile:
 The PK profile determines the effective concentration of drugs at site of infection for
adequate length of time.
 E.g. Chloramphenicol and macrolides are extensively metabolized and so are not used
to treat urinary tract infections (e.g. nalidixic acid, nitrofurantoin are preferred).
 The fluoroquinolones have excellent tissue penetration and attain high concentrations
in body tissues.
 Sulphonamides and chloramphenicol are readily enter into CSF, whereas penicillins
and aminoglycosides penetrate poorly into CSF.
Route of administration:
• For critically ill patients, a parenteral route, in particular intravenous route, is
preferred.
• Intrathecal injection prefer to attain effective concentration in the CSF.
• Oral route is preferred for long-term administration, for non-hospitalised animals and
when target is GIT infection.
• Aminoglycosides, penicillin G, many cephalosporins and vancomycin have to given
by injection only.
Drug interactions:
• Antimicrobials are often used in combination with analgesics and anti-inflammatory
agents, in some cases decrease efficacy or enhance toxicity of antimicrobial agents
may observed.
• E.g. NSAIDs enhance CNS toxicity of fluoroquinolones.
• Concurrent use of procaine antagonises action of sulphonamides.
Relative toxicity:
• Penicillins are among the least toxic of all antimicrobial drugs, so should be preferred
over aminoglycosides and chloramphenicol.
• However, penicillins are contraindicated in patients those are hypersensitive to the
group.
• Drugs like chloramphenicol and clindamycin are reserved for specific or life-
threatening infections because of their potential for serious toxicity.
Antimicrobial policy:
• In general, a narrow spectrum and specific antimicrobial should be used and newer
and broad spectrum drugs should be reserved for situations where they are
specifically intended.
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• E.g. Fluoroquinolones are not recommended in food-animals due to increase chance
of developing bacterial resistance in humans.
Cost of therapy:
• Several drugs may show similar efficacy in treating an infection, but vary widely in
cost.
• In such cases, a less costly and easily available drug should be preferred in
veterinary.
3. Host related factors
Host-defence mechanisms:
• Elimination of infecting organism depends on the status of host defence mechanisms.
• If good immune status, bacteriostatic drugs are preferred whereas poor immune status
then bactericidal drugs are preferred.
• Higher than usual doses of bactericidal agents and longer treatment are required to
eliminate infecting organisms in immuno-compromised patients.

Pathological conditions:
• Renal insufficiency, hepatic dysfunction and meningitis often alter response and toxic
potential of some antimicrobial agents.
• Renal disease: Predispose to toxic effects of the aminoglycosides.
• Hepatic dysfunction: e.g. tetracyclines are contraindicated in treating patients with
liver diseases.
• Meningitis: Penicillins should not be used in meningitis because they concentrate
more in CNS and increases chances of CNS seizures.
Local factors:
• Pus: Presence of pus, tissues debris and body secretions decreases efficacy
ofsulphonamides and aminoglycosides.
• Haematomas: It favour bacterial growth and impair activity of penicillins,
cephalosporins and tetracyclines.
• pH: The pH of body fluid determines the efficacy of certain drugs. E.g.
Aminoglycosides are more active in alkaline urine whereas methenamine and
nitrofurantoin are more active in acidic urine. Penicillin G is inactivated in acidic
pH.
Age:
• Renal and hepatic elimination processes are often poorly developed in newborns
therefore are more susceptible to toxic effects of chloramphenicol and
sulphonamides.
• Tetracyclines are contraindicated in young animals because they accumulate in
developing bone and teeth and discolour and weaken them.
• Fluoroquinolones are contraindicated in growing dogs because they damage joint
cartilage.
Species:
• E.g. Tetracyclines by any route may be associated with enterocolitis in horses, hence
TCs should not be used in horses.

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• Broad-spectrum antimicrobial agents are usually not administered by oral route in
ruminants because they disrupt bacterial fermentation.
• Cats are more susceptible to chloramphenicol toxicity due to deficient glucuronide
conjugation (glucuronide transfersae enzyme absent).
Pregnancy:
• Antimicrobials should be avoided in pregnant animals except when essentially
required, because many drugs cross placenta.
• Aminoglycosides causes hearing loss and tetracyclines decreases bone growth in
foetus.
• Some anthelmintics are embryotoxic and teratogenic.

Genetic factors:
• Certain genetic abnormalities must be considered while choosing antimicrobial
agents.
• E.g. sulphonamides and chloramphenicol may produce acute haemolysis in patients
with glucose-6-phosphate dehydrogenase deficiency.
 COMBINATION OF ANTIMICROBIAL DRUGS
The combined use of two or more antimicrobial drugs is occasionally required to treat certain
infections.
Advantages of Combination of AMA:
 To broaden the spectrum of antibacterial activity.
 To treat mixed bacterial infections in which organisms are not susceptible to a single
antimicrobial drug.
 To achieve synergistic antimicrobial activity against some resistant strains of bacteria.
 To prevent emergence of resistant strains of bacteria.
 To minimise toxicity of an antimicrobial drug
Disadvantages of Combination of AMA:
 Two drugs may interfere with each other's action.
 It increases chances of superinfection and also bacterial resistance.
 It may also increase the cost of therapy.
Guidelines (Rules) for combination of antimicrobial drugs
1) Bactericidal drugs + bactericidal drugs = synergistic effect (1+1= >2)
e.g. penicillin G + streptomycin; sulphamethoxazole + trimethoprim
2) Bacteriostatic drugs + bacteriostatic drugs = additive effect (1+1= 2)
3) Bactericidal drug + bacteriostatic agent = antagonistic effect (1+1= <2)
e.g. tetracyclines (or chloramphenicol) + penicillins

Bactericidal Drugs Bacteriostatic Drugs

Penicillins Chloramphenicol
Cephalosporins Tetracyclines
Aminoglycosides Macrolides

RESISTANCE TO ANTIBACTERIAL DRUGS

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Since the 1940s, the development of effective and safe drugs to deal with bacterial
and other infections has revolutionised treatment and the morbidity and mortality associated
with these diseases has been dramatically reduced. Unfortunately, the development of
effective antibacterial drugs has been accompanied by the emergence of drug-resistant
organisms. The phenomenon of resistance imposes serious constraints on the options
available for the treatment of many bacterial infections.
Antibiotic resistance in bacteria spreads in three ways:

 by transfer of bacteria between animals

 by transfer of resistance genes between bacteria (usually on plasmids)
 by transfer of resistance genes between genetic elements within bacteria, on
transposons.

GENETIC DETERMINANTS OF ANTIBIOTIC RESISTANCE

CHROMOSOMAL DETERMINANTS: MUTATIONS

The spontaneous mutation rate in bacterial populations for any particular gene is very low,
and the probability is that approximately only 1 cell in 10 million will, on division, give rise
to a daughter cell containing a mutation in that gene. However, as there are likely to be very
many more cells than this over the course of an infection, the probability of a mutation
causing a change from drug sensitivity to drug resistance can be quite high with some species
of bacteria and with some drugs.

Resistance resulting from chromosomal mutation is important in some instances, notably

infections with methicillin-resistant S. aureus (MRSA) and in tuberculosis, but this type of
resistance is of limited clinical relevance, possibly because the mutants often have reduced
pathogenicity

EXTRACHROMOSOMAL DETERMINANTS: PLASMIDS

In addition to the chromosome itself, many species of bacteria contain extrachromosomal

genetic elements called plasmids that exist free in the cytoplasm. These are also genetic
elements that can replicate independently. Structurally, they are closed loops of DNA that
may comprise a single gene or as many as 500 or even more. Only a few plasmid copies may
exist in the cell but often multiple copies are present, and there may also be more than one
type of plasmid in each bacterial cell. Plasmids that carry genes for resistance to antibiotics (r
genes) are referred to as R plasmids. Much of the drug resistance encountered in clinical
medicine is plasmid-determined. It is not known how these genes arose.

THE TRANSFER OF RESISTANCE GENES BETWEEN GENETIC ELEMENTS

WITHIN THE BACTERIUM
Transposons

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Some stretches of DNA are readily transferred (transposed) from one plasmid to another and
also from plasmid to chromosome or vice versa. This is because integration of these segments
of DNA, which are called transposons, into the acceptor DNA can occur independently of the
normal mechanism of homologous genetic recombination. Unlike plasmids, transposons are
not able to replicate independently, although some may replicate during the process of
integration resulting in a copy in both the donor and the acceptor DNA molecules.
Transposons may carry one or more resistance genes (see below) and can 'hitch-hike' on a
plasmid to a new species of bacterium. Even if the plasmid is unable to replicate in the new
host, the transposon may integrate into the new host's chromosome or into its indigenous
plasmids. This probably accounts for the widespread distribution of certain of the resistance
genes on different R plasmids and among unrelated bacteria.

Gene cassettes and integrons

Resistance-in fact, multidrug resistance-can also be spread by another mobile element, the
gene cassette, which consists of a resistance gene attached to a small recognition site. Several
cassettes may be packaged together in a multicassette array, which can, in turn, be integrated
into a larger mobile DNA unit termed an integron. The integron (which may be located on a
transposon) contains a gene for an enzyme, integrase (recombinase), which inserts the
cassette(s) at unique sites on the integron. This system-transposon/integron/multiresistance
cassette array-allows particularly rapid and efficient transfer of multidrug resistance between
genetic elements both within and between bacteria.

THE TRANSFER OF RESISTANCE GENES BETWEEN BACTERIA

The transfer of resistance genes between bacteria of the same and indeed of different species
is of fundamental importance in the spread of antibiotic resistance. The most important
mechanism in this context is conjugation. Other gene transfer mechanisms, transduction and
transformation, are of little importance in spreading resistance genes.

Conjugation

Conjugation involves cell-to-cell contact during which chromosomal or extrachromosomal

DNA is transferred from one bacterium to another, and is the main mechanism for the spread
of resistance. The ability to conjugate is encoded in conjugative plasmids; these are plasmids
that contain transfer genes, which, in coliform bacteria, code for the production by the host
bacterium of proteinaceous surface tubules, termed sex pili, that connect the two cells. The
conjugative plasmid then passes across from one bacterial cell to another (generally of the
same species). Many Gram-negative and some Gram-positive bacteria can conjugate. The
transfer of resistance by conjugation is significant in populations of bacteria that are normally
found at high densities, as in the gut.

Transduction

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Transduction is a process by which plasmid DNA is enclosed in a bacterial virus (or phage)
and transferred to another bacterium of the same species. It is a relatively ineffective means
of transfer of genetic material but is clinically important in the transmission of resistance
genes between strains of staphylococci and of streptococci.

Transformation

A few species of bacteria can, under natural conditions, undergo transformation by taking up
DNA from the environment and incorporating it into the genome by normal homologous
recombination. Transformation is not of importance clinically

BIOCHEMICAL MECHANISMS OF RESISTANCE TO ANTIBIOTICS

1) THE PRODUCTION OF AN ENZYME THAT INACTIVATES THE DRUG
Inactivation of β-lactam antibiotics : The most important example of resistance caused by
inactivation is that of the β-lactam antibiotics. The enzymes concerned are β-lactamases,
which cleave the β-lactam ring of penicillins and cephalosporins. Cross-resistance between
the two classes of antibiotic is not complete, because some β-lactamases have a preference
for penicillins and some for cephalosporins

Inactivation of chloramphenicol : Chloramphenicol is inactivated by chloramphenicol

acetyltransferase, an enzyme produced by resistant strains of both Gram-positive and Gram-
negative organisms, the resistance gene being plasmid-borne. In Gram-negative bacteria, the
enzyme is produced constitutively, resulting in levels of resistance fivefold higher than in
Gram-positive bacteria, in which the enzyme is inducible.

Inactivation of aminoglycosides : Aminoglycosides are inactivated by phosphorylation,

adenylation or acetylation, and the requisite enzymes are found in both Gram-negative and
Gram-positive organisms. The resistance genes are carried on plasmids, and several are found
on transposons.

2) ALTERATION OF DRUG-SENSITIVE OR DRUG-BINDING SITE

The aminoglycoside-binding site on the 30S subunit of the ribosome may be altered by
chromosomal mutation. A plasmid-mediated alteration of the binding site protein on the 50S
subunit also underlies resistance to erythromycin , and decreased binding of
fluoroquinolones because of a point mutation in DNA gyrase A has recently been described.
An altered DNA-dependent RNA polymerase determined by a chromosomal mutation is
reported to be the basis for rifampicin resistance.

In addition to acquiring resistance to β-lactams susceptible to β-lactamase, some strains of S.

aureus have even become resistant to some antibiotics that are not significantly inactivated
by β-lactamase (e.g. methicillin), because they express an additional β-lactam-binding protein
coded for by a mutated chromosomal gene.
3) DECREASED DRUG ACCUMULATION IN THE BACTERIUM
An important example of decreased drug accumulation is the plasmid-mediated resistance to
tetracyclines encountered in both Gram-positive and Gram-negative bacteria. In this case,
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resistance genes in the plasmid code for inducible proteins in the bacterial membrane, which
promote energy-dependent efflux of the tetracyclines, and hence resistance. This type of
resistance is common and has greatly reduced the therapeutic value of the tetracyclines in
human and veterinary medicine. Resistance of S. aureus to erythromycin and the other
macrolides, and to fluoroquinolones, is also brought about by energy-dependent efflux.

Multidrug resistance

 Many pathogenic bacteria have developed resistance to the commonly used

antibiotics. Examples include:
o some strains of staphylococci and enterococci that are resistant to virtually all
current antibiotics, the resistance being transferred by transposons and/or
plasmids; such organisms can cause serious and virtually untreatable
nosocomial infections
o Some strains of Mycobacterium tuberculosis that have become resistant to
most antituberculosis agents.

SULPHONAMIDES
 Sulphonamides (Sulfonamides) are a group of synthetic antibacterial drugs (they are not
antibiotics).
 They were the first chemotherapeutic agents used systemically for prevention and
treatment of various bacterial infections.
 Sulphonamides was first discovered by Domagk in 1935, who demonstrated that
prontosil dye is effective against streptococcal infection in mice and its antibacterial
activity is due to the release of an active metabolite, the sulphanilamide.
 For this discovery, he was awarded with noble prize in 1938.
 Sulphanilamide was synthesised and introduced in market as the first sulphonamide for
antibacterial use.

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 Since then, a large number of sulphonamides with variable pharmacokinetic and
antibacterial spectrum have been developed for use in human and veterinary
medicines.
Chemical Properties and Solubility
 Sulphonamides are weak organic compounds.
 Most of these compounds are relatively insoluble in water, but their sodium salts are
water-soluble.
 The sodium salts have an alkaline pH (except sulphacetamide) and sulphonamides are
about twice or more soluble in alkaline pH.
 In acidic urine, sulphonamides may form crystals because of their decreased solubility.
Structure-Activity Relationship:
 Sulphonamides possess a common chemical nucleus, which is closely related to
para-aminobenzoic acid (PABA).
 This nucleus is essential for antibacterial activity.
 Sulphonamide nucleus possesses two amine groups, which have been designated as N4
and N1.

 The para-amino group (NH2) is designated as N4; the Sulphamoyl (SO2NH2) as N1.
 Presence of para amino group is essential for antibacterial activity
 Substitution at N1 leads to systemic acting where as N4 leads to gut acting.
 Substitution at N1 by heterocyclic aromatic nuclei yield high potent compound
(sulphadimidine)- Systemic acting.
 Any substitution on benzene ring results in loss of antibacterial activity.
 Acetylation at N1 may not alter chemotherapeutic activity but such compound become
more water soluble and less toxic. e.g. sulphacetamide.
 Acetylation at N4 may decrease water solubility and increase renal toxicity
Classification
A) Based on their site of action
1. Gut-acting sulphonamides
e.g. succinylsulphathiazole, phthalylsulphathiazole, phthalylsulphacetamide,
sulphaguinidine and sulphasalazine.
2. Topically acting sulphonamides
e.g. sulphacetamide, mafenide and silver sulphadiazine.
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3. Renal sulphonamide
e.g. Sulfisoxazole
4. Opthalmic sulphonamide
e.g. Sulphacetamide

B) Based on their duration of action

1) Short acting sulphonamides (duration <12 hours)
e.g. sulphadiazine, sulphafurazole, sulphamerazine, sulphachlorpyridazine,
sulphathiazole and sulphanilamide.
2) Intermediate acting sulphonamides (duration 12-24 hours)
e.g. sulphadimidine, sulphamethoxazole, sulphamoxole and sulphaphenazole
3) Long-acting sulphonamides (duration 24 - 48 hours).
e.g. sulphadimethoxine, sulphaethoxypyridazine, sulphamethoxypyridazine and
sulphabromomethazine.
4) Ultra-long acting sulphonamides (duration > 48 hours)
e.g. sulphadoxine and sulphamethopyrazine.
Mechanism of Action
 Sulphonamides are structural analogues of para-aminobenzoic acid (PABA).
 PABA is an essential component of folic acid (Vitamin B9). Mammals require
preformed folic acid in their diet whereas many bacteria utilise PABA for the synthesis
of folic acid & this folic acid is vital for bacterial multiplication and growth.
 When a sulphonamide is given then due to its structural similarity with PABA, it
blocks utilisation of PABA in susceptible bacteria and, thus, inhibits synthesis of
folic acid.
 Sulphonamide act by competitively inhibiting dihydropteroate synthetase enzyme
in folic acid biosynthesis path.
 The sulphonamides are primarily bacteriostatic and have no effect on resting bacteria
(mature).
 Sulphonamides are more effective in acute stage of infection because in acute
infections bacteria multiply at a much faster rate utilising large amounts of PABA.
 Pus and tissue debris may also contain large amount of PABA therefore,
sulphonamides are less effective in the presence of necrotic tissues, pus and tissue
extracts.
 Sulphonamides do not affect animal cells because mammalian cells utilise the
preformed folic acid.

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Figure: Mechanism of Action of Sulphonamides and Trimethoprim
 Note: Sulphonamides show synergistic action with trimethoprim. Trimethoprim is a
potent and selective competitive inhibitor of dihydrofolate reductase enzyme in
susceptible microorganisms. Thus combination of sulphonamide and trimethoprim
produces sequential blocks in the synthesis of folic acid. This combination showed
bactericidal action.
Antimicrobial Spectrum
 Sulphonamides are broad-spectrum antimicrobial drugs.
 They are primarily bacteriostatic with moderate to good activity against many gram-
positive and gram-negative bacteria including Streptococcus spp., Haemophilus
influenzae, Actinomyces spp., Bacillus spp., Brucella spp., C hl amydi a spp.,
Past eurel l a spp., K l ebsi el l a spp., Enterobacteriaceae and some Clostridium
spp.
 Leptospira, Pseudomonas, Mycobacterium, Mycoplasma and Rickettsia species and
spirochetes are resistant to sulphonamides.
 Some protozoa like Coccidia and Toxoplasma are also sensitive to sulphonamides.
Bacterial Resistance
Bacterial develop resistance to sulphonamides is very fast. Acquired bacterial resistance to
sulphonamides is common.
Various mechanism includes:
a) An alteration in the enzymes those utilise PABA i.e. the dihydropteroate synthase
enzyme.
Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019
b) Adoption of alternate pathway for synthesis of folic acid.
c) An increase capacity of bacteria to destroy or inactivate sulphonamides.
d) An increased production of PABA or essential metabolites.
e) Decreased drug permeability into the bacterial cell or active efflux of drug from the
target bacteria.
To reduce bacterial resistance, sulphonamide therapy should be initiated in acute stage
of disease & it should be continued atleast for 3 days or till compete recovery. Give high
initial doses and followed by smaller maintenance doses of sulphonamide.
Pharmacokinetics
 Systemically acting sulphonamides are usually well absorbed (70-100%) following
oral administration mainly from the small intestine.
 The absorption rate is affected by the solubility of sulphonamides and presence of
ingesta in the GI tract. In general, dogs, cats and birds absorb sulphonamides rapidly,
pigs take some time, and cattle require much longer time.
 Parenteral administration of sulphonamides can be painful, as the solutions of
sulphonamides are strongly alkaline.
 After absorption, sulphonamides diffuse well into body tissues and fluids. All
sulphonamides bind to plasma proteins (albumin) to variable extent.
 The sulphonamides are primarily metabolised by acetylation process.
 The acetylated metabolites can conjugate with glucuronic acid or sulphate which do
not have any antimicrobial activity.
 Acetylation of sulphonamides reduces their solubility thus promoting crystallization
 In cattle sulphonamides are more toxic due to extensive acetylation.
 Dogs lack in the ability to acetylate sulphonamides., therefore, toxicity of
sulphonamides is comparatively less in dogs.
 The main metabolic pathway of sulphonamides in dogs is glucuronide conjugation and
the conjugate metabolites are soluble.
 Sulphonamides or their metabolites are excreted mainly by kidney through glomerular
filtration although renal tubular secretion and reabsorption also occur
 Alkalinisation of urine favours ionisation of sulphonamides and its rapid elimination.
Sulphonamides are also excreted in tears, faeces, bile and sweat.
 Gut acting sulphonamides are poorly absorbed from GIT and mainly excreted in
faeces.
Side effects/Adverse effects
The most important toxic effects of sulphonamides are on kidneys.
Acute Toxicity:
a. Renal toxicity:
 Renal toxicity occurs due to precipitation of the sulphonamide in the glomerular
filtrate leading to crystallisation, haematuria and obstruction of renal tubules, ureter
and even bladder.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 Chances of crystalluria are more in dehydrated animals as the urine may contain drug
concentrations above solubility limits resulting in crystal formation.
 Clinical use of less water soluble sulphonamides or rapidly excreting sulphonamides
(e.g. sulphathiazole) have greater tendency to get precipitated in the renal tubules.
 In general, carnivores and omnivores (acidic urine- dogs & cats) are more prone to
renal toxicity than herbivores (alkaline urine). Drug crystalised in acidic urine.
Crystalluria can be minimised or prevented by
 Appropriate doses and frequency of administration
 Supply enough drinking water .1.e"

 Do not continue therapy more than 7 days

 Use of urinary alkalizer e.g. sodium bicarbonate in dogs or cats.
 Use of combination of sulphonamide e.g. sulphonamides mixture (e.g. triple sulpha=
sulphapyridine + sulphamerazine + sulphadiazine) or sulphonamides whose acetylated
forms are more soluble (e.g. sulphadiazine or sulphadimidine).
b. Blood dyscrasias:
 Dyscrasia: Constituents of blood are abnormal or are present in abnormal quantity.
E.g. Leukemia, hemophilia
 Sulphonamides leads to haemolytic anaemia may occur either due to sensitisation or in
individuals with glucose-6-phosphate dehydrogenase deficiency.
c. Hypersensitivity reactions:
 Allergic skin rashes are frequent complication of sulpha therapy.
 Exfoliative dermatitis or cutaneous eruption may occur and are more common with
long acting sulphonamides.
 Sulphadiazine containing preparations may promote a reversible immune-mediated
sterile polyarthritis in Doberman breed. A syndrome similar to serum sickness or
immediate reactions of anaphylactoid type may also occur.
d. Other effects
 These include anorexia, vomiting, nausea and abdominal discomfort.
 Too rapid IV injection of a large dose of sulphonamide may produce ataxia,
convulsions, collapse and even death.
2. Chronic toxicity: Chronic toxicity occurs in dose-dependent manner
a) Hypoprothrombinaemia:
 Prolonged administration of certain sulphonamides may lead to vitamin K deficiency
due to inhibition of enzyme vitamin K epoxide reductase.
 This results in hypoprothrombinaemia and deficiency of other vitamin K dependent
clotting factors causing prolongation of bleeding and clotting time.
 It is mostly seen in poultry with sulphaquinoxaline (used for coccidiosis).
b) Kerato-conjunctivitis sicca (KCS) (Dry eye)

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 Prolonged treatment with certain sulphonamides (e.g. sulphasalazine, sulphadiazine
and sulphamethoxazole) may cause keratoconjunctivitis sicca in dogs.
c) Inhibition of carbonic anhydrous enzyme - poultry
 Inhibition of carbonic anhydrous enzyme resulting in accumulation of carbon dioxide
leading to acidosis.
 Carbonic anhydrous is also involved in eggshell production in poultry, so its inhibition
by sulphonamides may result in thin egg shells or even absence of egg shells.
d) Hepatic necrosis - dogs
 The slow acetylation often results in increased sulphadehydroxylamine metabolite,
which is hepatotoxic.
 Since dogs are slow acetylators, they are more susceptible to hepatic injury.
 Commonly observed with the use of Sulphadiazine + Trimethoprim or
Sulphamethoxazole + Trimethoprime or potentiated sulphonamide therapy.
e) Aplastic anaemia and thrombocytopenia:
 It may occur from a direct myelotoxic effect or due to an immune-mediated
component.
 Reduction in serum folate concentration, presumably by inhibition of folate production
by intestinal bacteria may also induce anaemia.
f) Other effects:
 Several other adverse effects of sulphonamides reported in domestic animals include
reduction in weight gain, decrease in egg production, formation of methaemoglobin,
drug-induced fever, hypoglycaemia or cardiomyopathy.
 In lab animal sulphamethazine leads to thyroid cancer.
Clinical Uses
 Sulphonamides are used in the treatment of various systemic and local infections
caused by susceptible bacteria in all species of animals. Also useful in Chlamydia,
Toxoplasma & Coccidia infection.

Route of administration

Sulphonamides are administered by various routes depending on the type of salt, solubility,
action required and species.

a. Oral route: It is commonly used to administer sulphonamides in domestic animals. The

drug may be administered orally in the form of tablet, bolus, powder or mixed in feed and
water.
b. Intravenous route: IV route is generally used for treatment of acute infections. It may be
followed by oral dose for maintenance therapy.
c. Intramuscular or Subcutaneous route: Sulphonamide preparations buffered to a neutral
pH may be administered by IM or SC route. Strong alkaline solutions must not be given by
IM or SC because they may cause severe irritation and sloughing of tissues.
Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019
d. Intrauterine route: Sulphonamide combined with urea is occasionally prescribed for
uterine infections.
e. Intramammary route: Oily suspensions of some sulphonamides are occasionally used for
the treatment of mastitis.
f. Topical route: Sulphonamides are generally not considered suitable for wound treatment
because of tissues debris.
Sulphacetamide solution is used for eye infection.
Mafenide and silver sulphadiazine are used topically to treat severe burns.

POTENTIATED SULPHONAMIDES
 Potentiated sulphonamides are the combinations of sulphonamides with 2,4-
diaminopyrimidines and related agents.
The combinations commonly used are
(1) sulphamethoxazole and trimethoprim (co-trimoxazole)
(2) sulphadiazine and trimethoprim (cotrimazine)
(3) sulphadimethoxine and ormetoprim
(4) sulphadimethoxine and baquiloprim
 Other 2,4-diaminopyrimidine derivatives used for combination with sulphonamides
include aditoprim, brodimoprim, iclaprim, methoprim, tetroxoprim and pyrimethamine.
 The choice of the sulphonamide and 2,4- diaminopyrimidine for combination depends
largely on their having similar pharmacokinetic (absorption and distribution) properties.
Mechanism of action
 The combination of sulphonamide with 2,4-diamino-pyi-imidine derivative results in
synergistic effect via blockade of sequential stages in the synthesis of tetrahydrofolate.
 Selective toxicity for microorganisms is achieved in two ways and the combination
becomes bactericidal [sulphonamides and 2,4-diaminopyrimidine (trimethoprim) when
used separately are bacteriostatic].
 The combination reduces by several folds the MIC of both drugs against a wide variety
of pathogenic organisms. This reduces the dose of sulphonamide required for
therapeutic effect and also chances of dose-dependent adverse effects.
 This combination also broadens the antibacterial spectrum and reduces chances of
bacterial resistance to drugs.
 Selectively inhibits the dihydrofolate reductase enzyme of microorganisms with
no/negligible effect on the enzyme of mammals. This is vitally important because
mammals also utilise dihydrofolate reductase enzyme in folic acid metabolic pathways.
1. Trimethoprim + Sulphamethoxazole (Co-trimoxazole)

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 The combination of trimethoprim with sulphamethoxazole, called co-trimoxazole. It is
widely used in therapeutics in human and veterinary practices.
 It contains 5 parts of sulphamethoxazole and 1 part of trimethoprim (ratio-5:1).
 The combination has broad spectrum activity against many gram-positive and gram-
negative organisms.
 In susceptible organisms, resistance usually develops due to acquisition of a plasmid
that codes for an altered dihydrofolate reductase.
 Absorption of co-trimoxazole is rapid with peak blood levels occurring between 1-4
hours after oral administration.
 It has a good distribution in the body as trimethoprim is more lipid soluble.
 In ruminants the combination is not given orally.
 Side effects are the same as observed with sulphonamides.

Clinical uses
 Co-trimoxazole is used in human and veterinary medicines for the treatment of a
variety of upper and lower respiratory tract infections, renal and urinary tract
infections, GIT infections, skin and wound infections, septicemia and infections caused
by sensitive bacteria.
 It is also used for treatment of coccidiosis in small animals.
 Cotrimoxazole is marketed in powder and tablets forms for oral administration and in
injectable formulation for parenteral use.
2. Trimethoprim + Sulphadiazine (Co-trimazine)
 Combination of trimethoprim + sulphadiazine (1:5).
 Its pharmacological properties, adverse effects and clinical uses are similar as Co-
trimoxazole. Co-trimazine is commercially available as injection.
 Commercially available in injection form contains 400 mg sulphadiazine and 80 mg
trimethoprim/ml of injection.
 Oral preparation like powder, tablet, oral paste, oral suspension, oral granules
and bolus are also available.
3. Ormatoprim + Sulphadimethoxine
 This is a newer combination, it has a longer duration of action than trimethoprim-
sulphamethoxzole combination.
 This is mainly used for the treatment of skin and soft tissue infection caused by
susceptible bacteria esp. in dogs.
 It is also approved for treatment and prophylaxis of coccidiosis in small animals.
4. Baquiloprim + Sulphadimethoxine
 It is used for dog and cats.
5. Baquiloprim + Sulphadimidine
 This combination is used clinically for the treatment of bacterial infections in cattle
and swine.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 The combination usually contains 5 parts sulphadimidine and 1 part baquiloprim
Examples of Potentiated Sulphonamides
I. Trimethoprim Combinations
1. Trimethoprim + Sulphamethoxazole
2. Trimethoprim + Sulphadiazine
3. Trimethoprim + Sulphadoxine
4. Trimethoprim + Sulphachlorpyridazine
5. Trimethoprim + Sulphadimethoxine
6. Trimethoprim + Sulphadimidine
7. Trimethoprim + Sulphafumzole
8. Trimethoprim + Sulphamerazine
9. Trimethoprim + Sulphamethoxypyridazine
10. Trimethoprim + Sulphatroxazole

II. Baquiloprim Contbinations

1. Baquiloprim + Sulphadimethoxine
2. Baquiloprim + Sulphadimidine
III. Ormetoprim Combinations
1. Ormetoprim + Sulphadimethoxine
IV. Pyrimetbamine Combinations
1. Pyrimethamine + Sulphadoxine
Individual Sulphonamides (self study):
 Sulphadiazine: widely used with trimethoprim, Treat Toxoplasmosis, form crystalluria
 Sulphisoxazole: Treat UTI in dogs & cats
 Sulphathiazole: used P.O. & Inj.
 Sulphadimidine: Widely used in ruminants & swine. Bolus, IV & SC. Metabolites are
soluble- less chance of crystalluria.
 Sulphadimethoxime: Systemic infection in animal, coccidiosis in poultry.
 Sulphachlorpyridazine: Treat diarrhea in cattle, swine (caused by [Link])
 Succcinyl Sulphathiazole, Phthalyl Sulphathiazole:Gut-acting drug- treat gut infection,
Inactive, prodrug for sulphathiazole.
 Sulphaguinidine: Gut-acting drug- treat gut infection
 Sulphasalazine: metabolized to sulphapyridine
 Sulphacetamide: used to treat eye infection.
 Mafenide: Used for burn dressing.
 Silver sulphadiazine: used topically to treat severe burns & ulcer.
 Sulphadoxine: Single dose effect remain for a week, Used to treat malaria &
toxoplasmosis in human.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

SULFONE:
Antibacterial agent chemically related to sulphonamide. e.g. Dapsone. Effective against
Mycobacterium leprae. Sulfone (Dapsone) is drug of choice for treatment of Leprosy in man.

PENICILLINS (BETA-LACTAM ANTIBIOTICS )

 Beta-lactam antibiotics constitute one of the most important and frequently used
groups of antimicrobial agents.
 According to their core molecular structure they have been mainly categorized into
four subgroups are there
1. Penicillins
2. Cephalsporins
3. Carbapenems
4. Monobactams
PENICILLINS
 The penicillins are a large group of naturally occurring and semi-synthetic
antibiotics.
 They have a common nucleus, the 6-aminopenicillanic acid (6-APA) and belong to
the sub-group of penam beta-lactam antibiotics.
History
 Sir Alexander Fleming discovered Penicillins from penicillium notatum in 1928.
 Subsequently, Australian pathologist Howard Florey and British biochemist Ernst
Boris Chain isolated and purified penicillin in the late 1930s, and by 1941 an
injectable form of the drug was prepared for therapeutic use.
 Since then, numerous (>50) penicillins have been discovered and many are being
used in clinical practice.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Figure: Basic structure of penicillin and their hydrolysis

Chemistry
 All penicillins contain the basic structure of a 5 member thiazolidine ring (A)
connected to a beta-lactam ring (B) having a secondary amine group (-NH-) to form
6-aminopenicillanic acid (6-APA), so called the basic nucleus of penicillins.

 The beta-lactam ring is a four membered ring in which an amide linkage joins a
carbonyl group and a nitrogen.
 A side chain (R) is attached to the beta-lactam ring, which mainly determines type of
penicillin.-COOH attached to thiazolidine ring is the site for salt formation.
Properties of Penicillin
• The beta-lactam ring is the key structural feature of all beta-lactam antibiotics.
Cleavage of beta-lactam ring destroys antibiotic activity; some resistant bacteria
produce betalactamases (penicillinases) which cleaves ß-lactam ring.
• The 6-aminopenicillanic acid (6-APA) found in all penicillins is responsible for
antibacterial activity and determines the type of penicillin group. Chemical alteration
of 6-APA nucleus leads to loss of antibacterial activity.
• The side chain attached to ß-lactam ring determines mainly the individual penicillin
characteristics.
• The carboxyl group attached to thiazolidine ring is the site of salt formation (e.g.
sodium, potassium and procaine).

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

• 6-APA is commonly used in producing semi-synthetic penicillins.

Solubility
• They are poorly soluble, weak organic acids those are sensitive to heat, light,
extremes in pH, heavy metals, strong alcohols, and oxidising and reducing agents.
• A pH of 6-6.5 is optimal for stability of penicillins in aqueous solution with a
practical range of 5.5-7.5.
• Prolonged exposure of penicillin to water promotes hydrolysis, therefore some
penicillins are available in powder form which are reconstitution.
• Some penicillins are rapidly hydrolysed and inactivated by gastric acid & beta-
lactamase.
• The sodium and potassium salts of natural penicilllins eanhance water solubility
& therefore it is given parenterally.
• The trihydrate forms of the semi-synthetic penicillins have high water solubility and
are usually administered by both parenteral and oral routes.

Classification of Penicillins
Based on their chemical nature
(A) Natural Penicillins
Penicillin-G (Benzyl penicillin)
Penicillin-V (Phenoxymethyl penicillin)
Phenathicillin (Phenoxy ethyl penicillin)

(B) Broad spectrum penicillins: also known as Aminopenicillin

Ampicillin
Amoxycillin
Metapicillin
Bacampicillin / Pivampicillin / Hetacillin
(C) Penicillinase-resistant penicillin or β -lactamase resistant penicillins or Anti
Staphylococcal penicillins
Cloxacillin
Oxacillin
Flucloxacillin
Methicillin,
Dicloxcillin
Nafcillin
(D) Extended spectrum penicillins
Carboxy penicillins - Carbenicillin, Ticarcillin
Ureido-penicillins - Mezlocillin, Azlocillin
Piperazine penicillins - Piperacillin
(E) Potentiated penicillins/Beta-lactamase protected penicillins
Amoxicillin-clavulanic acid
Ticarcillin- clavulanic acid

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Ampicillin-sulbactam,
Ampicillin-flucloxacillin piperacillin-tazobactam.

Unitage of Penicillin
 1 I.U. of Penicillin G is the specific penicillin activity contained in 0.6µg crystalline
sodium penicillin-G
1mg of sodium Pen-G= 1667 I.U
 Potency of Pen-G is expressed in terms of units
 All other semi-synthetic penicillins their potency and doses are expressed in mg
Pharmacodynamic of penicllin/MOA
 Penicillins and other beta-lactam antibiotics are bactericidal agents and interfere
primarily with the synthesis of the peptidoglycan layer of bacterial cell walls (inhibit
bacterial cell wall synthesis).
 The antibacterial effects of penicillin are due to binding to a family of proteins called
penicillin-binding proteins (PBPs).
 There are about 7 types of PBP have been identified: PBPs- 1A, 1B, 2, 3, 4, 5 and 6.
 Inhibition of one or more of these PBPs by β-lactam antibiotics produces antibacterial
effects.
 PBP 1B performs the role of transpeptidase enzyme responsible for formation of
cross-links between peptidoglycan strands in the cell wall.
 Due to inhibition of transpeptidase enzyme leads to formation of defective bacterial
cell wall.
 Inhibition of PBP 1A and 1B resulting in lysis of the bacterium.
 Beta-lactam antibiotics are most active against rapidly growing and replicating
bacterial cells.
 The efficacy of beta-lactam antibiotics is time-dependent. Therefore, the plasma tissue
concentrations must be maintained above the MIC for long period of time to achieve
maximal efficacy.
Antimicrobial Spectrum
 In general, gram-positive bacteria are more ssusceptible to penicillins because cell
wall is located close to the cell surface and is readily cross by penicillins.
 In contrast, gram-negative bacteria contain a capsule and outer lipopolysaccharide
membrane surrounding the cell wall that prevents many penicillins to reach cell wall
and target PBPs.
 Narrow spectrum penicillins (e.g. penicillin G) are active against only gram-positive
organisms.
 Broad-spectrum penicillins are active against a large number of gram-positive
(mainly) and gram-negative organisms.
 Penicillins and other beta-lactam antibiotics are inactive against organisms which do
not possess cell wall such as mycobacterium, fungi, protozoa and viruses.
Bacterial Resistance
Acquired resistance to penicillins is a serious problem and occurs mainly through transfer of
plasmids (also chromosomes).

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

a. Beta-lactamase activity:
 Inactivation of ß-lactam antibiotics by ß-lactamase (penicillinase) enzymes by
bacteria is the most important and clinically significant mechanism of acquiring
resistance.
 Several types (at least 6) of ß-lactamase are produced by bacteria, some are active
exclusively against penicillins (called penicillinases), some are active against
cephalosporins (called cephalosporinases), and others are active equally against
both penicillins and cephalosporins (called broad-spectrum ß-lactamases).
 G+ve bacteria generally produce large amount of ß-lactamases whereas G-ve bacteria
produce ß-lactamases in small quantities.
b. Decreased permeability to drug:
 Decreased penetration of through outer membrane prevents the drugs from reaching
the target penicillin binding proteins.
 Some gram-negative bacteria become resistant to penicillins by loss or alteration of
aqueous channels (porins) in the outer membrane.
 Active efflux of antibiotics through cell membranes also serves as another mechanism
of acquiring resistance.
c. Altered penicillin-binding proteins:
 Some microorganisms acquire resistance because of modified PBPs. As this
proteins have lower affinity for β-lactam antibiotics.
 This mechanism may explain meticillin-resistant staphylococci, which have
acquired PBP possessing low affinity for ß-lactam
Pharmacokinetics
Absorption:
 The penicillins are weak acids, which favour oral absorption. However, many types of
penicillin are destroyed by the gastric acid and hence cannot be given orally.
 Most penicillins in aqueous solution are rapidly absorbed from IM or SC site with
peak plasma concentration occurring in 15-30 minutes.
 Absorption is slow and prolonged when depot preparations (e.g. procaine penicillin G
and benzathine penicillin G) are used.
 The prolonged absorption from depot penicillins results in longer persistence of
plasma and tissue drug concentration, but the peak concentrations may not be
sufficiently high to produce antibacterial effect unless the MICs are low.
 Oral absorption of some penicillins (e.g. penicillin G and penicillinases resistance
penicillins) is decreased by food.
 Sodium and potassium penicillin remain effective for 18 hrs
 Procain penicillin maintained for several days following single injection
 Benzathine penicillin G absorbed very slowly & a single injection remains effective for 7 or
more days. This preparation is also called as Repository form of penicillin
Distribution:
 After absorption, penicillins are widely distributed throughout the body.

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 Therapeutic concentration of penicillins is readily achieved in body tissues and fluids,
but they do not penetrate into some sites such as brain, bone, cartilage, cornea, CSF
and bronchial secretions, unless these sites are inflamed.
 During inflammation such as meningitis, pleuritis and peritonitis, the drug
penetrability barrier is generally impaired and penicillins easily enter the inflamed
site.
 Penicillins do not penetrate living phagocytic cells to a significant extent.
 Penicillins are bound to plasma proteins to variable extent (20-80%).
Metabolism:
 Penicillins do not undergo significant biotransformation and are generally excreted
unchanged.
 Some Penicillins like Pen-G, Pen-V, Nafcillin, Ticarcillin & Aminopenicillin get
metabolised to some extent & metabolites are inactive.
 Hetacillin or Bacampicillin (pro drug) metabolized to Ampicillin (Active metabolite)

Excretion:
 Penicillins are excreted rapidly in urine mainly by glomerular filtration (20%) and
renal tubular filtration (80%).
 Some excretion of penicillins also occurs in milk.
 Renal tubular secretion can be deliberately inhibited by probenecid and other weak
organic acids to prolong the effective levels of penicillins in body.
 Elimination half-lives of most penicillins vary between 30-120 minutes.
 E.g. Penicillin-G-30 min in dog
Carbenicillin-120 min in cattle

Side Effects/Adverse Effects

Penicillins are among the safest antimicrobial drugs. Organ toxicity with penicillins is rare.
(1) Hypersensitivity:
 Most important and serious adverse effect of penicillins.
 The major antigenic determinant of penicillin hypersensitivity reaction is its
metabolite penicilloic acid, which reacts with proteins and serves as a haptan to cause
an immune reaction ranging from maculopapular rash to angioneurotic oedema;
anaphylaxis is rare, but could be fatal.
 Important manifestations of allergic reactions in animals, particularly cattle, may
include rash, urticaria, drug fever, angioedema, serum sickness, vasculitis and rarely
anaphylaxis.
(2) GIT disturbances:
 The use of broad-spectrum penicillins may cause Gl disturbances, particularly diarrhoea and
superinfection due to disruption of normal balance of Gl microflora
(3) Platelet dysfunction:
 Some penicillins (e.g. antipseudomonal penicillins) may cause thrombocytopenia and
decreased agglutination.
 It is generally a concern when treating patients predisposed to haemorhage or those
receiving anticoagulant therapy.
Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019
4) Organ toxicity:
 Irritate neuronal tissue and cause seizures when administered in high doses or when
injected intra-thecally
 High dose or prolonged use may cause neurotoxicity and ataxia in dogs
 As penicillins are accumulated in renal tissues at high concentrations, they have a potential to
cause acute interstitial nephritis.
5) Cation toxicity:
 Observed with Na and K salts of penicillins
 Sodium excess may aggravate the congestive heart failure
 Rapid IV administration of K penicillin may cause hyperkelemia
Contraindications and Precautions
 Patients those are hypersensitive to penicillin
 High doses of sodium or potassium penicillins with a pre-existing electrolyte abnormality,
renal disease or CHF should be avoided as they may precipitate the existing condition.
Clinical Uses
 Penicillins are widely used in both human and veterinary medicines for a wide range
of systemic infections caused by susceptible bacteria.
 They are also used topically in eye, ear and on skin to treat or prevent local infections.
 Intramammary administration of penicillins is widely used to prevent or treat bovine
mastitis.
INDIVIDUAL PENICILLINS:
Penicillin-G:
 Also known as benzyl penicillin.
 Obtain from penicillium chrysogenum.
 It was the first penicillin for clinically used and still it is useful.
 Na+, K+, procaine & benzathine penicillin G commercially available.
 Penicillin G not administered orally because it is inactivated by gastric acid.
 Potency of penicillin G expressed in I.U./ Units
 1 I.U.=0.625µg Pen. G
 1mg = 1667 I.U.
 Streptomycin + Penicillin G= choice for many bacterial infecions.
Penicillin –V:
 It is also called phenoxymethyl penicillin
 It is Orally effective because adding of phenoxymethyl group impart more acid
stability.
 Potency expressed in mg.
Pheneticillin
 It is a first clinically useful true semi-synthetic penicillin.
 Now a days it is not useful.
Cloxacillin:
 It is semi-synthetic penicillin.
 It is useful in case of skin, bone, soft tissue infection, bovine mastitis.
 Ophthalmic preparation is also available.
Oxacillin
Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019
 Same as cloxacillin
 Intra mammary & ophthalmic preparation is used.
Dicloxacillin & Flucloxacillin: Same as above
 Used orally in severe penicillinase resistant staphyloccal infection in dog & cats.
Methicillin:
 Used incase of st. aureus infectins.
 It is inactive orally as it is destroyed by the gastric acid.
 Now, it is rarely used due to its limitations because of MRSA production
Nafcillin: Mastitis by st. aureus
Ampicillin
 Widely used in all domestic animals
 Mostly in gram negative aerobs.
Amoxycillin: Similar as ampicillin.
Hetacillin & bacampicillin: metabolised to ampicillin in body.
Carbenicillin:
 Rapidly excreted within 1 hrs through urine.
 Treatment of serious psudomonas & proteus infection in dogs.
Ticarcillin
 Treatment of psudomonas aerginos infection.
 2-4 times potent than carbencillin.
Mezlocillin & Azlocillin
 Both are used in case of psudomonas aerginos and klebsiella infection
Pipracillin
 Usually combined with aminoglycoside
Amoxycillin + clavulanic acid (Co-amoxiclav):
 Ratio is 4:1
 It is not destroyed by gastric acid.
 Treatment of skin , soft tissue, urinary, biliary , Resp. tract infection, canine dental
disease, mastitis in cow.
Ampicillin+Sulbactam:
 Sulbactam is a semi-synthetic β-lactamase inhibitor
 Combined with ampicillin & given parentrally
 Used in mixed aerobic-anaerobic infection including intra-abdominal, surgical and
skin and soft tissue infections

CEPHALOSPORINS , CARBEPENEMS and MONOBACTAMS

 Cephalosporins are a class of frequently used ß-lactam antibiotics which are
structurally and pharmacologically related to the penicillins.
 Cephalosporins are derived semi-synthetically from 'cephalosporin-C' obtained from a
fungus Cephalosporium acremonium.
 Like the penicillins, they possess a beta-lactam ring structure and interfere with
synthesis of the bacterial cell wall.
Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019
Chemistry
All cephalosporins contain the basic structure of a dihydrothiazine ring fused to a beta-
lactam ring having a secondary amine to form 7-aminocephalosporanic acid, the
cephalosporin nucleus.

 By addition of different side chains to position 7 of the ß-lactam ring (R1) and
position 3 of dihydrothiazine ring (R2) a large number of semisynthetic antibiotics
have been produced.
 The modifications at position 7 are generally associated with alterations in the
spectrum of antibacterial activity
 Substitutions at position 3 of the cephalosporin nucleus are associated with changes in
the pharmacokinetic properties.
 The physical and chemical properties are generally similar to those of penicillins,
although cephalospoüns are more water soluble and acid stable.
 Cephalosporins are used either as the free base form for oral administration or as
sodium salt in aqueous solution for parenteral administration. Some antibiotics such
as aminoglycosides inactivate cephalosporins when mixed in vitro.
Classification of Cephalosporins
Based on chronology & antibacterial spectrum
I. First-generation cephalosporins
 High activity against gram-positive bacteria but weaker activity against gram-
negative bacteria.
 e.g. cefadroxil, cefazolin, cefalexin, cefalothin, cefapirin, cefaloridine
II. Second generation cephalosporins
 Greater activity against gram-negative organisms, but somewhat less activity
against gram-positive bacteria.
 e.g cefaclor, cefuroxime, cefamandole, cefonicid, ceforanide, cefotiam and
cefprozil.

III. Third-generation cephalosporins

 Most active against gram-negative bacteria, especially enteric bacteria, but are less
active against gram-positive cocci & active against strains of Pseudomonas
aeruginosa.
 e.g. cefotaxime, ceftiofur, ceftriaxone, ceftazidime, cefoperazone, cefovecin,
Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019
cefixime, cefpodoxime and ceftizoxime.
IV. Fourth-generation cephalosporin
 Broad-spectrum of activity, which include gram-positive cocci, gram-negative
bacilli and Pseudomonas aeruginosa.
 Highly resistant to β-lactamases hence they are useful against many bacteria
resistant to earlier drugs.
 e.g. cefepime, cefpirome (for human uses) and cefquinome (for vet./animal use only).
V. Fifth-generation cephalosporins
 Recently introduced, active against MRSA.
 Have powerful antipseudomonal characteristics and are less susceptible to
development of resistance.
 e.g. ceftobiprole and ceftaroline.
Bacterial Resistance
 Mechanisms of bacterial resistance to cepholosporins are essentially the same the
penicillins.
 These include:
a. Beta lactamases (cephalosporinases) enzyme which destroy cephalosporins.
b. Alterations in target proteins which reduce affinity for cephalosporins.
c. Decreased permeability to cephalosporins so that drugs do not reach their site of
action in sufficient quantity.
Mechanism of Action
 All cephalosporins are bactericidal.
 They inhibit bacterial cell wall synthesis in a manner similar to that of penicillins.
 However, they bind to different proteins (PBP) than those required by penicillins
and are less susceptible to penicillinases.
 More effective against actively growing bacteria.
Pharmacokinetics
Absorption
 Only a few cephalosporins are acid stable and are given orally.
 Most of them given parenterally either intramuscularly or intravenously.
 The orally administered cephalosporins are well absorbed with bioavailability values
of 75-90%.
 Absorption from IM injection site is achieved within 30 minutes of dosing.
Distribution
 Widely distributed in body tissues and fluids including lungs, kidneys, bone, placenta,
and soft-tissues and pleural, pericardial and joint fluids.
 Some third generation agents (e.g. cefoperazone) also cross the blood-brain barrier in
significant amount and are drugs of choice for meningitis due to gram-negative
bacteria.
 Most cephalosporins have poor penetration into prostatic tissue and aqueous and
vitreous humours.
 The plasma protein binding of cephalosporins is highly variable (20-80%) and species
specific. Cephalosporins enter milk in low concentrations.
Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019
Biotransformation
 Most of them do not undergo significant biotransformation and are excreted
unchanged.
 Some agents (e.g. cefalotin, cefotaxime) are actively deacetylated in the liver and
some other tissues and are excreted as inactive or mildly active metabolites.
Excretion
 Cephalosporins and their metabolites (if any) are excreted mainly by the kidneys in
urine via tubular secretion (mainly) and glomerular filtration.
 Plasma half-lives are usually 30-120 minutes, but some third-generation
cephalosporins tend to have longer plasma half lives.
 Blood levels are usually maintained for only 6 to 8 hours.
 Like penicillins, probenecid increases half lives of cephalosporins.
Side Effects/Adverse Effects
 Cephalosporins has low frequency of allergic reactions/ hypersensitivity
 About 10% of the penicillin sensitive individuals show some cross-reactivity to
cephalosporins. Other adverse reactions include Gl disturbances (nausea, vomiting
and diarrhoea), superinfection, pain at IM injection site and lethargy.
Contraindications and Precautions
 Hypersensitive patients to them or penicillins.
 Prolonged administration of cephalosporins should be avoided in animals, particularly
cats, as they may lead to anaemia or superinfection.
 Dosage adjustment may be required in patients with renal insufficiency
Clinical Uses
 The high cost of cephalosporins has limited their frequent use in veterinary medicine
in particular in large animal medicine.
 The first-generation cephalosporins, in particular, have proved useful in veterinary
medicine for many infections including skin, soft tissues, and urinary and respiratory
tract infections.
 1st generation cephalosporins (cephalexin) are use for treatment of stapylococcus
infection and for surgical prophylaxis
 Ceftiofur sodium is used for bovine respiratory disease and urinary infection in dogs
 Cephapirin benzathine salts:- used for prevention of mastitis in dry cow.
 Cephapirin sodium salts:- used for treatment of clinical mastitis in cattle.
INDIVIDUAL CEPHALOSPORINS
1. Cefalothin- G+ve aerobes, injectable, widely used
2. Cefazolin- Inj. Preferred, long half life
3. Cefalexin- G+ve cocci, P.O.
4. Cefadroxil-One of the most commonly used, P.O.
5. Cefapirin-requires less frequency of dosing, used in mastitis (dry & lactating cow)
6. Cefaclor-P.O., not used in vety
7. Cefamandole- Inj. cause hypoprothrombinaemia
8. Cefotaxime- Meningitis by G-ve in small animals
9. Ceftiofur-
10. Ceftriaxone-Lyme‘s disease
11. Ceftazidime- Pseudomonas, G-ve bacteria
Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019
12. Cefoperazone- Pseudomonas, G-ve bacteria
13. Cefepime-
14. Cefquinome-Vet use only, Bovine mastitis pneumonia
15. Cefaloridine-most nephrotoxic
16. Cefalonium-I/mammary in dry cow, persistence in udder
17. Cefuroxime- Inj. Meningitis by G-ve bacteria in human
18. Ceftobiprole-5th generation recently introduced, available for human medicine
19. Ceftaroline-5th generation recently introduced, Pseudomonas & MRSA

Figure: Basic structure of four important beta-lactam antibiotics

CARBAPENEMS
 It is a new class of beta-lactam antibiotics.
 They contain a fused ß-lactam ring and a 5 membered ring which differs from
penicillins in being unsaturated and having a carbon on the five membered ring instead
of a sulphur
 They have very broad-spectrum of activity and are resistant to most ß-lactamases.
 They are derived from Streptomyces species.
Mechanism of Action
 They are bactericidal ß-lactam antibiotics.
 Similar to penicillins and cephalosporins.
 They disrupt peptidoglycan synthesis in cell wall formation by binding to penicillin
binding PBP-1 & PBP-2 results in cell lysis & death
Antibacterial Spectrum
 They have a broader specttum of activity than do most other β-lactam antibiotics
Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019
 Antibacterial Spectrum includes
Many aerobic and anaerobic gram-positive bacteria
Enterobacteriaceae
Pseudomonas aeruginosa and
Listeria spp.
 High antibacterial activity of carbapenems is attributed mainly due to their stability
against most of the beta lactamases and to their unique chemical structure. which
allows penetration through porin channels usually exclude other drugs.

Imipenem
 Imipenem is commonly used in combination with cilastatin, (an inhibitor of renal
tubular dipeptidase enzyme).
 It is derived from Streptomyces cattleya.
 The imipenem- cilastatin sodium is marketed in two formulations -a preparation for
IV infusion and a suspension for IM injection (do not used interchangeably).
Antibacterial spectrum
 Its range of activity includes almost all bacteria which may be resistant to other
drugs like Pseudomonas aeruginosa, Enterobacteriaceae, streptococci (including
penicillinase producing strains), staphylococci (including penicillinase producing
strains), most enterococci and Listeria Spp.
 Imipenem is not active against meticillin resistant staphylococci
Pharmacokinetics
 Imipenem is not absorbed orally, so it must be given parenterally.
 After IM injection, bioavailability is >95% and widely distributed throughout the
body with exception of CSF.
 Imipenem when given alone is hydrolysed rapidly by the dipeptidase enzyme found
in brush border of the proximal renal tubule resulting in low urinary drug levels,
which are inadequate for an antibacterial action& therefore cilastatin is given along
with it.
 Cilastatin induced decreased renal metabolism of imipenem also protects the
kidneys from proximal tubular necrosis that occurs when imipenem is used alone.
 When used with cilastatin. imipenem is eliminated by both renal (75%) and non-
renal (25%) mechanisms.
 Half life-1 to 3 hrs.
Side effect/Adverse effects
 GI disturbances (vomiting, diarrhoea, anorexia)
 CNS toxicity (tremors, seizures)
Clinical uses
 The combination is very useful in genito-urinary and lower respiratory tract
infections.
 In veterinary medicine, it may be used in small animal or equine medicine for
serious infections. Very costly combinations.
Meropenem
 Meropenem is another carbapenern antibiotic with an extremely broad spectrum of
Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019
activity.
 It does not require coadministration with cilastatin as it is not hydrolysed by renal
dipeptidase enzyme.
 It is more soluble than imipenem hence it requires less fluid for dilution and can be
administered IV in less volume.
 Used IV or SC in dogs & cats. SC injection causes slight hair loss at site of
injection.
 Among all the available antibiotic it is most expensive drug available today
MONOBACTAMS
 Monobactams are simple monocyclic ß-lactam compounds.e.g. Aztreonam
 It has also mild affinity for negative aerobic bacteria with no action against gram-
positive organisms or anaerobes.
 Their antibacterial spectrum, therefore, resemble more closely to that of
aminoglycosides than that to pemcillins.
 They are resistant to most ß-lactamases.
 Currently, only one drug aztreonam is available for clinical use.
Aztreonam
 Aztreonam is a monocyclic ß-lactam antibiotic isolated from Chromobacterium
violaceum.
 It interacts with penicillin-binding protein 3 (PBP-3) of susceptible organisms and
induces formation of long-filamentous bacterial structures and inhibition of cell
wall synthesis.
 It is poorly absorbed when given via the oral route, so it must be administered as
an intravenous or intramuscular injection. It has plasma half-life of about 2
hours in man
 It does not cross-react immunologically with penicillins or cephalosporins.
Therefore it may be used in penicillin-sensitives individuals.

BETA-LACTAMASE INHIBITORS
 Beta-lactamase inhibitors are agents which bind to and inactivate ß-lactamase enzyme
produced by many gram-positive and gram-negative bacteria.
 Usually administered with penicillins or cephalosporins.
 This includes (1) Clavulanic acid
(2) Sutbactam
(3) Tazobactam
Clavulanic acid
 ß-lactam ring containing compound obtained from Streptomyces clavuligens.
 It has no antibacterial activity of its own but it enhances antibacterial activity of some
penicillins by inhibiting a wide variety of ß-lactamases produced by bacteria.
 Combinations of clavulanic acid with amoxicillin and ticarcillin are available for clinical use.
Mechanism of action
 It contains a ß-lactam ring in its structure & because of structural similarities with penicillins,
it binds to and inactivates ß-lactamase enzyme produced by certain bacteria.
 Clavulanic acid is called a progressive inhibitor because its binding with ß-lactamase
enzyme is reversible initially but becomes irreversible after some time.
Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019
 It is also called a ―suicide inhibitor” because clavulanic acid itself gets degraded after
binding to the enzyme.
Pharmacokinetics
 Clavulanic acid is well absorbed from Gl tract after oral administration and from parenteral
injection sites.
 Clavulanic acid is eliminated primarily after metabolism in the urine via glomerular filtration.
Its elimination half-life in human beings is about 1 hour.
Clinical uses
 Amoxicillin + Clavulanic acid (Co-amoxiclav) is available for oral use (4:1 ratio).
 Clavulanic acid + Ticarcillin is available for parenteral use.
Sulbactam
 Sulbactam is a semi-synthetic ß-lactamase inhibitor.
 It resembles clavulanic acid structurally as well as pharmacologically.
 However, it is 2 to 3 times less potent than clavulanic acid.
 It is preferably given parenterally.
 E.g. Ampicillin+Sulbactam, Cefoperazone+Sulbactam, Cefotaxime+Sulbactam.
Tazobactam
 It is ß-tactamase Inhibitor similar in activity to clavulanic acid and sulbactarm.
 It has been combined with piperacillin and is available for parenteral use.
 The combination has the broadest antibiotic spectrum of the penicillins.
 E.g. Piperacillin+Tazobactam, Ceftriaxon+Tazobactam.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

AMINOGLYCOSIDES
History
 Streptomycin was the first member of aminoglycoside antibiotics discovered in
1944 by Waksman from Streptomyces griseus.
 Neomycin in 1949 followed by kanamycin in 1957 and gentamicin in 1963.
 Amikacin was the first semi-synthetic compound.
 Presently, aminoglycosides have many members used extensively in veterinary
medicine.
Source
 Most aminoglycosides are obtained from Streptomyces spp. (soil
actinomycetes).
 Few aminoglycosides are obtained from Micromonospora spp. (e.g. gentamicin,
netilmicin and sisomicin).
 Few are semi-synthetic: Amikacin, arbekacin
 Aminoglycosides derived from Streptomyces carry the suffix -mycin, where
those obtained from Micromonospora have names ending with -micin.
Aminoglycosides produced from Streptomyces spp :
• Streptomycin - Streptomyces griseus,
• Neomycin - Streptomyces fradiae,
• Kanamycin - Streptomyces kanamyceticus,
• Tobramycin - Streptomyces tenebrarius,
• Paromomycin - Streptomyces paromomycinus
Aminoglycosides produced from Micromonospora spp.
 Gentamicin - Micromonospora purpurea,
 Sisomicin - Micromonospora inyoensis,
 Netilmicin - semisynthetic derivate of Sisomicin
Chemistry
 Aminoglycosides (Aminocylitols) are a group of natural and semi-synthetic
antibiotics having aminosugars linked to an aminocyclitol ring by glycosidic
bond.
 They are mostly bactericidal drugs.
 The presence of amino group in the structure imparts basic nature to
aminoglycosides and the hydroxyl group on sugars provide high water solubility
(or poor lipid solubility) to the drugs.
 If these hydroxyl groups are removed (e.g. tobramycin), the drug becomes more
active.
 Minor differences in the chemical structure of these drugs may lead to
differences in efficacy and toxicity.
Properties
Some common properties of the aminoglycoside group are:
 Water soluble and polar compounds which generally ionise in solution.
 Not absorbed orally, distribute only extra-cellularly and excrete mainly
unchanged in urine.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 Bactericidal in action and are more active against gram-negative bacilli
 Poorly penetrate into mammalian cells and limited action in infections caused
by intracellular bacteria.
 Interfering with protein synthesis in susceptible bacteria
 Mainly used as sulphate salts, which are highly water soluble
 Aqueous solutions of aminoglycosides are stable for months.
 More active in alkaline pH.
 Have a tendency to cause ototoxicity and nephrotoxicity.
 Narrow margin of safety
 Bacterial resistance to many aminoglycosides develop rapidly.
 Synergistic antibacterial effect with beta-lactam antibiotics.
Classification
Classify on the basis of Antibacterial spectrum :-
1. Narrow spectrum aminoglycoside
Streptomycin
Dihydrostreptomycin
2. Broad spectrum aminoglycoside
Neomycin and framycetin
Kanamycin
Paromomycin
Arbekacin
3. Extended spectrum aminoglycoside
Gentamicin
Tobaramycin
Amikacin
Sisomicin
Netilmicin
Mechanism of Action
 Aminoglycosides acts by inhibiting protein synthesis in susceptible bacteria
by binding with 30 S ribosomal subunit.
 They are bactericidal in nature and its effect is concentration dependent.
Two major steps required to produce their action
1. Entry of aminoglycoside into bacterial cell
2. Binding of aminoglycoside to bacterial ribosome
1. Entry of aminoglycoside into bacterial cell:
 Aminoglycoside reach to the periplasm of G -ve bacteria via aqueous channel
by concentration dependent manner.
 Now aminoglycosides are carried from periplasmic space to the bacterial
cytoplasm with help of O2 dependent process (hence AG are ineffective against
anaerobic bacteria)
2. Binding of aminoglycoside to bacterial ribosome
 Aminoglycoside interact with bacterial ribosome (mostly 30S ribosomal
subunit) and inhibit protein syntesis.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 By binding aminoglycoside affect number of steps in protein synthesis;
Interference with protein synthesis. Distortion of m-RNA (misreading of the
codon), Incompletely synthesized proteins or inhibit ribosomal translocation.
This leads to synthesis of abnormal structural and functional proteins in
bacteria.
The important antimicrobial feature of aminoglycosides includes:
 Concentration dependent bactericidal action, therefore single large dose is more
effective instead to divided dose.
 More effective against rapidly multiplying bacteria.
 Aminoglycosides show a long post-antibiotic effect (PAE).
 Aminoglycosides show synergistic effect with beta-lactam antibiotics (because cell
wall injury increases entry of aminoglycosides). e.g. Streptomycin + Penicillin G
Antibacterial Spectrum
 Narrow-spectrum AGs are mainly active against G-ve bacteria.
 Broad spectrum AGs are active against many G-ve and G+ve bacteria, but not
Pseudomonas.
 Extended-spectrum AGs are active against Pseudomonas aeruginosa and a variety of
aerobic bacteria.
 They are mostly ineffective against fungi and viruses.
Bacterial Resistance
 The susceptible microorganisms may develop resistance by several mechanisms. The
resistance may be plasmid mediated or acquired by mutation.
1. Production of inactivating enzymes: The susceptible microorganisms produces
transferase enzymes and inactivate most AGs except amikacin.
2. Impaired transport: Impaired transport of aminoglycosides across the cell
wall/membrane may occur due to changes in the pore size that becomes less permeable
to AGs. Anaerobes are inherently resistant to aminoglycosides.
3. Alteration in ribosomal structure: Alterations in the ribosomal structure leads to
decreasing the binding of aminoglycosides with their target sites. e.g. Some strains of E.
coli develop resistance to streptomycin by this mechanism.
Pharmacokinetics
 For most of the aminoglycoside the theraputic range is very narrow so chances of
toxicity are more than others antimicrobial.
Absorption:
 Aminoglycosides are poorly absorbed from GIT (<10%). Absorption from GI tract
takes place only in presence of inflammation or ulceration.
 The absorption from IM injection site is rapid and Cmax are achieved within 30 to 45
minutes of administration.
 IV and IP routes produce rapid effects but are generally avoided because of serious
side effects.
 The repeated intrauterine administration in endometritis may result in sufficient
absorption to achieve bactericidal concentration.


Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Distribution:
 AGs are extensively distributed in extracellular fluid, but do not readily enter into
cells due to their polar nature (water soluble).
 Therefore, they are largely excluded from brain, CSF, eye and most body tissue
except the kidneys and inner ear.
 Accumulation of aminoglycosides in high concentrations in kidney cause
nephrotoxicity and in inner ear ototoxicity
 Aminoglycosides may cross placental barrier causing deafness in young ones
(foetus).
 The aminogtycosides bind poorly to plasma proteins (<20%).
Biotransformation and excretion:
 AGs are not metabolised in body and are excreted unchanged in urine by glomerular
filtration.
 Plasma half-lives are vary between 2 to 4 hours in patients with normal renal function
& in renal insufficiency, half-lives may increase to 24-48 hours.
Toxicity /Adverse effects
Three main adverse effects observed with aminoglycosides includes nephrotoxicity,
ototoxicity and neuromuscular blockade.
1. Nephrotoxicity:
 Nephrotoxicity occurs as a result of excessive accumulation of aminoglycoside (40 to
50 times higher than blood) in the proximal tubular cells in kidneys.
 Nephrotoxicity is reversible in the initial stages because of the regenerative capacity
of tubular epithelium but on prolonged exposure causes permanent renal damage.
 Manifestations of nephrotoxicity include presence of enzymes of brush border in
urine, proteinuria, presence of casts and low GFR.
 Nephrotoxic potential of AGs: neomycin (most nephrotoxic) > tobramycin and
gentamicin > dihydrostreptomycin (least nephrotoxic).
 Nephrotoxicity can be prevented by avoiding use of potentially nephrotoxic AGs,
ensuring adequate hydration status of patient and avoiding concurrent use of other
nephrotoxic drug.
2. Ototoxicity:
 Administration of aminoglycosides can produce both vesicular and auditory
dysfunctions.
 Ototoxicity is greater when the plasma concentration of drug is persistently high.
 Ototoxicity once occur is usually irreversible .
 Ototoxicity leads to nystagmus, incoordination , vertigo, head tilt, ataxia and loss of
righting reflex
 Deafness may be produced by permanent damage and loss of organ of Corti.
 Cats are more susceptible to ototoxic effect of AGs than dogs.
 Impaired renal function increases chances of ototoxicity.
 Ototoxic potential of AGs: Streptomycin (most ototoxic) > gentamicin & neomycin >
kanamycin and amikacin.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

3. Neuromuscular blockade:
 All aminoglycosides have potential to produce neuromuscular blockade with curare-
like action.
 The effect is produced mainly by interference with acetylcholine release and
chelation of Ca++ that is normally required for exocytosis.
 However, concomitant administration of neuromuscular blocking agents and general
anaesthetics with aminoglycosides may increase this toxicity.
 Muscular weakness, apnoea, respiratory arrest have been associated when
aminoglycosides, used in very high doses.
 Neomycin and streptomycin have high propensity to cause neuromuscular blockade.
 Neuromuscular blockade may be treated by IV administration of calcium salts or
neostigmine.
4. Other effects:
 Other toxic effects include allergic reaction, peripheral neuritis (by streptomycin)
and dysfunction of optic nerve.
 Toxicity may occur when they are applied topically for long period, especially on
wounds, bums or skin ulcers.
Contraindications and Precautions
 Contraindicated in hypersensitive patients.
 Drugs should be used with extreme caution in pre-existing renal disease and in
neonatal or geriatric animals.
 Dose rates should be reduced in renal failure and in neonate, geriatric and obese
animals.
 Aminoglycoside not given to animals with myasthenia gravis.
 Not given during pregnancy (toxic to foetus)
 Not prefer for cats.
 Plasma concentration and renal function (BUN & creatinine) should be monitored
during therapy.
Drug Interactions
 Concurrent use of AG with loop diuretics (e.g. furosemide) and osmotic diuretics
(e.g. mannitol) may increase the nephrotoxic and ototoxic effects.
 AG are used with inhalant anaesthetic or neuromuscular blocking drugs (e.g. d-
tubocurarine) than increase chances of neuromuscular blockade and respiratory
paralysis.
 AG + halothane increases cardiovascular depression.
Clinical Uses
 AGs are widely used in veterinary practice to treat local and systemic infections
caused by susceptible bacteria, generally gram-negative bacteria.
 Used to treat infections of GIT, urinary tract, respiratory tract and skin.
 They are also effective against septicaemia, osteoarthritis, mastitis and wounds. Also
used intrauterine to treat endometritis and intramammary to treat mastitis.
 Some time used topically eyes and ears infection.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

INDIVIDUAL ANIINOGLYCOSDES
Streptomycin:
 Oldest aminoglycoside obtained from Streptomyces griseus.
 First antibiotic used to treat tuberculosis.
 Water-soluble, use has declined in veterinary.
 It is mainly active against aerobic gram-negative bacilli.
 Streptomycin + penicillin combination used to treat mastitis. (Dose: lactating cows-
100 mg/quarter; dry cows- 500 mg/quarter, intramammary infusion)
Dihydrostreptomycin:
 Ototoxic, restricted its use in veterinary and medical practices.
Neomycin
 Broad-spectrum AG obtained from Streptomyces fradiae.
 Highly toxic to internal ear (mainly auditory) and kidneys.
 Used topically for skin, eye or ear infections.
 Combined with penicillins used intramammary in mastitis.
Framycetin/Neomycin B
 Used with corticosteroids for treatment of skin, nose, ears and eyes infections.
Paromomycin
 Effective in G-ve and G+ve bacteria, tapeworm, amoebiasis and Giardia infection
Gentamicin:
 Most widely used AG with extended spectrum of antibacterial activity.
 It is obtained from Micromonospora purpurea.
 Freely water soluble, low cost
 Used most of animal by all routes i.e. IM, SC, Intra-uterine, Intra-mammary
 Effective against a wide-range of G-ve and G+ve infections of respiratory tract,
urinary tract, GIT, bones, soft tissue and skin infections.
 Used topically for skin, ear and eye infections.
 Not given in food producing animals due to prolonged residues.
 Heat-stable antibiotics & remain active even after autoclaving (121°C).
Amikacin
 Semi-synthetic AG, have broadest spectrum.
 Used to treat serious G-ve infections resistant to gentamicin.
Arbekacin:
 Semi-synthetic AG, Used to treat G-ve and G+ve bacteria & meticillin-resistant
Staphylococcus aureus (MRSA) infection.
Tobramycin
 Very similar to those of gentamicin.
 Used clinically to treat serious G-ve infections those resistant to gentamicin.
Sisomicin and Netilmicin:
 Extended spectrum AG used primarily in human practice.
 These drugs are presently undergoing clinical trials for use in veterinary practice.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

TETRACYCLINE
Tetracycline are broad spectrum antibiotics having a nucleus of four cyclic rings.
Sources:
 They are either obtained naturally from Streptomyces spp. (soil actinomycetes) or
prepared semi-synthetically.
 Chlortetracycline derived from Streptomyces aureraciens introduced in 1948.
 Oxytetracycline obtained from Streptomyces rimosus.
 Removal of chlorine atom from chlortetracycline produced semi-synthetic tetracycline
introduced in 1952 like metacycline, doxycycline and rolitetracycline.
 Doxycycline and minocycline are relatively newer tetracyclines with high lipid
solubility and longer duration of action.
 Tigecycline is new subgroup of tetracyclines (glycylcyclines) was introduced to treat
infections which are resistant conventional tetracyclines.
Chemistry and Properties
 They are four ringed amphoteric compounds
 TCs are acidic and hygroscopic compounds in which aqueous solution form salts with
both acids and bases.
 Tetracyclines form insoluble chelate with cations like Ca++, Mg++, Fe++ and Al+++
 Tetracyclines are stable as powders but their aqueous solutions are not stable so
parenteral injection are formulated in propylene glycol or polyvinyl pyrrolidine to
prolong elimination half-life (Single Inj. OTC-LA effect remain for 3-4 days while
OTC plain < 1 day).
 TCs are formulated as injections, boluses, capsules, powders, feed additives and
ointments for veterinary use.
Classification
Classify according to their duration of action.
1. Short-acting TCs (Half life = <8 hours)
e.g. oxytetracycline, tetracycline and chlortetracycline
2. Inter-mediate acting TCs (Half life = 8- 16 h )
e.g. demeclocycline and metacycline
3. Long-acting TCs (Half life = >16 hours)
e.g. doxycycline, minocycline and tigecycline.
Mechanism of action
 Tetracyclines inhibit bacterial protein synthesis by binding with 30 S ribosomal
subunit and are primarily bacteriostatic.
 Action of TCs can be divided into two processes passage of tetracyclines into
bacterial cell and interaction of TCs with bacterial ribosomes (similar to AGs).
 TCs enter into bacteria by passive or active transport process. The more lipid soluble
members (e.g. doxycycline and minocycline) pass directly through the lipid bilayer by
passive diffusion.
 Once the TCs gain enters into bacterial cell, they bind to the 30S ribosomal subunit &
this prevents addition of amino acids to the growing peptide chain resulting in
inhibition of protein synthesis in bacteria.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 Tetracyclines are highly effective against multiplying microorganisms and are more
active at pH 6-6.5.
 Responsive host-defence system is essentially required to remove static bacteria (b/c
bacteriostatic effect)
 Penetration of TCs in host/ mammalian (eukaryotic) cells through cell membrane is
poor due to lacking of specific carrier transport system. (Q: Why mammalian cell
protein synthesis are less sensitive to TCs).
Antimicrobial Spectrum
 TCs are broad-spectrum antibiotics.
 They are active against a wide range of G+ve and G-ve, aerobic, anaerobic bacteria.
 They are also active against Mycoplasma, Rickettsia, Chlamydia and some protozoa
like anaplasma, haemobartonella and amoebae.
 Presently, many strains of bacteria become resistant to TCs.
 TCs are ineffective against fungi and viruses.
Microbial Resistance
 Resistance to TCs develops slowly in a graded manner.
 Resistance to TCs may be acquired by three mechanisms: decreased penetration into
cells, enzymatic inactivation and ribosomal alterations.
 Resistance to TCs is primarily plasmid mediated.
 Microorganisms those have become resistant to one tetracycline are usually resistant
to other members of the group (showed cross resistance) except minocycline.
Pharmacokinetics
Absorption:
 The oral absorption of tetracyclines is variable with older drugs being less
bioavailable and newer lipid soluble tetracyclines being 100% bioavailable.
 Absorption of tetracyclines from GIT is decreased in presence of polyvalent cations
(Ca++, Mg++, Fe++ and Al+++ ) which are present in food milk and milk products (hence
TC given before meal/ not given with food/milk).
 All TCs produce varying degree of tissue irritation on parenteral administration,
especially chlortetracycline (most irritating drug).
 Therefore for parenteral administration, buffered solutions are prepared. Procaine is
added to tetracyclines solution for IM administration in small animals.
Distribution:
 TCs bind to plasma proteins to varying degrees and are widely distributed in most
tissues including kidneys, liver, lungs, bile and bones.
 Exception as doxycycline & minocycline do not penetrate the CSF and brain.
 TCs are stored in the reticulo-endothelial cells of liver, spleen and bone marrow.
 They are also incorporated into growing bone & teeath in yough animals.
 TCs cross the placenta and enter foetal circulation and amniotic fluid.
Biotransformation and excretion:
 TCs are not metabolised to a significant extent in the body (except lipid soluble TCs).
 Most TCs are excreted in urine (60%) via glomerular filtration pathway and in faeces
(40%) via biliary excretion.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 Tetracyclines undergo enterohepatic circulation, which may affect their duration of
action.
Side effects/ Adverse effects
TCs have a relatively low toxicity at normal dosage levels
1. Gastrointestinal upsets:
 All tetracyclines produce GI irritation to varying degree-in some patients, particularly
after oral administration.
 Anorexia, abdominal pain, diarrhoea, and nausea and vomiting in small animals may
occur.
 Superinfection of Candida albicans is common with TCs.
 The oral administration of tetracyclines may lead to fatal diarrhoea in horses and
deleterious effect on rumen microbes in ruminants (Why TCs are not administered
orally in horse/ cattle?).
2. Effect on bones/teeth:
 TCs are deposited in growing teeth and bones due to their chelating properties with
calcium (decrease bone growth in foetus).
 They form tetracycline-calcium complex which inhibits calcification and results in
permanent discolouration (first yellowish then brownish) of the teeth.
 High concentrations of TCs can interfere with the calcium deposition in bones and
delay fracture healing.
3. Hepatotoxicity:
 TCs in excessive doses produce fatty infiltration of liver.
 Hepatotoxicity with jaundice due to large doses of TC been reported in pregnant
women and in some animals.
4. Nephrotoxicity:
 Tetracyclines are potentially nephrotoxic, particularly in renal insufficiency &
increase blood urea nitrogen (BUN) levels .
 The administration of expired tetracycline products may lead to acute tubular
nephrosis in animals.
5. Hypersensitivity reactions:
 Not common. Rarely, TCs may produce skin rashes, urticaria, pruritus and exfoliative
dermatitis.
 Angioedema and anaphylaxis are extremely rare.
6. Cardiovascular effects
 The rapid IV administration of TCs may result in hypotension, collapse and sudden
death in animals.
 This has been related to rapid chelation of blood calcium.
 Pre-treatment with calcium borogluconate and slow rate of IV infusion prevent these
unwanted effects.
7. Other effects:
 TCs cause irritation, swelling, necrosis and yellow discolouration usually occur at
injection site.
Contraindications and Precautions

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 In patients having hepatic insufficiency, renal diseases and hypersensitive to them.
 Oral administration of TCs to ruminants and horses.
 Not given during last trimester in pregnant animals and up to 4 weeks in neonates.
 Never used beyond their expiry date because they cause 'Fanconi syndrome‗ damage
to the proximal renal tubule. [In Fanconi syndrome glucose, amino acids, uric acid,
phosphate and bicarbonate are passed into the urine, instead of being reabsorbed].
 TCs should never be administered with food/milk because they reduce bioavailability
of TCs so they generally given at least 1-2 hours before or after food.
 Doxycycline and minocycline may be taken with food
 TCs should not be given intrathecally.
 Note: TCs should not be administered mixed with IV fluids (RL and calcium
preparations).
Clinical Uses
 Tetracyclines are used in treatment of infection caused by bacteria, mycoplasma,
chlamydiae and rickettsiae, anaplasma, hemobartonella, ehrlichia and borrelia.
 Used in the treatment of psittacosis in birds.
 Used to treat number of infection include bronchopneumonia, urinary tract infections,
metritis, mastitis, prostatitis, cholangitis and pyodermatitis.
 Actinomycosis and actinobacillosis also respond to TCs.
 Chlortetracycline used in food producing animals as growth promoters.
Administration of TCs
 TCs may be administered by oral, parenteral, topical or intramammary route.
 Most of TCs can be administered by slow IV or deep IM route (cause tissue
irritation).
 Sometimes local application of TCs in ophthalmic ointments or buffered solutions is
employed for conjunctivitis.
 Intramammary infusion of TCs for mastitis in dairy animals is extensively used in
veterinary medicine.
INDIVIDUAL TETRACYCLINES (Self Study)
Oxytetracycline:
 One of the most commonly used TC in veterinary practice.
 Obtained from Streptomyces rimosus.
 Broad-spectrum TC effective against bacteria, mycoplasma, spirochetes, chlamydia
and rickettsia.
 F=60-80%, OTC LA (Depot preparation in 2-pyrrolidone) remain effective for 3-4
days.
 OTC produces irritation at injection site.
 Drug withdrawal and milk discard time for OTC in cattle and swine: 14-22 days and
in poultry: 5 days.

Tetracycline:
 Broad spectrum obtained from Streptomyces aureofaciens.
 Almost similar to OTC, irritate at injection site.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Chlortetracycline:
 First TC isolated from Streptomyces aureofaciens.
 AM spectrum similar to OTC.
 Due to irritant action IM injection is not recommended, used orally (No Inj.).
 Mainly use as a growth promoter in food-producing animals.
Demeclocycline and metacycline:
 Currently less used in veterinary practice (Demeclocyclin inhibit ADH effect,
photosensitivity reactions in human).
Doxycycline:
 Semi-synthetic TC, Lipid soluble TC, longer duration of action.
 Oral F= 90-100%, Half life= 16-20 h, excreted in faeces.
 Used in treatment of ehrlichiosis in dogs, psittacosis in poultry and anaplasmosis in
calves.
 Used in the treatment and prophylaxis of Bacillus anthracis infection (Anthrax).
Minocycline:
 Almost similar to doxycycline but limited used in Veterinary.
 Most lipid-soluble TC, longer duration of action
 Undergoes enterohepatic circulation which prolonged half-life in the body.
Tigecycline
 Newly introduced TC antibiotic (glycylcycline antibiotic)
 Derivative of minocycline.
 Broad spectrum like TC, also active against MRSA.
 Used in human medicine, available as an injection form.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

AMPHENICOL (CHLORAMPHENICOL AND RELATED DRUGS)
 Amphenicols are a group of broad-spectrum bacteriostatic drugs which act by
blocking protein synthesisis of susceptible bacteria
 Amphenicols include chloramphenicol and its related drugs thiamphenicol,
florfenicol and azidamfenicol.

CHLORAMPHENICOL
 It is a broad-spectrum bacteriostatic antibiotic obtained from Streptomyces
venezuelae in 1947, but now is manufactured synthetically.
 It is first synthetic antibiotic.
 It is used in a variety of infections in human and Veterinary medicines, particularly
those caused by anaerobic Bacteria.
Properties:
 Highly lipid soluble antibiotic, yellowish white crystalline solid.
 It is freely soluble is alcohol and acetone, fairly soluble in ether, less soluble in water
and insoluble in benzene.
 Aqueous solutions are neutral and quite stable, but need protection from light.
 It is marketed either as a free base or in ester forms (e.g. palmitate, succinate or
panthothenate salts).
 Chloramphenicol palmitate is insoluble is water and sparingly soluble in alcohol, so is
used for oral administration.
 Chloramphenicol succinate (sodium succinate) is freely soluble in both acetone and
water and, therefore, is used for parenteral injection
Chemistry and SAR
 It is a derivative of nitrobenzene and of dichloroacetic acid.
 It is unique among natural compounds having a nitrobenzene moiety in its structure.
 The para-nitro group is not important for antibacterial activity.
 The p-nitro phenyl group may be changed to ortho-or meta-nitro compounds or even
be replaced by halogens without significant loss of activity .
 The p-nitro group has been implicated in the irreversible suppression of bone
marrow.
Mechanism of action
 Chloramphenicol inhibits protein synthesis by binding to 50S ribosomal subunit in
susceptible bacteria.
 It readily penetrates into bacterial cells, probably both by passive and facilitated
diffusions.
 The effect of chloramphenicol is usually bacteriostatic, but at high concentrations it
can be bactericidal.
Antimicrobial spectrum
 It is a broad-spectrum antimicrobial agent.
 It is active against many G+ve and G-ve bacteria, and both anaerobes and aerobes
including Staphylococcus, Streptococcus, Salmonella, BruceIla, Shigella, Neisseria
and Haemophilus species.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 Its efficacy against Salmonella is very useful (to treat typhoid).
 It is also has active against Nocardia, Chlamydia and Mycoplasma.
 It has no activity against Mycobacterium, protozoa, fungi and viruses.
Bacterial Resistance
 Main three mechanisms of resistance to chloramphenicol: inactivate by
chloramphenicol acetyltransferase enzyme, reduced membrane permeability and
mutation of the 50S ribosomal subunit.
 This type of resistance is usually acquired through plasmids.
Pharmacokinetics
 It is a highly lipid-soluble drug, so it is very rapidly and efficiently absorbed after oral
administration.
 Cmax is generally achieved within 30 minutes after oral dosing.
 In ruminants, it is not available for absorption after oral administration because
ruminal microflora readily reduces the nitro group and inactivates the
chloramphenicol.
 The water soluble succinate form is well absorbed after IM or SC injection, but it also
requires hydrolysis in plasma and liver to release the active antibiotic.
 After absorption, It diffuses throughout the body and reaches sites of infection.
 It readily crosses cellular barriers and achieves high levels in most tissues and fluids
including CSF, brain, aqueous humour, placenta and synovial fluid.
 It is primarily eliminated by liver via glucuronide conjugation.
 Mainly excreted in urine.
 Cats are deficient in glucuronide conjugation, so elimination of chloramphenicol is
slower in cats than in dogs.
 Half life in cats: 4-8 h (long) while in small horse: < 1 h (unsuitable for treatment)
Side effects/Adverse effects
Bone marrow depression:-
 Chloramphenicol may produce dose-dependent (reversible) and dose-independent
(irreversible) bone marrow depression.
 The reversible bone marrow depression may be observed in all species of animals.
 The p-nitro phenyl group is responsible to cause irreversible bone marrow depression.
 The bone marrow is often hypoplastic or aplastic.
 The signs of bone marrow toxicity includes vacuolation of many of the early cells of
myeloid and erythroid series, lymphopenia and neutropenia.
 Aplastic anaemia develops and peripheral blood shows pancytopenia.
Gastrointestinal effects
 It may produce vomiting, diarrhoea and anorexia in animals.
Cardiovascular effects
 Rapid IV infusion of chloramphenicol especially that containing propylene glycol
may result in collapse, haemolysis and death in large animals.
Hypersensitivity reactions
 Some dogs and cats may show hypersensitivity reactions to chloramphenicol & may
produce rashes and fever.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Other effects
 In human neonates and premature infants, chloramphenicol produces Gray-baby
syndrome characterised by vomiting, hypothermia, as grey cyanosis, cardiovascular
collapse and death (it is b/c of lack of necessary liver enzymes to metabolized
chloramphenicol in neonates).
Contraindications and precautions
 In hypersensitive patients.
 Unsuitable for patients with pre-existing haematological disorders.
 In patients with impaired hepatic and renal functions.
 Avoided in neonates because of less developed metabolising enzymes, especially in
kittens.
 Not be given to nursing bitches and queens (first week after parturition).
Drug interactions
 It is not used with beta-lactam and aminoglycoside (bactericidal drugs).
 It may impair immune response to vaccines (vaccine should be postponed)
Clinical Uses:
 It is useful in the treatment of anaerobic bacterial infection, salmonellosis
Bacteroides spp., chronic respiratory infections.
 It is most effective against Salmonella typhi in humans (in typhoid).
 Used topically (as ointments and eye drops) in bacterial conjunctivitis.
 Chloramphenicol is not approved for use in food animals in many countries.
THIAMPHENICOL
 Thiamphenicol is semi-synthetic derivative of chloramphenicol.
 It is produced by replacing the p-nitro phenyl group of chloramphenicol by methyl-
sulfonyl group.
 It is more water soluble, less potent & less toxic (safe) than chloramphenicol (devoid
of irreversible bone marrow suppression)
 Not metabolised to significant extent in liver.
 It is safe & effective antimicrobial for use in food producing animals (cattle, swine,
poultry).
FLORFENICOL
 Florfenicol is a fluorinated analogue of thiamphenicol in which the hydroxy group
oxide chain is replaced with fluorine.
 It is effective against certain bacteria which are even resistant to chloramphenicol
 It is more active than either chioramphenicol or thiamphenicol.
 It is safe alternative of chloramphenicol for use in food producing animals.
AZIDAMFENICOL
 It is another amphenicol antibiotic, with profile to chloramphenicol
 Used only topically as eye drops and ointment for susceptible bacterial infections.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

MACROLIDES AND LINCOSAMIDES
MACROLIDES
 The macrolides (macrocyclic lactones) are a group of bacteriostatic antibiotics.
 Exert their antibacterial effect by inhibiting proteins synthesis in susceptible bacteria
mainly by binding irreversibly to the 50S ribosomal subunit.
 The macrolide contain large lactone ring attached to one or more deoxy sugars by
glycosidic linkages.
Sources:
 Macrolides are mostly obtained from various species of Streptomyces.
 Some are prepared semi-synthetically.
Natural sources are:
 Erythromycin: Streptomyces erythreus
 Tylosin: Streptomyces fradiae
 Spiramycin: Streptomyces ambofaciens
Properties:
 All macrolide antibiotics are weak bases & this basic nature is due to the presence of
dimethylamine group in their structures.
 Macrolide concentrated in acidic fluids such as milk and prostatic fluid by process of
―ion trapping‖.
 Colourless crystalline substances, poorly soluble in water
 Maximum activity seen at pH 7.8 to 8.
 They are lipid soluble but are often used in ester forms to enhance oral bioavailability
and to improve oral tolerance.
Classification
I. Macrolide antibiotics.
1. Older macrolide antibiotics: E.g. Erythromycin, tylosin, tilmicosin, spiramycin,
oleandomycin and troleandomycin
2. Newer macrolide antibiotics: E.g. Clarithromycin and roxithromycin
II. Azalide antibiotics: e.g. Azithromycin and Tulathromycin.
III. Ketolide antibiotics: e.g. Telithromycin.
Mechanism of action
Macrolides inhibit bacterial protein synthesis by binding to 50S ribosomal subunit in
susceptible bacteria (Usually in G+ve).
MOA divided into two processes:
1. Passage of macrolides into bacterial cell.
2. Interaction of macrolides with bacterial ribosomes.
1. Passage of macrolides into bacterial cells:
 Macrolides are transported into bacteria by an active transport system.
 G+ve bacteria accumulate about 100 times more antibiotics than do G-ve.
 Macrocyclic showed enhanced antimicrobial activity at alkaline pH.
2. Interaction of macrolides with bacterial ribosomes.
 The macrolides bind to 50S ribosomal subunit and interfere with bacterial protein
synthesis.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 The effect is more pronounced on rapidly dividing bacteria and mycoplasma.
 Macrolides generally do not bind to mammalian ribosomes.
Antimicrobial Spectrum
 Macrolides are effective against most aerobic and anaerobic G+ve bacteria.
 Antibacterial spectrum similar to or slightly wider than that of penicillin (Substitute to
penicillin).
 Beta- haemolytic Streptococci, Pneumococci, Staphylococci and Enterococci are
susceptible to macrolide.
 Generally not active against G-ve bacteria except some strains of Pasteurella,
Haemophilus and Neisseria species.
 Also active against Mycobacterium, Mycoplasma, Chlamydia and Rickettsia species.
 Macrolides ineffective against protozoa, viruses and fungi.
Bacterial Resistance
 Acquired resistance in susceptible G+ve bacteria result mainly from changes in 50S
ribosomal subunit and loss of macrolide affinity.
 This is associated primarily to decreased permeability into bacteria, active efflux of
drug, increased production of inactivating enzyme.
 The bacterial resistance is mostly plasmid mediated that may develop rapidly (e.g.
erythromycin) or slowly (e.g. tylosin).
 Cross-resistance with other macrolides, lincosamides and chloramphenicol may occur
due to their similar binding sites on the ribosome.
Pharmacokinetics
Absorption:
 Macrolides are lipid soluble which are rapidly absorbed from the GI tract. If not
inactivated by gastric acid.
 Oral preparations are often enteric-coated to prevent gastric acid inactivation.
 Presence of food usually interferes with the GI absorption.
 Cmax of macrolide occur within in 12 hours after oral dosing.
 Absorption of macrolides after IM or SC injection is rapid.
Distribution:
 Macrolides are widely distributed in tissues
 Accumulate in macrophages and leukocytes because of ion trapping & also showed
high tissue concentrations than plasma.
 They cross the placenta, but not blood-brain barriers.
 Their concentration in milk is usually several times greater than in plasma, especially
in mastitis.
 Macrolide are 70-80% protein bound mainly to alpha-1-acid glycoproteins and not to
albumin.
Biotransformation and excretion:
 Macrolide are extensively metabolized (>80%) in liver through microsomal enzyme
system.
 Excreted in both active form and inactive metabolites in bile (>60%) and undergo
enterohepatic cycling.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 Plasma half-lives is 1 to 3 hours in domestic animals.
Side Effects / Adverse Effects
 GIT disturbances:
 Vomiting, anorexia, diarrhoea, regurgitation and epigastric pain.
 Horses are more susceptible to the macrolide-induced GIT disturbances.
 Hypersensitivity:
 Other effects:
 Commonly produce pain and swelling at the injection site.
 Tylosin and Tilmicosin have tendency to produce cardiovascular toxicity.
Contraindications and Precautions
 In hypersensitive patients.
 In patients with pre-existing liver dysfunction.
 In horses and rabbits, due to chances of a reaction causing fatal digestive disturbance.
 Avoided in lactating animals (concentrate in milk)
Drug Interactions
 Not used with chloramphenicol or lincosamides b/c they compete for 50S ribosomal
subunit.
 Macrolides inhibit microsomal enzymes and depress metabolism of many drugs.
 Activity decreases in acidic environment.
Clinical Uses
 Macrolide are widely used in human and veterinary to treat both systemic and local
infections.
 They are often used as penicillin substitutes (in penicillin allergic patient).
 Macrolides are mainly used in upper respiratory tract infections, bronchopneumonia,
enteritis, metritis, urinary tract infections, mastitis and arthritis.
INDIVIDUAL MACROLIDES:
Erythromycin:
 Most widely used, obtained from Streptomyces erythreus in 1952.
 Pain & swelling at injection site- IM, SC.
 Used in dogs and cats, sheep, cattle & swine.
 Drug of choice for Campylobacter & Rhodococcus equi in foals.
 Not recommended in adult horses (cause fatal diarrhea)
Tylosin:
 Obtained from Streptomyces fradiae.
 Pharmacologically (PD, MOA, PK) related to the erythromycin.
 Drug of choice for CRD in poultry, CBPP in cattle, CCPP in goats (Mycoplasma
infections).
 Clinically use to treat pneumonia, foot rot and metritis in cattle; pneumonia,
erysipelas and dysentery in swine.
Tilmicosin:
 Used to treat pneumonia acused by Pasteurella spp. in cattle, sheep & swine (HS).
 Not recommended by IV route (Used SC route)
 High affinity for lung tissues, single injection remain effective for 3 days.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

 Clarithromycin:
 Used to treat Helicobacter pylori infections in humans.
 Used to treat Rhodococcus equi infection in combination with rifampin.
Roxithromycin
 Longer acting and more stable than erythromycin.
 Mostly used as an alternative to erythromycin in the treatment of respiratory tract,
skin, soft tissues and genital tract infections.
Tulathromycin:
 Long half-life of 92 hours in cattle, remain effective for long duration.
 Recommended for treatment of bovine respiratory disease (BRD) in cattle.
 Not recommended in meat producing animals.
 Swelling, irritation and pain at injection site may be observed.
Azithromycin:
 Recently introduced, acid stable- orally effective with no need of protection from
gastric acid.
 Longer half life 18 h in horse, 30 h in dogs.
 Ability to concentrate in respiratory tissues so used in respiratory tract infections.
Telithromycin:
 Semi-synthetic, acid stable, used in respiratory tract infection in human.

LINCOSAMIDES
 Lincosamides are a group of monoglycoside antibiotics containing an amino acid like
side chain.
Chemistry and properties
 They are more stable in salt forms.
 They are basic compounds, so are more concentrated in acidic fluids.
 The first lincosamide to be discovered was lincomycin, isolated from Streptomyces
lincolnensis in a soil sample from Lincoln (USA).
Mechanism of Action
 Lincosamides inhibit the bacterial protein synthesis by binding with the 50S
ribosomal subunit (similar to macrolides) and are primarily bacteriostatic.
 Lincosamides, macrolides and chloramphcnicol are not structurally related, they all
act at sites with close proximity.
 Lincosamides are more active at an alkaline pH and may become bactericidal at high
concentration.
Antibacterial Spectrum
 Lincosamides have antibacterial spectrum similar to that of macrolides
Bacterial resistance
 Resistance appears gradually and slowly.
 Alteration of 50S ribosomal subunit is mostly involved for resistance against
lincosamides.
 Lincosamides show cross-resistance with macrolides.

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

Pharmacokinetics
 Lincosamides are absorbed to variable extent (60-90%) after oral administration.
 In many species these drugs have the ability to diffuse across the placenta.
Side Effects/Adverse Effects
 Lincosamides do not produce serious adverse effects in all animals, but GIT
disturbances (diarrhoea, vomiting and anorexia) are common.
 Lincosamides may inhibit neuromuscular transmission and cause paralysis of skeletal
muscle.
 Hypersensitivity reactions and pain at injection site is common.
Contraindications and Precautions
 Contraindicated in animals with fermenting GIT like ruminants and horses due to
development of fatal colitis.
 Do not prescribe to neonates, lactating animals, rodents & rabbit.
Drug Interaction
 Lincosamides increase the neuromuscular blocking effect of general anaesthetics and
skeletal muscle relaxants.
 Concurrent use of chloramphenicol or macrolide antibiotics reduces the efficacy of
lincosamides.
INDIVIDUAL LINCOSAMIDES
Lincomycin:
 Obtained from Streptotnyces lincolnensis.
 Used to treat infections caused by Staphylococci, Streptococci, anaerobes
Erysipelothrix and Mycoplasma.
 Growth promoter in poultry.
Clindamycin:
 Used primarily to treat anaerobic infections.
 Used in patients - hypersensitivity to penicillins.
 Useful in the treatment of bone, joint & deep tissue infections.
 Used to treat toxoplasmosis in dogs.
 Not used in horses, ruminants and rabbits due to serious GI disturbances.
Pirlimycin
 Useful against Staphylococcus aureus and Streptococcus spp. (G+ve) infection in
human.
 Limited used in animals

Chemotherapy / Aminoglycosides / C V Sc & A , AAU, Anand / 2019

QUINOLONES/ FLUOROQUINOLONES

 They are most recent (latest) antibacterial drug group.

 They are synthetic antibacterial agents having a 4- quinolones structure.
 They are primarily active against G-ve bacteria, although newer fluorinated agents
also inhibit selected G+ve bacteria.
 They are minimally toxic and are very important in veterinary medicine.
History
 Nalidixic acid was first member of quinolones family introduced in 1964.
 Oxolinic acid and rosoxacin with more potency but limited spectrum were introduced
in 1970.
 Pipemidic acid and cinoxacin were also introduced in the 1970.
 These were followed by second-generation quinolones called fluoroquinolones with
extended spectrum and systemic antibacterial effects in 1980.
 Since then (1980 onwards), structural modifications have resulted in several second,
third and fourth generation fluoroquinolones, which have found valuable place in
human and veterinary practices.
Chemistry and Structure Activity Relationship
 Quinolones contain a basic structure of 4-quinolone with a carboxylic acid moiety at
position 3.
 Various modifications on the basic ring structure leads to produces compounds with
differing physical, chemical, pharmacokinetic and antimicrobial properties.
 The majority of quinolones in clinical use belong to the subset fluoroquinolones,
which have fluorine atom attached at the C-6 position.

Basic structure of fluoroquinolone

 The carboxyl group (-COOH) at position 3 and ketone group at position 4 are
essential for antibacterial activity.
 Substitution at position 6 with a fluorine moiety markedly enhances activity against
G-ve and G+ve bacteria as well as mycoplasma and chlamydia.
 All fluorinated 4-quinolones are called fluoroquinolones.
 Addition to piperazine ring at position 7 on fluoroquinolones significantly increases
tissue and bacterial penetration and improves spectrum of activity to include
Pseudomonas (e.g. ciprofloxacin and enrofloxacin).
 Substitution with an oxygen atom at position 8 improves activity against G+ve and
anaerobic organisms without affecting the bactericidal profile.

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Properties
 Quinolones are amphoteric compounds.
 They exhibit poor water solubility (high lipid solubility) between pH 6 and 8.
 In concentrated acidic urine, some quinolones form needle-shaped crystals.
 Quinolones are available for oral and parenteral administration and can be given as
water-soluble salts or as free bases.
Classification
 Quinolones are classified on the basis of their pattern of evolution (generation) and
antibacterial spectrum.
 The first generation quinolones consist of older non-fluorinated quinolones, whereas
the later generation quinolones are predominantly fluorinated compounds.
1) First-generation quinolones:
e.g. nalidixic acid, oxolinic acid, flumequine, cinoxacin, pipemidic acid, piromidic
acid and rosoxacin.
2) Second-generation quinolones:
e.g. enrofloxacin & danofloxacin (animal use only), ciprofloxacin & norfloxacin
(human use only), difloxacin, orbifloxacin, marbofloxacin, ofloxacin, pefloxacin,
sarafloxacin lomefloxacin and enoxacin.
3) Third-generation quinolones:
e.g. levofloxacin, sparfloxacin, pradofloxacin, ibafloxacin, grepafloxacin,
balofloxacin, pazufloxacin, temafloxacin and tosufloxacin.
4) Fourth-generation quinolones:
e.g. moxifloxacin, gatifloxacin, gemifloxacin, sitafloxacin, besifloxacin, clinafloxacin,
garenoxacin, trovafloxacin and prulifloxacin.
Mechanism of Action
 Quinolones inhibit the replication of bacterial DNA by interfering with action of
DNA gyrase (topoisomerase II) enzyme.
 They are bactericidal drugs.
 Drugs enter in susceptible microorganisms by the passive diffusion through porins in
the outer membrane. Once inside bacterial cell, quinolones target the enzyme DNA
gyrase, which is responsible for introducing negative supercoils into DNA.
 [Super coiling is a process where double stranded DNA molecule coils on itself so
that DNA can be tightly and compactly packed inside the bacterial cell].
 This negative supercoiling introduced by DNA gyrase is essentially required to
relieve the super helical tension while double-stranded DNA is being unwound by
helicase.
 The negative supercoiling introduced by DNA gyrase is an energy dependent reaction.
 Bacterial DNA gyrase is composed of A and B subunits.
 The A subunits carry out the strand-cutting function, whereas the B subunits cause the
ATP hydrolysis necessary for gyrase supercoiling.
 The A subunits are the primary site of action of quinolones.
 The DNA gyrase is inhibited by quinolones than the negative supercoiling not take
place that leads to disruption in bacterial DNA replication. This leads to bactericidal
effect.

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 Mammalian DNA gyrase has 1000 times less affinity than bacterial DNA gyrase.
 FQs are highly effective at very low concentration.

Antimicrobial Spectrum
 First-generation quinolones (e.g. nalidixic acid) have moderate G-ve activity and
minimal systemic distribution.
 Fluoroquinolones are broad spectrum drug effective against a wide range of G-ve
& G+ve bacteria, Mvcoplasma and Chlamydia.
 However, spectrum of activity varies with the type of fluoroquinolone.
 Second-generation FQs have expanded G-ve activity but limited gram-positive
activity. These agents are most active against aerobic gram negative bacilli.
 Third-generation FQs have expanded G-ve and atypical intracellular activity &
also improved G+ve coverage.
 Fourth-generation FQs show improved G+ve coverage, maintain G-ve coverage,
and gain anaerobic coverage.
 FQs showed concentration dependent antibacterial activity.
 Fluoroquinolones have long post-antibiotic effect.
 Growing bacteria are more susceptible & co-administration of bacteriostatic drugs
may decrease the efficacy.
 Anaerobic and acidic environments (e.g. abscesses) decrease the AB activity.
Bacterial Resistance
 Bacterial resistance develops rapidly to nalidixic acid and older quinolones.
 Staphylococcus aureus, enterococci and Streptococcus pyogenes now exhibit
resistance worldwide.
 Resistance is either due mutation in bacterial DNA gyrase or reduced permeability to
FQs.
 Efflux of drugs out of the bacteria is also possible.
 FQs have been recommended to be reserved for the use in patients those are seriously
ill and may soon require immediate hospitalization.
Pharmacokinetic
 Pharmacokinetic of quinolones varies with type of drug and Species.
 Absorption:
 Quinolones have good bioavailability after oral administration in monogastric
animals and pre-ruminating calves.
 Bioavailability is often >80% for most quinolones, except in ruminates and peak
levels are achieved in 0.5-2 hours after administration.
 However, presence of aluminium, magnesium, calcium, iron and zinc reduces
absorption and bioavailability of FQs.
 Absorption from IM or SC injection is rapid.
 Distribution:
 FQs distribute well into all body tissues and fluids including CNS, bone and prostrate.
 Tissue penetration is higher than the concentration achieved in plasma, stool, bile,
prostatic tissue and lung tissue.

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 They also accumulate in macrophages and leucocytes thus being effective against
intracellular microorganisms.
 Quinolones also penetrate well in urine and kidneys when renal clearance is the route
of drug elimination.
 The degree of PPB is extremely variable. e.g. 10% for norfloxacin while >90% for
nalidixic acid.
 Biotransformation and excretion:
 Some quinolones are eliminated unchanged (e.g. ofloxacin), some are partially
metabolised (e.g. ciprofloxacin), and a few are completely metabolised (e.g.
pefloxacin).
 Metabolites of a few quinolones are active i.e. enrofloxacin metabolized to
ciprofloxacin (active metabolite).
 Pefloxacin is metabolized to norfloxacin (active metabolite).
 Renal excretion is the major route of elimination for most quinolones.
 Renal tubular secretion results in high urinary concentration.
 The alkaline urine increases reabsorption of FQs and may prolong elimination half-
life.
 The half-lives of most FQs range from 3 to 6 hours.
 FQs show significant post-antibiotic effect. Therefore, most of these drugs are
administered every 12 to 24 hours.
 FQs appear in the milk of lactating animals in high concentration.
Side Effects/Adverse Effects
 Side effects with older quinolones are relatively common, but newer quinolones are
generally well tolerated.
 Cartilage deformities, chondro-destruction (chondrotoxicity) and joint growth
disorders have been documented in young animals, particularly in dogs and foals,
after administration of FQs.
 In heavy breed dogs, the weight bearing joints are specifically susceptible often
leading to permanent damage.
 FQs may causes seizures or convulsion at high dosage.
 They can produce crystalluria in dogs due to their low solubility in acidic urine.
 Haemolytic anaemia has been reported in some animals with FQs.
 Recently blindness in cats caused by high doses of FQs has attracted attention.
 Sometime GIT disorders resulting in nausea, vomiting and diarrhoea.
 IM injection of some quinolones causes pain at site of injection.
 Large doses in pregnant animals may cause foetal toxicity.
 In humans, FQs are sometimes causes cardiac arrhythmias, CNS effects and
hypoglycemia.
Contraindications and Precautions
 Contraindicated in hypersensitive patients
 FQs are not recommended in growing dogs under 12-18 months of age.
 Used with extreme care in pregnant animals and in patients with seizures disorders.
 In dehydrated patients.
 In patients with cardiac arrhythmia.

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 Drug Interactions
 They are potent chelators of Mg++, Ca++, Zn+++, Fe+++ and Al+++, so products
containing cations, including sucralfate, non systemic antacids, nutritional
supplements and multivitamin and mineral supplements orally (within 2-4 h) may
interfere FQs absorption.
 FQs inhibit theophylline metabolism leads to increase chance of toxicity.
 Sometime combination of FQs with NSAIDs increases seizure threshold.
 Simultaneous use of corticosteroids has increase tendon rupture in animals.
Clinical Uses
 FQs are become drug of choice for treatment of G-ve bacterial infections.
 Older quinilones like nalidixic acid primarily used as urinary antiseptic.
 FQs are effective in the treatment local and systemic infections caused by susceptible
organism especially for intracellular and deep seated infections.
 Useful in treatment of respiratory tract, intestine, urinary and prostrate infections.
 Also useful in the treatment of meningoencephalitis, osteomyelitis and arthritis and
staphylococcal endocarditis.
INDIVIDUAL FLUOROQUINOLONES (Self Study):
Nalidixic acid:
 Non-fluorinated first-gen. drug, Used primarily as a urinary antiseptic, used orally in
dogs & cats.
Oxolinic acid: Non-fluorinated, CNS toxicity, used to treat fish diseases.
Flumequine: Withdrawn from clinical use in several countries.
Enrofloxacin:
 Excellent drug, Animal/Vet Use only, Broad spectrum, bactericidal, approved for use
in dogs, cats, cattle, buffalo, sheep, goat, horse, swine and poultry. Dose: 2.5 - 5
mg/kg.
 Avoid high dose in cats-retinotoxic.
Ciprofloxacin:
 Active metabolite of enrofloxacin, Similar to enrofloxacin, widely used in human
medicine.
Difloxacin:Mainly used in dogs, poultry, sometimes in horse, orally.
Orbifloxacin:Mainly used in dogs & cats, Also sheep, goats, horse, orally/IM.
Danofloxacin:Treat respiratory tract infections in cattle, chick, and pigs (vet. use only).
Pefloxacin:Metabolized to norfloxacin (active metabolite), used in human medicine
Gatifloxacin:
 Banned for systemic use in India (cause serious hyperglycemia), ophthalmic use-safe.
Marbofloxacin:Long elimination half life- 10 h
Moxifloxacin:
 Increase usage in clinical practice, potent against TB, Drug of last resort when all
other antibiotics have failed.
Note: Enro, Dan: Vet. use only while Cipro, Pe, Nor: Human medicine.

Unit-V/Chemotherapy / C V Sc & A , AAU, Anand /2019

MISCELLANEOUS ANTIBACTERIALS & URINARY ANTISEPTICS

Classification of other Antibacterials:

I. Natural and semi-synthetic antibacterials
1. Polypeptide antibiotics e.g. polymyxins (polymyxin B and colistin), bacitracins
2. Glycopeptide antibiotics e.g. vancomycin, teicoplanin
3. Aminocyclitol antibiotics e.g. spectinomycin and apramycin.
4. Rifamycins e.g. rifampicin.
5. Pleuromutilins e.g. tiamulin, valnemulin and retapamulin
6. Streptogramins e.g. streptogramin, virginiamycin
7. Amonocoumarins e.g. novobiocin
8. Miscellaneous antibiotics e.g. fusidic acid, mupirocin, daptomycin, fosfomycin and
cycloserine
II. Synthetic antibacterials
1. Nitrofurans e.g. nitrofurantoin, furazolidone, nitrofurazone
2. Nitroimidazoles e.g. metronidazole and dimetridazole.
3. Oxazolidones e g linezolid, torezolid and eperezolid.
4. Arsenicals e.g. arsanilic acid and sodium arsanilate
5. Hydroxy quinolines e.g. clioquinol

1. POLYPEPTIDE ANTIBIOTICS
• Polypeptide antibiotics have low molecular weight produced by various bacterial
species.
• They possess strong bactericidal action, but are not used systemically due to toxicity.
• E.g. polymyxins, bacitracins
Polymyxins
• Polymyxins is a generic name used for a group of six strongly basic cyclic
polypeptides namely polymyxins A, B C, D, E and M.
• Polymyxin B and polymyxin E (called colistin) are therapeutically useful.
Polymyxin B
• Bactericidal antibiotic obtained from Bacillus polymyxa.
• Used only by topical and oral administration because parenteral administration often
leads to toxicity.
• MOA: Polymyxin B is a rapid acting bactericidal agent with a detergent like action
on the bacterial cell membrane.
• Polymyxin B strongly interacts with negatively charged lipopolysaccharide (LPS) in
the outer membrane of Gram-negative bacteria causing permeability changes and
disruption of bacterial cell membrane.

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• Antimicrobial spectrum
• It effective against gram-negative bacteria only due to presence of LPS in outer cell
memberane.
• It is active against Enterobacter, Klebsiella, Salmonella, Pasteurella, Bordetella,
Pseudomonas, E coli and Shigella.
• Bacterial resistance: very slow development
• Pharmacokinetics
• Not absorbed following topical & oral administration.
• Metabolized and excreted in urine as inactive metabolites.
• Plasma half-lives in animals are about 3-6 hours.
• Adverse effects:
• Adverse effects are minimal on topic application because of its complete lack of
absorption from the site.
• Parenteral administration produces nephrotoxicity and neurotoxicity.
• Clinical uses
• Used topically to treat gram-negative infections of skin, eye and ear (e.g. otitis
externa) in all species.
• Treatment of bovine mastitis caused by Pseudomonas aeruginosa and Klebsiella.
• It is mostly used with bacitracin.
Colistin (Polymyxin E)
• Colistin obtained from Bacillus colistinus.
• It is available as colistin sulphate for oral use and colistin sodium methanesulphonate
for parenteral use.
• Colistin has an antibacterial spectrum, mode of action, pharmacokinetic patterns,
clinical uses and toxicity similar to those of polymyxin B.
• However, colistin is more potent on Pseudomonas, Salmonella and Shigella.
Bacitracin
• Bacitracin is isolated from Bacillus subtilis.
• Bacitracin A is the most active and major component.
• It is used either topically or by oral administration.
MOA:
• Bacitracin is a bactericidal drug that acts by inhibiting the cell wall synthesis in
susceptible bacteria.
Antimicrobial spectrum
• Similar to penicillin, but it is also effective against penicillinase producing
Staphylococcus aureus. Bacitracin is effective against gram-positive bacteria and
spirochetes.
Clinical Uses:
• Bacitracin is mostly used topically for susceptible skin, ear and eye infections.
• often used in combination with neomycin and/or polymyxin B
• Bacitracin as zinc or magnesium is also added to swine and poultry ration to prevent
and treat clostridial enteritis and also as growth promoter.
Toxicity: Nephrotoxicity, pain at the site of injection

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2. GLYCOPEPTIDE ANTIBIOTICS
Vancomycin
• Obtained from Streptococcus orientalis.
• freely soluble in water
• MOA: Vancomycin is a bactericidal antibiotic that acts by inhibiting the bacterial
cell wall synthesis.
• AB Spectrum: Vancomycin is effective against gram-positive bacteria include
Staphylococcus, Streptococcus, Enterococcus, Clostridium and Corynebacterium
species.
• PK: vancomycin is not absorbed from GI tract after oral administration. After IV
administration, it is widely distributed in body tissues and fluids, except the CNS.
• It is excreted unchanged in urine.
• Toxicity: It produce dose-and time-dependent ototoxicity and nephrotoxicity.
Intramuscular injection is often painful and irritating.
• Clinical uses
• Used for meticillin-resistant Staphylococcus aureus (MRSA) infections of the bones
and soft tissues in dogs and cats.
Teicoplanin
• Mixture of several related compounds extracted from Actinoplanes teichomyceticus.
• Teicoplanin can be administered IM.
• Used in the treatment of MRSA infections, penicillin-resistant enterococcal
infections and in penicillin allergic patients.
3. AMINOCYCLITOL ANTIBIOTICS
• Chemically related to aminoglycosides
• The amino groups are present on the cyclitol ring hence called aminocyclitols.
• e.g. Spectinomycin and apramycin are the clinically useful drugs
Spectinomycin
• It obtained from Streptomyces spectabilis.
• soluble in water and alcohol
• Spectinomycin is bacteriostatic, binds to the 30S ribosomal subunit and inhibits the
bacterial protein synthesis.
• It is active against many gram-negative bacteria and mycoplasma.
• Resistance in susceptible bacteria develops rapidly.
• The pharmacokinetics behaviour of spectinomycin is similar to that of
aminoglycosides. No significant adverse effects.
• Spectinomycin is used in dogs, cats, horses, pigs and poultry for treatment of enteric
and respiratory infections caused by the susceptible bacteria.
Apramycin
• It obtained from Streptomyces tenebrasius.
• It is bactericidal against many gram-negative bacteria.
• Used for treatment of colibacillosis and salmonellosis in calves and pigs.
4. RIFAMYCINS
• Rifamycin are produced by Streptomyces mediterranei.
• They are effective against gram-positive bacteria (mycobacteria)
Unit-V/Chemotherapy / C V Sc & A , AAU, Anand /2019
• Used to treat tuberculosis & leprosy.
• Semi-synthetic rifamycin derivatives are clinically useful includes rifampicin &
rifabutin
Rifampicin/Rifampin
• Lipophilic , slightly soluble in water and alcohol, red solid in colour.
• Rifampicin act by inhibiting DNA-dependent RNA polymerase in susceptible
bacteria.
• Rifampicin is bactericidal drug.
• Effective against Gram positive bacteria and Mycobacterium tuberculosis.
• Staphylococcus, Haemophilus, Neisseria and Chlamydia org are also susceptible.
Bacterial resistance develops quickly.
• PK: well absorbed (40-70%) from the GI tract after oral administration, C achieve
max
within 2-4 hours. Absorption from IM injection site is rapid.
• Rifampicin is rapidly distributed in body tissues and fluids.
• Rifampicin is metabolised by liver.
• It is primarily excreted in bile and to a lesser extent in urine.
• Active metabolites undergo enterohepatic cycling, which may enhance the duration
of action.
• Toxicity: Rifampicin is generally well tolerated in normal doses.
• Hepatotoxicity may occur in animals with pre-existing liver disease. Some time
Gastrointestinal disturbances & CNS depression may also seen.
Rifabutin
• Semi-synthetic rifamycin.
• Mechanism of action similar to rifampicin.
• It is effective against Gram-positive and some Gram-negative bacteria.
• It is primarily used in human medicine in the treatment of tuberculosis.
5. PLEUROMUTILINS
Tiamulin
• It obtained from Pleurotus mutilis.
• It act by inhibiting protein synthesis in bacteria by binding to 50S ribosomal subunit.
• Broad-spectrum antibacterial activity.
• Mainly used for the treatment of enzootic pneumonia in pigs.
• Used as growth promoter in swine.
Valnemulin
• MOA similar to tiamulin, Used in treatment of swine dysentery in pigs.
Ritapamulin
• First drug in the class to be approved for human use.
• Used in methicillin-resistant Staphylococcus aureus (MRSA).
• It is marketed as an ointment for topical use on skin.
6. STREPTOGRAMINS
• e.g. streptogramin & virginiamycin
• Novel class of antibiotics which act by inhibiting the protein synthesis by binding to
50S ribosomal subunit.

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• Streptogramin & virginiamycin obtained from Streptomyces virginiae.
• Mostly used as a growth promoter in swine and poultry.
7. AMINOCOUMARINS
Novobiocin
• Obtained from the Streptomyces niveus.
• Freely soluble in water.
• MOA: Inhibition of bacterial DNA gyrase, thereby interference with bacterial protein
and nucleic acid synthesis.
• Mostly active against gram-positive bacteria.
• It is well absorbed orally with peak plasma levels reaching in 1-4 hours.
• Toxicity: GI disturbances and blood dyscrasias. Fever, rashes and hypersensitivity
reactions are occasionally observed.
• Novobiocin is mostly used in combination with procaine penicillin G in the
treatment of mastitis.
• Also used in the treatment of MRSA.

8. MISCELLANEOUS ANTIBIOTICS
• e.g. fusidic acid, mupirocin, daptomycin, fosfomycin and cycloserine.
Fusidic acid
• Obtained from Fusidium coccineum.
• It acts by inhibiting protein synthesis in bacteria.
• Primarily effective on gram-positive bacteria (MRSA, Staphylococcus species,
Streptococcus species and Corynebacterium species)
II. SYNTHETIC ANTIBACTERIALS
1. NITROFURANS
• e.g. Nitrofurantoin & furazolidone
• It acts by inhibiting carbohydrate metabolism in susceptible bacteria.
• Broad-spectrum of activity & also active against coccidia, trichomonads, amoebae
and giardia.
• More active in acidic environment
• Used topically for cutaneous infections and wound dressings in all species & orally as
urinary antiseptics in dogs and cats.
• Adverse effects: Several toxic effects in animals include GI disturbances and CNS
signs. Depression of spermatogenesis. hypersensitivity reaction can also occur.
Carcinogenic in laboratory animals.
Nitrofurantoin
• It is a synthetic nitrofuran used mainly for prevention and treatment of urinary tract
infections.
Furazolidone
• Synthetic nitrofuran used orally for enteric infections & topically on skin.
• It has wide spectrum of antibacterial activity & also active against Giardia,
Trichomonas, Coccidia and Histomonas.
•

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2. NITROIMIDAZOLES
• Antiprotozoal and antibacterial activities.
• E.g. Metronidazole and dimetridazole
• Metronidazole
• Widely used in the treatment of trichomoniosis, giardiasis and amoebiasis.
• Bactericidal used to treat most gram-negative and gram positive anaerobic bacterial
infections.
• Metronidazole acts mainly by disrupting DNA synthesis in the susceptible
.
microorganisms.
• Dimetridazole is a synthetic 5-nitroimidazole antiprotozoal drug similar to
metronidazole.
URINARY ANTISEPTICS
• Urinary antiseptics are drugs which attain useful antibacterial concentrations only in
the urine and are used exclusively for urinary tract, bladder or renal pelvis
infections.
• E.g. nalidixic acid, nitrofurantoin and methenamine.

Methenamine (Hexamine)
• Synthetic compound
• Their salts are freely soluble in water
• MOA: The antibacterial activity of methenamine occurs due to release of
.
formaldehyde gas in water.
• Methenamine → Formaldehyde gas
• PH dependent hydrolysis reaction.
• Methenamine is primarily a bacteriostatic agent, but it becomes bactericidal in acidic
urine.
• Used in urinary tract infections in dogs & cats.

Unit-V/Chemotherapy / C V Sc & A , AAU, Anand /2019

Chemotherapy of Tuberculosis

 Cattle : Mycobacterium bovis

Dogs : Mycobacterium tuberculosis / Mycobacterium avium complex

Pigs : Mycobacterium avium complex

Man: Mycobacterium tuberculosis / Mycobacterium avium complex

Mycobacterium kansasii / Mycobacterium fortuitum complex

Mycobacterium leprae cause Leprosy

Sheep, Horse and cat – Relatively Resistant

 First line drugs for TB: Isoniazid, Rifampin, Pyrazinamide, Ethambutol and
Streptomycin.
1. Isoniazid

 Primary drug for tuberculosis.

 Discovered in 1945 by chorine.
 It is hydrazide salt of isonicotinic acid
 Resting bacilli-bacterioststic, Rapidly dividing bacilli – bactericidal
 MIC: 0.025 – 0.05 µg/ml.
 Penetrates bacterial cell easily.
 MOA: Several hypothesis includes effects on lipids, nucleic acid biosynthesis and
glycolysis.
 Primary action is to inhibit biosynthesis of mycolic acid which is important
constituent of mycobacterial cell wall.
 Mycolic acid – unique to mycobacteria so high degree of selectivity.
 Rapid absorption following oral or parenteral administration.
 Distributed to tissues and body fluids. Therapeutic concentration achieved in CSF,
Pleural and ascetic fluid.
 75-90% metabolized and mainly excretion through urine
 Major Metabolites- 1) Acetyl isoniazid (acetylation)
2) Isonicotinic acid (hydrolysis)
 Globally the most preferred drug to treat all types of T.B.
 Isoniazid alone for prevention whereas isoniazid + other drugs for treatment.
 Dose: 3-5 mg/kg PO/IM. May be given with Pyridoxine/ Vitamin B6 (15 – 50 mg/kg)
to minimize side effects of isoniazid
 Prominent reactions – Rash, fever, jaundice and peripheral neuritis
 Peripheral neuritis is common.
 Isoniazid causes pyridoxine (vitamin B6) deficiency.

2. Rifampin

 Rifamycins – complex macrolcyclic antibiotics (Streptomyces mediterranei)

 Rifampin – Semisynthetic derivative of Rifamycin B
 High activity against Mycobacterium tuberculosis and other mycobacterium spp.

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 Active against most G+ve (High activity against S. aureus) and some G-ve bacteria
([Link], Pseudomonas, Proteus & Klebsiella). Also active against Neisseria and
Hemophillus.
 Bactericidal action on intra and extra cellular microorganisms.
 Inhibits DNA-dependent RNA-polymerase enzyme – suppress initiation of RNA
synthesis in mycobacterium and other microorganisms.
 Less affinity for eukaryotic nuclear RNA-polymerase.
 High concentration inhibits viral RNA-polymerase and reverse transcriptase.
 Variable oral absorption, widely distributed including CSF.
 Metabolized to active deacetylated metabolites.
 Rifampin (150mg) + isoniazid (300 mg): most effective drugs for treatment of TB.
 Side effects: Rash, fever, nausea and vomiting.
 Potent inducer of hepatic microsomal drug metabolizing enzyme system.
 Decrease half-life of digitoxin, quinidine, ketoconazole, propanolol, metoprolol,
clofibrate, verapamil, barbiturate, halothane etc.
3. Ethambutol

 All strains of M. tuberculosis and M. avium complex are sensitive.

 No activity against other bacteria.
 MOA: Inhibits incorporation of mycolic acid in to the mycobacterial cell wall.
 Bioavailability: 75-80 % (PO), 75% excreted unchanged in urine (24h).
 Treatment of TB: Isoniazid + ethambutol.
 Replaced use of para-aminosalycylic acid (PAS).
 Side effects: rash, fever, optic neuritis-dose related and resolve following withdrawal
of drug
4. Streptomycin

 First drug used to treat TB, Bactericidal

 Use for pulmonary TB has reduced.
 Side effects: Rash, fever, dysfunction of auditory and vestibular function.
5. Pyrazinamide

 High activity on intracellular tubercle bacilli

 Following oral administration, well absorbed and distributed.
 Hydrolyzed into pyrazinoic acid & 5-hydroxy pyrazinoic acid
 Used as component of short term (6 month) multi drug therapy of TB
 Side effect – Hepatic damage.
6. Ethionamide

 Effective against M. tuberculosis.

 Use: secondary line drug for treat of T.B.
 Side effects: Anorexia, nausea and vomiting.
7. Para Amino Salicylic Acid (PAS)

 Bacterioststic (M. tuberculosis), Second line drug.

 Structural analog of PABA- inhibit folic acid synthesis in mycobacterium
 Side effects: GI upsets, nausea, epigastric pain and diarrhea.
8. Cycloserine

 Antibiotic : obtain from Streptococcus orchidaceus, Second line drug.

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 Inhibits M. tuberculosis (MIC : 2-20 µg/ml)
 Side effects: CNS disturbances (headache, tremors, vertigo, confusion, nervousness
etc.)
TB chemotherapy - Strategies

 Treatment – Always use two drug combinations.

First 2 months: Isoniazid+ Rifampin + Pyrazinamide, Nest 4 months: Isoniazid+
Rifampin

Note:

 DOTS: Directly Observed Treatment (short-course)

 DOTS is the most effective strategy available for controlling TB.

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69. ANTIVIRAL DRUGS

INTRODUCTION
 Antiviral drugs are agents that used to limit growth and replication of viruses.
 One of the least use drugs in veterinary practices.
 Development of effective and safe antiviral therapy is difficult. So far limited antiviral
drugs for animals and human were available.
 The conventional approach is to develop effective vaccines.
 The treatment of viral infection in animals are usually consists of nursing, control of
secondary bacterial infections, use of analgesics and other symptomatic
therapies.

[Virus: Obligate intracellular parasites, need host genetic machinery for replication,
narrow therapeutic index and lack enzymes that function in energy metabolism. Virus
shows cell dependant replication. Hence they multiply only within the cells. Virus lack
both cell wall & cell memberane.
 Viruses are the smallest infective agents with size ranging from 20 nm
(Picornaviruses) to 300 nm (Poxviruses).
 Animal viruses may be single stranded or double stranded RNA or DNA viruses.]

Difficulties in development of antiviral drugs/ Reasons for failure of antiviral therapy

 Viruses are intracellular pathogen therefore antiviral drugs that target viral process
must penetrate the host cell.
 Viral biochemistry is not fully understood in all types of viruses.
 Lack of broad spectrum antiviral drugs.
 Lack of in vitro susceptibility testing procedures.
 Viruses utilize host cell machinery for replication so antiviral drugs may injure host
cell resulting in narrow margins of safety.
 Chances of easier development of resistance due to mutation
 Inhibits only actively replicating virus, unable to eliminate non replicating/latent viral
infection.
 Mostly virustatic, hence success depends on host immune response.
 They are effective prophylactically and in early stage.

CLASSIFICATION OF ANTIVIRAL AGENTS

1) Agents preventing attachment and penetration: Gamma-globulin, Interferon,
Arbidol, Pleconaril
2) Inhibitors of viral assembly: Amantadine, Rimantadine, Tromantadine
3) Nucleoside analogues:
DNA virus-Idoxuridine, Trifluridine (pyrimidine analogues), Aciclovir Valaciclovir,
Ganciclovir,
Vidarabine (purine analogues) and Foscarnet (Pyrophospahte analogues).
RNA virus- Ribavirin
4) Inhibitor of reverse transcription: Zidovudine
5) Inhibitor of mRNA translation: Antisense oligopeptides
6) Protease inhibitors: Saquinavir, Ritonavir, Indinavir
7) Immunomodulators: Interferons, Inosiplex, levamisole, Poly I (Polyriboinosinic
acid) and Poly C (Polyribocytidylic acid)
8) Inhibitors of viral release: Zanamivir and Oseltamivir

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9) Other agents: Methisazone, Rifampicin, Dactinomycin, Suramin and Dextran
sulphate.

Figure: Mechanism of Action / Targets for Antiviral Drugs

AMANTADINE
 Amantadine and its derivative Rimantadine are synthetic tricyclic amine.
 They lead to inhibition or delay of the uncoating process and also interfere with early
stage of viral mRNA transcription, inhibit viral assembly.
 At usual concentration inhibit replication of different strains of Influenza virus.
 Almost completely absorbed from GIT and 90% is excreted unchanged in urine.
 It produces fever, side effects related to CNS. Aerosol administration reduces the
toxicity.
 Veterinary uses: Prophylaxis in equine influenza.

IDOXURIDINE, VIDARABINE AND TRIFLURIDINE

 Potent inhibitors of DNA synthesis of Herpes virus. Inhibition takes place during
synthesis of DNA strand. These drugs are incorporated into the growing chain of viral
DNA, resulting in misinterpretation of genetic code.
 Inhibit DNA polymerase and defective viral proteins are synthesized.
 Toxicity- Anemia, neutropenia, loss of hair etc.; Because of toxicity reserved for
topical application.
 Idoxuridine, Trifluridine - analog of thymidine; Trifluridine is less toxic and better
penetration than Idoxuridine.
 Vidarabine- analog of adenosine; Acts on Herpes, Pox, Rhabdo, Vaccinia viruses.
 50% excreted in urine

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 Used for the treatment of Herpes simplex, Keratitis, Encephalitis, Mucocutaneous
infection and Cytomegalo viral infection
 Veterinary use: Feline herpes keratitis, bovine vulvovaginitis and kerato-
conjunctivitis, local herpes infection
 Vidarabine: Local bovine herpes, Vaccinia teat lesions.
 Dose: Idoxuridine: 1 drop of 0.1% sol, every hour in infected eye. Trifluridine: 1 drop
of 0.1% sol, 4-6 times/day in infected eye.

ACYCLOVIR
 Synthetic, one of the most prescribed drug, available as sodium salts - water soluble.
 It is selective for viral rather than normal cells.

 Less cytotoxic, breakthrough in antiviral chemotherapy.

 Acyclovir is not phosphorylated in normal cell because of lack of viral thymidine
kinase, non toxic to uninfected cell.
 Valacyclovir, Desiclovir are prodrugs developed because of 90% of acyclovir is
excreted in urine intact
 Human use - Herpes simplex 1 and 2, Varicella Zoster virus – chicken pox
 Veterinary use - Equine herpes in foals
 Available in oral, topical and IV preparations.
 Topical - Local herpes, bovine herpes mammillitis, equine coital exanthema, feline
rhinotracheitis, viral kerato conjunctivitis
 Dose: Dogs & cats: 3mg/kg, PO, 5 time daily for 10 days than 10 mg/kg for next 10
days. Horses: 10 mg/kg, slov IV, 2 time daily; Birds: 80 mg/kg, PO, 3 time daily
GANCICLOVIR
 Guanosine analogue, more active against cytomegalo herpes virus than acyclovir in
immune compromised patients.
 Administration through I/V. Neutropenia and thrombocytopenia are adverse effects.
 Veterinary use: Cytomegalovirus infection

RIBAVIRIN
 Guanosine analogue
 It is activated by viral phosphorylation and subsequently prevents the formation of
mRNA and translation of viral genome. Broad antiviral activity against many RNA &
DNA virus. Resistance is rare.
 Aerosol- Respiratory syncytial virus broncholitis and influenza.
 Veterinary use: Influenza, parainfluenza, bovine herpes virus, canine distemper, blue
tongue, marek's disease, feline calcivirus.
 Topical: Local herpes infection (not feline), vaccinia teat lesions.

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AZIDOTHYMIDINE/ZIDOVUDINE
 Zidovudine effective against retrovirus – HIV virus (AIDS).
 Act by selectively inhibition of viral reverse transcriptase enzyme (RNA dependent
DNA polymerase).
 Toxicity- Dose dependent Anemia, neutropenia, hepatotoxicity & GIT disturbances
 Veterinary Use: Retrovirus, feline leukemia virus (FeLV), feline immunodeficiency
virus (FIV), Equine infectious anemia (EIA)
 In HIV patients – First line of drug in treatment of AIDS in human being.
ANTISENSE OLIGONUCLEOTIDE
 The sequence of a nucleotide chain containing information for protein synthesis is
called sense sequence. The complementary strand is called antisense sequence.
 Antisense drugs recognize and bind to sense sequence of specific mRNA and thereby
prevent synthesis of specific proteins
 Destruction of mRNA by ribonuclease in cell and inhibit viral mRNA translation.

IMMUNIZATION AND INTERFERONS

Immunization
 Passive immunization by IM, IV or SC injection with immunoglobulin can prevent
entry of virus into cells (orally ineffective).
 This is useful to control CD, rabies, gastroenteritis in swine, ICH, Measles,
Poliomyelitis, chicken pox.
 If hyper immune serum is not available pooled sera from the recovered or vaccinated
animals may be used.
 To avoid anaphylactic shock only one injection should be given.
 Gamma globulins (concentrated antibodies= IgG) extracted from normal blood may
also be useful in preventing viral infections in animals.
Interferons
 Interferons are potent cytokines or interrelated group of proteins released by cells
infected by virus. They are highly species specific.
 Interfron (IFN) possesses antiviral, immunomodulatory and antiproliferative actions.
 Liberated from host cells infected by viruses and make other cells to resist the virus.
 Their effect results from binding to specific viral surface receptors and thus
preventing uncoating or penetration by the virus or inhibition of sythesis of viral
proteins.
 Three types are recognized: α, β and γ interfrons.
 IFN-α – Leucocytes.
 IFN-β - Fibroblasts antiviral action in response to RNA virus infection.
 IFN-γ or lymphokines – Lymphocytes, antigen/mitogen stimulation, immuno
modulation.
 They inhibit all the steps in viral multiplication. Bind to specific cell surface receptors
and inhibit viral penetration, uncoating, synthesis of mRNA, translation, assembly and
release.
 It can be administered SC, IM or IV. It is an important part of defense mechanism.
 Its activity expressed as International Units (I.U.).
 Clinical use: Rhino virus, Papilloma virus and herpes simplex infections, Cat- Feline
leukemia virus. Bovine IFN α, γ produced by Genetic engineering.
Interferons inducers/ Host modulators
 Interferon production in host cells can be induced by viruses, bacteria, bacterial
products, Poly-I, Poly-C and Inosine. It induce production of its own interferon.

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ANTINEOPLASTIC DRUGS
Cancer: Disease of cells characterized by loss of regulatory mechanisms which control cell
growth and maturation required for homeostasis in complex multicellular organisms.
Neoplasm/tumour: Uncontrolled growth of cells coupled with malignant behavior, invasion
and metastasis.

VARIOUS PHASES OF CELL CYCLE:

G1 phase (Pre synthetic phase)
 It is interval following cell division to DNA synthesis starts.
 It lasts for 10-72 hrs where in cell sends growth signals / mitogens start the process of
cell division.
 Protein synthesis and RNA transcription occurs during this stage.
S phase (synthesis phase)
 DNA synthesis period for chromosome doubling.
 It lasts for 10-20 hrs in preparation for mitosis and is the target for many
antineoplastic drugs.
G2 phase (Post synthetic phase)
 RNA and protein synthesis period; cell activity increases.
 The duration is 1- 3 hrs.
M phase (Mitotic phase)
 The duration is very short < 1 hr.
Go Phase (Resting/non proliferative phase)
 Antineoplastic drugs are rarely effective in this stage.
 Cells like myocytes and neurons enter Go and rarely / never cycle again (Muscle &
nerve cell not regenerate).

[M=Mitotic phase, S=Synthetic phase, G1=Pre synthetic phase, G2= Post synthetic phase,
G0= True resting phase.]
 Antineoplastic agents are broadly divided into two classes.
a) Cell cycle phase specific drug
 This group act at a certain phase of the cell cycle, usually at S or M phase. The effect
is more when the cells are actively proliferating.

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 Cells in the Go phase are troublesome because they are not susceptible to cytotoxic
drugs.
 e.g. Methotrexate , Pyrimidine and Purine analogues, Hydroxyurea and Vincristine.
b) Cell cycle phase non specific drugs
 This group act at all stages except Go phase. Increased drug level kills the cells.
 These drugs are given in large doses for a short period but capable of causing bone
marrow suppression.
 e.g. Cyclophosphamide, Nitrogen mustard and Chlorambucil.

ANTINEOPLASTIC DRUGS
 Antineoplastic drugs are agents that are used to either kill or modify or arrest growth
of tumour cells.
 Their uses are becoming increasingly important in veterinary practice.
 These drugs are often used in combination with surgery and/or radiotherapy.
 It must possess selective toxicity to malignant cells at normal dose than the host cells.
They react with important substrates of enzymes that are related to DNA or RNA
synthesis. Hence they are selectively toxic to cells that are rapidly dividing or those
with high mitotic index.
CLASSIFICATION OF ANTINEOPLASTIC AGENTS
1) Alkylating agents
 Nitrogen mustard: Mechlorethamine, Cyclophosphamide, Melphalan, Uracil, Mustard
& Chlorambucil
 Alkyl Sulfonates: Busulfan
 Nitrosoureas: Carmustine, Lomustine, Semustine, Streptozocin.
 Triazene: Dacarbazine
2) Antimetabolites
 Folic acid analogues: Methotrexate
 Pyrimidine analogues: Fluorouracil, Floxuridine, Cytarabine
 Purine analogues: 6 mercaptopurine, 6 thioguanine.
3) Natural products:
 Vinca alkaloids: Vincristine, Vinblastine
 Antibiotics:
Dactinomycin (Actinomycin D)
Anthracycline antibiotics – Daunorubicin, Doxorubicin
 Glycopeptides – Bleomycin, Mitomycin
 Enzymes : L-asparaginase
4) Hormones and their antagonists
 Adrenocorticosteroids - Glucocorticoid
 Progestins: Hydroxy progesterone
 Estrogens: Diethylstilbesterol
 Anti estrogens: Tamoxifen
 Androgens: Testosterone
5) Miscellaneous
 E.g. Cisplatin, Carboplatin, Mitotane, Hydroxyurea and Procarbazine
TOXICITY OF ANTINEOPLASTIC AGENTS
 Antineoplastic drugs are among the most toxic drugs because they lack selectivity and
affects neoplastic as well as normal proliferating cells.
 Bone marrow depression resulting in leucopenia, increased incidence of infection,
thrombocytopenia and uncontrolled bleeding.

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 GI disturbances including anorexia, nausea, vomiting, diarrhea, stomatitis and
ulcerative enteritis. Antiemetics can be administered before the commencement of
treatment.
 Suppression of immune response
 Alopecia, Superinfection
 Secondary malignancy due to the use of antineoplastic agent
 Teratogenicity and infertility
 Hypersensitivity

DOSE:
2
 The dose is calculated based on body surface area and expressed as m . Since
chemotherapeutic agents are highly toxic to other normal cells and certain parameters
like BMR, blood volume, cardiac output and renal function were found to correlate
better with BSA (body surface area) than body weight, the dose is expressed in m2.

BSA= B.Wt0.67 x K/104 [BSA in m2, [Link] in g and K= 10 for cat; 10.1 for dogs]

1) AKYLATING AGENTS
 These compounds are highly reactive intermediates that are able to transfer alkyl
group to DNA. They add alkyl / methyl group to DNA.
 Miscoding of DNA - Strand leakage or disruption leads to cell death.
 Cross resistance between alkylating agent exists.

Monofunctional Alkylating agent

 Transfer single alkyl group (7-N guanine residue).
 Inhibit correct utilization of base pair instead of AT CG.
 Guanine pairs with thymine.
 Miscoding of DNA.
 Strand breakage or disruption.
 Cell death/ mutagenesis/ carcinogenesis.
Polyfunctional alkylating agents
 Alkyl group is added to both the strands of DNA.
 Cross linking of DNA strand prevents uncoiling.
 Inhibition of cell growth, apoptosis leads to cell death.
 Alkylating agents are activated by CYP450 and resistance to one alkylating agent
induces resistance to others.
 Though not cell cycle specific rapidly dividing cells are more affected.
Side effect
 Bone marrow depression.
 Nausea and vomiting, some degree of GI toxicity.
 Reversible hair loss.
NITROGEN MUSTARDS
 Limited use in combination with other agents for lymphoma, lymphoreticular
neoplasia, pleural and peritoneal effusions and mast cell tumor.
 Extremely short duration of action. GI toxicity is prominent unlike other alkylating
agents.
2
 Dose of mechlorethamide in dogs: 5 mg/m , IV.
Cyclophosphamide
 It is a cytotoxic and immunosuppressive drug

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 A broad spectrum anticancer drug given alone or in combination and is widely used in
veterinary medicine.
 Indication: Lymphoma, Lymphoreticular neoplasm, sarcomas, carcinoma of lung,
ovary, mammary gland and multiple myeloma.
 Can be given orally or parenterally. At normal dose it is cell cycle specific and at high
dose – Cell cycle non specific
 Toxicity: Neutropenia, bladder damage, necrotising haemorrhagic cystitis (bleeding)
Melphalan
 Phenylalanine derivative of Mechlorethamine. Recommended for oral administration
before food.
 Widely used for neoplastic diseases like mammary carcinoma, malignant melanoma,
multiple myeloma, ovarian carcinoma and testicular seminoma.
Side effect: Dose limiting bone marrow depression & GI disturbances.
Chlorambucil
 Slowest acting and least toxic.
 Substitute for cyclophosphamide when haemorrhagic cystitis is exhibited.
 Indications: Chronic lymphocytic lymphoma, multiple myeloma, ovarian carcinoma

ALKYL SULPHONATES: Busulfan

 Indications – Chronic granulocytic leukaemia.
 Well absorbed orally and also be given through intravenously.
 Patients should be premedicated with phenytoin. Since it crosses BBB.

NITROSOUREAS
Carmustine, Lomustine, Semustine
2
 Oral administration – Dog: 50 mg/m – Single dose every 6 weeks.
 Need biotransformation, highly lipid soluble and crosses the BBB.
 Indication: Brain tumours, cancer of lung, stomach and Colon.
 Streptozocin: Obtained from Streptomyces acromogens. Used for treatment of
malignant pancreatic insulinoma.
TRIAZENE
Dacarbazine
 Indication: Malignant myeloma and soft tissue carcinoma
 Not much used in veterinary practice
 Side effects: Nausea, vomiting, bone marrow depression, hepato & neurotoxicity.
2) ANTIMETABOLITIES
 Resemble normal cellular metabolites and therefore interfere with normal metabolic
pathways in a toxic manner.
 Tetrahydro folate deficiency blocks reaction requiring folate coenzymes and inturn
disrupt DNA and RNA synthesis.
 It is cell cycle specific - S phase is most sensitive
 Side effect: Bone marrow suppression, Severe GI toxicity

FOLIC ACID ANALOGUE

 E.g. Methotrexate (Oldest & highly efficacious drug- widely used in dog, cats)
 Folic acid analog used against a variety of neoplasms.
 Inhibits dihydrofolate reductase enzyme & prevent the formation of tetrahydro folate
and thereby the purine and pyrimidine nucleotides.
 Administration– Parenteral or intrathecal in CNS neoplasia
 Excreted in urine and at high dose precipitate in renal tubules.

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 Side Effect: Bone marrow suppression following high dose

PYRIMIDINE ANALOGUE
5-Fluorouracil
 It is converted to active phosphate form and inhibits thymidylate synthase and inturn
causes DNA and RNA synthesis inhibition.
 Indication: GI, liver, skin and mammary carcinomas
 Administration: IV as well as topical, Metabolized in the liver and enters into the CSF
 Side Effect: CNS disturbance, neurological signs, seizures and death
 GI disturbance, oral ulceration & mild myelosuppression.
Cytarabine/Cytosine arabinoside
 Analogue of deoxycytidine and must be activated by conversion to monophosphate
nucleotide Cytarabine.
 Administration: IV or SC.
 Indication: Canine and feline lymphomas & leukemia.
 Toxicity: Leucopenia with megaloblastic changes and GI disturbances.

PURINE ANALOGUE
Mercaptopurine
 Sulphydryl Substituted analogue of hypoxanthine.
 Needs intracellular activation and inhibits a number of enzymes of purine nucleotide
inter conversion leading to inhibition of DNA and RNA synthesis.
 Administration: oral. Undergoes rapid degradation and some renal excretion.
 Side Effect: Bone marrow suppression, GI disturbances, Nausea and Vomition.
 Indication: Acute lymphocytic leukemia & granulocytic leukemia.
Thioguanine
 Similar to 6 – Mercaptopurine
 Inhibits several enzymes in purine nucleotide pathway, inhibition of nucleotide
interconversion, decreased intracellular guanine and interference with DNA and RNA
synthesis.
 Indication: Acute non lymphocytic leukemia & adult acute leukemia.

3) NATURAL PRODUCTS
Vince alkaloids: Vincristine & Vinblastine
 Mitotic inhibitors.
 These are large and complex molecules derived from Vinca rosea.
 Vincristine active only in M phase.
 Bind to the tubulin and interfere with mitotic spindle formation and thus segregation
of chromosomes in metaphase is arrested.
 Administration: IV, metabolised in the liver, partially excreted unchanged in urine.
 Indication: Transmissible venereal tumour (Vincristine), Lymphoreticular neoplasm
 Soft tissue sarcoma - Vincristine + Doxorubicin + Cyclophosphamide
 Vinblastine – used as a substitute for vincristine when the vincristine-induced
neuropathy is noted.
2
 Dose: Vincristine - 0.5 to 0.75 mg/m IV once weekly.
Antibiotics
 Dactinomycin (Actinomycin-D): Obtained from various Streptomyces.
 Binds with the double stranded DNA – intercalate and blocks the actions of RNA
polymerase prevent transcription.
 Administration: IV infusion.

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 Indication: Lymphoreticular neoplasm, testicular carcinoma, rhabdomyo sarcoma and
malignant melanomas.
Anthracycline antibiotics:
 E.g. Doxorubicin, Daunorubicin
MOA:
 It blocks DNA and RNA synthesis, strand break.
 Inhibits topoisomerase II.
 Alteration in cell membranes transport.
Doxorubicin: One of the most widely used cytotoxic drug in small animals.
 solid tumors – breast cancer and hematologic malignancies
Daunorubicin
 Cell cycle non specific, maximum effect during S phase.
 Side effect: Myelosuppression, cardio toxicity, phlebitis and urticaria (Should be
premedicated with corticosteroids and antihistamines.)
Glycopeptide
 E.g. Bleomycin: Obtained from Streptomyces verticillus.
 Cell cycle specific (G2 & M phase)
 MOA: It inhibit DNA repair enzymes
 Indication – Testicular tumors, squamous cell carcinoma, lymphoma and seminoma
 Side Effect – Lung toxicity and little myelosuppression.
Enzymes
 L-asparaginase enzyme derived from E-coli.
 G1 phase specific drug.
 Side effects: Anaphylaxis and hypersensitivity
 Indication: Lymphoreticular neoplasm.

4) HORMONES AND THEIR ANTAGONISTS

 E.g. Estrogens, antiestrogens, androgens, antiandrogens, progestogens & GnRH
analogues.
 Glucocorticoids: Cell cycle non specific agent.
 Prednisone and prednisolone: Lymphoreticular neoplasm in combination with other
chemotherapeutic agent.
 Dexamethasone, prednisone & prednisolone: Leukemia and lymphoma of the CNS.
 Immunomodulators used are corticosteroids and interferons.
 Estrogens (Diethyl stilbesterol, Oestradiol): Prostatic hyperplasia, Peri anal glandular
neoplasm.
 Complications: Life threatening bone marrow suppression and aplastic anemia,
Feminization and fluid retention.
Tamoxifen
 Antiestrogen
 Indication: Early stage and metastatic breast cancer.
 Chemopreventive agent in women at high risk of breast cancer & endometrial cancer.

Progestins (Megestrol, Medroxy progesterone)

 Oppose the effects of hormones in endometrial, prostatic, breast, renal cell and
ovarian carcinoma.
 Androgens: Breast carcinoma & hypernephroma.
 Antiandrogen: Prostatic tumor.

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5) MISCELLANEOUS AGENTS
Carboplatin
 It‘s a derivative of platinum, causes inter and intra strand DNA alkylation.
 Cell cycle non specific drug administered IV with mannitol to promote dieresis.
Mitotane
 Used in adrenal tumor. It act by inhibiting ACTH steroid production and causes
atrophy of inner zones of adrenal cortex.
Hydroxyurea
 Inhibits ribonucleotide reductase, leading to depletion of essential DNA precursors.
 Indication: Granulocytic leukemia & management of polycythemia vera in dogs &
cats.
NEWER APROACHES
 Hematopoietic stem cell transplant for hematologic malignancies like myeloma,
lymphoma and leukemia.
 Isolated infusion approaches to overcome toxicity but not useful in metastasis.
 Isolated limb perfusion, Isolated infusion into lung and liver for solid tumors.
 Specially targeted drug delivery - vehicle specific and target tumor cells.
 Nanoparticles - useful vehicle for poorly soluble agents such as Paclitaxel.

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ANTHELMINTICS
INTRODUCTION
 Antiparasitics are drugs that reduce the parasitic burden by killing (vermicide) or
inhibiting their growth (vermifuge).
 Anthelmintics are drugs or agents that eliminate the worms from gastrointestinal
tract, other tissues and organs of body.
 Anthelmintics are broadly divided into 3 groups:
o Anti-nematodal drugs: Effective against Nematodes / round worms
o Anti-cestodal drugs: Effective against Cestodes / tapeworms
o Anti-trematodal drugs: Effective against Trematodes / flukes

CHARACTERISTICS OF IDEAL ANTHELMINTICS

1) It should have broad spectrum of activity.
 It should be active against a large variety of helminths in all animals and also
effective against mature, immature worms and larval stages.
o Antinematodal - Effective against hypotactic and migrating larva.
o Fasciolicide – It should kill immature flukes.
o Anticestodal – It should be able to remove the scoleces and strobilae.
 An ideal broad spectrum anthelmintic should be active against all the three categories.
e.g. Albendazole, closantel, Netobomin.
2) It should have wide margin of safety: Safety margin of at least six fold is expected for
modern anthelmintics
3) No residue period in tissue
 The drug should not have a tendency to accumulate in tissue or secreted in milk.
 The withdrawal period should be minimal. However in non-food animals prolonged
persistence may be beneficial by providing extended period of protection against
reinfection.
4) Easy to administer to herd/flock: It should be effective on a single dose.
5) Economical: Easily available, cheap and stable under normal storage conditions.
6) Compatible with food/feed

MECHANISM OF ACTION OF ANTHELMINTICS

 The mode of action of anthelmintics can be broadly categorised into two types:
a) Interference with energy metabolism of parasite
b) Neuromuscular paralysis of the worm.
a) Drugs affecting energy metabolism
 The normal metabolic process is affected.
Inhibition of fumarate reductase in mitochondria
 Failure to synthesize ATP. The worms die in the absence of energy. e.g
Benzimidazoles and its pro drugs (Albendazole, Fenbendazole, flubendazole).
Inhibition of tubulin polymerisation
 Binding of drugs with tubulin block polymerisation and microtubule formation. As a
result inhibition of mitosis, embryonation, egg hatching, secretory function etc. e.g.
Benzimidazole (Mebendazole).
Inhibition of mitochondrial phosphorylation/uncoupling of oxidative phosphorylation
 These act as protonophores, allowing hydrogen ions to leak through the inner
mitochondrial membrane and interfere with ATP synthesis eg. Salicylanilide‘s
(oxyclozanide, rafoxanide) and substituted phenols which are mainly flukicides.
Inhibition of glycolysis

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 Glycolytic enzymes like phosphoglycerate kinase and mutase are selectively inhibited
leading to depletion of energy eg. Clorsulon (flukicide) and Thiacetarsamide (heart
worm).
b) Drugs causing neuromuscular paralysis of the worm
 Interfere with the normal neuromuscular function of worms and induce spastic or
flaccid paralysis, the parasites are removed from the host and expelled out. The killing
is generally rapid.
 The drug categories are:
Acetyl cholinesterase (AChE) inhibitors
 Increased concentration of Ach at neuromuscular junction leads to spastic paralysis
eg. Organophosphates (OP): Coumaphos, dichlorovos. trichlorofon, haloxon etc.
 OP irreversibly inhibit AchE enzyme.
Cholinergic agonist
 It acts as agonist at nicotinic receptor of nematode. Ganglionic stimulation causes
sustained muscle contraction initially followed by depolarizing neuromuscular
blockade which in turn leads to spastic paralysis. E.g. Levamisole, Butamisole,
Pyrantel and Morantel.
Muscle hyperpolarization
 Block neuromuscular transmission in parasite by hyperpolarising the nerve membrane
leading to flaccid paralysis and expelled by peristalsis eg. Piperazine. It also blocks
succinate production by the worm. It may also act through GABA.
Potentiation of inhibitory transmitters / GABA agonists
 They act as agonist at GABA receptor -> Opens chloride channel -> flaccid paralysis.
e.g. Piperazine
 Ivermectin causes paralyse the pharynx (unable to feed), the body wall and uterine
muscles of nematodes.
 It is not active against cestodes/ trematodes since they do not have receptor at
glutamate gated chloride channel.
OTHER MECHANISMS
 Affecting the permeability of the cell and vacuolation of tegument e.g. Praziquantal
increases the permeability of trematode tegument to calcium and result in spastic
contraction of muscle.
 Disruption of tegument e.g. Bunamidine, Espirantel, Praziquantal.
 Inhibit glucose metabolism of Fasciola e.g. Diamphenethide, Clorsulon
 Interferes with Arachidonic acid metabolism of filarial parasite e.g.
Diethylcarbamazine Citrate (DEC).

Endectocide:
 An antiparasitic drug that is active against both endoparasites and ectoparasites.
 e.g. Avermectins (ivermectin, abamectin, doramectin & eprinomectin) and
Milbemycins (moxidectin). They are active against both internal nematodes and
ectoparasites/arthropods.

Note: Albendazole is teratogenic, not recommended during first trimester of pregnancy.

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TABLE: CLASSIFICATION OF ANTHELMINTIC DRUGS AND ITS SPECTRUM

Group Drug Anthelmintic activity

Benzimidazoles Thiabendazole Nematodes (Also mites & fungi)
Parbendazole Nematodes
Oxibendazole Nematodes
Flubendazole Nematodes (Pigs)
Canbendazole Nematodes and cestodes
Fenbendazole Nematodes and cestodes
Mebendazole Nematodes and cestodes
Oxfendazole Nematodes and cestodes
Luxabendazole Nematodes and Flukes (sheep)
Triclabendazole Trematodes
Albendazole Nematodes, Cestodes, mature flukes

Benzimidazole Febantel (Fenbendazole) Nematodes

Pro- drugs Thiophanate (Lobendzole) Nematodes
Netobimin (Albendazole)

Imidazothiazoles Levamisole Nematodes

Butamisole Nematodes
Tetramisole Nematodes
Salicylanilides Closantel Broad spectrum
Niclosamide Cestodes and intestinal trematode
Oxyclozanide Mature flukes
Rafoxanide Trematode and some nematodes.
Substituted phenols Diamphenethide N, T, C
Niclofolan Trematode
Bithionol C, T
Nitroxynil N, T
Nitroscanate N, C (dogs)
Disophenol Hookworm in dogs &cats
Clorsulon Adult & immature flukes.
Tetra hydro Pyrantel Nematode & Horse tape worm
pyrimidines
Morantel Nematodes
Oxantel Nematodes

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Macrocyclic lactones Ivermectin
Nematodes & ectoparasites
Doramectin
(Endectocide)
Moxidectin
Milbemycin oxime
Heterocyclic Piperazine Nematodes (Ascarids)
compounds Diethyl carbamazine Nematodes (dogs), Heart Worm,
(DEC) Microfilaria

Isoquinolones Praziquantel Trematode & cestode

Epsiprantel Cestodes
Miscellaneous Phenothiazine Nematodes
Arecoline Cestodes (dogs)
Bunamidine Cestodes
CCl4 Trematodes

ANTHELMINTIC RESISTANCE
 It is commonly seen in Haemonchus, Trichostrogylus, Ostertagia, Nematodirus and
Oesophagastomum.
 Cross resistance is common between members of the same group.
 The predisposing factors for development of anthelmintic drug resistance by parasites
are
o Use of drug below the therapeutic / recommended dose.
o Continuous use of particular group for a long period.
o Overuse /unwarranted use
o Extensive use of anthelmintic with long withdrawal period.
o Poor management practices
 Measures to overcome resistance:
o Rotational use of anthelmintics
o Avoid indiscriminate use and follow the dosing schedule
o Narrow spectrum compound suitable for developing stage.

ANTI-CESTODAL DRUGS:
Classification: Three types
1. Natural organic compounds e.g. Arecoline, male fern
2. Synthetic compounds e.g. Praziquantel, epsiprantel, niclosamide
3. Inorganic compounds e.g. Lead arsenate, tin oxide, tin chloride
1) PRAZIQUANTEL
 It is a novel anthelmintic with excellent activity against all spp of Schistosomes and
larval cestodes of both animals and humans.
 MOA: It interferes with cell memberane permeability causing rapid influx of Ca++
and it produce spastic paralysis of the parasites.
 It is quickly and almost completely absorb from the alimentary canal.
 In dogs 60-80% of drug is excreted in urine and remaining from faces.

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 Main site of inactivation is liver.
 Adverse effects: It is safest anti-cestodal drug available for clinical use in animals
 Dose: Dogs & Cats – 5mg/kg orally.
2) NICLOSAMIDE
 Highly effective against tape worm like Diphylidium caninum, Taenia spp and
Echinococcus spp in dogs, Moniezia spp of cattle, sheep and dogs.
 It has taeniacidal action.
 MOA: Anti-cestodal activity is due to inhibition of absorption of glucose by the
tapeworm and inhibiting oxidative phosphorylation process in the mitochondria of
cestodes.
 Niclosamide is poorly absorbed from the host GI tract, which perhaps accounts for its
low toxicity.
 Small quantities absorbed are transformed into an inactive metabolite.
 It is administered orally after 12 hrs fast. Saline purgative is required to remove all
dead segments.
 Adverse effects: It has wide margin of safety i.e. safety indexis more than 40 times
than the therapeutic dose. No embryotoxic or teratogenic effect.
 Dose: Cattle- 50 mg/kg orally, 70mg/kg in feed
Sheep/Goats/Dogs/Cats– 100 mg/kg orally
3) EPSIPRANTEL
 It has excellent activity against tape worm of cattle, dog, sheep and horses.
 It has less activity against Schistosome.
 It is very safe drug having safety index more than 90%.
 Dose: – Dog. : 5.5mg/kg orally, Cattle 2.25mg/kg orally.
4) BUNAMIDINE
 Bunamidine is use to treat tape worm infestation in dog and cat, also can be given to
pregnant bitch.
 Its activity against Diphylidium caninum is varies about 50-90%.
 It acts by decreases glucose uptake in the susceptible worm.
 It affects the integument of the parasite and cause death of parasite.
 Dose: Dogs/Cats- 25-50mg/kg orally as single dose after fasting of 3 to 4 hrs.

ANTI-TREMATODAL DRUGS
1) HEXACHLOROPHENE
 It has high efficacy against mature forms of Fasciola hepatica & Fasciola gigentica
in cattle & sheep.
 It is excreted in bile as glucuronide metabolites which are also highly active against
adult form since they occupy the bile duct.
 Dose: Cattle/Sheep- 25 mg/kg, orally
 Overdosing produce nervous symptoms such as excitability or depression and
impairment of vision.
2) OXYCLOZANIDE
 It is active against adult and immature form of liver flukes.

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 It is also excreted as glucuronide metabolites in bile & is also active.
 This drug require 0 day withdrawal period for milk in cattle, so can be given to
lactating animals.
 Safety index is more than 4 (Low toxicity). Dose: Cattle/Sheep – 15 mg/kg, orally
 The maximum tolerance dose in cattle and sheep is up to 60 mg/kg.
3) RAFOXANIDE
 It is active against immature and mature liver fluke in cattle and sheep.
 Following oral administration peak plasma concentration observe within 24-48hrs.
 It is contraindicated in lactating animals (not used).
 Dose : Cattle/Sheep: 7.5 mg/kg, orally
4) NITROXYNIL
 It is active against mature form of liver flukes.
 It is given parenterally because if it is given orally than reduction of nitro-group by
rumen micro-organism make the drug inactive.
 Dose– Cattle/Sheep : 10 mg/kg, SC
5) CLORSULON
 It is anthelmintic sulfonamide, active against immature and mature liver fluke of
cattle and sheep
 Dose: Cattle: 7 mg/kg, orally or given by S/C route @ 4 mg/kg.
6) DIAMPHENETHIDE
 High activity against immature larval stage of F. hepatica of sheep.
 It has no activity against liver fluke of cattle.
 Amine metabolites of this drug are also more active against immature form of fluke.
 Dose: Sheep- 100 mg/kg, orally.

ANTIPROTOZOAL DRUGS
INTRODUCTION
 Parasitic protozoa are responsible for a wide range of diseases in both animals and
man and protozoal diseases are difficult to eliminate as they are frequently transmitted
by ticks, flies and mosquitoes.
Disease Therapeutic drug
Anaplasmosis Imidocarb, tetracyclines
Babesiosis Diminazene aceturate, Trypan blue, Acriflavin, Amicarbalide
Imidocarb, Phenamidine, Tetracycline
Theileriosis Buparvaquone, Parvaquone, Tetracycline
Trypanosomiasis Quinapyramine (sulphate/chloride salt), Diminazine, Suramin, Trypan
blue
Rickettsia Tetracycline
1) DIAMIDINES
 The diamidines are a group of chemotherapeutic compounds found to have a
trypanocidal activity related directly to the guanyl organic group.
 Mechanism of action: Interferes with aerobic glycolysis and DNA synthesis.

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 The diamidines are used either as free bases or as one of the three salts:
dihydrochloride, dimethylsuphonate or isethionate. In veterinary field isethionate are
used most commonly.
 When administered internally, the diamidines cause an arterial dilatation, lowering of
blood pressure and increase tone of the intestinal muscles.
 Kidney and liver damage are the main toxic effects.
 E.g. Imidocarb, Phenamidine, Propamidine, Pentamidine and Diminazene.

Diminazine aceturate (Brand name: Berenil)

 In addition to trypanocidal activity, it is babesicidal and bactericidal (mainly
Brucella and Streptococcus species).
 Dosage is in the form of injection which consists of 8.75% phenazone and 7%
diminazene aceturate and may be administered either by intramuscular or
subcutaneous route.
 For Babesia infection single dose at the rate of 3.5 mg/kg, body weight will be
adequate in horse, cattle, sheep and dogs. Disappearance of symptoms may be
expected within 24 hours.
 For Trypanasoma vivax infections the same dosage as babesia may be given but the
dosage rate should be doubled for T. brucei infections.
 Local reactions may occur at the site of infection, they may be severe in horse.
Phenamidine Isothionate
 The use of phenamidine is confined to the treatment of Babesia infection in cattle,
horse and dogs.

2) QUINAPYRAMINE COMPOUNDS
Quinapyramine chloride and sulphate
 There are two quinapyramine compounds of use – the sulphate which is rapidly
absorbed and mainly trypanocidal with low prophylactic value and the chloride which
is more slowly absorbed and has a strong prophylactic effect.
 It is administered as 10 % solution by SC injection @ 4.4 mg/kg.
 Overdosage may cause trembling, sweating, salivation, increase in respiration, heart
rate, collapse and death.
Suramin
 This is a complex aromatic organic compound, freely soluble in water.
 It has good activity against Trypanosomia evansi in horse, camels, cattle and dogs;
against T. brucei in horse, dogs and cattle and against T. equinum in horses.
 It has been used in veterinary practice for both curative and prophylactic control of
trypanosomiasis.
 IM or SC injection often causes localized reaction and necrosis of tissues, so it is
given only by IV route.
 Suramin is potentially toxic, because the therapeutic index is very narrow. Horse and
donkeys are very susceptible, but camels are quite resistant. Symptoms are those
associated with liver, kidney, spleen and adrenal gland damage.

3) IMIDOCARB DIPROPIONATE
 Mechanism of action: Vacuolization of the cytoplasm and alteration in size of the
nucleus. Interfere with DNA synthesis.
 Well absorbed and distributed through out the body

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 Bound to plasma protein and detectable amounts are found in all major tissues up to 4
weeks after IM administration.
 Excreted unchanged in urine and 10% in faeces.
 Recommended for the treatment and prophylaxis of babesiosis, anaplasmosis and
ehrlichiasis.
 Administered through subcutaneous and intramuscular route but not through
intravenous route.
 Narrow margin of safety. In cattle, a dose of 10 mg/kg body weight can cause death.
 Dose:
Babesiosis Cattle 1-3 mg/kg, body weight, IM or SC

Horse 2-4 mg/kg, body weight, IM or SC

Dog 6.6 mg/kg, body weight, IM, single dose

Anaplasmosis Cattle 3 mg/kg, body weight, SC

4) QUINURONIUM SULPHATE
 The drug is used against babesiosis.
 If it is used in early febrile stages of the disease, clinical cure achieved in 24-48 hours,
though a second injection may be needed on the next day.
 The course of treatment should not be repeated for a period of at least 2 weeks,
preferably 3 months; this is due to occasional development of sensitization, which
may result in severe shock and death when treatment is repeated.
 This drug only clinically cures the animals but not eradicate the infection. So on
recovery, these animals retain a number of organisms in their system which maintains
the resistance of the animal to reinfection. This phenomenon is known as premunition.
5) TRYPAN BLUE
 It is an azo dyes and related to the sulfonamides
 It was one of the older agents used against babesiosis, but ineffective against B. equi,
B. bovis and B. gibsoni.
 The drug is relatively non-toxic but stains tissues and secretions, including milk, a
blue green colour which may persist for several weeks.
6) NAPTHOQUINONES
 These drugs are recently introduced for use in theileriosis.
 Causes marked degeneration of macro schizonts and suppression of parasitemia.
Parvaquone
 Most cost effective synthetic compound in the series of napthoquinones.
Buparvaquone
 A parvaquone analogue in which cyclohexyl moiety is substituted by an alkyl group,
this substitution slows down the metabolic degradation of parent compound.
 Most active during incubation period and also after the outbreak of bovine
theileriosis.
 Withdrawal period for milk and edible tissue is 2 and 42 days respectively.
 Dose: Cattle- 2.5 mg/kg, IM as a single dose (Costly).
ANTICOCCIDIAL CHEMOTHERAPY
INTRODUCTION
 Coccidiosis mostly causes bloody diarrhea and heavy mortality in poultry.
 It also affects cattle, sheep, goat, pigs, dogs and cats.
 Two intestinal protozoan parasites of coccidia namely Eimeria (poultry, cattle, sheep,
goat) and Isospora (dog, cat & man) with numerous species have been identified.

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 In broiler Eimeria tenella and E. necatrix are the most commonly encountered
protozoans.
 Solid immunity develops following exposure and it is species and strain specific.
 Control is possible by continuously feeding a coccidiostat for a prolonged period.
 In layer immunization procedure would be most suitable e.g., administration of
coccivac (vaccine) containing 7 species of protozoan oocyst.
 Preventive anticoccidial may be given for 6-22 weeks
 Two programmes are followed.
o Shuttle programme– Use of two or more drugs subsequently during the early
growth period of birds (single growout).
o Rotation programme– Use of pharmacologically different anticoccidials in
relation one after another in succeeding growout of birds.

ANTI COCCIDIAL DRUGS

 A large number of anticoccidial drugs are available for prevention and treatment of
coccidiosis in animals.
st nd
 Most of the drugs show the greatest activity during 1 or 2 asexual cycle and some
inhibit the sexual stage.
st
o 1 asexual cycle: Clopidol, Quinolones, Monensin, Robenidine, Amprolium
nd
o 2 asexual cycle: Zoalene, Nicarbazine, Sulfonamide, Dinitolmide
Amprolium
 It is a thiamine (Vitamin B1) antagonist. Acts on the early first generation schizonts
and merozoites.
 It is used prophylactically in combination with other anticoccidial inorder to increase
the spectrum against E. Brunetti and E. Maxima.
 It has good activity against E. tenella and E. acervulina.
 It is used for the treatment of coccidiosis in chicken, turkey and ruminants.
 The major advantage of this drug is slow development of resistance.
Clopidol
 It is a pyridine derivative active only against the sporozoites of Eimeria. Hence it is
not effective if given after the day of exposure of coccidial oocyst. It is a coccidiostat
and does not allow natural immunity to develop.
 Dose: 125 g/tone feed in chickens and 200g/ tone feed in rabbits.
 Withdrawal period is about 5 days in chickens.
Quinolones
 They act on Sporozoite stage and selectively inhibit electron transport and thus
respiration in coccidial mitochondria, not in the host.
 They are insoluble in water, poorly absorbed hence non-toxic.
 Rapid development of resistance.
 Eg., Decoquinate – not suitable for laying and breeding birds but suitable for calves.
 Methyl benzoquate – most potent quinolones.

Sulfonamide
 More effective against intestinal than caecal species of coccidia.
nd
 They are effective against 2 generation schizonts. Hence it is effective when
outbreak is noticed.
nd
 2 generation schizonts are important for developing immunity, hence natural
immunity develops in chicken on sulphonamides prophylactic program.
 Sulphaquinoxaline is used for treatment alone and with amprolium in turkey, chicken
and rabbit.

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 Withdrawal period is about 5 days in chickens.
Ionophores (Polyether antibiotics)
 Most effective and widely used anticoccidials (growth promoter)
 They interfere with the transport of ions through membranes, causing an influx of
positively charged ions. This upsets the osmotic balance of the cell. Mainly active
towards Sporozoites and 1st generation Schizonts and Merozoites. Hence it should be
fed continuously and not recommended for established infection.
Monensin
 Source: Streptomyces cinnamonensis
 It forms complex with Na and K ions, affects permeability of membrane
 Low therapeutic index
 Highly effective against all species of coccidian in field.
 It is used for prevention of coccidiosis in broilers, cattle and [Link] recommended
for laying hens and equines.
 Withdrawal period is 3 days in chickens.
Lasalocid
 Source: Streptomyces lasaliensis
 Not recommended for other birds and animals except broilers and replacement layers
 Least toxic at normal dosage but net litter may be a problem because
Narasin
 Source: Streptomyces aurefaciens
 Effective against intestinal and caecal coccidia in broiler if administered continuously.
 Not effective in layers and other animals
Salinomycin
 Source: Streptomyces albus
 Similar to Narasin
 Prophylaxis in broiler. Withdrawal period is not required.
Maduramycin
 Source: Actinomadura yumaense
 Most potent ionophore for broilers.
 Withdrawal period is of 5 days.
Robenidine
 A guanidine derivative inhibits oxidative phosphorylation, primarily coccidiostat
against first generation schizont and some coccidiocidal effect against second
generation schizont.
 Recommended for broiler, turkey and rabbit continuously in feed.
 Contraindicated in laying hens and not to be combined with other anticoccidials.
 Withdrawal period: 5 days.
 Side effect: Unpleasant taste of meat and egg.
Dinitolmide
 It is a dinitrobenzamide with greatest activity against asexual stage of coccidian.
 Prolonged treatment induces coccidiocidal effect.
 It is highly active against E. tenella and E. necatrix.
 It is also used for prophylaxis of coccidiosis in chicken
 It is contraindicated in layers.
 Withdrawal period is 3 days.
Nicarbazin
 Predominantly coccidiocidal, suppressing second generation schizonts.
 It is also used for prevention rather than treatment.
 It can be used to overcome heat stress during hot climate in broilers.

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 Contraindicated in layers and with other anticoccidials.
 Withdrawal period is about 4 days.
Arprinocid
 It is a purine analogue.
 Highly active against the early invasive and intracellular stages of Eimeria and affects
sporulation of oocyst.
 Inhibit microsomal metabolism & DNA synthesis in coccidia.
 Rapid development of resistance.
Halofuginone
 Highly toxic to all coccidia of chicken and turkey.
 It has both static and cidal activity against early developing stages (asexual).
 Contraindicated in layers.
 Withdrawal period is about 5 days in chickens and turkeys.
Toltrazuril
 Potent coccidiocidal, active against both sexual and asexual stage of Eimeria in
chickens, turkey and rabbits.
 Withdrawal period is about 21 days.
Diclazuril
 Safe and potent coccidiocidal drug has a zero day withdrawal period. Effective
against both schizonts and gametocytes
 Recommended at the rate of 1 ppm in feed for broiler, turkey and rabbits.

ECTOPARASITICIDES
INTRODUCTION
 Ectoparasiticides are used on animals to control ticks, mites, fleas, lice and flies
infecting the external surface of body.
 They are widely used in veterinary medicine to control severe parasitic infestations
and prevent spread of external parasite borne diseases.

1) ORGANOPHOSPHATES (OP)
 E.g. Coumaphos, malathion, parathion, fenthion, diazinon, ethion, famphur,
dicholorovos and chloropyriphos.
Mechanism of action
 The OP insecticides inhibit Ach breakdown by inhibiting AChE enzyme
irreversibly.
 Compounds are lipophilic, well absorbed through the skin.
 Metabolism of OP occurs mainly in the liver. Compounds have no residue problem.
 Used topically in animals.

Adverse effects
 Toxic signs include salivation, lacrymation, urination, defecation, fasciculation, ataxia
and convulsion.
 Chronic toxicity or delayed toxicity seen with some OP compounds with a delayed
onset of paralysis due to progressive demylination of motor neurons.
 Organophosphate Induced Delayed Neuropathy (OPIDN)
 Treatment involves administration of atropine sulphate, pralidoxime (2-PAM),
DAM.

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2) CARBAMATES
 E.g. Carbaryl and propoxur. They are used in the treatment of ectoparasites in small
animals as powder, shampoo and collar formulations.
 Mechanism of action – It reversibly inhibits AChE enzyme. Their effects are more
reversible than those of OPC since the binding between carbamates and cholinesterase
is noncovalent.
 Adverse effects similar to OP poisoning. Atropine sulphate is an effective antidote.

3) ORGANOCHLORINE/CHLORINATED HYDROCARBONS
 E.g. DDT, BHC, methoxychlor, lindane, aldrine, dialdrine, endrine, endosulfan &
chlordane.
 DDT and methoxychlor are very effective synthetic insecticides. Environmental
Protection Agency (EPA) banned these compounds.
Mechanism of action
 These insecticides increase intracellular sodium and calcium via two mechanisms.
 High sodium cause depolarization and calcium will over stimulate neurotransmission,
which paralyze the insects.
Pharmacokinetic properties
 Highly lipophilic, fat in feed promotes absorption however, obese animals are more
resistant to insecticide toxicity, because fat adsorbs lipophilic chemicals.
 DDT is metabolized into DDD and DDE which is water soluble and is excreted in the
urine.
 DDE is permanently stored in the adipose tissue of animals, causing residue problems.
Adverse effects
 CNS stimulation lead to convulsion, cardiac arrhythmia may be induced.
 Egg shell thinning results from the ability of DDT to block estrogen receptors that
mediate the deposition of calcium into the egg shell.
Lindane
 It increases excitability of excitable cells by blocking GABA gated chloride channels
to induce depolarization.
 Lindane is more toxic than DDT. Young animals, especially, calves and toy breeds of
dogs are sensitive to poisoning.

4) PYRETHROIDS
 E.g. Allethrin, permethrin, Deltamethrin, cypermethrin, fenvalerate.
 They are alkaloids of pyrethrum which increases excitability of ectoparasite neurons
by prolonging the opening of sodium channels, thereby causing arthropod paralysis.
They are generally safe but may cause local irritation hypersalivation and vomition.
 Pyrethroids should not be used in cats.
 They are widely used in veterinary practices. They posses wide spectrum of
parasiticidal action with minimal residual action.

5) INSECT DEVELOPMENT INHIBITORS

Diflubenzuron
 This drug inhibits chitin synthesis in larvae and eggs of insects. They have no effects
on adult insects.
Insect growth regulators
 Cyromazine & Pyriproxyfen : They interfere with reproductive organ differentiation.
Cyromazine is administered orally for 4-6 wks to control fecal maggots in poultry. It
is also used as a spray on to surface of manure.

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6) OTHER ECTOPARASITICIDES
Amitraz
 It is ectoparasiticides use in dogs, pigs and cattle.
 It activates octopamine receptors in arthropods, which inhibits neurotransmission,
resulting in flaccid paralysis.
 Amitraz should not be applied to swine before 3 days of slaughter.

Disease Causative Organism Drug of Choice

Protozoal disease

Babesiosis Babesia spp. Diminazene aceturate

Theileriosis Theileria spp Buparvaquone

Trypanosomiasis Trypanosoma spp Quinapyramine sulphate and chloride

Anaerobes protozoa Amoeba/Giardia Metronidazole, Tinidazole

Malaria Plasmodium spp. Chloroquine

Endoparasites

Lung worm infection Dictiocaulas viviparous Albendazole + oxbendazole

Tape worm infection Tape worm Praziquantel

Fascillosis Fasciolla. Spp. Oxyclozanide, Rafoxanide

Anaplasmosis Anaplasma spp. Imidocarb

Microfilariasis Dirophylaria immitis Diethyl carbamazine (DEC)

Heart worm- Adult Dirophylaria immitis Thiacetarsamide

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ANTIFUNGAL DRUGS
 Eukaryotic
 Yeast: Unicellular Oval/Spherical form e.g. Candida albicans
 Mold: Multicellular filamentous form e.g. Aspergillus spp.
 Commonly two types of fungal infections occurred : Superficial & Systemic

INTRODUCTION
 Antifungal (Antimycotic) drugs are agents which are used to prevent growth and
multiplication of fungi (Fungistatic) or kill the fungi (Fungicidal).
 In general, fungal infections are more difficult to treat, are slowly eradicated, and
the antifungal drugs are more toxic to host than antibacterial drugs.

CLASSIFICATION
Antifungals are classified based on the chemical structure and clinical use:
I. Antifungal antibiotics
1. Polyenes e.g. amphotericin B, nystatin, natamycin, hamycin and candicidin.
2. Heterocyclic benzofurans e.g. griseofulvin.
II. Antimetabolites e.g. flucytosine.
III. Azoles
1. Imidazoles
e.g. ketoconazole, miconazolc. enilconazole, tiabendazole, clotrimazole, econazole,
butoconazole, oxiconazole and sulconazole.
2. Triazoles
e.g. fluconazole, itraconazole, voriconazole, posaconazole and terconazole.
IV. Allylamines e.g. terbinafine, butenafine and naftifine
V. Echinocandins e g caspofungin, anidulafungin and micafungin.
VI. Iodides e g. sodium iodide and potassium iodide.
VII. Miscellaneous agents
1) Organic acids e.g. benzoic acid and salicylic acid.
2) Fatty acids and salts e.g. propionates and undecylenate.
3) Dyes e.g. gentian violate
4) Phenols and phenolic ethers e.g. phenol, thymol and haloprogin.
5) Hydroxy quinolines e.g. clioquinol
6) Thiocarbamate e.g. tolnaftate
7) Sulphur and sulphur preparations e.g. sulphur and sulfiram.
8) Copper preparations e.g. copper sulphate and copper naphthenate.
9) Others antifungal drugs e.g. Ciclopiroxolamine, dichlorophen, hexitidine, tiacetin,
sodium thiosulphate, benzoyl disulphide, selenium sulphide and nitrofuroxine.

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Figure: Mechanism of Action (Fungal Targets) of Antifungal Drugs
History :
 Two important antifungal drugs like Amphotericin B for Systemic mycoses and
Griseofulvin for dermatophytosis introduced around 1960.
 Flucytosine and Imidazoles in 1970s and Triazoles in 1980.
 Terbinafine introduced recently.
Sources:
Antifungal Drugs Sources
Amphotericin B Streptomyces nodosus
Nystatin Streptomyces noursei
Natamycin Streptomyces natalensis
Griseofulvin Penicillium griseofulvum
Hamycin Streptomyces pimprina

I. ANTIFUNGAL ANTIBIOTICS
1. Polyenes / Polyene Antibiotics
• Polyene antibiotics obtain from actinomyces
• MOA: The polyenes bind to ergosterol in the fungal cell membrane and promote
leakiness which may contribute to fungal cell death.
• They are poorly soluble in water and common organic solvents.
• Amphotericin B is the prototype drug of this group.
Amphotericin B
• Amphotericin B is obtained from Streptomyces nodosus
• Two types A & B but only B is used clinically because it is significantly more active
in vivo.

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• B is insoluble in water & is often used intravenously for systemic fungal infections.
• Rapidly decomposes on exposure to light.
Mechanism of action
• The amphotericin B and other polyene antibiotics have high affinity for ergosterol,
present in fungal cell membranes.
• High concentration of amphotericin B directly disrupts the fungal cell membrane
permeability and leakage of cellular contents.
• Amphotericin B is fungistatic at normal dosages, but it can become fungicidal at
higher concentrations.
Antimicrobial spectrum
• Amphotericin B have broad-spectrum antifungal against is useful against several
systemic fungi including Candida, Histoplasma, Cryptococcus, Blastomyces,
Coccidioides, Aspergillus and Sporithrix spp.
• Some algae and protozoa (e.g. Leishmania, Trypanosoma, Trichomonas and
Entamoeba spp.) are sensitive to the polyene antibiotics.
• Amphotericin B is not effective against clinical dermatophytosis.
Pharmacokinetics
• Amphotericin B is poorly absorbed from the GI tract and, therefore, oral used only
for gastrointestinal fungal infection. For systemic infection, it is given by repeated
daily slow IV injections because it is not absorbed after IM or other parenteral routes.
• It distribute very unevenly throughout the body & can not pass the CSF, vitreous
humour and amniotic fluid.
• For fungal meningitis, it has to be given intrathecally.
• It is extensively bound to plasma lipoproteins, longer terminal half-life of about 15
days.
• Drug eliminate via urine & bile.
Side effects
• The nephrotoxicity generally occurs via two mechanisms intense renal
vasoconstriction and binding of drug to membrane cholesterol in the renal tubular cell
membrane.
• Other adverse effects includes anorexia, nausea, vomiting, anaemia, cardiac
arrhythmias, CNS signs (if given intrathecally), hepatic dysfunctions and
thrombophlebitis at injection site.
• Cats are more sensitive to the renal toxic effects.
• During the therapy monitored patient's renal function by urine analysis of BUN
& creatinine.
Clinical uses
• Amphotericin B is effective antifungal agent mainly in dogs & other spp. for serious
life-threatening systemic infections.
• It is usually diluted in 5% dextrose and administered IV.
• Oral preparations are used to treat thrush (oral candidiasis).

Nystatin
• Nystatin is produced by Streptomyces noursei.

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• It is structurally similar to amphotericin & has same mechanism of action.
• It is used topically and orally.
• Nystatin is primarily used for skin, mouth, intestinal or vaginal candidiasis in dogs,
cats and birds.
Dose:
• Dogs : 50,000- 150,000 Units (total), PO,3 times daily.
• Cats: 1,00,000 Units (total), PO, 4 times daily.
Natamycin (Pimaricin)
• It is obtained from Streptomvces natalensis found in soil.
• Natamycin is used to treat fungal infections, including Candida, Aspergillus,
Cephalosporium, Fusarium and Penicillium.
• Used to treat fungal kerati
• tis in eye infection.
• Mainly used topically.
Hamycin
• It from Streptomyces pimprina.
• It is similar to nystatin and is used mainly topically for oral thrush, cutaneous
candidiasis and Trichomonas vaginitis.
2. Heterocyclic Benzofurans
Griseofulvin
• It is a systemic antifungal obtained from Penicillium griseofulvum.
• Odourless, bitter tasting, white powder that is very slightly soluble in water and
most organic solvents.
• Particle sizes of griseofulvin vary from 1μm (ultramicrosized) to up to 10 μm
(microsized) in diameter.
Mechanism of action
• Fungistatic drug that enters into the susceptible fungi through an energy-dependent
transport system.
• It acts by interfering with the polymerisation of microtubules that leads to interferes
with the spindle formation in dividing cells thereby arresting the metaphase of
cell division in susceptible fungi.
• This leads to production of multinucleate fungal cells.
Antimicrobial spectrum
• Narrow-spectrum antifungal agent active Only against dermatophytes i.e.
Microsporum, Trichophyton and Epidermophyton.
• Griseofulvin is unique among all antifungal which on oral administration
accumulates into keratin and produces action against superficial fungi.
Pharmacokinetics
• After oral administration, the absorption, in general, depends of the particle size and
preparation; and a fatty diet facilitate its absorption (F= 25% to 70% in microsized ,
100% for ultramicrosized).
• It is concentrated in skin, hair, nails, fat, skeletal muscle and liver.
• It has high affinity for keratinised tissues & found within 4-8 hours of dosing.
• For this reason, the new growth of hair or nails is the first to become free of fungal
infection.
• The drug action is slow requiring 4 to 6 weeks of therapy for skin infections and up
to 1 year for toenails infection.

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• It is metabolised by the liver via oxidative demethylation and conjugation to inactive
metabolites.
• one-half of the drug is excreted in urine; remain in faeces.
• It remains in the skin for a much longer period.
Side effects/Adverse effects
• Less toxic, Gastrointestinal disturbances, hepatotoxicity, CNS signs and haemolytic
alterations have been reported.
• Cats, particularly kittens, are more susceptible to adverse effects than other species
(produce teratogenic and carcinogenic effects in cats).
• Griseofulvin is a potent inducer of microsomal enzymes.
• Clinical uses
• primarily used for treatment of dermatophytic fungal infections (ring worm) of
skin, hair and claws in dogs, cats, calves, horses and some other species.
• Treatment should continue up to at least one week after disappearance of clinical
signs.
• At least 4 weeks, and sometimes 3 months or more, may be needed for successful
therapy.
Dose
• Dogs &cats : 20- 50 mg/kg (microsized), PO, once daily or in 2 to 3 divided doses
with fatty meal or corn oil.
• Cattle &horses:5 -10 mg/kg, PO, once daily for 4 to 6 weeks or longer.
• Sheep &goats : 10 -20 mg/kg, PO, once daily.
• Swine : 20 mg/kg, PO, once daily for 6 weeks.

II. ANTIMETABOLITES
• Flucytosine
• It was originally synthesised as an antineoplastic drug, but later on it was found to
have good antifungal activity.
• White crystalline powder, stored in air tight container and protected from light to
prevent decomposition.
Mechanism of action of flucytosine:

[5-FC: 5-Fluorocytosine, 5-FU: 5-fluorouracil, 5-FUMP: 5-fluorouracil ribose mono-phosphate, 5-FUDP: 5-fluorouracil
ribose diphosphate , 5-FUTP: 5-fluorouracil ribose triphosphate , 5-FdUMP: 5-fluorodeoxyuracil ribose monophosphate]

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Antimicrobial spectrum
• It is fungistatic.
• Its spectrum of activity is limited and includes Cryptococcus, Candida, Aspergillus,
Sporothrix and few other pathogenic fungi.
Pharmacokinetics
• Flucytosine is rapidly and almost completely absorbed after oral administration.
• Cmax achieved in 1-2 hours after oral dosing.
• Flucytosine is distributed widely throughout the body and has good penetration into
CSF, synovial fluid and aqueous humour.
• Only about 2-4% of the drug is bound to plasma protein.
• About 80-95% of the drug is excreted unchanged in urine.
Side effect/Adverse effects
• It has relatively low toxicity, Bone marrow depression & other side effects may be
seen.
Clinical uses
• Useful in systemic infections caused by Candida albicans and Cryptococcus
meningitis.
• It is mostly combined with amphotericin B the treatment of cryptococcosis in dogs
and cats.
• It is used alone in treating aspergillosis and candidiasis in birds.
Dose : Dogs & cats : 25-50 mg/kg, PO, 3-4 times daily in combination with amphotericin B.

III. AZOLES
• The important antifungal azoles consist of two subgroups — imidazoles and
triazoles.
• Imidazoles contain two, whereas triazoles have three nitrogen atoms in the basic five-
membered ring structure.
• Relatively non-toxic and effective antifungal compounds.
Mechanism of action of Azoles:

1. Imidazoles
• Synthetic drugs
• They are active against fungi, bacteria, helminths and protozoa.
• Generally poorly soluble in water
• Mechanism of Action
• Azoles acts by inhibiting 14α-demethylase enzyme on the fungal cell membrane and
alter the membrane permeability of susceptible fungi by inhibition of ergosterol

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synthesis.
• Fungistatics
Ketoconazole
• Synthetic imidazole antifungal drug for systemic use.
• It was the first azole given orally to treat systemic fungal infections and is still
considered the prototype drug.
Antimicrobial spectrum
• Broad-spectrum of antifungal activity includes Candida, Cryptococcus, Coccidioides,
Blastomyces,Hisptoplasma species.
• Also effective Microsporum, Trichophyton, Aspergillus and Sporothrix.
Pharmacokinetic
• Oral absorption of ketoconazole is variable.
• Widely distributed in body except CNS. It has high PPB (>95%), mostly to albumin.
• Metabolised mainly in liver & excreted through bile & urine.
Side effects/Adverse effects
• Gastrointestinal disturbances, hepatotoxicity & has antiandrogenic effect.
• Cats are more susceptible to the hepatotoxic effects than dogs.
• Ketoconazole is cytochrome P450 inhibitor.
Clinical Use:
• Ketoconazole has been used to treat systemic mycosis in dogs, cats, horses, birds and
some other species.
Dose :
• Dogs & Cats : 5 -20 mg/kg, PO, 2 to 3 times daily
• Cats : 5 -20 mg/kg, PO, 1 to 2 times daily, Horses : 10 mg/kg, PO, once daily.
Miconazole
• Primarily used topically & persists for about 4 days in the stratum corneum.
• Miconazole is available as a 2% cream and a 1% lotion for treatment of local
dermatophytosis in dogs and cats.
• Also used for oral or vaginal thrush (yeast infection).
Enilconazole
• Topical antifungal agent with action similar to miconazole.
• It has excellent antifungal activity and a good residual effect after topical
application.
Clotrimazole
• Topical antifungal agent used for candidiasis, trichomoniosis and dermatophyte
infections of the skin and vagina.
2. Triazoles
• Like imidazoles, have same mechanism of action and antifungal spectrum.
Fluconazole
• Synthetic, white crystalline powder that is slightly soluble in water.
• Used in the treatment and prevention of many superficial and systemic fungal
infections.
Pharmacokinetics
• Completely absorbed after oral dosing.
• Fluconazole is readily distributed into body tissues and fluids and its concentrations in
the CSF, eye, peritoneal fluid, saliva and urine are good.
• Mainly excreted in urine and sweat.
• Side/Adverse effects similar to ketoconazole.
Clinical uses

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• Use for treatment and prophylaxis of fungal infections where other antifungals have
failed in dermatophytes, yeasts and a variety of systemic fungi.

Itraconazole
• It having both topical and systemic actions.
• Broader spectrum of antifungal activity than ketoconazole or fluconazole
• Itraconazole is used primarily in veterinary practice.
• Voriconazole
• New drug structurally similar to fluconazole .
• Orally effective (F=96%) , used to treat serious fungal infections like aspergillosis.

IV. ALLYLAMINES
Terbinafine
• Synthetic drug , recently introduced
• White fine crystalline powder, freely soluble in methanol, ethanol and slightly
soluble in water.
• Highly lipophilic in nature and tends to accumulate in skin, nails and fatty tissues.
Mechanism of action
• Terbinafine is a fungicidal drug.
• It acts by selectively inhibiting squalene epoxide enzyme, leads to decrease
synthesis of ergosterol from squalene in the fungal cell wall.
• Terbinafine is more selectively (1000 fold) inhibited fungal enzyme as compared to
the mammalian cell wall enzyme.
Pharmacokinetics
• Terbinafine is well absorbed after oral administration, but it undergoes significant
first-pass
• It is highly plasma protein bound (-99%). metabolism that decreases its bioavailability
to about 40%.
• Its lipophilic nature permits wide distribution in body metabolised in the liver.
• The metabolites are excreted in urine (80%) and faeces (20%).
• Terbinafine is usually well tolerated with few adverse effect.
Clinical uses
• Used for treatment of dermatophyte infection in dogs, cats, birds and some exotic
species. Used orally (tablets) or topically (as 1% solution or cream).

V. ECHINOCANDINS
• Newer group which inhibit synthesis of fungal cell wall.
• fungicidal against some yeasts, Fungistatic against some moulds.
Caspofungin
• First echinecandin, approved for clinical usage in 2006.
Mechanism of action
• It inhibits β-glucan synthesis in the fungal cell wall.
• Caspofungin and other echinocandins are relatively-selective in their action because
glucan synthase enzyme is not present in mammalian cells.
Antifungal actions
• Mainly effective against Candida & Aspergillus spp.
Pharmacokinetics
• Administered only IV due to low oral bioavailability.
• Distributed to most tissues and organs & metabolites are excreted in the urine and

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faeces.
Clinical uses
• Caspofungin is largely used in the treatment of candidiasis and aspergillosis.
VI. IODIDES
• Sodium Iodide & Potassium Iodide
• Occasionally used in the treatment of fungal infections like sporotrichosis in dogs
and cats.

VII. MISCELLANEOUS ANTIFUNGAL AGENTS

Benzoic acid
• Benzoic acid has both bacteriostatic and fungistatic actions.
• For fungal infections, it is mostly combined with salicylic acid to make Whitfield
ointment.
• Useful in dermatophytosis (ringworm infection)
Salicylic acid
• Used topically as keratolytic, anti-seborrhoeic, antiseptic and fungistatic.
• Its keratolytic action helps in the dermal penetration of drugs.
Gentian violet
• It has antibacterial, antifungal and anthelmintic activity.
Tolnaftate
• Synthetic topical antifungal agent with significant activity against Trichophyton spp.
infection.
Sulphur
• Sulphur is externally used as ointment, powder or lotion to treat ringworm and
eczema.
Copper sulphate
• Used topically in ringworm infection- fungicidal action.

Table: List of systemic & Topical antifungal agents

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INDIGENOUS DRUGS WITH PROVEN PHARMACOLOGICAL &
THERAPEUTIC EFFICACY
Introduction:
Indigenous drugs refer to pharmacologically active principles primarily obtained from the
medicinal plants with proven therapeutic value.
 A large number of medicinal plants have been recognized to possess therapeutic value
in the treatment of a variety of diseases.
 The medicinal plants contain pharmacologically active principles such as alkaloids,
glycosides, resins, tannins, fixed oils, volatile oils etc.
 Ethno-veterinary medicine (EVM) is commonly defined as a system of folk beliefs,
knowledge, skills, methods and practices relating to the health care of animals.

MEDICINAL PLANTS AND ITS PHARMACOLOGICAL ACTIONS

Name of the plant Active principle Pharmacological action

Rauwolfia serpentine (Sarpagandha) Reserpine Tranqulizer and Antihypertensive
Vinca rosea (Barmasi) Vincristine and Anticancer drug – common used
Vinblastine for the treatment of transveneral
tumour in dogs.
Withania somnifera (Ashwagandha) Somniferine General tonic and
Immunostimulant
Laptadenia reticulate (Dodi, Jivanti) Laptadine Galactagogue
Zingiber officinalis (Ginger) Gingerol Carminative and Stomachic
Ricinus communis (E:Castor, H: Ricin Purgative
Arandi, G: Divel)

INDIGENOUS ANTIBACTERIAL/ANTISEPTIC AGENTS

 Curcuma longa (Turmeric/Haladi)
 Azadirachta indica (Neem)
 Allium sativum (Garlic)
 Ocimum sanctum (Tulsi)
 Zingiber officinalis (Ginger)
 Asparagus racemosus (Shatavari)
 Glycirrhiza glabra (Licorice /Jethi-madh)

INDIGENOUS ANTIFUNGAL AGENTS

 Curcuma longa
 Pongamia glabra (S:Karanja; E: Pongam)
 Azadirachta indica
 Ocimum basilicum (Sweet Basil/Tulsi)
 Cassia tora (E:Foetid cassia)

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INDIGENOUS ANTICANCER AGENTS
 Catharanthus roseus (G-Barmasi, H-Sadabahar) Vinca alkaloids, vinblastine and
vincristine
 Podophyllum peltatum (G- Venivel, H- Ban kakari, E- Mayapple)
 Taxus brevifolia
 Taxus baccata and Taxus cuspidata

INDIGENOUS ANTHELMINTIC
 Areca catechu (G-Sopari, E-betel nut palm) - Anti-cestodal
 Azardirachta indica
 Carica papaya
 Cucurbita maxima (G-Lal kolu) - Anti- trematodal action
 Embelia ribes (G-Vavding, E-Embelia) - very effective in treatment of ascarides
 Butea frondosa (G-Khakaro/Palas) seeds exhibits good activity against ascarides
 Punica granatum (G-Dadam, E-Pomegranate)
 Ocimum basilicum (Sweet Basil/Tulsi)
 Pongamia glabra (S:Karanja; E: Pongam)

INDIGENOUS ARTHROPODE REPELLANTS/ INSECTICIDAL AGENTS

Acorus calamus (Sweet Flag) Repellant of Ixodid ticks
Azadirachta indica wide range insecticidal
Curcuma longa Against ticks and mites
Chrysanthemum indicum Against scabies
Pongamia glabra (G, H -Karanja) Against sarcoptic mange
Ricinus communis (E:Castor, H: Arandi, G: Divel) Against mites
Tinospora cordifolia (Galo/Gado) Against scabies

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GROWTH PROMOTERS

 Growth promoters are agents which increase growth rate and feed conversion
ability of animals.
 These agents are often used in food animals in which high conversion of feed into
animal tissues is required at short time.

Classification
I. Antibiotics
a. lonophore antibiotics e.g. monensin, lasalocid and salinomycin.
b. Non-ionophore antibiotics e.g. zinc bacitracin, flavomycin, virginiamycin, tylosin,
avilamycin, spiramycin and avoparcin.
2. Synthetic antimicrobials e.g. carbadox and olaquindox.
II. Probiotics
e.g. Lactobacilli and Streptococci.
III. Prebiotics
e.g. fructo-oligosaccharides, xylo-oligosaccharides and manno-oligosaccharide
IV. Hormones
1. Steroidal sex hormones and analogues
e.g. estradiol, progesterone, testosterone, melengestrol acetate, zeranol and
diethylstilbestrol.
2. Growth hormone
e.g. naturally occurring growth hormone and recombinant growth hormone.
V. Miscellaneous drugs
1. Beta2-adrenoceptor agonists
e.g. clenbuterol, salbutamol, terbutaline, cimaterol and ractopamine.
2. Metallic compounds
e.g. copper and arsenic.
3. Enzymes
e.g. amylases, lipases, phytases, galactosidases and proteases.
I. Antibiotics
 Antibiotics are widely used in therapeutics for their antimicrobial purposes in
animals and humans.
 In ruminants, they act primarily on rumen microflora and alter rumen
fermentation.
 They enhance the microbial production of gluconeogenic fatty acid propionate
and to some extent acetate, at the cost of butyrate.
 The altered rumen fermentation also decreases production of methane with less loss
of high-energy in rumen.
 In monogastric animals, similar action may be observed in small intestine.
a. Ionophore Antibiotics
 Ionophore antibiotics are fermentation products of Streptomyces species and are
primarily used as anticoccidial drugs.

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 Some agents such as monensin, lasalocid and salinomycin also possess growth
promoter activity when used in beef and dairy cattle.
 These compounds mainly modify the movement of cations across the biological
membrane to produce their antimicrobial action.
Monensin
 Monensin obtained from Streptomyces cinnamonensis.
 Monensin is widely used in veterinary practice as an anticoccidial in poultry and as
a growth promoter in cattle.
 Monensin is toxic to ruminants and other species at high doses.
Lasalocid
 Lasalocid obtained from Streptomyces lasaliensis.
 It is widely used in the control of coccidiosis and to increase feed conversion
efficiency in cattle.
Salinomycin
 Salinomycin used for prophylaxis of coccidiosis in poultry and to improve growth
rate and feed conversion efficiency in pigs.
 It is toxic to horses and other equidae and should not be used in turkeys.
b. Non-lonophore Antibiotics
 These agents selectively modify the microbial population of animals to improve
production efficiency.
 Non-ionophore antibiotics can be administered in milk replacers for young
animals or in supplementary concentrates.
Zinc bacitracin
 Bacitracin is a topically used polypeptide antibiotic obtained from a strain of Bacillus
subtilis.
 Zinc bacitracin is permitted for veterinary use as a feed additive for growth
promotion purposes.
 Used as a growth promoter in feed to young ruminants, piglets and pigs, broiler
and laying hens, and fur-bearing species excluding rabbits.
 It should not be used in lactating cows.
Tylosin
 Tylosin is a macrolide antibiotic isolated from a strains of Streptomycetes fradiae.
 Tylosin is active against mainly gram-positive organisms and is used as an
antibacterial and growth promoter.
 It concentrates in milk for a long time; therefore it should not be administered to
lactating cows.
 Withdrawal period for slaughter may vary from 0 to 14 days, depending on the use
and species.
2. Synthetic Antimicrobials
Carbadox
 It is primarily active against gram-positive bacteria and is more effective under
anaerobic conditions than aerobic conditions. It is marketed both as growth
promoter and antibacterial agent for use in swine.

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 Carbadox possesses several adverse/toxic effects when used as daily feed additive in
concentration more than 100 ppm.
Olaquindox
 Olaquindox is another synthetic antibacterial drug used for increasing growth rate
and feed conversion efficiency in animals.

[Link]
 Probiotics are products containing live micro-organisms which are thought to be
beneficial to the host organism.
 Probiotics are used clinically in cases of digestive upsets (e.g. diarrhoea), to improve
digestion, to enhance growth rate and feed efficiency and to overcome stress due to
weaning or transport of livestock.
 Probiotics are safe to use with zero day slaughter withdrawal period.

III. PREBIOTICS
 Prebiotics are carbohydrates that cannot be digested by the human body.
 They are food for probiotics.
 Prebiotics are mainly dietary products which are selectively fermented by beneficial
gut bacteria and therefore, support a healthy gut microflora.

IV. HORMONES
 Steroidal sex hormones such as estradiol, progesterone and testosterone have been
used for anabolic purposes in animals.
 Testosterone increased protein synthesis, enhanced muscle development and
better feed efficiency resulting in net-weight gain.
 Estradiol is used as growth promoter in ruminants.
 Synthetic analogues of testosterone or progesterone possess significant anabolic
growth promoter activity in farm animals.
 Growth hormone (Somatotropin) promotes growth of all organs. It is more useful in
cattle and sheep, but not in poultry.

V. MISCELLANEOUS DRUGS
 Beta2-adrenoceptor agonists are occasionally used in cattle, pigs and poultry as
growth promoter.
 Copper salts may also be used in dairy cattle and goats (not sheep) for production
enhancing and growth promoting effect.
 Many enzymes (amylases, lipases, phytases, galactosidases, glucanases, xylanases,
proteases, pepsin and polygalacturonase) are supplemented in human and animals
diets for promoting the growth and enhancing the production.

Unit-V/Chemotherapy / C V Sc & A , AAU, Anand /2019

ANTISEPTICS AND DISINFECTANTS

Antiseptics: A substance that prevents the growth of micro organism on living tissue either
by inhibiting their activity or by destroying them (use on skin or mucous membrane).

Disinfectant: An agent that destroying the disease causing microorganism on inanimate (non
living) objects.

Germicide: An agent that kill microorganisms, especially pathogenic organisms.

IDEAL PROPERTIES OF ANTISEPTICS

 It should have a broad spectrum of activity, including bacteria, fungi and virus.
 It should be rapidly effective and should be germicidal.
 It should not allow the emergence of resistant pathogens.
 It should not be inactivated by protein or organic matter or tissue debris.
 It should be non-staining, non irritant and non-corrosive or non toxic.
 It should be odorless and deodorizing.
 It should have detergent property
 It should have residual action after rinsing.
 It should be simple, easily available, stable and economical to use.

CLASSIFICATION OF ANTISEPTICS AND DISINFECTANTS

1) Oxidizing agents
a. Peroxides – Hydrogen peroxide, Potassium permanganate
b. Halogens – Chlorine, Iodine, Iodophores
2) Reducing agents - Formaldehyde, Glutaraldehyde, Sulphur dioxide
3) Acids and Alkalies – Sulphuric acid, Sodium hydroxide, Boric
acid, Benzoic acid, Quick lime, Salicylic Acid
4) Alcohols - Ethyl alcohol, Isopropyl alcohol
5) Phenols and cresols
6) Dyes - Acriflavine, Gentian violet
7) Surfactants/Detergents e.g. Cetrimide, Benzalkonium chloride & Biocides
8) Biguanides: Chlorhexidine
9) Others: EDTA, ethylene oxide etc.
10) Physical agents: Dry and moist heat, Radiation (UV light)

1) OXIDIZING AGENTS
 Two types of oxidizing agents are
o Those which release gaseous oxygen – Hydrogen peroxide.
o Those which cause oxidation without the release of oxygen – Potassium
permanganate, halogens.
Solution of hydrogen peroxide (3%)
 Produces nascent oxygen in contact with organic mater, which is partly due to the
enzyme catalase.
 In turn is responsible for oxidizing effect.
 Organic matter affects the action.
Benzoyl peroxide
 Slowly release oxygen, oxidizing antiseptic, keratolytic and antiseborrheic – useful in
pyoderma in dogs.

Unit-V/Chemotherapy / C V Sc & A , AAU, Anand /2019

 Skin irritation limits its use.
Sodium perborate
 White crystalline powder; decompose in solution to give sodium metaborate and
hydrogen peroxide which in turn release nascent oxygen.
Potassium permanganate
 Dark purple crystals with metallic luster forming pink or deep purple solutions in
water (Widely used for wound washing).
 1 in 1000 (0.01%) solution is used to clean the wound and as mouth lotion (antiseptic
and deodorizer)
 5% solution reduces excess granulation.
 Once the solution turns brown it is inactive (Prepare fresh and used).
 Stains the tissues (Destainer - oxalic and sulphurous acid).

HALOGENS
Chlorine
 Inexpensive, easily available, bactericidal and broad spectrum.
 Strong oxidizing agent, oxidation of peptide links and denaturation of protein.
 It accumulation inhibits essential enzyme system.
 It is inactivated in the presence of organic matter.
 Two derivatives of chlorine are
o Inorganic compound
 Eg. Na hypochlorite – Dakin‘s Solution ( 0.4 % available chlorine )
 It is unstable and releases Cl- slowly when exposed to the atmosphere or
organic material.
 It can be used as teat dip at a concentration of 4% available chlorine.
o Organic derivatives
 Eg. Chloramine T and Chlorinated lime (Bleaching powder)
 Chloramine T - slowly release oxygen, disinfection of udder and sanitation of
dairy utensils.
 Chloramine releases Cl- and HoCl which acts as oxidizing agent. They are also
used to treat swimming pool and drinking water.
 Mixture of calcium hypochlorite and CaCl2 yields 30% chlorine and is used
for disinfection of water supply, live-stock premises, disposal of carcasses etc.

Iodine
 Used for antiseptic wound dressing, but it is an irritant and retards wound healing.
 Interacts with proteins of cytoplasmic membrane.
 Two forms
o Those releasing free iodine
 Lugol‘s Iodine
 Tincture of iodine - Weak and Strong
o Iodophors - Complex between iodine and vehicle polyvinyl pyrrolidone –
povidone iodine (Betadine).
 Increases the solubility of iodine
 Sustained release
 Improves the activity of Iodine
 Use: Skin scrub, low iodine concentration prevents staining hence used in mastitis
control as teat dip (0.5 % available iodine).
 Toxicity: Cutaneous and systemic absorption leads to iodism.

Unit-V/Chemotherapy / C V Sc & A , AAU, Anand /2019

2) REDUCING AGENT /ALDEHYDES
 Formaldehyde
 Glutaraldehyde
 Sulphur dioxide
Formaldehyde
 Highly bactericidal and action is not affected by organic matter.
 Formalin – strongly astringent and antiseptic, precipitates protein on the skin and
hardens it.
 Fumigation: 10% formaldehyde solution is used for room disinfection followed by
closing the room for 24 hrs.
 In combination with KMnO4 (3:5) or boiling formaldehyde alone.
 It is an irritant and has corrosive action on the skin. The irritant vapours can be
neutralised with ammonia solution.
Glutaraldehyde (gold standard antiseptic)
 Chemo sterilizing agent, less irritant and active against bacteria, fungi, virus & spores.
 MOA – Denaturation of protein and is an alkylating agent.
 Use: Disinfection for lensed clinical equipment (endoscope or cryoscope) and
treatment of blood products. It is more active at alkaline pH- 7.5 to 8.5.
Sulphur dioxide
 Liberates gas when sulphur is ignited, 0.5 kg should be burned/100 [Link]. and
atmosphere should be moist and ventilation should be sealed.

3) ACIDS AND ALKALIES

+ -
 Release H & OH ion and denature protein, potent bactericidal except mycobacteria.
Acids
Boric acid
 Mild germicidal activity does not irritate the skin or tissues.
 2% solution is used as eye cleanser and mouth wash.
 Borax glycerine (12% W/V borax with glycerine) and boro glycerine (31% boric acid
in glycerine) is used for treating wound lesions.
 Boric acid (2.5 g) with Salicylic acid (1.5 g) and talc (upto 50 g) is used as dusting
powder.
Benzoic acid
 Along with salicylic acid it acts as a fungicide on skin (treat ring worm).
Acetic acid
 2-5 % solution is used as antiseptic wound dressing and possesses bacteriostatic
property.
Alkalies
 Sodium carbonate (Washing soda)
 4% solution is used as antiseptic cleansing for wound.
 Calcium oxide (Lime)
 It is used as general disinfectant in farm yard by scattering in the drains or by
sweeping on the floors.
 Calcium hydroxide (Milk of lime)
 For disinfecting the areas contaminated with excreta.
4) ALCOHOLS
Ethyl alcohol
 70% is used as skin antiseptic at injection site and as preoperative skin swab. It is
virucidal and less toxic.

Unit-V/Chemotherapy / C V Sc & A , AAU, Anand /2019

Isopropyl alcohol
 50% possess bactericidal action and is used as skin antiseptics.
Uses
 Alcohol acts by denaturing the protein and inhibition of cell metabolites
 It is used alone or in combination with Iodine, Phenol or Chlorhexidine.
 Not active in the presence of physical dirt and not recommended for surgical
instruments (not sporicidal).
5) PHENOL AND CRESOL
Phenols
 First disinfectant and antiseptic used by Joseph Lister in 1867.
 It is coal tar derivative.
 It acts by denaturing the bacterial protein. It acts as a protoplasmic poison when
applied to tissues and may even cause necrosis.
 Act on cytoplasmic membrane and cause leakage.
n
 It is mainly used as a general disinfectant (1-2% sol ) and chemical sterilizer (5%)
 Phenol is used as a standard to measure the effectiveness of other disinfectants and
antiseptics in terms of phenol coefficient.

Cresol
 Impure mixture of ortho, meta and para methyl deriatives of phenol and is obtained
from coal tar distillation
 It is a better disinfectant and less toxic than phenol
 2% solution of cresol with soap is commercially available as Lysol and is used as
disinfectant
Toxicity
 Both phenol and cresol are toxic to dogs and cats hence should not be used to
disinfect the kennels or cat cages (Not use for feline)
 Cats and dogs should NOT be bathed with soaps containing carbolic acid.
 Toxic signs include convulsion, coma and death due to respiratory and cardiac failure.
6) DYES
 Acridine dyes possess antibacterial activity and are occasionally used as antiseptics.
 They are more active against G+ve bacteria & gonococci. They remain active in
presence of pus, serum and organic matter.
 Acriflavin is mostly used as 0.1% emulsion, solution, lotion, cream or jelly.
 Gention violet possesses antiseptic & antifungal activities. More active against G+ve
bacteria. It is used as 0.5% in form of jelly, lotion or solution on burns.
 Equal parts of gention violet & brilliant green are used in treatment of ringworm,
eczema and chronic ulcers.
7) DETERGENTS
 Detergents are surface active agents, reduce surface and interfacial tension and act
as cleansing- emulsifying agents with antibacterial property. They are also called
as surfactants and are of two types:
o Ionic - Anionic and Cationic
o Nonionic - not antibacterial
 Detergent antiseptics are non irritant and non toxic at the recommended
concentration.
 Their activity is reduced in the presence of organic matter and has no effect on
spores, virus and fungi.
Cetrimide
 It acts as a foaming agent

Unit-V/Chemotherapy / C V Sc & A , AAU, Anand /2019

 1% solution is used for skin cleansing and wound dressing
 0.1% solution is used to disinfect dairy equipments, utensils, clothes and hands
 0.5% cream is used as a prophylactic agent against mastitis
Benzalkonium chloride
 0.1% alcoholic solution is used for skin antiseptics.
 0.01-0.05% solution is used on mucous membrane and to clean deep wounds

8) OTHERS
Chlorhexidine hydrochloride
 It is a potent bactericidal agent and acts by disrupting the bacterial cell wall.
 Active against both G+ve and G-ve bacteria.
 Incompatible with soap and anionic detergents.
 Ineffective against fungi, virus and spores.
 0.5% alcoholic or 1% aqueous solution is used as skin antiseptic.
 1% aqueous solution is used as antiseptic teat dip.
 Toxicity is low and irritation is uncommon.
 Useful in prophylaxis and treatment of oral diseases.

Unit-V/Chemotherapy / C V Sc & A , AAU, Anand /2019

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METAL POISONING

Toxic Metals: i.e. Arsenic (As), Mercury (Hg), Lead (Pb), Copper (Cu), Molybdenum (Mo),
Cadmium (Cd), Iron (Fe), Zinc (Zn) and Thalium (Tl).
1) ARSENIC (As) POISONING
➢ Arsenic (As) is an irritant and cumulative poison that is found mainly in soil, water
and air as a common environmental toxicant.
➢ Occurs in three form
(1) Elemental (As3)
(2) Trivalent (As3+ or arsenite) – more soluble and more toxic (5-10 times)
than pentavalent
(3) Pentavalent (As 5+ or arsenate)
➢ In general, toxicity increases in the sequence of organic arsenicals < As 5+ < As3+ <
Arsine (AsH3).
Sources of toxicity:
Major sources are
➢ Indiscriminate use of arsenic as a drug in ruminatoric preparations, skin tonics and
for control of ectoparasites (e.g. lead arsenate as dip) and blood parasites (e.g. sodium
thiacetarsamide).
➢ Excessive use or accidental ingestion of arsenical pesticides i.e. insecticides (e.g.
copper acetoarsenite or Paris green), defoliants/herbicides (e.g. sodium or potassium
arsenite or arsenate, monosodium methanearsonate),
rodenticides (e.g. arsenic trioxide), wood preservatives (e.g. arsenic pentoxide) and
ant baits (e.g. sodium or potassium arsenate).
➢ Arsenic-contaminated soils or burn masses, which are often licked by animals that
crave for salt or minerals.
➢ Contaminated drinking water especially well water containing high concentrations
of arsenic.
➢ Overdosage or extended use of organic arsenical feed additives in poultry or swine
as growth promoters (e.g. arsanilic acid and sodium arsanilate).
➢ Burning of wood products treated with arsenical preservatives or coals which
have variable concentration of arsenic.
➢ Smelting of copper, zinc, lead and other ores can release arsenic as a by-product
into the environment.
➢ Arsine gas and arsenic trioxide used in the manufacture of most computer chips
using silicon based technology. These may cause occupational toxicosis.
➢ Litter from poultry fed phenylarsenic compounds.
➢ Pastures and crops near smelters contaminated with arsenic.
➢ Malicious poisoning with arsenic trioxide (very common).
Factors affecting toxicity
• Toxicity of arsenic in animals varies with several factors such as
Species:
➢ Herbivores are commonly poisoned due to ingestion of contaminated forages.

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➢ Cats and dogs are poisoned less while fowl and swine are rarely affected due to their
limited exposure to arsenic.
Oxidation state:
➢ Inorganic arsenic in the trivalent state is more toxic (up to ten times) than the
inorganic pentavalent form
Solubility / Form:
➢ Finely divided soluble arsenic compounds are more toxic than coarse and poorly
soluble ones
Status / Health of animal:
➢ Dehydrated, weak, ill and poor conditioned animals are more susceptible to
arsenic toxicity due to slow renal excretion of arsenic.
Tolerance:
➢ Constant exposure to arsenic may confer some degree of tolerance to its toxicity.
Toxicokinetics
• Soluble arsenicals (both trivalent and pentavalent) are readily absorbed from all
body surfaces including GI tract and skin.
• After absorption, arsenic is distributed throughout the body but tends to reach higher
concentration in liver, kidneys, heart and lungs.
• Because of high sulphydryl contents in keratin, high concentrations of arsenic are
found in hair and nails where it stays for months.
• Because of its chemical similarity to phosphorus, arsenic is deposited in bone and
teeth and retained there for long period.
• In domestic animals, arsenic does not stay in tissues for very long and is partly
methylated (detoxification) in the liver and rapidly excreted in the urine, faeces,
bile, milk, saliva and sweat.
• Some portion of pentavalent arsenic (arsenate) is reduced to the more toxic
trivalent arsenic.
• In this process, the pentavalent arsenic (As 5+ or arsenate) is reduced to form
trivalent arsenic (As3+ or arsenite) which is further methylated to form
monomethylarsenite and then dimethylarsenite which is readily eliminated from
the body.

Figure: Biotransformation of pentavalent arsenic (arsenate)

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Mechanism of action (Toxicodynamic)

➢ Two Forms: pentavalent or trivalent
➢ Major effects are believed to be attributable to the trivalent form.
a. Trivalent arsenic compounds
➢ It binds primarily to sulphydryl compounds especially lipoic (thioctic) acid to
form stable compounds that subsequently disrupt enzymes involved in cellular
respiration.
➢ Lipoic acid is an essential co-factor for the enzymatic decarboxylation of keto
acids such as pyruvate, ketoglutarate and ketobutyrate.
➢ By inactivating lipoic acid, arsenic inhibits formation of acetyl, succinyl and
propionyl coenzymes-A.
➢ The major effect of lipoic acid inhibition is slowing or inhibition of glycolysis and
TCA cycle.
➢ Tissues with high oxidative energy requirement (e.g. actively dividing cells such as
intestinal epithelium, kidneys, liver, skin, lungs etc.) are most affected.
➢ Trivalent arsenic affects capillary integrity of GIT:
➢ Loss of capillary integrity and dilation in GI tract allows transudation of plasma
fluids into the intestinal mucosa and lumen with reduced blood volume,
hypotension, shock and circulatory loss.
➢ Oedema, vesiculation and eventual loss of GI mucosa also occur that further
aggravate fluid loss and shock.

Figure: Pathogenesis from trivalent arsenicals

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b. Pentavalent inorganic arsenicals

➢ The arsenate (pentavalent) ion substitute for phosphate in oxidative
phosphorylation.
➢ Pentavalent organic arsenicals which are commonly used as feed additives cause
demyelination and axonal degeneration, which perhaps is due to interference with
the B vitamins required for maintenance of nervous tissue.
➢ Arsine gas (AsH3) causes haemolysis and pulmonary oedema.
Clinical signs
a. Trivalent inorganic or organic arsenicals
Acute and Peracute toxicity:
➢ Per acute cases- Animal dies without any symptoms
➢ Acute cases- Severe gastroenteritis, colic, staggering gait, extreme weakness,
trembling, salivation, vomiting (in dogs, cats and pigs), increased thirst, watery
diarrhoea, (shooting), blood in faeces, fast and weak pulse, hypotension, dehydration,
oliguria or anuria, rumen atony, hind limbs paralysis, prostration, normal or
subnormal temperature, coma and death in 1-3 days.
Subacute toxicity
➢ Signs include colic, anorexia, depression, staggering, weakness, diarrhoea with blood
and/or mucous discharge, polyuria followed by anuria, dehydration, polydipsia,
partial paralysis of rear limbs, cold extremities and hypothermia. Convulsions rarely
occur. Acidosis and azotemia may cause death.
Chronic toxicity:
➢ Rarely seen & characterized by wasting, poor condition, thirst, brick red
discolouration of visible mucous membranes, normal temperature and weak irregular
pulse.
➢ Animal have reduced production and reproduction.
➢ Chronic arsenic poisoning in animals is generally encountered in industrial regions
following ingestion of forage contaminated by industrial pollutants.
b. Pentavalent organic arsenical feed additives:
➢ Early signs are apparent after 2-4 days and include nervous derangement such as
ataxia, incoordination and blindness.
➢ Blindness is characteristic of arsinilic acid poisoning and not of other arsenicals.
➢ Affected animals (mostly swine) become weak, assume a sitting dog posture, and
eventually become paralysed in lateral recumbency.
Post-mortem findings
➢ Peracute arsenic toxicosis- no lesions
➢ Acute poisoning –inflammation of GI tract, oedema, rupture of blood vessels and
necrosis of epithelial and subepithelial tissues. Contents of the gut are fluid, often
foul smelling and blood tinged and may contain shreds of epithelial tissue.
➢ In subacute cases- pale swollen kidneys, pale liver, petechial haemorrhages of
intestinal serosa and mucosa.
➢ Microscopic lesions in the GI tract include intestinal capillary dilatation, intestinal
epithelial necrosis, renal tubular necrosis & fatty liver degeneration.

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Diagnosis
➢ Based on history, circumstantial evidences, clinical signs and PM lesions.
➢ A sudden onset of severe colic, bloody or watery diarrhoea containing mucosal
shreds, and postmortem findings of haemorrhagic gastroenteritis and
degenerative changes in liver and kidneys should always be interpreted as possible
arsenic poisoning.
➢ No other metal or metalloid, with the possible exception of thallium, causes such a
speedy onset of severe GI damage.
➢ Antemortem samples (live animal) include urine, vomitus, faeces and hair.
➢ After death- hepatic, renal and nervous tissues (organic pentavalent toxicosis) may
be taken.
➢ Liver and kidney tissues of Healthy animal rarely contain > 1 ppm arsenic (wet
wt.), whereas toxicity is associated with concentrations > 3 ppm.
➢ Urinalysis reveals high arsenic content for many days, proteinuria, increased specific
gravity and casts.
Treatment
Chelation of arsenic is main objective of treatment.
a. Dimercaprol/British Anti-Lewisite (BAL) :
➢ It is a dithiol-containing chelating agent that can form a relatively non-toxic and
easily excretable complex with arsenic.
➢ Large animals: 3 mg/kg (5% sol. In 10% sol. Of benzyl benzoate in arachis oil) by
deep I.M. injection, q4h -1st 2 days, q6h on 3rd day and q12h next 10 days or untill
recovery.
➢ Small animals: 2.5-5 mg/kg (10% sol. In oil). Dose intervals are same as in large
animals.
➢ Dosage and frequency of BAL is highly specific otherwise animal may die due to
dimercaprol poisoning.
➢ Dimercaprol also has toxic effects (vomiting, tremors, and convulsions) which limit
its dosage and frequency of administration.
➢ Renal function should be monitored during therapy.
b. Thioctic acid: (α-Lipoicacid)
➢ Considered more effective than dimercaprol for arsenic poisoned cattle
➢ However, it is not available in a commercial dosage form
➢ Used alone or in combination with dimercaprol
➢ Cattle: 50 mg/kg body wt., I.M., thrice a day as 20% solution
c. Sodium thiosulphate:
➢ Safe antidote to arsenic poisoning.
➢ Horses and cattle: 8-10 g (total dose) I.V. as 10-20% solution followed by 20-30 g
orally in about 300 ml water.
➢ Sheep and goats: One fourth of above dose.
d. Meso dimercapto succinic acid (MDSA) /Dimercapto succinic acid (DMSA)
➢ Water soluble derivatives of dimercaprol
➢ Supportive therapy includes emetics, gastric lavage, activated charcoal, fluid
therapy and multivitamin administration.

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2) MERCURY (Hg) POISONING

➢ Heavy metal that exists in liquid form at room temperature.
➢ Liquid metal having a bright silvery lustre which is volatile even at room
temperature.
➢ Found in 2 forms
1. Inorganic
Elemental mercury (Hg0 , metallic mercury or mercury vapour) - Most volatile of various
forms of metal and main concern is exposure to industrial occupational worker
(thermometers)
Mercury salts - monovalent mercurous salt & divalent mercuric salts
2. Organic (Organomercurial)
➢ Organic mercurials are considered more toxic than inorganic mercury
compounds.
Sources of Toxicity
➢ Ingestion of grains and seeds treated with organomercurial fungicides (e.g. ethyl
mercuric-chloride and -hydroxide).
➢ Occupational exposure in industries where mercury is used in the manufacture of
electrical equipments, anti-foul paints, small batteries, thermometers, mirrors,
semiconductor cells, fingerprinting products, fluorescent and mercury lamps,
infrared detectors, chloroalkali (e.g. bleach), plastics, dental amalgams etc.
➢ Ingestion of fish contaminated with organomercurials such as methyl mercury
(Minamata disease in japan- Fish poisoning).
➢ Due to volatile nature, there is a constant emission of the mercury vapour from
underground deposits, fossil fuels (coals), volcanic action and sea water evaporation.
➢ Indiscriminate use of some mercury containing drugs such ointments (e.g. red
mercuric iodide); antiseptics (e.g. mercurochrome and phenylmercuric nitrate) and
diuretics (mersalyl).
➢ Contamination of water with sewage sludge containing industrial waste.
➢ Chronic exposure to mercury in ambient air after inadvertent mercury spills in
poorly ventilated rooms, scientific laboratories etc.
➢ Dental amalgams (mixture) used for filling teeth.
Factors affecting toxicity
➢ Species: Ruminants, particularly calves and cows, show the highest sensitivity to
mercury. Horses, pigs and fowls are relatively less susceptible.
➢ Chemical form: Organic mercury compounds are more toxic than inorganic
mercury compounds.(more lipid soluble)
➢ Solubility: Insoluble inorganic mercury salts are less toxic than soluble inorganic
salts as they are slowly absorbed.
➢ Route of exposure: Elemental mercury is virtually non-toxic after oral
administration but highly toxic after inhalation.
➢ Dietary factors: Interacting substances in diet like selenium and vitamin E decrease
toxicity of organic mercurials.

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➢ Duration of exposure: Short term exposure to elemental mercury produces

corrosive and pulmonary lesions due to its irritant action, whereas long-term
exposure produces mainly neurological signs.
➢ Bioaccumulation: Organic mercurials like methyl mercury are continuously
taken in small amounts by fishes from marine water and accumulate them in very
high concentration. This becomes a source of potential toxicity in fish eating animals
and human beings.
Toxicokinetics
Elemental Mercury:
➢ Elemental (liquid) mercury do not get absorbed after oral administration and
therefore cannot cause acute poisoning.
➢ It volatilised to mercury vapour at room temperature, which is lipid-soluble and can
be absorbed by inhalation (70-90%).
➢ It is rapidly oxidised to inorganic divalent mercuric ions (Hg+2) within 15-20 min.
➢ The Hg+2 ions combine with the blood plasma proteins.
➢ Some mercury vapours which remain unoxidised penetrate the blood brain-
barrier and cause severe lesions in the CNS.
Inorganic mercury:
➢ Inorganic mercury salts are poorly absorbed from skin and GI tract, usually not
exceeding 10% of the ingested amount.
Organic mercurials :
➢ Organic mercurials are absorbed via all routes of exposure including dermal.
➢ Intestinal absorption after oral administration may be as high as 90% of the dose in
some species.
➢ It gets uniformly distributed throughout the body, accumulating in the brain, kidneys,
liver, muscles, hair and skin.
➢ It crosses the blood brain barrier and placenta and penetrate erythrocytes,
attributing to neurological symptoms, teratogenic effects and high blood to plasma
ratio, respectively.
➢ Mercury is eliminated from via faeces and urine and in negligible amounts in milk
and saliva.
Toxicodynamics
➢ Mercurial ion interact with the sulphydryl (-SH, thiol) groups of enzymes and
other proteins.
➢ Inhibition of sulphydryl groups in essential enzymes and proteins blocks several
metabolic processes.
➢ Organic mercurial compounds, due to their high affinity for sulphydryl groups,
combine with several membrane and intracellular proteins. They interfere with
metabolic activity and prevent synthesis of essential proteins, leading to cellular
degeneration and necrosis. Their most important target is brain.
➢ Inorganic mercurial salts cause direct tissue necrosis and renal tubular necrosis.
➢ Soluble inorganic salts precipitate proteins and produce strong corrosive action on
GI mucosa. They intensively damage the membranes of renal canaliculi.

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Clinical signs
➢ Acute toxicity usually is related to the inhalation of elemental mercury or
ingestion of inorganic mercury.
➢ Exposure to organic mercury leads to chronic toxicity and occasionally, acute
toxicity.
Elemental mercury:
➢ Short term exposure to the vapour of elemental mercury may produce weakness,
chills, nausea, vomiting, diarrhoea, dyspnoea and cough.
➢ Acute exposure can lead to pulmonary signs, which may progress to an interstitial
pneumonitis with severe compromise of respiratory function.
➢ Chronic exposure causes neurological signs like depression, irritability, excessive
shyness, vasomotor disturbances (such as excessive perspiration, uncontrolled
flushing), salivation, gingivitis and tremors.
Inorganic salts of mercury
➢ The most pronounced lesions in acute oral exposure are severe corrosion of the
mucous membranes of mouth, pharynx and intestine which produces intense pain,
colic, vomiting and bloody diarrhoea
➢ Animal usually dies within 2-4 days
Organic mercurials
➢ The onset of signs usually is delayed (days to weeks) after exposure.
➢ Early signs are erythema of skin, conjunctivitis, lachrymation and stomatitis.
➢ Neurological signs related include visual disturbance (occasional blindness), ataxia,
paralysis, coma and death.
Post-mortem findings
➢ Gross gastrointestinal lesions include gastric ulcers, necrotic enteritis, colitis etc.
➢ There is focal congestion of lungs and GI mucosa. Liver is pale and reduced in size.
➢ Renal lesions include pale, swollen kidneys with renal tubular necrosis, especially
affecting the proximal tubular epithelium.
➢ Inhalation of mercury vapour may produce acute, corrosive bronchitis and
interstitial pneumonia.
➢ In elemental mercury and organomercurials toxicosis, degenerative lesions in the
brain may be seen.
➢ In contrast to inorganic mercury salts, organomercurials have no corrosive action
on the mucous membranes.
➢ Microscopic lesions include fibrinoid degeneration of cerebral arterioles, neuronal
necrosis, neuronophagia, cortical vacuolation, axon swelling and gliosis in the CNS.
Diagnosis
➢ On the basis of clinical signs and PM lesions is difficult because multiple organ
systems are affected (e.g. CNS, kidneys and mucous membranes)
➢ Analytical evidences.
➢ Laboratory diagnosis
Tissues and feed (< 1 ppm) – Normal conc. of Hg
Elevated in kidneys (> 10-15 ppm), liver and brain- Acute poisoning of Hg.

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Treatment and management

a. Dimercaprol (BAL):
➢ The dimercaprol (British anti-lewisite) is an effective chelator of mercury and
doasge is same as As
➢ It is effective in inorganic Hg poisoning but its use is contraindicated in organic
Hg poisoning because (1) Only a small fraction of organic mercury is in plasma
and hence is not readily available for excretion. (2) Administration of BAL leads to
release of Hg from other tissues which leads to increase the brain concentration.
Dimercaprol is also contraindicated with pre-existing liver or kidney damage.
b. D-Penicillamine:
➢ It is an effective chelator of some metals including mercury
➢ All species: 15-50 mg/kg daily by oral route.
c. Meso dimercapto succinic acid (DMSA) and Dimercapto propane sulphonate
(DMPS):
➢ Water soluble analogues of dimercaprol which are less lipid soluble and less toxic
than the dimercaprol.
➢ DMSA: 10 mg/kg, orally, three times daily.
d. Sodium thiosulphate
➢ Used in mercury poisoning in combination with dimercaprol.
➢ Sodium thiosulphate (20% sol.): 10 ml/45 kg body wt. by I.V. route, 4 doses at 8
hour intervals.
Supportive therapy
➢ Gastric lavage with sodium formaldehyde sulphoxalate (100-250 ml, 5%
solution).
➢ Egg white or activated charcoal may be administered orally to adsorb ingested
mercury.
➢ Saline cathartic or sorbitol promotes clearance of mercury from the intestinal tract.
➢ Fluid therapy and selenium and vitamin E Supplementation.
➢ Seizures, if present, may be controlled with CNS depressants like diazepam or
barbiturates.

3) LEAD (Pb) POISONING

• Lead (Pb) intoxication is one of the most frequently diagnosed poisoning in
veterinary medicine world-wide and has been reported in all domestic and several
zoo species.
• It exists in elemental, inorganic and organic forms.
• Inoganic- lead arsenate (taenicide/insecticide), lead sulphide (eye liner), lead
tetroxide (sindur)
• Organic- Tetraethyl Pb (motor petrol), Pb acetate (astringent in lotion)
Sources of toxicity
• Accidental ingestion of lead objects such as batteries, gun shots, lead solders and
candy bar wrappers carelessly thrown near animal farms
• Ingestion or licking of lead-based paints (freshly painted walls, dry pealing paints)
and related products (lead primers, putty of caulking materials)

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• Ingestion of grass near busy highways may contain toxic amounts of lead from auto
exhausts.
• Pastures and vegetation contaminated by atmospheric fallout from smelters and
mining operations contain significant of lead.
• Lead parasiticide sprays, particularly lead arsenate, may cause toxicity in cattle
grazing in recently sprayed orchards or vegetable crops.
• Drinking water from old lead pipes or glazed crockery pots may contain toxic
amounts of lead.
• Vapours, fumes and powder generated from lead based industries such as lead
smelting, lead refining and battery manufacturing constitute major environmental
source of lead poisoning.
• Accidental consumption or licking of used engine oil filters, motor oil spilt, grease
or other farm products
• Ingestion of lead contaminated soil may be a major problem in animals with pica.
• Milk secreted from lead-poisoned animals can be dangerous for the young animals.
Factors affecting toxicity
➢ Age: Young animals are more susceptible than the adults.
➢ Species: Dogs, cattle, horses and water fowl are more susceptible. Cats and sheep
are intermediate sensitive. Goats, swine and chickens are comparatively tolerant.
➢ Pregnancy: Pregnant ewes are more sensitive than non pregnant ewes.
➢ Rate of ingestion: Large amounts of lead ingested in 1 or 2 days may be fatal, but
smaller amounts ingested over a period of several weeks may not be.
➢ Form: Soluble salts (e.g. lead acetate) are more readily absorbed so are more toxic
than insoluble salts (e.g. lead oxide).
➢ General status: Poorly nourished, weak and emaciated animals are more susceptible
to lead toxicity.
Toxicokinetics
➢ Most common route of lead exposure is oral ingestion.
➢ Only a small proportion (< 10%) is absorbed because of the formation of insoluble
lead complexes which are excreted in faeces.
➢ After inhalation, 90% of lead is absorbed into blood.
➢ Inorganic lead cannot easily penetrate skin, but organic lead (e.g. tetraethyl lead in
regular petrol) can penetrate intact skin readily.
➢ Once lead is absorbed, 85-90% of it binds to haemoglobin in erythrocytes. The
remainder is bound to serum albumin (9%).
➢ Only <1% of the circulating lead is free and available to tissues and is responsible
for the toxic effects.
➢ Inorganic lead is distributed initially in the soft tissues, particularly the tubular
epithelium of kidney and liver.
➢ With time, lead is redistributed and deposited in bone, teeth and hair. About 95%
of the body burden of lead is found in bone (bone acts as a sink of lead).
➢ Only small quantities of inorganic lead accumulate in the brain with most of it in
grey matter and basal ganglia.
➢ The presence of lead in bone marrow suppresses haematopoiesis.

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➢ It readily passes membrane barriers such as the blood-brain barrier and placenta.
➢ It gets readily excreted in urine, faeces & milk around 5%
➢ The half-life is 1 to 2 months and a steady state is achieved in about 6 months.
➢ Clinical signs of toxicosis may suddenly appear when bones get saturated.
Toxicodynamics
➢ Lead affects multiple tissues, especially the nervous system, GIT and
haematopoietic system.
➢ It inhibits sulphydryl groups of essential enzymes of cellular metabolism.
➢ It also interferes with Na+/K+-ATPase and alters cellular and mitochondrial
membranes, thereby increasing cellular fragility.
Neurotoxicity:
➢ It causes damage to capillary endothelium and inactivates blood brain barrier with
resulting cerebral oedema and haemorrhage.
➢ In growing rats, brain capillary endothelial buds (angioblasts) appear to be primary
target. Death of these buds may lead to encephalopathy. Damage to other kinds of
cells could be secondary to endothelial damage and circulatory deficiency. This may
also lead to neuronal necrosis in the CNS.
➢ It interferes with the action of neurotransmitter like GABA and dopamine.
➢ There is a demyelination & reduced conduction velocity in PNS.
Gastrointestinal toxicity
➢ Specific mechanisms for the gastro-intestinal effects of lead (e.g. anorexia, vomiting
and colic) are not described, but could be secondary to neurological mechanisms.
➢ Gastroenteritis is also produced by the caustic action of lead salts on the GI
mucosa.
Haematopoietic toxicity
➢ Chronic lead poisoning leads to depression of bone marrow and hypochromic
microcytic anaemia.
➢ It interferes with haeme and reduce haeme synthesis by inhibiting certain key
enzymes lilke Delta- aminolcvulinic acid dehydratase (ALAD) and haeme
synthetase (ferrochelatase)
➢ This reduces heme synthesis and causes accumulation of heme precursors (e.g
coproporphyrins, zinc protoporphyrin) in the blood.
➢ Basophilic stippling (the aggregation of ribonucleic acid) and increased fragility of
erythrocytes is usually an indication of bone marrow/ response to anaemia. Occurs
most often in dogs.
Immunotoxicity:
➢ Lead can suppress production of antibodies to certain viral and bacterial agents.
Nephrotoxicity:
➢ The proximal tubule appears to be the main target of lead toxicity.
➢ Lead nephropathy develops because of the inhibitory effects of lead on cellular
respiration.
➢ One characteristic of lead poisoning is the presence of lead inclusion bodies in the
nucleus of tubular cells.

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Endocrine toxicity:
➢ Impair the release of growth hormone and insulin growth factor and interferes
with skeletal calcium resulting in abnormalities in bone growth. Chronic exposure to
lead may also result in reduced thyroid functions.
Reproductive toxicity:
➢ Causes low sperm count and abnormal sperm morphology in males and infertility,
spontaneous abortion and still births in females.
Clinical signs
➢ It produces different symptoms in different species
➢ In general it causes encephalopathy accompanied by GI malfunction.
➢ Onset of clinical signs may take few hours, days or weeks depending upon the
amount ingested, species involved and other factors.
Cattle:
➢ Clinical signs observed in 2-3 days following ingestion
➢ The animals may bellow, stagger, show maniacal excitement, crash into objects
and appear blind.
➢ Death may occur within 2 hours or convulsive episodes may be interspersed with
periods of depression, ataxia and erratic behaviour i.e. circling and leaning, pacing
and pushing on objects (due to cerebral oedema).
➢ Shaking, irritability, muscle twitching, twitching of ears, 'snapping' of eyelids and
grinding of teeth are common.
➢ In some cases, dullness and anorexia along with signs of colic predominate.
➢ Abortion (in mid to late gestation), opisthotonos, salivation, lachrymation, nasal
discharge and paralysis may also be observed. Death may occur within several hours
to several days.
➢ Chronic ingestion of lead for weeks or months, during which cattle are
asymptomatic, may suddenly culminate in a seizure and death.
Dogs:
➢ The initial signs are anorexia, emesis colic and diarrhoea.
➢ It is followed by neurological signs include hyperesthesia, hysterical barking,
muscular spasms and seizures.
➢ These signs are intermittent with periods of nearly normal behaviour, presence of
many nucleated erythrocytes without severe anaemia is pathognomonic for lead
poisoning.
Horses:
➢ A chronic lead syndrome is characteristic in horses with a peripheral neuropathy
leading to respiratory signs.
➢ The important signs include anorexia, weight loss, depression, weakness, stiffness,
knuckling of fetlocks and often anaemia.
➢ Death in horses can occur from respiratory paralysis during convulsions.
Birds (Swans and waterfowl):
➢ Clinical signs are often unclear and may include non-specific gastrointestinal, renal
and neurological dysfunctions.

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Post-mortem findings
➢ Gross lesions in most species are mild and non-specific.
➢ Ingested lead containing material (paint chips, used motor oil, etc:) may be found in
the GI tract.
➢ There may be gastritis or enteritis, hyperaemia, petechiae or echymoses in various
organs and brain oedema.
➢ In chronic poisoning, plasma may fluoresce under ultraviolet light because of the
presence of excess porphyrins.
➢ Microscopically, cerebral cortical necrosis and poliomalacia may occur in cattle.
➢ Hepatocytes and renal tubular epithelium may contain eosinophilic acid-fast
intranuclear inclusions.
➢ Neutrophilic leucocytosis, moderate anaemia and basophilic stippling of RBCs
are frequently observed in dogs.
Diagnosis
➢ Depends on history, circumstantial evidences, clinical signs and PM lesions.
➢ Liver, kidneys, urine, faeces, bones and suspected materials (fodder, feed-stuffs
and drinking water) should be analysed for lead.
➢ The concentration of lead in renal cortex (>4 ppm), liver (4 ppm) or whole blood
(0.6 ppm) provides definitive confirmation of lead exposure.
➢ Measurements of blood 6- aminolevulinic acid dehydratase and free erythrocyte
protoporphyrin are useful.
➢ Increase in nucleated red blood cells in greater proportion than the degree of
anaemia indicates lead toxicosis.
➢ In young dogs, radiograms may have lead lines in images of long bones.
Treatment
➢ Specific treatment of lead intoxication involves use of chelating agents.
a. Calcium disodium edetate: (CaNa2EDTA, ethylene diamine tetra acetate)
➢ It form soluble complex with Pb and excreted in urine.
➢ Do not use EDTA-acid or sodium EDTA because they chelate blood calcium and
produce hypocalcaemia.
➢ Injudicious use of CaNa2EDTA should be avoided as it may cause gastrointestinal
and renal toxicosis with clinical signs of anorexia, depression, diarrhoea and
vomiting. This occurs largely due to large mobilisation of lead from bones that
increases its concentration in blood and soft tissues and kidneys may not be
capable of excreting a large amount of chelated lead quickly.
➢ Horses & cattle: 110 mg/kg (as 1-2% solution in 5% dextrose), IM, IP, or slow IV, 2
times daily for 4 to 5 days. Drug may be repeated after a gap of 2 days for another 4
to 5 days.
➢ Dog: 25 mg/kg (as 1% solution in 5% dextrose), SC, 4 times daily for 5 days
b. D-penicillamine
➢ It is an oral sulphydrylcontaining chelating agent
➢ The drug should be given on an empty stomach.
➢ It should not be used in cattle, horses or sheep. It is contraindicated when lead is still
present in the GI tract.

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➢ Dogs: 110 mg/kg, PO, daily in 3 to 4 divided doses for 2 weeks

➢ Supportive therapy like thiamine (Vit.B1), corticosteroids, osmotic diuretics and
Diazepam & barbiturates for seizure control.

4) COPPER (Cu) POISONING

- Cu is essential trace element which is required for haeme synthesis and Fe absorption.
- It also acts as cofactor for the functioning of the cellular enzyme such as tyrosinase,
cytocrome oxidase and peroxidase.
- It also involves in nerve conduction, connective tissue, CVS and immune system.
Sources:
- Acute toxicity is rare and it occurs through contamination of food and water or
excessive use of Cu in agriculture and veterinary practice.
- Excessive use of Cu as dietary supplement or accidental administration of excessive
amount of soluble Cu salt.
- Animal gets Cu from sprayed pasture having Cu level of 200 ppm.
- CuSO4 used as footbath, fungicides and anthelmentic. Indiscriminate and irrational
use leads to toxicity.
- Soil and plant fertilized with poultry litter or swine manure containing high copper.
Factors affecting toxicity:
- Sheep are most susceptible. It can accumulate more Cu in liver more readily than
other spp. Dogs and goats come next. Poultry is resistant.
- Low level of Mo and SO4 in diet increases chances of Cu toxicity.
Toxicokinetics:
- Absorption of Cu from GIT is relatively low and most of it gets eliminated in faeces.
- If it administered in form of sulphate around 5% gets absorbed from S.I. and
metabolic copper do not get absorbed from GIT.
- It is widely distributed in body as specially gets stored in liver.
- In liver, it combines with metallothionein and it remains in liver until its further
utilization.
- From hepatocytes it is transported to the peripheral tissue with the help of
ceruloplasmin for physiological function.
- 80% of absorbed Cu excreted in bile than faeces.
Toxicodynamics:
- Abnormal Cu accumulation in liver is responsible for toxicity.
- Accumulation progressively damage hepatocyte organelles leading to cellular
degeneration and necrosis.
- Excessive accumulation of copper inhibits essential metabolic enzymes. It also leads
to liver malfunction and initiates necrosis and inability of liver to excrete and store
more copper.
- Liver damage release large amount of copper and other oxidative substances in to
blood stream.
- Excess copper in blood oxidizes erythrocytes membrane causing massive erythrocyte/
RBC lysis, release large quantity of Hb, leading to haemolytic crisis.
- Excess Hb blocks renal tubules leading to renal tubular and glomerular necrosis.

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- Kidney becomes darken or bluish black in Cu poisoning known as Gun metal

kidney.
- In pig/ swine in addition to the mechanism observed in ruminants Cu also inhibits
absorption of Iron from GIT causing iron deficiency anemia.
Symptoms:
In acute toxicity:
- Severe gastroenteritis characterized by rapid onset of salivation
- Reduced feed consumption
- Abdominal pain
- Diarrhea with greenish tinge
- Dehydration followed by shock and death.
In chronic toxicity:
- Very common in sheep.
- Clinical signs in sheep and other ruminants are associated with hemolytic crisis
leading to acute anemia.
- Other symptoms include depression, sudden onset of weakness, trembling, anorexia,
excessive thirst, haemoglobinuria and jaundice.
- Death usually occurs in 1-4 days.
- If Cu intake is continuous then coagulation abnormalities are observed like petecheal
hemorrhage, blood in faeces (Melena) and epistaxis.
PM findings:
- Acute Cu poisoning: Gastroenteritis with erosion and ulceration in the stomach.
- Chronic Cu poisoning: Discoloring of tissues because of jaundice and
methemoglobinuria.
- Pale yellow liver
- Enlarged pulpy spleen
- Distended gall bladder and bluish black kidney (Gun metal kidney).
- Microscopic lesions include swollen, necrotic hepatocytes, periportal fibrosis, bile
duct proliferation and renal tubular necrosis.
Diagnosis:
- It is based on history, clinical signs, PM lesions and copper level in body fluid, faeces
and tissues.
- Presence of bluish green ingesta in the stomach and increased fecal level of Cu=
8000- 10000 ppm (8-10g/kg faeces).
- Increased Cu level in kidney > 15 ppm considered as case of acute copper poisoning.
- In chronic copper poisoning blood and liver Cu level are elevated during hemolytic
period.
- Blood level becomes 5 -20 µg/ml (Normal level is 1 µg/ml)
- Liver = >150 ppm.
- Serum biochemistry- increase billirubin, AST, LDH, SDH and arginase 3 – 6 weeks
prior to hemolytic crisis.
Treatment:
- It is usually unsuccessful.
- Specific therapy/ specific chelator like D- penicillamine

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- Dose: In sheep: 50 mg/kg b.w. orally for 6 days

- It can be given as single drug or combination with BAL. In Dog: 10-15 mg/kg b.w.
q12h, PO
- Ascorbic acid (Vitamin C): along with food as especially in dog to decrease
absorption of Cu and increase excretion. Dose: 0.5 – 1 g/day.
- Oral administration of Ammonium molybdate: Dose: 0.5 -1 mg/kg b.w./day
- Sodium sulphate: Dose: 6-20 mg/kg b.w./ day
- Orally effective in chronic Cu poisoning
- Oral zinc supplementation decrease absorption of Cu
- Dose in Dog: elemental zinc 5-10 mg/kg PO, 2 times daily
Supportive therapy:
- Vitamin E antioxidant
- Urinary alkalizers
- MO supplementation in sheep ration

5) MOLYBDENUM (Mo) POISONING (Peat scours/ Teart disease/ Molybdenosis)

➢ Molybdenum (Mo) is an essential trace element and a component of a number of
enzymes, including sulphite oxidase (metabolism of sulphur amino acids), xanthine
oxidase (oxidation of purines and pyrimidines and production of uric acid), and
aldehyde oxidase (oxidation of aldehydes).
➢ It is present in the earth's crest largely as molybdenum disulphide (MoS2) and is a
biogenic element of microorganisms, plants and animals.
Sources of toxicity
• Acidic soils, poorly drained soils, and those contaminated with mining waste also
contain high levels of molybdenum.
• Plants contains high Mo and low Cu (especially legume plants) may result in
molybdenosis.
• Excessive use of molybdenum containing fertilizers may occasionally result in high
molybdenum contents in soils and forages.
• Calves may be poisoned by milk from cows on high molybdenum diets.
Factors affecting toxicity
➢ Species: Cattle are the most susceptible species. Horses and pigs are not usually
affected.
➢ Age: Young animals are more susceptible than adult animals.
➢ Interactions: Toxicity of molybdenum increases when intake of copper is less. High
dietary sulphate increases Mo toxicosis by decreasing copper absorption.
➢ Form: Water soluble form of molybdenum (e.g. tetramolybdate) is more toxic
than water insoluble form (e.g. molybdenum disulfide).
➢ Types of plant : Legumes take up more of the element than other plant species.
➢ Season: High incidence are found during late summer and early autumn.
➢ Mo poisoning result due to inadequate Cu: Mo ratio in the soil, fodder and diet
[ideal ratio is 6:1, 2:1 to 3:1 is borderline and <2:1 is toxic]

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Toxicokinetics
➢ After oral administration, molybdenum compounds (except sulphides) are
absorbed readily from the intestine.
➢ In the blood, Mo is bound to plasma proteins and erythrocytes.
➢ The highest concentration is present in bones and liver, but liver does not store
molybdenum.
➢ Lower concentrations of Mo may be present in kidneys, spleen, heart and skeletal
muscles.
➢ It is eliminated very rapidly via the kidneys (>80%) and bile hence Mo usually
does not get stored in the body.
➢ High dietary sulphate increases excretion of Mo in the urine because it blocks the
reabsorption of molybdenum from the, renal tubules.
➢ Mo is also excreted in milk
Mechanism of action
➢ Molybdenum toxicosis results primarily due to copper deficiency induced by Mo
(secondary hypocuprosis).
➢ The interaction of copper, molybdenum and sulphate is complex
➢ Interaction of Mo and sulphides in the rumen gives rise to thiomolyhdates, which
decrease the availability of dietary Cu & also disturbs metabolism of tissue Cu &
inhibits Cu containing enzymes.
➢ Mo also promotes hepatic copper excretion by forming a copper-molybdate
complex that is readily excreted in urine causing a clinical copper deficiency.
➢ Copper deficiency ultimately causes deficiency of oxidases which leads to
decreased stability & strength of collagen in bones & elastin in major blood vessels
like aorta that leads to spontaneous rupture of major blood vessels.
➢ The decreased activity of tyrosinase that converts tyrosin to melanin interferes with
the production of melanine (cause leucoderma).
➢ It decreases integrity of RBCs.
➢ It decrease synthesis of phospholipids in the myelin sheaths that cover and protect
nerves that causes nerve damage and demyelination which is a important aspects of
enzootic ataxia and sway back observed in sheep.
Clinical signs
➢ In acute toxicity, clinical signs are prominent in ruminants. In cattle, diarrhoea occurs
8-10 days following access to pastures high in Mo which is characterised by
persistent, severe scouring making a parabola (shooting diarrhoea) and watery
faeces with unpleasant odour and full of gas bubbles (called as peat scours or
teart disease).
➢ Other signs are anorexia, excessive salivation, lachrymation, generalised weakness,
inability to stand, paresis and prolapsed third eyelid.
➢ Non-specific signs may include unthriftiness, anaemia (microcytic, hypochromic),
emaciation, loss of body weight, slower growth, joints pain, lameness, osteoporosis,
stiffness of legs with upright pastern and reluctance to get up.
➢ Young animals have deformed forelimbs. The hair coat is rough, dull and
depigmented.

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➢ Depigmentation is most noticeable in black animals and especially around eyes

called as spectacled eye
➢ Pica develops in sheep

Post-mortem findings
• Lesions are not specific.
• Enteritis, fluid filled intestine may be seen.
• Microscopically – degenerative changes in liver & kidney
• In lambs with enzootic ataxia or swayback, there is lysis of white matter of the
cerebrum and degeneration of motor tracts of the spinal cord. There is often
neuronal degeneration and demyelination.
Diagnosis
➢ Depends on clinical signs, lesions, circumstantial evidences (soil rich in Mo) and
response to therapy (diarrhoea stops within a few days of oral dosing with copper
sulphate).
➢ Confirmed by demonstrating abnormal concentration of molybdenum and copper
in blood
Blood: Mo> 0.1 ppm Cu<0.6 ppm
Liver: Mo> 5 ppm Cu <10 ppm
➢ The specimens for chemical examinations are feed, liver, kidney, urine, feed, bone &
hair.
Treatment
➢ For severe and subacute cases, copper glycinate is given @ 60 mg in calves & 120
mg in cattle S/C
➢ Copper sulphate (CuSO4) in diet or feed untill symptoms disappear @ 1-2 g/adult
cow/day
0.25 g/sheep/day/45 kg
➢ CuSO4 in salt licks @ 1-5%
➢ Pasture treatment with CuSO4

6) IRON (Fe) POISONING

Source:
- Major source of Fe are either through parenteral injection (excessive dose) of
preparation like iron-dextran, iron polysachharide or iron-sorbitol.
- Oral treatment with FeSO4, FeCl3, Ferrous glutamate, ferrous fumarate, ferrous
carbonate.
- Fe toxicity results from accidental ingestion of oral supplements or over dose.
Factors affecting toxicity:
- All animals are susceptible to Fe toxicity but it is commonly observed in baby pigs
- Usually in pigs toxicity is more severe with parenteral injection rather than oral.
- Vitamin E deficiency enhances Fe toxicity.

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Toxicokinetics:
- Fe is poorly absorbed from GIT and is depends upon level of Fe in body.
- A large dose of Fe damages the process of control of Fe absorption, excess Fe that
enters to circulation is most readily excreted due to the slow excretion process.
- Absorbed ferrous ion (Fe2+) gets oxidized to ferric ion (Fe3+) and it binds to
transferrin (which is β1- glycoprotein) present in blood and in this form it is distributed
throughout body.
- Excess Fe absorb over period of time gets stored in body in form of haemosiderin or
ferritin.
Toxicodynamics:
- Fe may cause a) corrosive toxicity, b) cellular toxicity or c) anaphylactoid
reaction.
- a) Corrosive toxicity: Fe causes direct damage to gastric mucosa. Damage to GI
cells leads to diarrhea and loss of electrolytes.
- b) Cellular toxicity: Large amount of free Fe in the circulation may cause damage to
critical cells in the liver, heart, kidney and lungs
- Absorption of excessive quantity of ingested Fe results into hepatotoxicity as a direct
irritant action on liver cells.
- Fe acts as a mitochondrial poison. It inhibits mitochondrial enzyme and cellular
respiration resulting in mitochondrial acidosis and cellular death.
- Free radicals production cause damage to cellular structures including lipids, nucleic
acid, protein and carbohydrate resulting in impairment of cellular function and
integrity. Excess Fe cause hypotension, CV collapse and shock.
- c) Anaphylactoid reaction: Parenteral Fe administration produces anaphylactoid
reactions due to release of histamine.
Symptoms of Fe toxicity:
Oral toxicity:
- Drowsiness, depression, vomiting and diarrhea (within 6 hrs) and upto 24 hrs- normal
- Again diarrhea starts with dehydration, shock and coma.
Parenteral toxicity:
- Three forms in baby pigs:
- Acute: Usually death occurs within 30 min to 6 hrs or peracute damage to muscle at
injection site. Affected piglet becomes weak, muscle tremors followed by convulsion.
- Subacute stage: Fe blocks body defence mechanism by affecting the phagocytic
cells. Due to this there are more chances of enteritis due to [Link] and death occurs in
2-4 days.
- Rare type of toxicity: Massive mobilization of calcium – calciphylaxis (vascular
calcification) is observed within several days of Fe injection, there is hard swelling at
injection site.
PM signs:
- Following oral administration lesions are mucosal necrosis, ulceration of GIT,
intestinal contents are fluidy and haemorrhagic.

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- Following parenteral administration lesions are pale skin and muscle oedema,
brownish black discoloration at injection site, degeneration at skeletal muscles,
haemorrhage in heart with necrosis in liver and kidney.
Diagnosis:
- Based on history and response to therapy
- 50-100% increase in serum iron level (normal 100-300 µg/dl)
Treatment:
- Specific antidote: Desferrioxamine/ Deferoxamine/ Iron chelator- which form non
toxic complex with iron and eliminate in urine.
- Dose: 15 mg/kg b.w./hr slow IV drip; 40 mg/kg, IM, q6h ; 1-2g (total) as 5% solution.
- Fast IV drip will produce hypotension and death.
- Oral administration of ascorbic acid helps in excretion of Fe.
- Supportive therapy includes oral administration of milk of magnesia (MgOH) to
precipitate iron.
- Fluid therapy can be given.
- Vit E as a supportive therapy.

7) ZINC (Zn) POISONING

- Zinc is essential element for mammals and birds.
- Zinc is component of metalloenzyme and it is required for growth, skeletal
development, collagen formation, feather development, skin health, wound healing
and reproductive performance.
Sources:
- Poisoning can occur by inhalation of industrial fumes which contain ZnO, ZnCl2,
ZnSO4.
- Consumption of feed mixture that contains high amount of Zn due to inappropriate
mixing.
- In farm animals, excessive zinc may enter through chewing of galvanized pipe, coins,
wire and licking of zinc coated containers.
- Drinking of rain water collected from galvanized iron roof.
- Chronic poisoning occur in animals living in proximity of factories Zinc processing
works “zinc ore roasting”
- Excessive use of zinc containing drugs i.e. ZnO, ZnCl2.
Factors affecting toxicity:
- Soluble salts (zinc chloride, sulphate, acetate) are more toxic than less soluble salts
(zinc carbonate, oxide).
- Ruminants, dogs and birds are more susceptible. Extremely toxic to birds.
- Zinc dectrease Cu, Fe absoption.
Toxicokinetics:
- 10-20% of total ingested zinc gets absorbed.
- Absorbed zinc gets bound to the plasma protein and is deposited in liver, kidney,
prostate, muscle and pancreas.
- Most of ingested zinc gets eliminated through faeces and small amount via bile, urine
& milk.

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21

Toxicodynamics:
- Corrosive and astringents action on GIT mucosa.
- Excessive zinc promotes deficiency of minerals and nutrients like copper and iron and
decrease haematopoiesis.
- High level of zinc inhibits catalase, acid phosphatase, acetyl cholinesterase, pepsin,
trypsin and –SH dependent amylase.
Clinical signs:
- Acute: painful local irritation, inflammation and corrosion of GI mucosa leading to
diarrhea which may be blood tinged, hypotension, vomiting.
- Damage to liver is manifested by jaundice (icterus) in visible mucous membranes-
cattle.
- Chronic: decreased milk production, decreased growth rate, fatigue.
- In pigs hind legs get weakened
- In foals lameness and stiffness at joints is more prominent sign.
- Death usually occurs after few months.
PM findings:
- Gastroenteritis
- Renal tubular necrosis, hepatocytic necrosis
- In pigs which are died due to chronic poisoning showed non specific degenerative
arthritis, osteoporosis, S/C haemorrhage.
Diagnosis:
- Based on history, clinical signs, PM lesions
- Confirmatory diagnosis by quantification of zinc in liver, feed, kidney, lung and hair.
- In liver normal 40-60 ppm, abnormal >60 ppm indicate Zn toxicity.
Treatment:
- Specific antidote – Calcium disodium EDTA @ 110 mg/kg/day in 5% dextrose, first
IV then SC OR
- D- Penicillamine- 110 mg/kg PO for 1-2 weeks
- Sodium carbonate which makes zinc insoluble (ZnCO3)
- Supportive Therapy: Tannic acid, egg albumin, emetics, laxatives

8) THALLIUM (Tl) POISONING

- Very toxic and most of the characteristics of it are similar to lead.
- Very commonly used in dye and glass industries for making optical lenses, imitation
jewellery
- Some insecticides, rodenticides also contain thallium
- Dogs are most susceptible to thallium poisoning
Toxicokinetics:
- Readily absorbed from GIT as well as skin, rapidly distributed throughout body.
- Highly concentrated in kidney.
- Kidney usually concentrates 15 times higher thallium than other tissues.
- Mainly excreted in bile

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22

Toxicodynamics:
- Exact mechanism is unclear
- It decreases activity of –SH containing enzymes like monoamine oxidase, succinic
dehydrogenase.
- It also inhibits sulphur containing micromolecules.
Signs:
- Appear after 1-3 days after ingestion.
- Signs are related to GIT, respiratory tract and nervous system
- Gastroenteritis, abdominal pain, dysponea, conjunctivitis, gingivitis, tremors and
seizures
- After few days, dermatitis characterized by alopecia, erythema and hyperkeratosis.
PM findings:
- Haemorrhagic gastroenteritis, inflamed respiratory mucosa, degenerative changes in
heart, kidney and liver
Diagnosis:
- Based on history, circumstantial evidences and toxicity signs
Treatment:
- Specific Antidote: Prussian blue which increase elimination of thallium from gut.
- Symptomatic treatment includes emetics, anti-diarrheal, gastric lavage, CNS
depressants and fluid therapy.

9) CADMIUM (Cd) POISONING

- Cd has become major environmental pollutant because of effluent from zinc, copper
and lead factories.
Sources:
- Contamination of soil and crops by the effluents of zinc, copper and lead using
industries.
- It is used in industry for the manufacturing of plastic, cadmium batteries, photocells
and rubber tires such factories contaminates environment.
- Cadmium added soil strongly absorb organic matter and uptake of Cd in plant
increase especially in leaf.
- Use of Cd containing fungicide like Cd chloride and Cd succinate on grasses.
- Excessive use of Cd chloride as feed supplements.
- Cigarette smoking is the major source of cadmium.
- 1 cigarette contains 1µg Cd [Out of that 30% goes to lungs, 70% goes to atmosphere
which is being inhaled by nonsmoker].
Factors affecting toxicity:
- Low level of dietary protein, zinc, calcium, iron enhances cadmium absorption from
GIT.
- Young animals absorb more Cd from GIT than adult.
- Cd is one of the most bioaccumulative poison.

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23

Toxicokinetics:
- Cadmium gets absorbed from GIT (upto 10%) and respiratory tract.
- Absorbed Cd binds to plasma protein and then goes to liver and kidney and stored
there.
- In liver it binds with glutathione and excreted in bile.
- It also binds to metallothionein and form complex i.e. Cd-metallothionein complex
which is taken up by kidney causing damage to proximal renal tubules
- Most of Cd gets excreted in faeces.
Toxicodynamics:
- Cadmium binds to the proteins. This reaction with protein, damages the mucous
membrane of GIT and respiratory tract.
- In the kidney Cd-metallothionein complex enters into lysosome and it is degraded to
aminoacid and Cd is released which damage the kidney tubules.
- Cd is stored in high quantity in testes cause testicular damage.
Clinical signs:
- Acute toxicity results from inhalation of Cd dust and fumes.
- Symptoms are irritation of respiratory tract, coughing, labored breathing, vomiting,
pulmonary oedema, bronchopneumonia
- Acute oral exposure: symptoms are GIT disorders in form of salivation, vomiting,
abdominal pain, spasm, ataxia and collapse.
- Chronic toxicity is more common. Symptoms are pulmonary emphysema, chronic
coughing, anemia, proteinuria, testicular retardation
- In birds ovaries become lossed and stops laying.
PM findings:
- Degenerative changes in testes, ovary, CNS and blood vessels.
Diagnosis:
- Based on history, clinical signs and circumstantial evidences.
- Confirmatory diagnosis based on quantification of Cd.
- Muscle: 0.1 ppm and visceral organs (kidney, liver, spleen): 0.5 ppm indicate toxicity.
Treatment:
- Chelation- No specific chelator
- CaNa2EDTA which decrease mortality in acute Cd poisoning
- D-penicillamine and dimercaprol are contraindicated in Cd poisoning because they
increase Cd concentration in the kidney and cause nephrotoxicity.
- Supportive therapy includes gastric lavage, administration of selenium (Selenium-Cd
complex protect testicular necrosis)
- In chronic toxicity feed supplementation with zinc, copper and iron give significant
protection.
- Ca and Cd are antagonist, so calcium suplement can help to remove cd.

Veterinary Toxicology / Metal Toxicity/CVSc&AH, Anand/2019

TOXICITY OF NON METALS
Department of Veterinary Pharmacology & Toxicology
Veterinary College, AAU, Anand-388001.

Non Metals i.e. Fluoride, Selenium, Nitrate & Nitrite, Common Salt, Urea, Sulphur and
Phosphorus.

1) FLUORIDE POISONING
Source of poisoning:
 Fluorine (F) is usually found in nature in the form of fluoride.
 Toxic quantities of fluorides containing in some feed supplements and mineral
mixtures (raw rock phosphates, superphosphates, defluorinated phosphates and
phosphatic lime stones).
 In certain areas the drinking water usually from deep wells contains high levels of
fluorides.
 Factory contamination also adds to increased fluorides in water. Sodium fluoride is
more toxic than calcium fluoride.

Factors affecting the toxicity:

 Chronic toxicity is seen in herbivores especially in dairy cows.
 Acute toxicity is rare and seen in dogs.
 Level of fluoride, duration of exposure, solubility of the ingested fluorides, age and
nutritional status of the animal alter the levels of toxicity.
 When solubility is higher, the toxicity is also higher.
 Young growing bone and teeth are more susceptible.

Toxicokinetics:
 Absorbed well from the gastrointestinal tract and distributed throughout the body.
 96-99% of the absorbed fluoride is incorporated into hydroxyapatite crystalline
structure of the bone. Bone is a natural sink for fluoride (like lead).
 Accumulation is proportional to the duration and rate of exposure.
 Fluoride is depleted slowly from the bones.
 Accumulation in skeleton is not of toxicological significance in foetal bone.

Toxicodynamics/Mechanism of toxicity:
 Excessive fluoride results in delayed and impaired mineralization of teeth and
skeleton.
 In the teeth, fluoride damages the ameloblasts and odontoblasts. This leads to
abnormalities in developing teeth.
 In fully developed teeth, enamel formation does not occur and this leads to rapid and
excessive wear of molars and incisors.
 Oxidation of organic material in the areas of wear results in brown or black
discolouration.
 In the bones fluorides disrupt osteogenesis, causes osteoporosis and remodelling with
production of abnormal bones (exostosis).

VPT (Veterinary Toxicology), Vet. College, Anand. Page 1

Clinical symptoms
 In acute cases the symptoms include excitement, clonic convulsions, bladder and
bowel incontinence, stiffness, weakness, weight loss, decreased milk production,
excessive salivation, nausea, vomiting, cardiac failure and death.
 Chronic fluoride poisoning is called fluorosis. Fluorosis is very common and occurs
mainly in two forms 1) skeletal/osteofluorosis and 2) dental fluorosis
 In chronic cases the symptoms include mottling (discolouration) and abrasion of teeth,
mottled and pitted enamel, unevenly worn teeth, apendicular lameness, unnatural
posture, generalized stiffness, cachexia, poor performance and dull hair coat. Lapping
of water indicates dental pain.
 Exostosis of long bone extremities which are painful. Lameness, stiffness, painful gait
and posture.

P.M. Lesions
 The teeth of affected animals will have periodic radiolucent areas.
 The affected bones will be enlarged and chalky white in colour with no luster & the
periosteal surface will be rough.
 Bone marrow cavity is diminished and shows gelatinous degeneration and aplastic
anaemia.

Treatment
 It includes oral administration of aluminium salts (aluminium sulphate or chloride),
calcium compounds (calcium carbonate or gluconate), milk and defluorinated
phosphates.

2) SELENIUM (Se) POISONING (Blind stagger or Alkali disease)

 Elemental selenium is insoluble in water and relatively non-toxic.
 Selenite and selenate are soluble in water and toxic.
 [Note: Small amount of Se is essential in diet; Se deficiency diseases such as white
muscle disease in cattle, exudative diathesis in chicks and liver necrosis in swine]

Sources:
 Plants have diverse tendencies to accumulate selenium.
 a) Obligate indicator plants require large amounts of selenium (100 – 15000 ppm)
for growth and survival. These plants can accumulate high concentrations of selenium
as water-soluble amino acid analogs of cysteine and methionine. Growth indicates the
presence of selenium in soil.
 Examples include Astralagus (locoweed) and Oonopsis (goldenweed).
 b) Facultative indicator plants absorb and tolerate large amounts of selenium (25-
100 ppm) if it is present in the soil, but they do not require selenium for growth.
 Examples include Aster, Acacia, Sideranthus and Atriplex (saltbrush).
 c) Non-accumulator plants may accumulate selenium if grown on seleniferous soils,
especially where selenium (1-25 ppm) has been brought to the soil surface, while
other plants cannot tolerate selenium and are stunted or killed by it. e.g. corn, wheat,
barley.

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 Plants containing high selenium are not palatable and eaten only when alternatives are
not available.
 Feed supplements, injectable drugs, industrial and commercial sources and seafood
are the other sources of selenium.
 Cattle, sheep and horses may graze selenium-containing plants. Swine and poultry
may develop toxicosis after consuming grains raised in seleniferous soil.
 Some of the medicated shampoos also contain selenium (Selenium sulphide shampoo
used in dogs).
 Industrial and commercial sources include photoelectric cells, glass and ceramics.
 Fish and shellfish can accumulate selenium that exists naturally in the ocean. But the
accumulation is not to a toxic level.
Toxicokinetics:
 At high concentrations naturally occurring seleno-amino acids and soluble selenium
salts are readily absorbed.
 Small intestine is the primary absorption site; no absorption takes place in the
stomach and rumen.
 It is readily distributed throughout the body. It crosses the placental barrier and also
enters into avian eggs causing embryo toxic effect.
 Selenium is metabolized both by reduction and methylation.
 Urine is the major route of excretion in monogastric animals.
 In Ruminants, a significant amount of selenium is excreted in the faeces.
Mechanism of toxicity:
 Selenium replaces sulphur in amino acids (cysteine and methionine), possibly
affecting some essential proteins. It results in synthesis of abnormal structural and
functional protein. i.e. hoof and hair defect in chronic selenosis.
 Glutathione depletion and lipid peroxidation are probable important factors in
toxicosis.
 Chronic selenosis depresses adenosine triphosphate formation possibly by inhibition
of sulphydryl enzymes.
 Tissue ascorbic acid (vitamin C) levels fall, possibly contributing to the vascular
damage caused by selenosis.
Clinical symptoms:
 Acute selenium toxicity
 Due to ingestion of obligate indicator plants clinical signs are noticed in 1-2 hours and
animals may die between 2 hours to 7 days.
 Symptoms include colic, bloat, dark watery diarrhoea, polyuria, fever, mydriasis,
uncertain gait, peculiar rooted-to-one-spot stance with head and ears lowered, fast and
weak pulse, pale and cyanotic mucous membrane, blood tinged froth from the
nostrils, prostration and death.
 Sub acute selenium toxicity (Blind staggers)
 Occurs due to ingestion of seleniferous plants and may develop after a relatively short
period.
 Poor appetite, staring coat, wander aimlessly, circling, disregarding obstacles and
stumbling over them or walking through them.
 Respiration and temperature are normal.
 In the second stage depression, in-coordination and fore leg weakness, animal goes
down on its knees.

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 In the third stage colic, subnormal temperature, emaciation, swollen eyelids, near
blindness.
 Salivation, lacrimation, severe abdominal pain, inability to swallow, complete
paralysis, collapse and death have also been reported.
 Chronic selenium toxicity (Alkali disease)
 The name alkali disease has been attributed to consumption of alkali waters.
 Chronic poisoning is caused by daily ingestion of cereals, grains and other forage
plants containing selenium.
 Lameness, hoof and hair abnormalities, partial blindness, paresis, in-coordination,
emaciation and lethargy may be noticed.
 Lameness is due to erosion of the articulate surface of long bones.
 Cracking of hoof & hoof begins to shed. Shedding is incomplete and old hoof fuses
with new hoof and form abnormally long rocker shaped hoof.
 In horses there will be loss of long hair from the mane and tail will occur.
 In cattle, there will be a rough coat, dullness and lack of vitality and emaciation with
deprived appetite.
Diagnosis
 Diagnosis is based on history, clinical signs and estimation of selenium in animal diet,
whole blood, liver and kidney.
Treatment
 Removal of the source, saline purgatives and high protein diet are said to be useful.
 Acetyl-cysteine a substitute for glutathione may be effective.
 In chronic selenium toxicity, addition of copper to the diet is useful to prevent
selenosis.
 Addition of inorganic arsenicals enhances biliary excretion of selenium and increasing
the dietary levels of sulphur containing proteins is also beneficial.
 One should not give vitamin E in selenium poisoning as it has synergistic action with
selenium.

3) NITRATES & NITRITE POISONING

 Nitrates (NO-3) & Nitrite (NO-2) poisoning is very common in ruminants, pigs, poultry
and birds.
 Nitrates get converted into nitrite which is responsible for toxicity.

Sources of Poisoning:
 Widespread use of nitrogenous fertilizers and herbicides increases nitrate contents in
the plants. i.e. Ammonium nitrate, calcium nitrate, urea and 2-4 D.
 Nitrogen in water occur as nitrate and it gets accumulated in ponds and wells due to
increased water-run off from the nitrate rich soil. Deep well water contains as high as
1700 – 3000 ppm of nitrate and consumption of such water leads to nitrite poisoning.
 Feeding of nitrate accumulator plants like cereal grasses (Oat, Millets and Rye),
maize, sunflower, sorghum and weeds (red root, wild sunflower, johnson grass,
jimson weed etc.).
 Animal waste, decaying organic matter, sewage, industrial affluent have high nitrate
content which is also responsible for increased soil and water nitrate content.

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 Certain plants have high uptake of nitrate especially in areas where soil is low in
Molybdenum, Sulphur and Phosphorus where there is less sunlight which affect the
activity of nitrate reducing enzymes.
 High nitrate content occurs in fast developing plants especially in hot and humid
weather. In drought condition immature plants accumulates more nitrates.

Factor affecting:
 Cattle are more affected spp because the ruminal microflora reduces nitrate to
ammonia (NH3) and this process nitrite is by product.
 Nitrite is 10 times more toxic than nitrates. In pigs usually nitrate poisoning is
common. Young pigs are more susceptible as compare to mature and adults.
 Soil deficient in molybdenum, sulphur or phosphorus increase nitrate intake by the
plants and soil deficient in copper, cobalt and manganese reduces nitrate intake by the
plants.
 Administration of drugs like monensin (anticoccidial) speeds up conversion of nitrate
to nitrite.

Toxicokinetics:
Following administration majority of the nitrate gets reduce to nitrite in GIT. The nitrite
gets absorbed quickly into the blood stream. The nitrate ion acts directly on the vascular
smooth muscles and enters easily into erythrocytes in exchange of chloride ions. Nitrite
ions also crosses placental barrier and is toxic to foetus. Nitrite converts haemoglobin to
met-haemoglobin (Met-Hb) and in this process it is getting converted to nitrate which is
excreted through urine. Met-haemoglobin has reduced O2 carrying capacity.

Toxicodynamics:
a) Mechanism of action of nitrite
Acute poisoning after nitrates or nitrites toxicity is due to nitrite ions. It has two
important actions.
1) Interaction with Hb: One mole of nitrite interacts with two moles of Hb and
converts it into Met-Hb by the process of oxidation. Ferrous (Fe+2) Hb gets
converted into Ferric (Fe+3) Hb. Met-haemoglobin has reduced O2 carrying
capacity. Under the normal conditions Met-Hb (1-2 %) converted back to Ferrous
Hb by the action of two enzymes. i.e. NAD dependent diaphorase-I and NADP
dependent diaphorase-II. If 20-40% Hb converts to Met-Hb than clinical sign of
anoxia is seen and 80-90 % than death of animal.
2) Effects on vascular smooth muscles: Nitrite ions directly relax vascular smooth
muscles (vasodilatation). There is an increased concentration of nitrite then it gets
converted into free radicals nitric oxides (NO) and this has direct effect on
vascular smooth muscles leading to relaxation. Ultimately it causes hypotension,
decrease cardiac output.
b) Mechanism of action of nitrate
Large dose of nitrate has effect similar to the excess common salt poisoning. There
may be death of animal before the animal exhibits the symptoms of nitrate poisoning
and most commonly GIT system is affected.

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Signs of nitrite poisoning: In most cases, they are acute in nature.
Acute Signs: Sign appear suddenly after administration within 30 minutes. During initial
stages there is rapid and weak heart beats, muscular tremors and weakness. Slowly as time
passes animal develop cyanotic mucus membrane. There is rapid and difficult breathing and
frequent micturation. Followed by violent respiratory efforts, open mouth breathing. Animal
then collapse and terminal convulsion. Death usually occurs within 24 hours.
Chronic Signs: Chronic toxicity is rare and only occurs when animal has exposure of nitrate
contenting forages for several weeks. The signs are anorexia, loss of body condition, decrease
milk production, abortion and dyspnoea.

PM Lesions: There is hemorrhagic gastroenteritis, congestions in internal organs and the

chocolate brown colour of blood. Tissues also stain brown and mucus membranes are
cyanotic.

Diagnosis: Based on history clinical signs, PM lesions and laboratory investigations.

Sign of respiratory distress without the involvements of lung causes impairment of O2
carrying capacity of blood. Sample can be collected and frozen except whole blood. The level
of Met-Hb formation in blood can be checked. The level of nitrite in various organs
especially in cattle (blood: 3.7 mg/100ml, Urine 1.5 mg/100ml, Liver 15.8 mg/100g, Kidney
9.5 mg/100g, Heart 12.4 mg/100g and water > 15000 ppm).

Treatment:
It should be highly specific. Methylene blue is to be administered @ 4mg/kg body wt, I/V. It
is used as 1% solution prepared in D/W or NSS. If lover dose is given repetition can be done
after 20-30 minutes.
Antidotal Mechanism: Methylene blue is reduce to leuco-methylene blue by NADPH2
dependent enzyme system. It reduce Met-Hb to Hb and Leuco-methylene blue is again
converted back to methylene blue as long as the NADPH2 is available.

Supportive therapy: Rumen lavage by cold water. Measures taken to reduce its absoption. O2
therapy, blood transfusion, saline purgatives. Provide ample water. Give balanced diet with
trace minerals.

4) COMMON SALT POISONING (WATER DEPRIVATION TOXICITY)

Common salts are naturally present in all living things. It is an essential component of
feed. It is added to the ration to increase palatability. It becomes toxic when excessive
quantities are ingested and intake of water is limited. If sufficient water is available salt
poisoning is less severe it is also known as water deprivation toxicity. Common salt
poisoning found in all animals, but most susceptible spp are pigs and chickens while sheep,
beef cattle and dairy cattle are less susceptible. It is more common in summer rather than
winter.

Toxicokinetics:
Sodium chloride gets rapidly absorbed and distributed throughout the body. If dietary intake
is more, kidney rapidly excretes excess salt as long as enough water is available. If animal is
unable to get water in response to increased thirst, excess sodium in blood produce toxicity.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 6

Toxicodynamics:
Presence of large concentration of salt in GIT act as saline purgative as it withdraws
water from surrounding tissue and produce diarrhoea. Salts get absorbed from the intestine
and result in hypertonicity of blood. Excess salt in blood shrinks capillary vascular
endothelium in brain, meninges and other organs. It leads to increased capillary permeability
and water escapes from blood to interstitial space. It causes oedema and is more predominant
in brain because of rich vascularity.
Excess sodium in CSF get diffused into the brain cells making it hypertonic than CSF.
Water enters into brain cells and cause over-hydration. Cerebral oedema and over-hydration
of brain cells are responsible for the nervous symptoms observed in salt poisoning.

Toxicity symptoms:
Signs are similar to encephalopathy. In pigs, early signs are increased thirst, pruritus,
salivation, serous nasal discharge, polyuria followed by anuria, dehydration and vomition.
Nervous signs include muscle tremors, shivering and seizures in later stage. Motor signs
include incoordination, ataxia and walking backward.
In cattle, characteristic signs are dragging of hind limbs while walking. Death occurs in few
hours to days.

PM lesions:
 In pigs, blood filled pin point ulcers in gastric mucosa, oedema of skeletal muscles,
hydropericardium and cerebral oedema. In poultry, congestion of liver and oedema of
various organs.
 Microscopic lesions include cerebro-vascular endothelial proliferation, neuronal
degeneration, renal tubular degeneration and distension of tubules in testis.

Diagnosis:
 Based on history of salt ingestion and relative water scarcity or deprivation.
 Based on symptoms and PM findings specially in pigs.
 Detection of sodium content in plasma/CSF, if > 150mEq/L then it is indicative of salt
poisoning. In cerebrum, if > 1800 ppm indicates common salt poisoning,
Treatment:
 No specific treatment is available & management of case.
 Provision of ample salt free fresh water.
 Remove source of salt.
 Symptomatic treatment like GIT sedatives and fluid therapy with isotonic solution.

5) UREA POISONING (RUMINAL ALKALOSIS):

Urea is used as a fertilizer on crop and pasture fields. It used as cheap source of non-
proteinous nitrogen (NPN) in ruminants ration. It is much better tolerated when mixed with
sufficient amount of other feeds.
Sources:
 Accidental ingestion of solid or liquid form of urea due to improper storage, feeding
of large quantity of NPN urea molasses feed to unaccustomed animals, improperly
mixed feed etc.
 If a cow is given 50 g urea first time then it is toxic. In poultry, litter system generates
large amount of ammonia which leads to urea toxicity.

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Toxicodynamics:
Urea gets converted to ammonia (NH3) by action of enzyme urease which is present
in rumen. Ammonia increases ruminal pH and it leads to Ruminal alkalosis. At pH > 9,
ammonia become unionized and gets readily absorbed.

Toxicity signs: In ruminants signs are salivation, restlessness, severe abdominal pain,
shivering, staggering, dyspnoea, animal dies after violent struggling and bellowing. In chicks,
ammonia causes conjunctivitis, corneal oedema, corneal ulcers, photophobia and anorexia.
These signs are observed when ammonia level reaches 170 ppm. Level of ammonia should
not get above 30 ppm under good managemental conditions.
PM lesions:
In Ruminants, haemorrhagic gastroenteritis, smell of ammonia on opening of rumen,
congestion and oedema of lungs, haemorrhage on kidney, epicardium and ruminal mucosa.
Diagnosis:
Based on history, symptoms, PM lesions and detection of ammonia in ruminal fluid
(>80mg/100ml) or in blood (2-4 mg/100ml).
Treatment:
 Acidifiers like 5% Acetic acid or Vinegar @ 2-3 L/100kg body wt diluted in cold
water and given through stomach tube.
 Symptomatic treatment includes purgatives, rumenotomy, ruminal lavage and I/V
glucose drips.

6) PHOSPHORUS (P) POISONING

 Phosphorus along with calcium is important for growth and maintenance of bone and
teeth. Inorganic phosphorus in form of phosphate is important for DNA and RNA. It
is also important in form of energy (ATP) and other cellular enzyme.
 Yellow or white phosphorous is toxic whereas red phosphorus is non toxic.
Sources:
 Accidental ingestion of phosphate fertilizers.
 Environmental contamination by factories manufacturing firework, gun powder,
smoke bombs, matchsticks etc.
 Use of phosphorus in hand grenades.
 Eating of rats died due to phosphate containing rodenticides.

Toxicokinetics:
White phosphorus is highly lipid-soluble and gets rapidly absorbed through GIT, also
gets rapidly absorbed following skin contamination.
Following absorption, phosphorus circulates and gets oxidized to phosphate, very small
portion of phosphate is eliminated in expired air and it imparts garlic-like smell. Vomitus of
GIT contents may be luminous and have the garlic-like odour. Phosphorus gets excreted in
the urine and expired air.

Toxicodynamics:
Phosphorus is strongly irritant and corrosive and causes necrosis of GIT mucosa.
Following absorption it acts as protoplasmic poison, it has direct cardiotoxic effect resulting
in cardio-vascular collapse. On dermal exposure, white phosphorus causes painful chemical
burn injury.

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Toxicity signs
Acute Toxicity: It can occur with white phosphorus and lead to quick death of animal after
exposure. Signs of oral exposure include GIT irritation, abdominal pain, profuse vomition,
severe diarrhea, garlic like odour from breath. Following symptoms, animal appears normal
for 3-4 days. Again animal shows symptoms of abdominal pain, vomition, jaundice then
animal again goes to terminal phase with depression, coma and death.
Signs of dermal exposure: Burn which are painful and slow to heal. Burns then turn into
necrotic area which looks like yellow in colour and gives garlic like smell. Absorption of
phosphorus from exposed area results in liver, heart and kidney damage.

Chronic Toxicity: The major typical clinical feature is necrosis of the jaw and it is called as
“Phossy Jaw”. Symptoms of Phossy jaw: toothache leading to extraction of tooth.

PM findings:
 Severe gastroenteritis.
 Fatty degeneration of liver, muscle and endothelium of blood vessel.
 Liver is enlarged, pale and yellowish.
 Spleen is small and atrophied. Carcass gives garlic odour.
Diagnosis:
 Based on history, clinical signs and lesions.
 Typical signs are garlic like odour, luminous of vomitus and other excreta.
 Hepatic enzymes and billirubin level gets elevated.

Treatment:
 No specific treatment is available.
 Gastric lavage with Potassium permanganate or 0.2% copper sulphate.
 Oral administration of activated charcoal, mineral oil to prevent its further absorption,
blood transfusion and fluid therapy.

7) SULPHUR (S) POISONING

Sulphur is found in sulphur containing amino acids like cysteine and methionine which are
required for polypeptide, protein and enzyme. It is also an important component of
coenzyme-A and glutathione.

Sources:
 Sulphur is widely used as fertilizer, insecticide and fungicide.
 Sulphur preparations are used for the treatment of ringworm and other dermal
infections.
 Farmer use sulphur as tonic to improve fur conditions.
 Sulphur is commonly used as part of process in various industries producing batteries,
detergent, gun powder, fireworks, match box and phosphate fertilizers.

Toxicokinetics:
Following oral administration, it gets absorbed either in form of amino acids or as
sulphides. Absorbed sulphate enters normal sulphate body pool and excess is excreted
through kidney.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 9

Toxicodynamics:
Following inhalation, sulphur has local effect on gut membrane causing laxative
effect, irritation on GI mucosa and abdominal pain. Sulphur is antagonist of copper,
potassium and calcium. Some of the adverse effects are observed due to antagonism of
essential metals.

Toxicity signs
 GIT effects are expressed in form of abdominal pain, diarrhea and anorexia.
 In ruminants, tympany with or without rectal spasm, ruminal hypomotility, staggering
gait and difficulty in getting up are observed.
 Neurological signs in ruminants include dullness, ataxia, mydriasis, abnormal
behaviour, tremors and convulsions.
 In horse, additional signs include sweating and jaundice. Inhalation of sulphur dust
causes irritation of eyes, nose, throat and lungs. Long term exposure causes
respiratory problems and inflammation of eyes.

PM findings:
Lesions are poorly characterized which include congestion, haemorrhage along with digestive
tract.
Diagnosis:
Based on history and clinical signs.
On PM examination, smell of Hydrogen sulphide (Rotten egg like) on opening of rumen
provide clue.
Treatment:
No specific treatment.
Symptomatic & supportive treatment is advisable. i.e. GIT sedatives and fluid therapy.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 10

TOXICOLOGY OF AGROCHEMICALS/ PESTICIDES

Pesticides are defined as "any substance or mixture of substances intended for

preventing, destroying, repelling or mitigating any pest".
In other words, pesticides are any chemical, physical or biological agents that
would kill or destroy unwanted plant or animal pests. Pesticides are one of the most
widely used agrochemicals of toxicological importance. Pesticides are used extensively
as acaricides/ ectoparasiticides in veterinary medicine to control insect pests of both the
animals and birds. Use of pesticides in animal husbandry improves the health and
productivity of animals and birds. Pesticide is a general term and insecticide is a class
of pesticides.

CLASSIFICATION OF THE PESTICIDES:

A) Insecticides: Used to kill insects
(I) Organochlorines: DDT, Aldrin, Dieldrin and Lindane.
(II) Organophosphates: Parathion, Malathion, Phosphate, Phosphonate and
Phosphoramidate.
(III) Carbamates: Carbaryl, Aldicarb and Propoxur
(IV) Pyrethrins and Pyrethroides: Deltametharin, Cypermethrin, Flumethrin,
Permethrin, Allethrin and Fenvalerate.
B) Herbicides or weedicides: Used to destroy undesirable plants/weeds.
e.g. Dinitrophenol, 2,4-D, 2,4,5-T, Paraquat and Atrazine.
C) Rodenticides: Used to destroy the rodent.
e.g. ANTU, Zinc Phosphide, Fluoroacetate, Warfarin and Red Squill.

SOURCES OF PESTICIDE POISONING:

The major sources of pesticide-poisoning are:
a) Accidental exposure:
 Ingestion of pesticide sprayed crops and drinking of water from paddy
fields treated with pesticide.
 Ingestion of pesticides contaminated concentrate feeds.
 Feeding or watering of animals in insecticide contaminated containers.
 Improper disposal of empty insecticide containers.
 Licking the walls and pillars by the animals sprayed with insecticides.
 Improper and indiscriminate use of insecticides.
 Contamination of ponds, lakes, rivers etc. due to spray of insecticides or
discharge of effluents from the pesticide industries.
b) Intentional exposure:
 Residues of pesticides in agricultural products e.g. grains, pulses,
vegetables, fruits etc.
 Residues of insecticides in animal products like meat, milk and eggs.
 Consumption of insecticide for committing suicide in human beings.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 11

c) Occupational exposure:
 Workers of pesticide manufacturing industries are constantly exposed to
the
hazards of pesticides.
 Faulty spraying of pesticides by unskilled workers.

(A) INSECTICIDES:
Insecticides are a heterogeneous group of chemicals. Chemicals used as insecticides
are not highly selective and result in poisoning in man and domestic animals. It is
extremely important to be aware of the potential danger of these chemicals to man and
domestic animals due to their indiscriminate and improper use. They are commonly
used to control ectoparasites of domestic animals, to control certain vector borne
diseases and as anthelrnintics in livestock. Most insecticides affect the nervous system
of insects but they also possess some activity against the mammalian nervous system,
their neurotoxic effects in man and animals are often prominent.

(I) ORGANOCHLORINE INSECTICIDES/ CHLORINATED HYDROCARBONS

The organochlorines are the first generation insecticides also known as
chlorinated hydrocarbons. They are mainly used as contact insecticides and
ectoparasiticides.e.g. DDT, Aldrin, Dieldrin and Lindane.
Sources of poisoning:
 Ingestion of organochlorine contaminated feeds and water by the animals.
 Inhalation or absorption from the skin during topical application as
ectoparasiticides.
Toxicokinetics:
They are water insoluble but soluble in oil and organic solvents. These are
rapidly absorbed from the oily preparations and are capable of penetrating the intact
skin when applied in oily solution or emulsion. All the compounds, in powder form,
can easily penetrate the cuticle of insects compared to mammalian skin and intestinal
mucosa which explains its greater toxicity to insects than in mammals. Except
methoxychlor, other organochlorine insecticides are stored in the body fat. However,
none of these agents are known to accumulate in other vital organs.
Toxicodynamics:
The chlorinated hydrocarbons are neuropoison. By virtue of their high lipid
solubility, these agents can enter the neural membrane with ease and interfere with
normal functioning of the nerve membrane sodium channels. They act by (1) reducing
the potassium transport through pores; (2) inactivating sodium channel closure; (3)
inhibiting Na+-K+ ATPases and Ca++-Mg++ ATPases and (4) inhibiting calmodulin-
Ca++ binding with release of neurotransmitter.
Clinical symptoms:
Initial stimulation of CNS followed by depression and death due to respiratory
failure. Grinding of teeth, difficult respiration, snapping of the eyelids and frequent

VPT (Veterinary Toxicology), Vet. College, Anand. Page 12

urination. Other signs include walking backwards, wall climbing, aimless jumping
and violent frenzied behaviour.
Behavioural changes involve initial anxiety, aggressiveness, abnormal
'posturing and madness syndrome. Neurological symptoms involve hypersensitivity to
external stimuli, twitching of the facial and eyelid muscles, spasm and twitching of
the fore- and hind quarter muscles and hyperthermia. Vomiting, marked salivation,
mydriasis, diarrhoea and micturation may also be observed.

Post-mortem lesions: No specific lesions in the nervous system. However, acute

aldrin poisoning may cause hepatitis and acute tubular nephrosis. Chronic DDT
toxicoses may produce focal centrilobular necrosis of the liver.
Diagnosis: Based on:
 History of exposure to the insecticide.
 Clinical symptoms and post-mortem lesions.
 Analysis of feeds and biological samples like liver and kidneys from dead
animals, blood and milk samples from living animals for the presence of
organochlorine compounds.
Treatment: No specific antidote is available. Treatment is only symptomatic and
supportive.
 Remove the source of poisoning at once.
 Administration of non-oily purgatives.

(II) ORGANOPHOSPHOROUS INSECTICIDES

Organophosphorous insecticides (OPIs) compounds are preferred among
various groups of insecticides due to their high selectivity, low toxicity in mammals
and their rapid degradation in animal body and ecosystem. With indiscriminate use of
these compounds, several cases of poisoning frequently occur in man, domestic
animals and wild life. OPIs have comparatively low toxicity in mammals than in
insects.
More than 30,000 different organophosphate compounds have been tested for
insecticidal activity so far. Products like diazinon, dimethoate and malathion possess
toxicity equivalent to that of organochlorine compounds in mammals. Some less toxic
ones like coumaphos, fenchlorvos and trichlorphon have been used as insecticides.
Other compounds like dichlorvos and haloxon are being used as anthelmintics.

Further, OPIs are categorised into two broad groups on the basis of their activity:
a) Direct acting OPls: These compounds act by directly inhibiting the cholinesterase
enzyme. e.g. dichlorvos, fenchlorvos, trichlorfon and chlorpyriphos.
b) Indirectly acting OPIs: These insecticides as such are inactive but are
biotransformed in the body to toxic metabolites which inhibit cholinesterase enzymes.
e.g. Malathion, Parathion and their active metabolites are Malaoxon and Paraoxon.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 13

Toxicodynamics:
The OPIs causes toxicity by inhibiting irreversible acetylcholinesterase, the
enzyme which is responsible for hydrolysis of acetylcholine to acetic acid and
choline, released from nerve endings.
Toxicokinetics:
OPls are highly lipid soluble and are rapidly absorbed by all routes including
gastrointestinal tract, skin, mucous membranes and lungs. The extent of absorption is
more if these are applied in organic solvents. The metabolism and excretion of OPls is
a very complex process and it is dependent on chemical nature of the compound,
route of entry and the species of animals involved. On reaching the tissues, the
directly acting OPls are rapidly hydrolysed enzymatically while exerting a direct
inhibitory action on cholinesterase. The indirectly acting OPls inhibit cholinesterase
in a similar manner after conversion into their active metabolites. OPIs are hydrolysed
in the body by a group of enzymes called phosphoryl phosphatases. These enzymes
are widely distributed in plasma and various tissues and are not inhibited by
organophosphorous compounds. Many OPIs are excreted in milk, urine and bile.
Some insecticides and their metabolites can cross the placenta and inhibit the foetal
AChE enzyme, producing toxicity to the foetus.
Clinical signs:
Various types of symptoms in animals are as follows:
 Muscarinic symptoms include bronchoconstriction and increased bronchial
secretions, hypersalivation with drooling of watery saliva, lacrimation, excessive
sweating, increased gastrointestinal tone, frequent and involuntary urination and
defecation, diarrhoea, nausea, vomition, abdominal cramps, bradycardia,
pupillary constriction (miosis) etc.
 Nicotinic symptoms include muscular weakness, twitching, cramps, tremors and
atrophy. Weakness of the muscles of respiration results into dyspnoea and
cyanosis.
 CNS symptoms include restlessness, convulsions, ataxia, depression of
respiratory and circulatory centres leading to cardiac and respiratory arrest,
tremors and coma. Death in OPI poisoning results from asphyxia due to
respiratory failure.
 Delayed neuropathy: The delayed neurotoxic effects of OPIs can result from
single toxic dose, the onset of neuropathy is generally delayed. The inhibition of
neurotoxic esterases (NTE) has been found responsible for the
organophosphorous induced delayed neuropathy (OPIDN).
Post-mortem lesions: No characteristic lesions of OPIs poisoning, however, some of
the common lesions are:
 Haemorrhagic gastroenteritis.
 Pulmonary oedema.
 Degenerative changes in liver and kidney.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 14

Diagnosis: Exposure to OPls can be diagnosed on the basis of following:
 History and circumstantial evidences.
 Symptomatic evidence.

Differential Diagnosis:-
Signs/Symptoms Organophosphate Organochlorines Insecticides (OCIs)
Insecticides (OPIs)
Salivation Watery & fall drop by drop Frothy & it sticks to nose, lips muzzle
and mouth
Pupil size Miosis (constriction) Normal
Body temperature Hypothermia Hyperthermia
Animals running Straight direction Moves in circle
Abnormal posture No Specific Posture Ophisthotonus, head between fore limbs
& animal continuously licking of skin.

Treatment: Treatment of OPls poisoning in man, domestic and wild animals should be
aimed at:
 To abolish the muscarinic effects due to excess of acetylcholine.
 To regenerate the inactivated enzyme.
Atropine sulphate at the dose rate of 0.2-0.5 mg/kg. Atropine is a physiological
antidote to OPI poisoning, is a competitive antagonist of ACh for muscarinic receptors.
Use of oxime as AChE reactivators such as Diacetyl monoxime (DAM), 2-pyridine
aldoxime methiodide (2-PAM) and obidoxime, which reactivate the phosphorylated
AChE enzyme and greatly accelerate clinical recovery. DAM is inexpensive and freely
available, is preferred over 2-PAM which is very expensive. 2-PAM and DAM are
administered at the dose rate of 30 mg/kg as 6 per cent solution in normal saline
intravenously or intramuscularly.

(III) CARBAMATE INSECTICIDES

Carbamares are not broad spectrum insecticides and these show erratic patterns of
selectivity to insects. Because of extreme toxicity they are recommended only for limited
use. They are used for the control of ectoparasites in both large and small animals.
Carbaryl is the most widely used carbamate to control of ectoparasites. e.g. Carbaryl,
Aldicarb and Propoxur.
Toxicokinetics: Carbamates are well absorbed through skin, lungs and gastrointestinal
tract and are widely distributed in tissues. Metabolism of carbamates by hepatic
microsomes is quite complex yielding several unidentified products. They get rapidly
metabolised and excreted in urine mainly as sulphate or glucuronide conjugates within 24
hours. A small amount is also eliminated via faeces and milk. Unlike the OPls most of the
carbamates produce low dermal toxicity.
Toxicodynamics: Carbamates are potent and reversible inhibitors of acetylcholinesterase
enzyme.
VPT (Veterinary Toxicology), Vet. College, Anand. Page 15
Clinical signs:
Symptoms of acute poisoning are salivation, lacrimation, miosis, convulsions and
death. Chronic toxicity produces signs of neuromuscular type which are characterized by
incoordination, ataxia and recumbency but there is no demyelination or damage to nerves.
Post mortem lesions: The post-mortem findings in acute poisoning are usually limited
to congestion and oedema of lungs, liver and kidneys and petechial haemorrhage of
gastric mucosa. Neuromuscular lesions are found in chronic poisoning.
Diagnosis: Based on history and the response of the animals to atropine therapy.
Treatment:
 Carbamate poisoning is treated by administration of atropine sulphate @ 0.2-0.5
mg/kg.
 Diuretics such as hydrochlorthiazide are helpful.
 Administration of oxime reactivators is contraindicated since they aggravate the
toxicity of carbamates.

(IV) SYNTHETIC PYRETHROIDS

Pyrethrins are natural insecticides obtained from the flowers of Chrysanthemum
roseum which possess potential insecticidal properties without mammalian toxicity potential.
Modification of the chemical structures of the natural pyrethrins was attempted to develop a
series of synthetic pyrethroids with improved physical and chemical properties and greater
biological activity. Pyrethrin -1 contains all the basic features for good insecticidal activity.
Synthetic pyrethroids are safer insecticide compare to organochlorine and
organophosphorous insecticides
e.g. Deltamethrin, Cypermethrin, Permethrin, Flumethrin, Allethrin, Fenvalerate etc.
Sources of poisoning:
 Ingestion of pesticide contaminated feeds or water.
 Dermal absorption from topical application such as spray or pour- on to control
external parasites.
Toxicodynamics: The synthetic pyrethroids are neuropoisons. The main target of
action is the nerve membrane sodium channels.
Clinical signs:
Restlessness, incoordination, hyperactivity, tremors, paralysis, aggressive behaviour
and hypersensitivity to external stimuli. In large animals, fenvalerate caused restlessness,
frothing of mouth, dyspnoea, erection of ear and tail, mydriasis, regurgitation of ruminal
contents, incoordination, tremors, clonic convulsions and recumbency. Deltamethrin spray
causes hypersalivation, lacrimation, mucoid nasal discharge, excitement, incoordination,
extension of limbs, anorexia and alopecia in buffalo calves. Pyrethroids are also known to
cause contact dermatitis.
Diagnosis: Based on
 History of exposure to synthetic pyrethroids.
 Clinical signs exhibited by the poisoned animals.

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Treatment: There is no specific treatment. Following general and supportive line of
treatment may be followed:
 Removal of source: wash the animal if the route of exposure is through skin.
 Emetic: Apomorphine @ 0.1 mg/kg, I/M in dogs.
 Adsorbents: Activated charcoal @ 2g/kg.
 Purgative: Magnesium sulfate @ 5g/kg as 10% solution.
 CNS depressants: Diazepam @ 0.2-2.0 mg/kg IV.

(B) HERBICIDES
Herbicides are any compound used to destroy undesirable plants/weeds. Herbicides
defined as any compound that have the potential of either killing or damaging unwanted plants
or weeds and are employed for the elimination of such plants or parts of a plant. The
biochemical differences in plants make it possible to design herbicides that have selective
toxicity potential against various species of plants with no deleterious effects on the crops.

CLASSIFICATION:
Herbicides classify to following groups on the basis of their chemical nature.
a) Dinitro compounds e.g. Dinitro ortho cresol (DNOC), Dinitrophenol etc.
b) Phenoxyacetic acids e.g. 2,4-D, 2,4,5- T etc.
c) Bipyridinium compounds e.g. Diquat, Paraquat etc.
d) Heterocyclic compounds or Triazenes e.g. Atrazine, Propazine, Simazine etc .
e) Chloroaliphatic acids e.g. Sodium chloroacetate, Sodium trichloroacetate etc. \
f) Substituted ureas e.g. Monouron, Diuron etc.
g) Substituted dinitroanilines e.g. Pendimethalin etc.

a) Dinitro compounds: Many dinitro compounds are used as herbicides. The commonly
employed ones are dinitro ortho cresol (DNOC) and dinitrophenol.
Sources of poisoning:
 Accidental ingestion of DNOC-sprayed foliage by animals
 Licking of empty containers by curious animals.
Toxicodynamics: Dinitro compounds act by interfering with electron transport chain of
energy metabolism. They uncouple the oxidative phosphorylation and convert all the cellular
energy in the form of heat producing severe hyperthermia. In ruminants, the ruminal
microflora reduces the dinitro compounds to diamine metabolites which induce
methaemoglobinemia.
Post mortem lesions: Rapid onset of rigor mortis. The dinitrophenol imparts a yellowish
green colour to tissues and urine (mild jaundice). Dark blood, gastroenteritis,
hyperkeratosis of skin and hyperplasia of urinary bladder mucosa may also be recorded.
Diagnosis:
 History of exposure to dinitro compounds.
 Clinical symptoms.
 Post mortem lesions.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 17

Treatment: No specific treatment or antidote available.
 Wash with soap and water if the source of poisoning is through skin contact.
 Keep the affected animal in cool and calm place. To control hyperthermia, use cold
bath or ice-water sponging. Use of antipyretics is contraindicated.
 Saline purgatives or gastric lavage.
 Fluid and other supportive therapy.

b) Phenoxyacetic acids:
The most commonly used chlorophenoxyacetic acids are 2,4-dichloro- phenoxyacetic
acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Both these agents are relatively
harmless to mammals.

Sources of poisoning:
 Accidental ingestion of herbicide itself.
 Ingestion of poisonous plants which have been treated with phenoxyacetic acids.
Toxicodynamics: The exact mechanism of toxicosis of phenoxy acetic acids is not precisely
known. However, they are known to produce reproductive toxicity in cattle and hepato-
carcinorna in laboratory animals.
Clinical signs: Anorexia, ruminal atony, weight loss, occasional diarrhoea, depression,
unthriftiness and muscular weakness of hind limbs may be observed. Abortion,
irregular oestrus, anoestrus and ovarian atrophy may be recorded in cattle.
Treatment: No specific antidote is available. Symptomatic and supportive therapies
include administration of diuretics and liver protectants.

c) Bipyridinium compounds:
Paraquat and Diquat are rapidly acting broad spectrum contact herbicides which are
extensively used in agriculture for preharvest of cotton and potatoes and weed control.
Bipyridinium herbicides are highly toxic compounds.
Sources of poisoning:
 Accidental poisoning due to direct ingestion of the compound or consumption of
freshly treated vegetation.
 Malicious poisoning- principal targets are the dogs.
Toxicodynamics: The bipyridinium compounds are caustic and irritant agents which cause
ulceration and necrosis of the skin and mucous membranes in dogs, pigs and man. They also
cause progressive irreversible pulmonary fibrosis.
Clinical signs: Clinical signs are seen after three days of exposure to paraquat. Symptoms of
intoxication are emesis, anorexia, abdominal pain, dyspnoea, jaundice and CNS depression.
If the affected animals survive for several days, animal may exhibit dehydration, cyanosis,
tachycardia, uremia, moist rales, pulmonary oedema and emphysema.
Post-mortem lesions: Pulmonary congestion, oedema and haernorrhages, progressive intra-
alveolar fibrosis, atelectasis, erosions and ulceration of buccal and pharyngeal tissues,
haemorrhagic gastritis and congestion of liver, kidney and spleen.

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Diagnosis:
 History of exposure to bipyridinium herbicides.
 Clinical symptoms.
 Post-mortem lesions.
 Analysis of the urine, suspected baits or the feeding material.
Treatment: No specific treatment for diquat or paraquat poisoning. Symptomatic and
supportive treatment includes:
 Check further absorption by giving emetics or gastric lavage or oral adsorbents
(activated charcoal) followed by saline purgatives.
 IV fluids and diuretics.
 Tranquilizers and sedatives.
 Vitamin A, C and E have some beneficial effect.
 Corticosteroids
 Biochemical antagonists like ascorbic acid, acetylcysteine, super oxide dismutase etc.

d) Heterocyclic compounds (Triazenes):

Triazenes include atrazine, simazine, propazine and aminotriazole. This group has a
very low mammalian toxicity potential. Atrazine is the most widely used and selective
herbicide for crops likes maize, sorghum, sugarcane, pineapple etc. The mechanism by
which these agents produce toxicity is not well understood.
Clinical signs: Weakness, hypersalivation, ataxia and posterior paralysis appear three weeks
after ingestion of the compound. Pulmonary oedema and severe gastric and intestinal
haemorrhages also observed.
Diagnosis: Based on the history of exposure and clinical signs.
Treatment: No specific antidote. Provide symptomatic and supportive treatment.

e) Chloroaliphatic acids:
The most commonly used compounds are sodium chloroacetate and sodium trichloroacetate.
These agents are relatively harmless.
The source of poisoning is accidental ingestion. Cattle, sheep and goats are frequently
affected animals.
Clinical signs: Commonly observed clinical signs are anorexia, diarrhea and mild cyanosis.
Treatment: No specific antidote. Symptomatic and supportive treatment may be provided.
The animals may recover spontaneously even without any treatment.

f) Substituted ureas:
Monouron and diuron are the most commonly used substituted ureas. They have low
toxicity potential. Poisoning with these agents is rare.
Clinical signs: Anorexia, abnormal gait, excitability followed by depression, occasional
respiratory difficulties, haematuria and hypersalivation may be noted.
Post-mortem lesions: They are non-specific. However, congestion of GIT, liver, kidneys
and haemorrhages in the heart and lungs may be seen.

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Treatment: No specific treatment is available. Provide symptomatic and supportive
treatment.

g) Substituted dinitroaniline compounds:

Pendimethalin have a broad spectrum weedicide activity and low mammalian toxicity.
Clinical signs: Cattle, sheep, goats and dogs are sometimes affected. General signs of
toxicity are anorexia, tympanism and diarrhea.
Treatment: Generally, prognosis is good; no specific treatment is available. Symptomatic
and supportive treatment is provided.

(C) RODENTICIDES
Rodenticides are agents which destroy the rodents. Rodents such as black rats (Rattus
rattus), mice (Mus musculus), squirrels etc. can consume substantial quantities of pre-harvest,
post-harvest and stored grains, pulses, vegetables and fruits. They also render the foodstuffs
unfit for consumption by soiling and contaminating with urine, faeces and pathogenic
microorganisms which are capable of infecting other animals and man.
e.g. Alpha-naphthyl thiourea (ANTU), warfarin, zinc phosphide, fluoroacetate, red squill etc.

1) Alpha naphthyl thiourea (ANTU):

ANTU is relatively selective rodenticide. It is toxic to the rats but harmless to human
beings.
Sources of poisoning: Accidental ingestion of baits intended for target rodents. Primarily
affected animals are the dogs and cats.
Toxicodynamics: ANTU interferes with effective uptake of O2 from pulmonary alveoli by
producing extensive oedema of the lungs due to increased capillary permeability and seepage
of fluid into the airways. This leads to formation of froth which further blocks the air passage
and virtually the poisoned animal drowns in its own fluids.
Clinical signs: Vomiting, dyspnoea, cyanosis, rales, tachycardia, anorexia, incoordination,
cough, asphyxiation, coma, clonic convulsions and death.
Post-mortem lesions: Cyanosis, dark coloured arterial blood, heavy and oedematous lungs,
presence of blood-tinged fluid and froth in the bronchi, hydrothorax and hyperemic tracheal,
bronchial and gastric mucosa, liver and kidneys etc.
Diagnosis:
 History of employing ANTU as baits.
 Clinical symptoms.
 Post-mortem lesions.
Treatment:
 Emetics or gastric lavage.
 Sedatives like barbiturates.
 Oxygen under positive pressure.
 Competitive ANTU antagonist, 1-ethyl-1-phenyl thiourea may reverse ANTU
toxicosis.

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 Alpha adrenoceptor antagonists to dilate pulmonary vessels.
 Osmotic diuretics (50% glucose or mannitol) to reduce the pulmonary oedema.

2) Warfarin:
Warfarin isolated from moldy sweet clover and its analogues are anticoagulant
rodenticides. The warfarins are readily inactivated by cytochrome P450 enzymes of the
liver. Therefore, repeated dosing for several days is recommended.
Sources of poisoning: Ingestion of residues of the rodenticides or baits intended for target
rodents. Pigs, dogs and cats often ingest warfarin poisoned dead rats or mice.
Toxycodynamics: Warfarin interferes with normal function of vitamin K and causes
coagulation defects characterized by decreased blood concentrations of coagulation
proteins - factor II, VII, IX and X. The decreased coagulation factors cause massive internal
haemorrhages. The onset time is 2-5 days and the affected animal dies due to tissue hypoxia.
Clinical signs: After ingestion of warfarins over a period of 2-5 days, the affected animals
may exhibit signs of haemorrhages of gum, epistaxis, massive internal haemorrhages, blood
discharge from body orifices, haematomas under the skin and at joints, dyspnoea, weakness,
shock and death.
Post-mortem lesions: Massive internal haemorrhages, blood in the GIT, thorax, joints and
pericardium.
Diagnosis:
 History.
 Clinical signs.
 Post-mortem lesions.
Treatment:
 Injection Vitamin K1 @ 5 mg/kg, slow IV in dogs and cats. Repeat for 2 days by I/M
route. In large animals @ 0.5-1.0 mg/kg by slow IV followed by oral vitamin K
administered daily for 4-6 days.
 Provide clotting factors by whole blood or plasma transfusion @ 20 ml/kg or 9 mllkg
body weight, respectively.
 Sedatives or tranquilizers.
 Artificial respiration.
The rationale of giving vitamin K in warfarin poisoning is that vitamin K is
biotransformed into vitamin K epoxide in the liver which is reduced by NADH to vitamin
K hydroquinone. This vitamin K hydroquinone accelerates the synthesis of prothrombin.

3) Zinc phosphide: Zinc phosphide (Zn3P2) is commonly used rodenticide for destroying
rats, mice, squirrels and dogs. This compound is widely employed in the developing
countries because it is the cheapest and quite effective rodenticide.
Sources of poisoning:
 Baits intended for target rodents may be eaten by other animals or birds.
 Malicious poisoning, particularly to kill dogs and cats.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 21

Toxicodynamics: Zn3P2 + H2O Zn++ + PH3
Zinc phosphide is directly irritant to gut and produces severe
gastroenteritis. Acute zinc phosphide toxicosis is neither due to zinc nor phosphorus. The
zinc phosphide liberates phosphine (PH3) in the stomach following a hydrolytic reaction
with water in the GIT. Absorbed phosphine is responsible for development of widespread
cellular toxicity with necrosis of the GIT, liver and kidneys.
Clinical signs: Anorexia, lethargy, increased rate and depth of respiration, abdominal pain,
bloat, ataxia, weakness, dyspnoea, gasping, convulsions, coma and death in 4-48 hours.
Post-mortem lesions: Pulmonary congestion and oedema, subpleural haemorrhages,
congestion of liver and kidneys and gastroenteritis. Acetylene odour detected in stomach.
Diagnosis:
 History.
 Clinical signs.
 Post-mortem lesions.
Treatment: No specific treatment. Symptomatic and supportive treatment given.
 Gastric lavage with 5% sodium bicarbonate.
 Anticonvulsants and treatment for shock

4) Fluoroacetate:
Fluoroacetate as such is non-toxic but becomes highly toxic after its metabolic
conversion in the body to fluorocitrate. Sodium fluoroacetate is commonly used rodenticide.
This compound is extremely toxic and its LD50 value is 0.22 mg/kg in rats.

Toxicodynamics: Fluoroacetate Fluorocitrate (Toxic)

Fluorocitrate then competes with citrate for the active site of Kreb's cycle enzyme
aconitase. This results in inhibition of aconitase leading to slowing of the Kreb's cycle and
decreasing cellular respiration. The brain and heart functions are most severely affected.

Clinical signs: Appear within 30 minutes to 2 hours include CNS excitation, restlessness,
vomiting, diarrhoea, urination, hyperirritability, hypermotility, barking, frothing at mouth,
terminal coma, gasping and death within 2-12 hours in dogs and guinea pigs. In horses,
cattle, sheep and goats show colic, unrest, trembling, staggering, cardiac arrythmias,
tachycardia, terminal ventricular fibrillation and death. Both CNS and cardiac signs are
observed in swine, cats and hamsters.
Diagnosis:
 History of accidental ingestion of fluoroacetate bait.
 Clinical signs.
Treatment: No specific antidote for fluoroacetate poisoning. Symptomatic treatment
provided.
 Barbiturates or benzodiazepines to control convulsions.
 Glycerol monoacetate @ 0.1-0.5 mg/kg, I/M.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 22

5) Red squill:
Red squill is obtained from the plant Urginea maritima (sea onion). Red
squill contains a cardiac glycoside-scilliroside. This compound is comparatively one of
the safest rodenticide as it is non-toxic to poultry and causes emesis in animals.

Clinical signs: Small doses of red squill cause convulsions and higher doses produce cardiac
arrest. In livestock, hyperaesthesia and incoordination were observed.
Post-mortem lesions: Gastritis and enteritis, swelling and congestion of kidneys, liver,
lungs, mesenteric vessels and myocardium.
Diagnosis:
 History.
 Clinical signs.
 Post-mortem lesions.
Treatment: No specific treatment. Provide symptomatic and supportive treatment.

@@@@@@

Classification of Mycotoxins :

Sr. No. Class of Mycotoxins Examples

1 Hepatotoxic Mycotoxins Aflatoxins, Rubratoxins, Sporidesmin

2 Nephrotoxic Mycotoxins Ochratoxin, Citrinin

3 Oestrogenic Mycotoxins Zearalenone (F-2 Toxin)

4 Cytotoxic Mycotoxins Trichothecenes

5 Neurotoxic Mycotoxins Penitrem A

6 Miscellaneous Mycotoxins Ergot poisning, Fescue

VPT (Veterinary Toxicology), Vet. College, Anand. Page 23

TOXICITY CAUSED BY VENOMOUS BITES AND STINGS/ ZOOTOXINS

 Zootoxins are the toxin produced by lower animals e.g. snakes, scorpions, spider, wasp,
toads, fish, ticks, ants etc. Most of the zootoxins are composed of proteins (both low and
high molecular weight). They may be amines, lipids, steroids, amino-polysaccharides,
quinines, 5HT, glycosides etc.

 Venomous animals produce venom in a highly developed secretary gland or group of

cells and deliver the toxin (venom) during a stinging or biting act.

 Poisonous animal possesses a toxin within its tissue that can have deleterious effects
when ingested.

CLASSIFICATION OF POISONOUS ANIMALS

1) Poisonous reptiles e.g. snakes and lizards
2) Poisonous insects e.g. bees, hornets, wasps and ants.
3) Poisonous arachnids e.g. spiders, scorpions and ticks
4) Poisonous amphibians e.g. toads
5) Poisonous fishes e.g. tetrotoxic fish, ciguatera and scombroid fish

 Factor affecting toxicity :

o Species of the venomous animal
o Route of entry
o Location/site
o Quantity of venom injected
o Accumulation
o Absorption from the site, Distribution, Metabolism and Excretion (ADME) and
o Species of animals affected
 In general the zootoxins either affect the nervous system or the cardiovascular system.
The venom components selectively target important sites of the nervous system in either
agonistic or antagonistic manners. Toxins acting on the cardiovascular system affect the
hemostasis.
 Venoms often have profound effects upon blood coagulation, acting directly upon
important clotting factors either by inappropriate activation or through prevention of
activation.

1) SNAKE POISONING
 Snake bite in animals generally occurs while grazing or hunting.
 Most cases of poisoning reported in dogs and horses.
 Snake venom is a complex mixture consisting of amino acids, polypeptides,
glycopeptides and biogenic amines. The venom also contains an enzymatic portion and a
non-enzymatic portion. Toxicity due to snakebite may be of two types – neurotoxicity and
cardio or haemo toxicity. The enzymatic portion of the venom produces neurotoxicity. Of
the 3500 types of snakes available, only 400 types belonging to six families are toxic.

 Factor affecting toxicity:

o Quantity of venom injected
o Proportion between the quantity of venom injected and the body size of the
animal to which the venom is injected
VPT (Veterinary Toxicology), Vet. College, Anand. Page 24
o Species of snake
o Location of the bite
o Species of animal involved, that horse is most susceptible, followed by sheep,
cattle, goat, dogs, pig and cats.
 Venoms of snakes contain necrotizing, anticoagulant, coagulant, neurotoxic, cardiotoxic
and haemolytic fractions.
 Cobra and krait venom is neurotoxic while viper and rattle venom is haemotoxic.
 Venomous snakes fall into two classes: 1) the elapines, which include the cobra, mamba,
and coral snakes; and 2) the viperines, (a) the true vipers (e.g., Russell’s viper) and (b)
the pit vipers (e.g., rattle snakes).
 There are 4 common poisonous snakes in India.
o Indian cobra (Nag),
o Indian krait (Kalotaro),
o Russel’s viper (Khadchitro) and
o Saw-scaled viper (Phoorso).

 Elapine snakes have short fangs and tend to hang on and ‘chew’ venom into their victims.
Their venom is neurotoxic and paralyzes the respiratory center.
 Viperine snakes have long, hinged, hollow fangs; they strike, inject venom (a voluntary
action), and withdraw.
Clinical signs
 Severe local tissue damage and pain at bite site.
 Salvation, hyper excitability, mydriasis, asphyxia, gasping, recumbency, convulsions and
death in 2-4 hours. Regurgitation of ruminal contents, paralysis of the tongue, oesophagus
and larynx are noticed in ruminants.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 25

Diagnosis:
 Diagnosis is based on sudden death, fang marks, local swelling and oozing of blood from
the site of bite. Typical pit viper bites are characterized by severe local tissue damage that
spreads from the bite site. The tissue becomes markedly discolored within a few minutes
and dark, bloody fluid may ooze from the fang wounds if not prevented by swelling.
Frequently, the epidermis sloughs when the overlying hair is clipped or merely parted.
Hair may hide the typical fang marks. Sometimes, only one fang mark or multiple
punctures are present. In elapine snakebites, pain and swelling are minimal; systemic
neurologic signs predominate.

Treatment
 Snake bite is an urgent emergency. In some cases, it is lethal in many it can cause
prolonged and disfiguring injury. Although the animal should receive veterinary care as
soon as possible, this should be done while keeping the animal as quiet as possible.
 Even if the snake is killed for identification purposes, caution must be exercised in
handling it after death. Envenomation is possible even after a poisonous snake has been
decapitated.
 Objectives of therapy are to neutralize the venom, prevent shock, and prevent secondary
infections; and sometimes to prevent the further spread of toxins, and remove the venom.
The use of alcohol to clean the wound is contraindicated because of its vasodilatory
effect, which would promote uptake and spread of venom.
 Includes administration of the specific anti-venom is the species of snake is known,
administration of polyvalent anti-venom if the species of snake is not known and
symptomatic.
 Broad-spectrum antibiotics should be given to prevent wound infection and other
secondary infections. Several potential pathogens, including Pseudomonas aeruginosa,
Clostridium spp., Corynebacterium spp. and staphylococci have been isolated from
rattlesnakes’ mouths. Antibiotics should be continued until all superficial lesions have
healed.
 Respiratory assistance (ventilator) may be needed for 48 - 72 hours for animals with coral
snake poisoning. The maintenance of a patent airway is critical. Large diameter tubing or
opened syringe cases are commonly placed in the nostrils of horses bitten on the face to
keep the airways open. Emergency tracheostomy may be required.
 Fluid therapy: Generally indicated in small animals. Hypotension is a common presenting
sign. Diuresis to facilitate excretion and renal damage has been reported to be useful in
man.
 Corticosteroids: Use is controversial. Useful in treating shock but increases in mortality
have been reported with their use. They can also alter results of laboratory tests that are
otherwise useful in monitoring an animal's progress. Generally used for prevention of
shock and hypotension. May not affect local swelling.
 Transfusions: Commonly indicated in dogs, if necessary, to treat anemia and hemorrhage.
 Tetanus antitoxin should always be given to the affected horse.
 Antihistamines have been reported to be contraindicated, but diphenhydramine
hydrochloride is frequently given along with antivenin to treat snakebite in humans.
Tranquilization in horses may be required.

Therapies generally contraindicated

 Tourniquet - The use of tourniquets is controversial and usually they are avoided. When
used they are most effective in first 30 minutes. Tourniquets increase local tissue damage
VPT (Veterinary Toxicology), Vet. College, Anand. Page 26
due to hypoxia. The general location of snake bites (e.g., face) may prevent use.
Recommended only for animals in which the tissues below the tourniquet will be
sacrificed to save the animal's life.
 Incision and suction also controversial. Requires restraint of animal to be effective.
Minimal benefit with regards to the local removal of venom. Not recommended unless
pocket of venom will clearly be removable.
 Cryotherapy - Commonly associated with increased tissue damage. Not recommended.
 Surgical debridement - Use has not been substantiated. May result in serious scarring and
loss of function. May not prevent systemic signs. Not recommended early in course of
treatment for envenomation.

2) SCORPION POISONING
 There are approximately 1000 species of scorpions but only around 75 are clinically
important.

 The most potent venoms are low molecular weight proteins that affect the nervous
system.
 The nomenclature of scorpion toxins recognizes two general classes, alpha and beta-
toxins.
 Scorpion alpha-toxins induce a prolongation of the action potential of nerves and muscles
by slowing down the inactivation of the sodium channel with receptor affinity dependent
upon membrane potential, while beta-toxins bind to a receptor site distinct from that of
the alpha toxins with binding being independent of voltage.
Treatment:
 Specific antivenom available in some part of world.
 Cold compresses can be applied to relieve pain.
 Atropine can be indicated to control excessive parasympathetic manifestation.
 Calcium gluconate given to reduce muscle spasm.

3) SPIDER POISONING
 Spiders use their venom to paralyze prey while they eat victim’s body fluids.
 The venom of spiders is a complex mixture of neuroactive proteins and other chemicals.
 Toxic principle is proteins which include protease, hyaluronidase, sphingomyelinase D
and esterase. They have direct lytic effect on RBCs.
 The most venomous spiders in the world include Brown recluse spider, Hobo spider and
Black widow spider.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 27

 Some spider venoms can kill a mouse at a dose as low as 0.006 mg.
 The black widow species venom is made up of large proteins thought to affect the
transmission of calcium ions of nervous system cells.
 The initial sting of the bite is followed by muscle cramps, sweating and possibly
decreased blood pressure.
 There is no adequate treatment but the bite is seldom fatal.
 Spider venom is 10-15 times more potent than rattle snakes.
Signs
 The bite initially stings, and then any one of the two forms may take place.
o The cutaneous form begins as edema, progresses to an ulcerated wound.
o The viscera-cutaneous form, which is severe, produces hemolytic anemia,
hemoglobinuria, icterus and hyperthermia.
 Ninety percent of the cases heal in 1-3 weeks. Some may need skin grafting.
Mechanism of action
 Unidentified venom component is cytotoxic to endothelial cells. This triggers
intravascular coagulation and microthrombi formation within capillaries. Capillary
occlusion, hemorrhage, and necrosis occur.
 Polymononuclear leukocytes and complements play important roles in potentiating the
response to envenomation.
Treatment
 Specific black widow spider antivenin given in man and small animal by I/V route.
 Steroids may be used to protect against systemic effects.
 Hemolytic anemia can be managed by use of fluids and bicarbonate to minimize
hemoglobin deposition in renal tubules and by blood transfusion if anemia is severe
enough to justify.

4) WASP STING
 A sting from a wasp, like that of other large stinging insects such as bees, hornets and
yellow jackets, capable of triggering allergic reactions varying greatly in severity and
scope from a localized reaction limited to swelling of the regions where the bite occurred
to life-threatening systemic reactions in which the airway can swell and get closed.
 Stings by bees, wasps, hornets, and ants usually cause pain, redness, swelling, and
itching.

 The venom may contain histamine, serotonin, kinins and hyluronidase.

 Allergic reactions are uncommon but may be serious. Allergic reactions may cause rash,
itching all over, wheezing, trouble breathing, and shock. In some cases, a red, swollen,
itchy patch develops instead of a blister. Isolated nerves may become inflamed, and
seizures may occur.
Treatment:
 Stingers should be removed as quickly as possible by scraping with a thin dull edge.
 An ice cube placed over the sting reduces the pain.
 A cream or ointment containing an antihistamine, an anesthetic, a corticosteroid, or a
combination of them is often useful.
 Severe allergic reactions are treated with epinephrine, intravenous fluids, and other drugs.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 28

5) TOADS
 Toad venom, a defensive mechanism, is secreted by glands located dorsal and posterior to
the eyes and by other dermal structures, including warts.
 The venom, a thick, creamy white, highly irritating substance, can be expelled quickly by
the contraction of periglandular muscles in the skin.
 Its many components include bufagins, which have digitalis-like effects, catecholamines,
and serotonin. Bufo vulgaris is the commonly available toad.
 It inhibite Na+ K+ ATPase pump so excessive cardiac stimulation occur (digitalis-like).
 The parotid gland secretions of Bufo toads contain bufagins, bufotoxins, bufotenins, and
other compounds. Bufotoxins are conjugated bufagins. Bufagin's and bufotoxin's action
is described as digitalis-like, often resulting in ventricular fibrillation. Bufotenins have
oxytocic action and frequently a marked pressor action.
 Other compounds found in Bufo toxin are epinephrine, cholesterol, ergosterol and 5-
hydroxytryptamine (5-HT).

Clinical symptoms
 Signs vary according to the animal's age, concurrent disease, amount of toxin absorbed
and length of time since exposure. Signs of poisoning range from local effects to
convulsions and death
 There are three primary aspects to Bufo toxicosis:
o the cardiac glycoside-like effects of the bufagins;
o the pressor effects of the catecholamines and
o the hallucinogenic effects of the indole alkylamines.
Treatment
 There is no specific antidote available.
 The mouth should be washed well with plenty of water.
 Give activated charcoal and osmotic purgatives.
 Atropine may reduce the volume of saliva and the risk of aspiration.
 Give antihistaminics and sedatives.
 If bradyarrhythmias exist, atropine or dopamine should be considered; tachyarrhythmias
should be treated with lidocaine, phenytoin, propranolol, or procainamide hydrochloride.

6) FISH POISONING
 Tetrodotoxin is a bacteria-derived organic molecule assimilated into the tissues of the
pufferfish or into the modified salivary glands of the blue-ringed octopus.
 About 100 species of puffer fish use the powerful tetrodotoxin to discourage consumption
by predators.

 The puffer fish is the best known neurotoxic fish.

 Tetrodotoxinis found in all organs of the fish but is highest in liver, skin, and intestine.
 Pufferfish may also have elevated levels of saxitoxin, a neurotoxin responsible for
paralysis in shellfish poisoning.

VPT (Veterinary Toxicology), Vet. College, Anand. Page 29

 Both saxitoxin and tetrodotoxin are heat stable and cooking does not reduce toxicity.
 Saxitoxin has a very different chemical structure to tetrodotoxin, but similar effects on
transport of cellular sodium; it produces similar neurological effects, but is less toxic that
tetrodotoxin.
 Tetrodotoxin causes paralysis by affecting sodium ion transport in both the central and
peripheral nervous system. so causes the membrane depolarization
 A low dose of tetrodotoxin produces tingling sensations and numbness around the mouth,
fingers, and toes.
 Higher doses produce nausea, vomiting, respiratory failure, difficulty in walking,
extensive paralysis and death.
 Ciguatera is fish borne poisoning of humans and pets caused by eating certain marine
fish that bioaccumulate a toxin called ciaguatoxin.
 Toxic signs are GIT distress, headache, ataxia and hallucination.
 Treatment involves only intestinal detoxification with gastric lavage and activated
charchol and artificial respiration.

7) TICK POISONING

 Tick paralysis is a paralytic disease in man, cattle, sheep and bison.

 Toxins are secreted by salivary glands of female ticks and type of toxin is neurotoxin.
 Ticks are not only carriers of a number of diseases but the saliva of some can cause
paralysis.
 The toxin causes paralysis of skeletal muscle by interfering with the release of Ach at
motor end plate.
 The first indication of tick bite is redness and swelling around the site of the bite.
 This is followed by neuromuscular weakness and difficulty in walking.
 Clinical sign observed after 3-7 days after attachment of ticks.
 If the tick is not removed eventual respiratory paralysis and death are noticed.
 Removal of the tick results in a quick recovery of function.
 Use ectoparasiticide to remove ticks.

8) ANTS POISONING
 Ants causes painful venomous sting.
 Formic acid is the primary constituents of ant venom.
 Toxicity is limited to the site of sting, causes haemolytic and cytotoxic action.
 Vesicles and pustules formation at site of sting.
 Wash the sing site with soap & water.
 Cold application and antihistaminic cream are helpful.

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1

TOXICOLOGY OF AGROCHEMICALS/ PESTICIDES

Pesticides are defined as "any substance or mixture of substances intended for preventing,
destroying, repelling or mitigating any pest".
In other words, pesticides are any chemical, physical or biological agents that would kill or
destroy unwanted plant or animal pests. Pesticides are one of the most widely used agrochemicals of
toxicological importance. Pesticides are used extensively as acaricides/ ectoparasiticides in veterinary
medicine to control insect pests of both the animals and birds. Use of pesticides in animal husbandry
improves the health and productivity of animals and birds. Pesticide is a general term and insecticide is
a class of pesticides.
CLASSIFICATION OF THE PESTICIDES:
A) Insecticides: Used to kill insects
(I) Organochlorines: DDT, Aldrin, Dieldrin and Lindane.
(II) Organophosphates: Parathion, Malathion, Phosphate, Phosphonate and Phosphoramidate.
(III) Carbamates: Carbaryl, Aldicarb and Propoxur
(IV) Pyrethrins and Pyrethroides: Deltametharin, Cypermethrin, Flumethrin, Permethrin, Allethrin
and Fenvalerate.
B) Herbicides or weedicides: Used to destroy undesirable plants/weeds.
e.g. Dinitrophenol, 2,4-D, 2,4,5-T, Paraquat and Atrazine.
C) Rodenticides: Used to destroy the rodent.
e.g. ANTU, Zinc Phosphide, Fluoroacetate, Warfarin and Red Squill.

SOURCES OF PESTICIDE POISONING:

The major sources of pesticide-poisoning are:
a) Accidental exposure:
 Ingestion of pesticide sprayed crops and drinking of water from paddy fields treated with
pesticide.
 Ingestion of pesticides contaminated concentrate feeds.
 Feeding or watering of animals in insecticide contaminated containers.
 Improper disposal of empty insecticide containers.
 Licking the walls and pillars by the animals sprayed with insecticides.
 Improper and indiscriminate use of insecticides.
 Contamination of ponds, lakes, rivers etc. due to spray of insecticides or discharge of
effluents from the pesticide industries.
b) Intentional exposure:
 Residues of pesticides in agricultural products e.g. grains, pulses, vegetables, fruits etc.
 Residues of insecticides in animal products like meat, milk and eggs.
 Consumption of insecticide for committing suicide in human beings.

c) Occupational exposure:
 Workers of pesticide manufacturing industries are constantly exposed to the
hazards of pesticides.
 Faulty spraying of pesticides by unskilled workers.

Veterinary Toxicology /Toxicity of Pesticides/CVSc&AH, Anand/2019

2

INSECTICIDES
Insecticides are a heterogeneous group of chemicals. Chemicals used as insecticides are not highly
selective and result in poisoning in man and domestic animals. It is extremely important to be aware of
the potential danger of these chemicals to man and domestic animals due to their indiscriminate and
improper use. They are commonly used to control ectoparasites of domestic animals, to control certain
vector borne diseases and as anthelrnintics in livestock. Most insecticides affect the nervous system of
insects but they also possess some activity against the mammalian nervous system, their neurotoxic
effects in man and animals are often prominent.

(I) ORGANOCHLORINE INSECTICIDES/ CHLORINATED HYDROCARBONS

The organochlorines are the first generation insecticides also known as chlorinated
hydrocarbons. They are mainly used as contact insecticides and ectoparasiticides.e.g. DDT, Aldrin,
Dieldrin and Lindane.
Sources of poisoning:
 Ingestion of organochlorine contaminated feeds and water by the animals.
 Inhalation or absorption from the skin during topical application as ectoparasiticides.
Toxicokinetics:
They are water insoluble but soluble in oil and organic solvents. These are rapidly absorbed
from the oily preparations and are capable of penetrating the intact skin when applied in oily solution
or emulsion. All the compounds, in powder form, can easily penetrate the cuticle of insects compared
to mammalian skin and intestinal mucosa which explains its greater toxicity to insects than in
mammals. Except methoxychlor, other organochlorine insecticides are stored in the body fat.
However, none of these agents are known to accumulate in other vital organs.
Toxicodynamics:
The chlorinated hydrocarbons are neuropoison. By virtue of their high lipid solubility, these
agents can enter the neural membrane with ease and interfere with normal functioning of the nerve
membrane sodium channels. They act by (1) reducing the potassium transport through pores; (2)
inactivating sodium channel closure; (3) inhibiting Na+-K+ ATPases and Ca++-Mg++ ATPases and
(4) inhibiting calmodulin- Ca++ binding with release of neurotransmitter.

Clinical symptoms:
Initial stimulation of CNS followed by depression and death due to respiratory failure.
Grinding of teeth, difficult respiration, snapping of the eyelids and frequent urination. Other signs
include walking backwards, wall climbing, aimless jumping and violent frenzied behaviour.
Behavioural changes involve initial anxiety, aggressiveness, abnormal 'posturing and
madness syndrome. Neurological symptoms involve hypersensitivity to external stimuli, twitching of
the facial and eyelid muscles, spasm and twitching of the fore- and hind quarter muscles and
hyperthermia. Vomiting, marked salivation, mydriasis, diarrhoea and micturation may also be
observed.
Post-mortem lesions: No specific lesions in the nervous system. However, acute aldrin poisoning
may cause hepatitis and acute tubular nephrosis. Chronic DDT
toxicoses may produce focal centrilobular necrosis of the liver.

Veterinary Toxicology /Toxicity of Pesticides/CVSc&AH, Anand/2019

3

Diagnosis: Based on:

 History of exposure to the insecticide.
 Clinical symptoms and post-mortem lesions.
 Analysis of feeds and biological samples like liver and kidneys from dead animals, blood and
milk samples from living animals for the presence of organochlorine compounds.
Treatment: No specific antidote is available. Treatment is only symptomatic and supportive.
 Remove the source of poisoning at once.
 Administration of non-oily purgatives.

(II) ORGANOPHOSPHOROUS INSECTICIDES

Organophosphorous insecticides (OPIs) compounds are preferred among various groups of

insecticides due to their high selectivity, low toxicity in mammals and their rapid degradation in
animal body and ecosystem. With indiscriminate use of these compounds, several cases of poisoning
frequently occur in man, domestic animals and wild life. OPIs have comparatively low toxicity in
mammals than in insects.
More than 30,000 different organophosphate compounds have been tested for insecticidal
activity so far. Products like diazinon, dimethoate and malathion possess toxicity equivalent to that of
organochlorine compounds in mammals. Some less toxic ones like coumaphos, fenchlorvos and
trichlorphon have been used as insecticides. Other compounds like dichlorvos and haloxon are being
used as anthelmintics.

Further, OPIs are categorised into two broad groups on the basis of their activity:
a) Direct acting OPls: These compounds act by directly inhibiting the cholinesterase enzyme. e.g.
dichlorvos, fenchlorvos, trichlorfon and chlorpyriphos.
b) Indirectly acting OPIs: These insecticides as such are inactive but are biotransformed in the
body to toxic metabolites which inhibit cholinesterase enzymes. e.g. Malathion, Parathion and their
active metabolites are Malaoxon and Paraoxon.
Toxicodynamics:
The OPIs causes toxicity by inhibiting irreversible acetylcholinesterase, the enzyme which
is responsible for hydrolysis of acetylcholine to acetic acid and choline, released from nerve endings.
Toxicokinetics:
OPls are highly lipid soluble and are rapidly absorbed by all routes including gastrointestinal
tract, skin, mucous membranes and lungs. The extent of absorption is more if these are applied in
organic solvents. The metabolism and excretion of OPls is a very complex process and it is
dependent on chemical nature of the compound, route of entry and the species of animals involved.
On reaching the tissues, the directly acting OPls are rapidly hydrolysed enzymatically while exerting
a direct inhibitory action on cholinesterase. The indirectly acting OPls inhibit cholinesterase in a
similar manner after conversion into their active metabolites. OPIs are hydrolysed in the body by a
group of enzymes called phosphoryl phosphatases. These enzymes are widely distributed in plasma
and various tissues and are not inhibited by organophosphorous compounds. Many OPIs are
excreted in milk, urine and bile. Some insecticides and their metabolites can cross the placenta and
inhibit the foetal AChE enzyme, producing toxicity to the foetus.

Veterinary Toxicology /Toxicity of Pesticides/CVSc&AH, Anand/2019

4

Clinical signs:
Various types of symptoms in animals are as follows:
 Muscarinic symptoms include bronchoconstriction and increased bronchial secretions,
hypersalivation with drooling of watery saliva, lacrimation, excessive sweating, increased
gastrointestinal tone, frequent and involuntary urination and defecation, diarrhoea, nausea,
vomition, abdominal cramps, bradycardia, pupillary constriction (miosis) etc.
 Nicotinic symptoms include muscular weakness, twitching, cramps, tremors and atrophy.
Weakness of the muscles of respiration results into dyspnoea and cyanosis.
 CNS symptoms include restlessness, convulsions, ataxia, depression of respiratory and
circulatory centres leading to cardiac and respiratory arrest, tremors and coma. Death in OPI
poisoning results from asphyxia due to respiratory failure.
 Delayed neuropathy: The delayed neurotoxic effects of OPIs can result from single toxic dose,
the onset of neuropathy is generally delayed. The inhibition of neurotoxic esterases (NTE) has
been found responsible for the organophosphorous induced delayed neuropathy (OPIDN).
Post-mortem lesions: No characteristic lesions of OPIs poisoning, however, some of the common
lesions are:
 Haemorrhagic gastroenteritis.
 Pulmonary oedema.
 Degenerative changes in liver and kidney.

Diagnosis: Exposure to OPls can be diagnosed on the basis of following:

 History and circumstantial evidences.
 Symptomatic evidence.

Differential Diagnosis:-
Signs/Symptoms Organophosphate Organochlorines Insecticides (OCIs)
Insecticides (OPIs)
Salivation Watery & fall drop by drop Frothy & it sticks to nose, lips muzzle
and mouth
Pupil size Miosis (constriction) Normal
Body temperature Hypothermia Hyperthermia
Animals running Straight direction Moves in circle
Abnormal posture No Specific Posture Ophisthotonus, head between fore limbs
& animal continuously licking of skin.
Treatment: Treatment of OPls poisoning in man, domestic and wild animals should be
aimed at:
 To abolish the muscarinic effects due to excess of acetylcholine.
 To regenerate the inactivated enzyme.
Atropine sulphate at the dose rate of 0.2-0.5 mg/kg. Atropine is a physiological antidote to OPI
poisoning, is a competitive antagonist of ACh for muscarinic receptors.
Use of oxime as AChE reactivators such as Diacetyl monoxime (DAM), 2-pyridine aldoxime
methiodide (2-PAM) and obidoxime, which reactivate the phosphorylated AChE enzyme and greatly
accelerate clinical recovery. DAM is inexpensive and freely available, is preferred over 2-PAM which is
very expensive. 2-PAM and DAM are administered at the dose rate of 30 mg/kg as 6 per cent solution in
normal saline intravenously or intramuscularly.
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(III) CARBAMATE INSECTICIDES

Carbamares are not broad spectrum insecticides and these show erratic patterns of selectivity to
insects. Because of extreme toxicity they are recommended only for limited use. They are used for the
control of ectoparasites in both large and small animals. Carbaryl is the most widely used carbamate to
control of ectoparasites. e.g. Carbaryl, Aldicarb and Propoxur.
Toxicokinetics: Carbamates are well absorbed through skin, lungs and gastrointestinal tract and are
widely distributed in tissues. Metabolism of carbamates by hepatic microsomes is quite complex yielding
several unidentified products. They get rapidly metabolised and excreted in urine mainly as sulphate or
glucuronide conjugates within 24 hours. A small amount is also eliminated via faeces and milk. Unlike
the OPls most of the carbamates produce low dermal toxicity.
Toxicodynamics: Carbamates are potent and reversible inhibitors of acetylcholinesterase enzyme.
Clinical signs:
Symptoms of acute poisoning are salivation, lacrimation, miosis, convulsions and death. Chronic
toxicity produces signs of neuromuscular type which are characterized by incoordination, ataxia and
recumbency but there is no demyelination or damage to nerves.
Post mortem lesions: The post-mortem findings in acute poisoning are usually limited
to congestion and oedema of lungs, liver and kidneys and petechial haemorrhage of
gastric mucosa. Neuromuscular lesions are found in chronic poisoning.
Diagnosis: Based on history and the response of the animals to atropine therapy.
Treatment:
 Carbamate poisoning is treated by administration of atropine sulphate @ 0.2-0.5 mg/kg.
 Diuretics such as hydrochlorthiazide are helpful.
 Administration of oxime reactivators is contraindicated since they aggravate the toxicity of
carbamates.
(IV) SYNTHETIC PYRETHROIDS
Pyrethrins are natural insecticides obtained from the flowers of Chrysanthemum roseum which
possess potential insecticidal properties without mammalian toxicity potential. Modification of the chemical
structures of the natural pyrethrins was attempted to develop a series of synthetic pyrethroids with improved
physical and chemical properties and greater biological activity. Pyrethrin -1 contains all the basic features
for good insecticidal activity. Synthetic pyrethroids are safer insecticide compare to organochlorine and
organophosphorous insecticides
e.g. Deltamethrin, Cypermethrin, Permethrin, Flumethrin, Allethrin, Fenvalerate etc.
Sources of poisoning:
 Ingestion of pesticide contaminated feeds or water.
 Dermal absorption from topical application such as spray or pour- on to control external parasites.
Toxicodynamics: The synthetic pyrethroids are neuropoisons. The main target of
action is the nerve membrane sodium channels.
Clinical signs:
Restlessness, incoordination, hyperactivity, tremors, paralysis, aggressive behaviour and
hypersensitivity to external stimuli. In large animals, fenvalerate caused restlessness, frothing of mouth,
dyspnoea, erection of ear and tail, mydriasis, regurgitation of ruminal contents, incoordination, tremors,
clonic convulsions and recumbency. Deltamethrin spray causes hypersalivation, lacrimation, mucoid nasal
discharge, excitement, incoordination, extension of limbs, anorexia and alopecia in buffalo calves.
Pyrethroids are also known to cause contact dermatitis.

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Diagnosis: Based on
 History of exposure to synthetic pyrethroids.
 Clinical signs exhibited by the poisoned animals.

Treatment: There is no specific treatment. Following general and supportive line of

treatment may be followed:
 Removal of source: wash the animal if the route of exposure is through skin.
 Emetic: Apomorphine @ 0.1 mg/kg, I/M in dogs.
 Adsorbents: Activated charcoal @ 2g/kg.
 Purgative: Magnesium sulfate @ 5g/kg as 10% solution.
 CNS depressants: Diazepam @ 0.2-2.0 mg/kg IV.

(B) HERBICIDES
Herbicides are any compound used to destroy undesirable plants/weeds. Herbicides defined as any
compound that have the potential of either killing or damaging unwanted plants or weeds and are employed
for the elimination of such plants or parts of a plant. The biochemical differences in plants make it possible to
design herbicides that have selective toxicity potential against various species of plants with no deleterious
effects on the crops.

CLASSIFICATION:
Herbicides classify to following groups on the basis of their chemical nature.
a) Dinitro compounds e.g. Dinitro ortho cresol (DNOC), Dinitrophenol etc.
b) Phenoxyacetic acids e.g. 2,4-D, 2,4,5- T etc.
c) Bipyridinium compounds e.g. Diquat, Paraquat etc.
d) Heterocyclic compounds or Triazenes e.g. Atrazine, Propazine, Simazine etc .
e) Chloroaliphatic acids e.g. Sodium chloroacetate, Sodium trichloroacetate etc. \
f) Substituted ureas e.g. Monouron, Diuron etc.
g) Substituted dinitroanilines e.g. Pendimethalin etc.

a) Dinitro compounds: Many dinitro compounds are used as herbicides. The commonly employed ones are
dinitro ortho cresol (DNOC) and dinitrophenol.
Sources of poisoning:
 Accidental ingestion of DNOC-sprayed foliage by animals
 Licking of empty containers by curious animals.
Toxicodynamics: Dinitro compounds act by interfering with electron transport chain of energy metabolism.
They uncouple the oxidative phosphorylation and convert all the cellular energy in the form of heat
producing severe hyperthermia. In ruminants, the ruminal microflora reduces the dinitro compounds to
diamine metabolites which induce methaemoglobinemia.
Post mortem lesions: Rapid onset of rigor mortis. The dinitrophenol imparts a yellowish green colour to
tissues and urine (mild jaundice). Dark blood, gastroenteritis, hyperkeratosis of skin and hyperplasia of
urinary bladder mucosa may also be recorded.
Diagnosis:
 History of exposure to dinitro compounds.
 Clinical symptoms.
 Post mortem lesions.
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Treatment: No specific treatment or antidote available.

 Wash with soap and water if the source of poisoning is through skin contact.
 Keep the affected animal in cool and calm place. To control hyperthermia, use cold bath or ice-
water sponging. Use of antipyretics is contraindicated.
 Saline purgatives or gastric lavage.
 Fluid and other supportive therapy.

b) Phenoxyacetic acids:
The most commonly used chlorophenoxyacetic acids are 2,4-dichloro- phenoxyacetic acid (2,4-D) and
2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Both these agents are relatively harmless to mammals.

Sources of poisoning:
 Accidental ingestion of herbicide itself.
 Ingestion of poisonous plants which have been treated with phenoxyacetic acids.
Toxicodynamics: The exact mechanism of toxicosis of phenoxy acetic acids is not precisely known.
However, they are known to produce reproductive toxicity in cattle and hepato-carcinorna in laboratory
animals.
Clinical signs: Anorexia, ruminal atony, weight loss, occasional diarrhoea, depression,
unthriftiness and muscular weakness of hind limbs may be observed. Abortion,
irregular oestrus, anoestrus and ovarian atrophy may be recorded in cattle.
Treatment: No specific antidote is available. Symptomatic and supportive therapies
include administration of diuretics and liver protectants.

c) Bipyridinium compounds:
Paraquat and Diquat are rapidly acting broad spectrum contact herbicides which are extensively used
in agriculture for preharvest of cotton and potatoes and weed control. Bipyridinium herbicides are highly
toxic compounds.
Sources of poisoning:
 Accidental poisoning due to direct ingestion of the compound or consumption of freshly treated
vegetation.
 Malicious poisoning- principal targets are the dogs.
Toxicodynamics: The bipyridinium compounds are caustic and irritant agents which cause ulceration and
necrosis of the skin and mucous membranes in dogs, pigs and man. They also cause progressive irreversible
pulmonary fibrosis.
Clinical signs: Clinical signs are seen after three days of exposure to paraquat. Symptoms of intoxication
are emesis, anorexia, abdominal pain, dyspnoea, jaundice and CNS depression. If the affected animals
survive for several days, animal may exhibit dehydration, cyanosis, tachycardia, uremia, moist rales,
pulmonary oedema and emphysema.
Post-mortem lesions: Pulmonary congestion, oedema and haernorrhages, progressive intra-alveolar
fibrosis, atelectasis, erosions and ulceration of buccal and pharyngeal tissues, haemorrhagic gastritis and
congestion of liver, kidney and spleen.
Diagnosis:
 History of exposure to bipyridinium herbicides.
 Clinical symptoms.
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 Post-mortem lesions.
 Analysis of the urine, suspected baits or the feeding material.
Treatment: No specific treatment for diquat or paraquat poisoning. Symptomatic and supportive treatment
includes:
 Check further absorption by giving emetics or gastric lavage or oral adsorbents (activated charcoal)
followed by saline purgatives.
 IV fluids and diuretics.
 Tranquilizers and sedatives.
 Vitamin A, C and E have some beneficial effect.
 Corticosteroids
 Biochemical antagonists like ascorbic acid, acetylcysteine, super oxide dismutase etc.

d) Heterocyclic compounds (Triazenes):

Triazenes include atrazine, simazine, propazine and aminotriazole. This group has a very low
mammalian toxicity potential. Atrazine is the most widely used and selective herbicide for crops likes
maize, sorghum, sugarcane, pineapple etc. The mechanism by which these agents produce toxicity is not
well understood.
Clinical signs: Weakness, hypersalivation, ataxia and posterior paralysis appear three weeks after ingestion
of the compound. Pulmonary oedema and severe gastric and intestinal haemorrhages also observed.
Diagnosis: Based on the history of exposure and clinical signs.
Treatment: No specific antidote. Provide symptomatic and supportive treatment.

e) Chloroaliphatic acids:
The most commonly used compounds are sodium chloroacetate and sodium trichloroacetate. These agents
are relatively harmless.
The source of poisoning is accidental ingestion. Cattle, sheep and goats are frequently affected
animals.
Clinical signs: Commonly observed clinical signs are anorexia, diarrhea and mild cyanosis. Treatment: No
specific antidote. Symptomatic and supportive treatment may be provided. The animals may recover
spontaneously even without any treatment.
f) Substituted ureas:
Monouron and diuron are the most commonly used substituted ureas. They have low toxicity
potential. Poisoning with these agents is rare.
Clinical signs: Anorexia, abnormal gait, excitability followed by depression, occasional respiratory
difficulties, haematuria and hypersalivation may be noted.
Post-mortem lesions: They are non-specific. However, congestion of GIT, liver, kidneys and haemorrhages
in the heart and lungs may be seen.
Treatment: No specific treatment is available. Provide symptomatic and supportive treatment.

g) Substituted dinitroaniline compounds:

Pendimethalin have a broad spectrum weedicide activity and low mammalian toxicity.
Clinical signs: Cattle, sheep, goats and dogs are sometimes affected. General signs of toxicity are anorexia,
tympanism and diarrhea.
Treatment: Generally, prognosis is good; no specific treatment is available. Symptomatic and supportive
treatment is provided.
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(C) RODENTICIDES
Rodenticides are agents which destroy the rodents. Rodents such as black rats (Rattus rattus), mice
(Mus musculus), squirrels etc. can consume substantial quantities of pre-harvest, post-harvest and stored
grains, pulses, vegetables and fruits. They also render the foodstuffs unfit for consumption by soiling and
contaminating with urine, faeces and pathogenic microorganisms which are capable of infecting other
animals and man.
e.g. Alpha-naphthyl thiourea (ANTU), warfarin, zinc phosphide, fluoroacetate, red squill etc.

1) Alpha naphthyl thiourea (ANTU):

ANTU is relatively selective rodenticide. It is toxic to the rats but harmless to human beings.
Sources of poisoning: Accidental ingestion of baits intended for target rodents. Primarily affected animals
are the dogs and cats.
Toxicodynamics: ANTU interferes with effective uptake of O2 from pulmonary alveoli by producing
extensive oedema of the lungs due to increased capillary permeability and seepage of fluid into the airways.
This leads to formation of froth which further blocks the air passage and virtually the poisoned animal
drowns in its own fluids.
Clinical signs: Vomiting, dyspnoea, cyanosis, rales, tachycardia, anorexia, incoordination, cough,
asphyxiation, coma, clonic convulsions and death.
Post-mortem lesions: Cyanosis, dark coloured arterial blood, heavy and oedematous lungs, presence of
blood-tinged fluid and froth in the bronchi, hydrothorax and hyperemic tracheal, bronchial and gastric
mucosa, liver and kidneys etc.
Diagnosis:
 History of employing ANTU as baits.
 Clinical symptoms.
 Post-mortem lesions.
Treatment:
 Emetics or gastric lavage.
 Sedatives like barbiturates.
 Oxygen under positive pressure.
 Competitive ANTU antagonist, 1-ethyl-1-phenyl thiourea may reverse ANTU toxicosis.
 Alpha adrenoceptor antagonists to dilate pulmonary vessels.
 Osmotic diuretics (50% glucose or mannitol) to reduce the pulmonary oedema.

2) Warfarin:
Warfarin isolated from moldy sweet clover and its analogues are anticoagulant rodenticides. The
warfarins are readily inactivated by cytochrome P450 enzymes of the liver. Therefore, repeated dosing for
several days is recommended.
Sources of poisoning: Ingestion of residues of the rodenticides or baits intended for target rodents. Pigs,
dogs and cats often ingest warfarin poisoned dead rats or mice.
Toxycodynamics: Warfarin interferes with normal function of vitamin K and causes coagulation defects
characterized by decreased blood concentrations of coagulation
proteins - factor II, VII, IX and X. The decreased coagulation factors cause massive internal haemorrhages.
The onset time is 2-5 days and the affected animal dies due to tissue hypoxia.
Clinical signs: After ingestion of warfarins over a period of 2-5 days, the affected animals may exhibit signs
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of haemorrhages of gum, epistaxis, massive internal haemorrhages, blood discharge from body orifices,
haematomas under the skin and at joints, dyspnoea, weakness, shock and death.
Post-mortem lesions: Massive internal haemorrhages, blood in the GIT, thorax, joints and pericardium.
Diagnosis:
 History.
 Clinical signs.
 Post-mortem lesions.
Treatment:
 Injection Vitamin K1 @ 5 mg/kg, slow IV in dogs and cats. Repeat for 2 days by I/M route. In large
animals @ 0.5-1.0 mg/kg by slow IV followed by oral vitamin K administered daily for 4-6 days.
 Provide clotting factors by whole blood or plasma transfusion @ 20 ml/kg or 9 mllkg body weight,
respectively.
 Sedatives or tranquilizers.
 Artificial respiration.
The rationale of giving vitamin K in warfarin poisoning is that vitamin K is
biotransformed into vitamin K epoxide in the liver which is reduced by NADH to vitamin
K hydroquinone. This vitamin K hydroquinone accelerates the synthesis of prothrombin.

3) Zinc phosphide: Zinc phosphide (Zn3P2) is commonly used rodenticide for destroying
rats, mice, squirrels and dogs. This compound is widely employed in the developing
countries because it is the cheapest and quite effective rodenticide.
Sources of poisoning:
 Baits intended for target rodents may be eaten by other animals or birds.
 Malicious poisoning, particularly to kill dogs and cats.

Toxicodynamics: Zn3P2 + H2O Zn++ + PH3

Zinc phosphide is directly irritant to gut and produces severe
gastroenteritis. Acute zinc phosphide toxicosis is neither due to zinc nor phosphorus. The zinc phosphide
liberates phosphine (PH3) in the stomach following a hydrolytic reaction
with water in the GIT. Absorbed phosphine is responsible for development of widespread cellular toxicity
with necrosis of the GIT, liver and kidneys.
Clinical signs: Anorexia, lethargy, increased rate and depth of respiration, abdominal pain, bloat, ataxia,
weakness, dyspnoea, gasping, convulsions, coma and death in 4-48 hours.
Post-mortem lesions: Pulmonary congestion and oedema, subpleural haemorrhages, congestion of liver
and kidneys and gastroenteritis. Acetylene odour detected in stomach.
Diagnosis:
 History.
 Clinical signs.
 Post-mortem lesions.
Treatment: No specific treatment. Symptomatic and supportive treatment given.
 Gastric lavage with 5% sodium bicarbonate.
 Anticonvulsants and treatment for shock

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4) Fluoroacetate:
Fluoroacetate as such is non-toxic but becomes highly toxic after its metabolic conversion in the body
to fluorocitrate. Sodium fluoroacetate is commonly used rodenticide. This compound is extremely toxic and
its LD50 value is 0.22 mg/kg in rats.

Toxicodynamics: Fluoroacetate Fluorocitrate (Toxic)

Fluorocitrate then competes with citrate for the active site of Kreb's cycle enzyme aconitase. This results in
inhibition of aconitase leading to slowing of the Kreb's cycle and decreasing cellular respiration. The brain
and heart functions are most severely affected.

Clinical signs: Appear within 30 minutes to 2 hours include CNS excitation, restlessness, vomiting,
diarrhoea, urination, hyperirritability, hypermotility, barking, frothing at mouth, terminal coma, gasping
and death within 2-12 hours in dogs and guinea pigs. In horses, cattle, sheep and goats show colic, unrest,
trembling, staggering, cardiac arrythmias, tachycardia, terminal ventricular fibrillation and death. Both CNS
and cardiac signs are observed in swine, cats and hamsters.
Diagnosis:
 History of accidental ingestion of fluoroacetate bait.
 Clinical signs.
Treatment: No specific antidote for fluoroacetate poisoning. Symptomatic treatment provided.
 Barbiturates or benzodiazepines to control convulsions.
 Glycerol monoacetate @ 0.1-0.5 mg/kg, I/M.

5) Red squill:
Red squill is obtained from the plant Urginea maritima (sea onion). Red
squill contains a cardiac glycoside-scilliroside. This compound is comparatively one of
the safest rodenticide as it is non-toxic to poultry and causes emesis in animals.

Clinical signs: Small doses of red squill cause convulsions and higher doses produce cardiac arrest. In
livestock, hyperaesthesia and incoordination were observed.
Post-mortem lesions: Gastritis and enteritis, swelling and congestion of kidneys, liver, lungs, mesenteric
vessels and myocardium.
Diagnosis:
 History.
 Clinical signs.
 Post-mortem lesions.
Treatment: No specific treatment. Provide symptomatic and supportive treatment.

@@@@@@

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POISONOUS PLANTS
(Toxicity of Plants/ Plant Poisoning)

Toxic Plant / Poisonous Plant:

 “Plant which detrimentally affects the health of animal or man when eaten in such
amount as would be taken normally or under extreme hunger known as toxic plant”
 Grazing animals are indiscriminate eaters.
 Animals are poisoned mostly when hunger or wrong management practices or during
scarcity period or drought.
 Poisonous plant cause great economic loss to livestock industry.
 Poisonous plants affect animals in many ways by death, illness of animals, decreases
weight, milk production, fertility, utility, production and reproduction performances and
induce photosensitization.
 Phytotoxins present in plants may enter the human food chain through animal products
like eggs, milk and meat.
 Hence, knowledge of poisonous plants is essential for veterinary students & field
veterinarians for their region of work.
List of toxic plants and weeds:
1) Cyanogenic plant poisoning (HCN)
2) Plant producing lathyrism
3) Bracken fern poisoning
4) Plant producing oxalate poisoning
5) Plant producing photosensitization
6) Lantana camara (ગગગગગગ)
7) Sweet clover (Melilotus alba & Melilotus officinalis)
8) Datura stramonium (ગગગગગ)
9) Abrus precatorius (ગગગગગ)
10) Ricinus communis (ગગગગગ)
11) Strychnos nux-vomica (ગગગ ગગગગગ)
12) Calotropis gigantea (ગગગગગ)
13) Cotton seed (Gossypium spp.) (ગગગગ)
14) Parthenium hysterophorus (ગગગગગગગ ગગગગગ)
15) Nerium indicum- Red Karen, Thevetia peruviana- Yellow Karen (ગગગગ)
16) Ipomea carnea (ગગગગગગગ)
17) Nicotina tabacum (ગગગગગ)
18) Allium sepa (ગગગગગગ)
1. CYANOGENIC PLANT POISONING/ CYANIDE POISONING
 Cyanide poisoning in animals occurs generally due to ingestion of certain plants
which contain cyanogenic glycosides.
 Cyanide is one of the most rapidly acting and deadly toxicants that affect all
mammals.

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Properties:
 Hydrogen cyanide (HCN) is a colourless, readily volatile gas having a
characteristic odour of bitter almond.
 A solution of HCN in water is called hydrocyanic acid or prussic acid.
 Normally, cyanogenetic glycosides are present in the plant as non-toxic form but
damage to plant tissue or in rumen which convert to toxic form HCN by enzyme β-
glucosidase (located in leaf tissue of plant).
Sources
 At least 1000 plants contain cvanogenetic glycosides but few plants causes cyanide
poisoning in humans or animals.
 Some important plants are sorghum, sudan grass, indian grass, corn, acacia, sugar
cane leaves or tops and linseed cake.
 Bitter almond and wild cherry contain amygdaline that liberates 250 mg of
HCN/100 g.
 Sorghum, millet and sudan grass contain dhurrin that liberates about 250 mg of
HCN/100 g.
 Linseed (Flax), velvet grass and wild clover contain linamarin that releases about
10-300 mg of HCN/100 g.
 Cyanide containing fumigants and rodenticides and drugs (e.g. nitroprusside).
 Cyanide containing fertilizers & laboratory chemicals (e.g. sodium and potassium
cyanide).
 HCN is used as a chemical weapon or warfare agents which cause general
poisoning.
Factors affecting toxicity
 Species: Ruminants are more susceptible to cyanide poisoning than other animals
because mildly acidic to alkaline rumen pH (6.5-7.0), high water content and rumen
microflora enzymes facilitate hydrolysis of cyanogenetic glycosides to HCN.
Among ruminants, cattle are more susceptible than sheep.
 Plant factors: Plants most commonly associated with HCN poisoning are sorghums,
sudan grass and Johnson grass. Grain sorghums are more toxic than forage
sorghums or sudan grass.
 Parts of plants: Leaves contain more HCN than stems and stalks. Further, upper and
newer leaves have more HCN than lower leaves. e.g. fodder plant seeds contain no
or low HCN, while almond and flax seeds contain high HCN levels.
 Age of plant: Young rapidly growing plants contain high concentrations of
cyanogenetic glycosides than the mature plants.
 Amount of degrading enzyme: Plants containing high concentration of β-
glucosidase enzyme release more of HCN.
 Injury to plant: Injured plants easily release HCN due to rupture of plant cells.
 Weather conditions: Rapidly growing plants after a period of draught contain
dangerously high levels of HCN due to origin of new shoots and leaves.
 Method of feeding: Grazing of leaves and young shoots contain high HCN.
 Time of cutting/grazing: cyanogenic glycosides levels in plants are usually high
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during morning and low in the afternoon and evening.

 Processing of material: Drying or making of silage reduces HCN content in plant
material. dangerous amount of HCN may remain in the silage.
 Gastric pH: Acidic pH decreases release of HCN so that humans, horses, dogs and
pigs are less susceptible to HCN poisoning than ruminant.
 Rapid ingestion of plants causes rapid release of HCN gas from cyanogenetic
glycoside.
 Water drunk after animals have eaten cyanogenetic plants enhances the hydrolysis
of the glycosides and increases chances of poisoning.
Toxicity
 Toxicity of cyanide varies with the type of salt, species, speed of ingestion and
individual animal tolerance.
 Numerous forms of cyanide exist, including gaseous hydrogen cyanide (HCN),
water-soluble potassium and sodium cyanide salts, and poorly water-soluble
mercury, copper, gold, and silver cyanide salts.
 Hydrocyanic acid or its alkaline salts (potassium or sodium) are highly toxic having
oral LD50 of 0.5-0.3 mg/kg in most of the species.
 Human being, exposure to 150 ppm HCN for 30-60 min may cause death while at
concentration of 300 ppm death may occure in few minutes.
 The plant material containing more than 20mg of HCN/100g is considered toxic to
animals.
 Salts of cyanic acid (cyanates) have low while salts of thiocyanic acid
(thiocyanates) have very low toxicity.
 Potassium ferrocyanide and potassium ferricyanide are practically non-toxic.
Toxicokinetics
 HCN is released rapidly from cyanogenetic glycosides when the ingested plant is
macerated as in chewing.
 Rumen and intestinal microflora also cause decomposition of glycosides and
release HCN.
 HCN is rapidly absorbed from GI tract and widely distributed to all organs and
tissue. It is also absorbed from lungs after inhalation.
 The cyanide ions are rapidly metabolised in liver and some other tissues.
 The principal excretion product is thiocyanate, production of which is catalyzed by
rhodanese enzyme widely occurring in most mammalian tissues.
 Some HCN is eliminated by exhalation from the lungs, giving a characteristic bitter
almond smell to the exhaled air.

Mechanism of action
 The toxic effects of cyanide are due to its affinity towards the cytochrome oxidase.
 After gastrointestinal or respiratory exposure, cyanide ion is rapidly absorbed and
readily reaches inside the cell.
 Cyanide combine with cytochrome oxidase enzyme and acts by inhibiting its

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enzymatic activity and arrest the cellular respiration.

 This results in blockade of electron transport system and hence respiration and cells
die due to lack of oxygen.
 All tissues are susceptible but death is primarily from tissue anoxia in the brain.
Clinical signs
 Percute and acute toxicity: The clinical course of acute cyanide poisoning depends
on the concentration of cyanogenetic glycoside in plant, amount of plant eaten and
rate and duration of consumption.
 In peracute cases, death may occur only in few minutes. Clinical signs may occur
within 15-20 min which includes restlessness, stumbling gait and dyspnoea which
develops shortly with tachycardia. Salivation, excessive lachrymation, mydriasis,
and voiding of urine and faeces may also occur.
 Gum and mucous membranes are bright red colour.
 Death occurs during severe asyphyxial convulsions due to respiratory paralysis.
 Most animals that survive for 2 hour after onset of clinical signs, usually recover.
 Chronic toxicity: No chronic toxicity for cyanide has been described. However,
lower concentrations for long periods may produce a neurotoxic syndrome.
Post-mortem findings:
 In acute or peracute cyanide toxicosis: blood may be bright cherry red initially but
may become dark red if necropsy is delayed.
 Mucous membranes are pink initially, then become cyanotic when respiration
ceases.
 The rumen may be distended with gas and bitter almond smell may be detected
after its opening.
Diagnosis:
 The acute onset, bright red mucous membranes, bright cherry red blood and odour
of HCN (bitter almond smell) are indicative of cyanide poisoning.
 Confirmatory diagnosis is based on detection of HCN in rumen contents.
Specimens include rumen or stomach contents, heparinized whole blood, liver and
muscles.
 Plants containing 200 ppm or more of HCN are potentially toxic.
 Rumen contents > 10 ppm and liver > 1.4 ppm of HCN are indicative of cyanide
poisoning.
Treatment and Management:
 Immediate treatment is necessary to save the life of animals.
 The major objective of treatment is to re-establish oxygen transport at the cellular
level.
 SODIUM NITRITE FOLLOWED BY SODIUM THIOSULPHATE IS USED AS
AN ANTIDOTE TO CYANIDE. Sodium nitrite is a toxic substance, alone should
not be used in treatment.
 Dose: Cattle & sheep: 20 mg/kg, slow IV as 1% solution followed by sodium
thiosulphate (500 mg/kg, slow IV as 25% solution).
 Horses: 16 mg/kg, slow IV as 1% solution followed by sodium thiosulphate (30-40
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mg/kg, slow IV as 20% solution).

 Sodium thiosulphate: It is alone also an effective antidote to cyanide poisoning.
 Dose: Cattle & Sheep: 500 mg/kg, slow IV as 25% solution + 30g per cow or 6g
per sheep, P.O.
 Horses: 30-40 mg/kg, slow IV as 20% solution.
 Other treatment includes Vitamin B 12 or cobalt in cyanide toxicity.
 In adult cattle 4L of vinegar in cold water to reduce cyanide poisoning.
 In Dogs: α-ketoglutaric acid @ 60 mg/kg, IV followed by Sodium thiosulphate @
1.25g/kg, IV.
Antidotal Mechanism- Cyanide Poisoning

 Cyanide react with cytochrome oxidase and form cyan-cytochrome oxidase.

 Sodium nitrite convers some Hb to MetHb in turn reacts with cyan-cytochrome
oxidase to produce cyan-methaemoglobin.
 The cyanide in presence of enzyme rhodanese takes sulphur from the donor
thiosulphate and forms sodium thiocyanate, which is relatively non-toxic and is
eliminated via the urine.
 Haemoglobin is released during the process.

2. PLANTS PRODUCING LATHYRISM:

 Lathyrism is a crippling disease of humans and domestic animals caused by eating
legumes of the genus Lathyrus (wild pea, common vetch).
 The disease is primarily restricted to Indian, Ethopia, Russia, and some areas of
Europe and North America and is seen mainly in draught conditions when people
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and animals are forced to eat large amount of Lathyrus spp. seeds.
 Two types of lathyrism are known to occur: osteolathyrism and neurolathyrism
A. Osteolathyrism
 Osteolathyrism is most common form of lathyrism seen in animals (Cattle)
consuming various Lathyrus species viz. L. odoratus (sweet pea) and L. pusillius.
 Toxic principles present in plant is β-N-(γ-L glutamyl)-amino propio nitrile
(BAPN). BAPN is heat labile and can be destroyed by cooking.
 Toxicity: BAPN exerts its toxic effect by inhibiting formation of elastic fibres in
the walls of arteries and by causing irregularities in the synthesis of collagen fibres.
Preventing the cross linkages between the collagen and elastin fibres thereby
weakening the bones and blood vessels walls.
 The disease is characterised by skeletal deformities and aortic rupture due to
defective synthesis of cartilage and connective tissue.
 Clinical signs: Characterised by lameness of hind legs, exostoses, pain in feet and
reluctance to rise. Severe connective tissues and skeletal abnormalities are seen.
 Treatment and management:
 Symptomatic and supportive.
 Emesis or gastric lavage may be performed.
 Activated charcoal and a saline cathartic may also used.
B. Neurolathyrism
 Neurolathyrism is a neurological disease affecting human beings, horses and cattle.
 It is caused by long term (>3 months) feeding of seeds of Lathvrus sativus (also
known as Grass pea or Indian pea) and L. cicera (Red Pea)
 Toxic principles: β-N-oxalyl-L-α,β-diaminopropionic acid (ODAP).
 Clinical signs: The onset may be either sudden or gradual with weakness of legs.
 There is muscular weakness, shifting of weights from one leg to another, stiffness
or stilted gait or both, paralysis of legs, paralysis of bladder and rectum muscles
and finally paralysis of laryngeal muscles leading to dyspnoea and roaring..
 Respiratory problems generally lead to death. Horses are more severely affected
than cattle.
 Treatment and management:
 There is no specific treatment of neurolathyrism. Symptomatic and supportive care
with skeletal muscle relaxants may help.

3. BRACKEN FERN POISONING/ PLANTS PRODUCING THIAMINE DEFICIENCY:

 Certain fern plants including Pteridium aquilinum (Bracken fern) contain
thiaminase enzyme that catalyses thiamine and produces vitamin B 1 deficiency in
animals.
 A similar thiaminase enzyme is also found in some other plants including the horse
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tail (Equisetum arvense), Australian fern and rock fern (mostly distributed in hilly
areas of the world.).
 Ingestion of significant quantities of bracken fern produces signs of acute
poisoning related to thiamine deficiency in monogastric animals and bone
marrow depletion (aplastic anaemia) in ruminants.
Toxic principles:
Bracken fern contains a number of toxic factors
 Thiaminase: Thiaminase produces thiamine (Vitamin B 1) deficiency in non-
ruminants.
 Aplastic anaemia factor: Ptaquiloside produces bone marrow suppression and
anaemia in cattle and sheep. Ptaquiloside suspected carcinogen for urinary bladder
tumor in cattle.
 Haematuria factor: Causing enzootic haematuria with haemorrhages.
 Quercetin: Quercetin acts a co-carcinogen produce malignant tumors in the mouth,
oesophagus and rumen in cattle.
Toxicity:
 All parts of the bracken fern plant are toxic.
 Horses and cattle are primarily affected by bracken fern poisoning, but toxic signs
are different.
 In horse it produces neurological signs but no anemia.
 In cattle it causes bone marrow depression leading to aplastic anemia.
Mechanism of action
 Toxicity of Bracken fern in non-ruminants is due to presence of thiaminase enzyme
which causes deficiency of thiamine/ vitamin B1 which characterized by CNS depression
and polioencephalomalacia.
 Horses and pi gs are m ost susceptible to the effects of thiaminase.
 Thiamine deficiency is generally not a problem of ruminant since the vitamin B1 is
synthesized in the rumen but the the toxicity in ruminants is mainly due to presence of
aplastic anaemia factor, ptaquiloside leads to development of tumours in the urinary
bladder.
 Cattle are most susceptible to the carcinogenic effects of bracken fern because they
have alkaline urine.
 In cattle, the compound quercetin acts as a co-carcinogen with papilloma virus to
produce malignant tumours in the mouth, oesophagus and rumen.

Clinical signs :
 Non-ruminants: In horses, clinical signs of thiamine deficiency occur after
consumption of fern for 1-2 months known as bracken staggers. Important signs
include emaciation, lethargy, anorexia, weight loss, incoordination and staggering
gait.

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 Animal stands with feet well spread and back arched. There is recumbency followed
by muscular tremors, cardiac irregularity, clonic spasms and opisthotonos.
 Horses may also show colic, haemoglobinuria, severe anaemia, hyperthermia and
tachycardia. If the animal remains untreated, death may occur in 2-10 days or in some
cases up to 30 days.
 Ruminants: Bracken fern poisoning seen in various forms depending on the quantity
and duration of exposure to the plant.
 In acute or subacute bracken poisoning, cattle develop severe bone marrow depression
that results in thrombocytopenia, anaemia, leucopenia and prolonged clotting time.
 There is often bleeding from body orifices. Affected animals are weak, anorexic,
pyrexic (106-110°F) and have pale mucous membrane with petechiae and clots of
blood in the faeces. The disease is mostly fatal with death occurring at 2 months.
 In calves, mostly laryngic form with excessive mucous discharge from mouth and
nostrils and oedema of throat region may occur with difficult breathing.
 In cattle, consumption of bracken fern for longer time results in chronic enzootic
haematuria characterized by intermittent haematuria and ultimate death due to
anaemia.
 In sheep, progressive retinal atrophy causing permanent blindness.
Post-mortem findings:
 In horses, no specific lesions are seen.
 Acute poisoning in cattle shows multiple haemorrhages throughout the carcass,
Necrotic ulcers in the GI tract. In chronic enzootic haematuria in cattle, the bladder
shows haemorrhages or tumors.
Diagnosis:
 It is made from history, clinical signs and PM lesions.
 Blood thiamine level in non-ruminants decreases to 2.5 µg/dl (Normal of 8.5 µg/dl),
while blood pyruvate level increases to 8.5 mg/dl (Normal of 2.0 mg/dl).
Treatment and management:
 Non-ruminants: Thiamine (0.1% solution) is given @ 5mg/kg, initialy IV at 3h
interval followed by IM route for several days. Then it should be followed by oral
supplementation for 1-2 weeks, although S.C. injection of 100-200 mg daily for 6
days is also successful.
 Cattle: No specific antidote is available for the bone marrow suppression and aplastic
anaemia.
 Other treatment includes Antibiotics, Animals should be removed from fern
predominate areas.
4. PLANTS PRODUCING OXALATE POISONING:
Sources:
 Oxalate poisoning in animals usually occurs after ingestion of oxalate containing
plants.

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 The principal oxalate containing plants belong to genera Halogeton (H. glomeratus),
Sarcobatus (S. vermiculatus or grease wood), Rheum Spp., Beta vulgaris (Sugar beet) and
Oxalis Spp.
Toxicity:
 Toxicity depends largely on species of animal, type of plant, form of oxalate present
in plant and duration of exposure.
 In general, oxalate poisoning is commonest in sheep and also occurs in cattle and
horses.
 Pregnant and lactating animals are more susceptible than others.
Toxicokinetics:
 When oxalate is consumed by a ruminant, it may undergo different pathways. It may be
degraded by rumen bacteria to form non toxic metabolites, it may be combined with
calcium or magnesium in rumen to form insoluble salt that is excreted faeces and/or it may
be absorbed from rumen into blood stream.
 Soluble oxalates readily combing with blood calcium and magnesium to produce
hypocalcaemia and hypomagnesaemia.
 Oxalates are also detoxified in the rumen and get converted to carbonate and
bicarbonate, which in excess can produce severe alkalosis.
Mechanism of action:
 Once the soluble oxalate has been absorbed into the body, it may produce toxicity
by number of ways:
 Oxalate forms a complex with serum calcium to form calcium oxalate which
causes hypocalcaemia.
 Hypocalcaemia interferes heart, muscles, and nerves activities, blood clotting
mechanism, interferes with milk production in lactating animals and bone growth in
pregnant animals.
 Deposition of insoluble calcium oxalate crystals in the renal tubules causes severe
renal tubular necrosis called oxalate nephrosis and death results from kidney failure.
 In some cases, oxalates get crystallize in brain tissues and cause symptoms of
paralysis and other CNS disorders. If oxalate accumulation in rumen epithelial lining
causes haemorrhages in the ruminal wall, in blood vessel .
 In rumen, Oxalates get converted to carbonate and bicarbonate and produce severe
alkalosis.
Clinical signs:
 Onset of clinical signs in sheep and cattle is noted within 2-6 hours of ingestion of
oxalate containing plants.
 Early clinical signs include dullness, reluctance to move, lowering of head, loss of
appetite, stasis of rumen motility and bloat.
 In acute poisoning, there is salivation, progressive weakness, incoordination, laboured
respiration, dilatation of pupil, twitching of muscles, tetany, convulsions and coma.

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Death mainly occurs due to shock within 9-12 hours of the onset of clinical signs.
 These signs are mainly due to oxalate induced hypocalcaemia.
 In swine, there is diarrhoea and severe GI haemorrhages.
 In subacute poisoning, there is stiff gait, frequent attempts to urinate and recumbency.
 Chronic poisoning primarily results from renal damage resulting in uraemia
(increased serum creatinine and BUN levels), albuminuria and sometimes haematuria.
Post-mortem findings:
 Oedema and haemorrhages of the rumen wall in ruminants and gastrointestinal
haemorrhages in swine.
 On examination of the cut surface of kidneys, oxalate crystals can be seen in the renal
tubules.
 Calculi may be found in urethral process of ram and sigmoid flexure of bull and ram.
Diagnosis:
 It is based on history, clinical signs and PM lesions.
 Suspected plants should be analysed for oxalate content.
 PCV decreases but BUN level may increase.
Treatment and management:
 There is no specific antidote available.
 Only supportive therapy is advised for treating nephrosis.
 Administration of calcium for correcting hypocalcaemia may be helpful.
 In early stages, calcium borogluconate- CBG @ 300-500 ml as 25% solution by IV or
SC in cattle has been found beneficial.
5. PLANTS PRODUCING PHOTOSENSITIZATION
 Photosensitization is a syndrome of abnormal sensitivity of the lightly pigmented
areas of skin to sunlight due to presence of photodynamic agent in the peripheral
circulation and skin.
 Among farm animals, it is rnost common in cattle and sheep.
Types of photosensitization:
 Photosensitization is of two major types: a) primary photosensitization and b)
secondary photosensitization.
Primary photosensitization:
 It occurs when a photodynamic agent is directly ingested or its metabolite which reaches
the skin and reacts with UV light to cause photosensitization.
 Plants containing polyphenolic pigments are capable of producing primary
photosensitization in animals.
 Primary photosensitization producing substances include hypericin (from Hypericum
perforatum / Saint John's wort), fagopyrin (from Fagopyrum esculentum / buck weed),
Ammi majus (Bishop's weed) and phenothiazene, sulphonamides, tetracyclines and
acridine dyes.
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 The photodynamic pigments are present at highest concentration in the green plant and
are readily absorbed from GI tract to circulate in the peripheral blood.
 In the non-pigmented skin they react with UV light to produce dermatitis and
photosensitization.
Secondary or hepatogenous photosensitization:
 It occurs due to ingestion of some substances that give rise to liver dysfunctions and/or
bile duct obstruction. Due to this obstruction the toxins goes to peripheral circulation and
give rise to photosensitization.
 It is most frequent type of photosensitization in livestock.
 It is cause by the photosensitizing agent "phylloerythrin" a bacterial breakdown product
of chlorophyll of plants.
 Normally phylloerythrine is removed by liver and is excreted in bile, but if the liver is
severely damaged or if the bile duct is occluded, the pylloerythrin accumulates in the
peripheral blood to cause photosensitization.
 Secondary photosensitization is caused by pyrrolizidine alkaloids containing several
plants (e.g. Lantana camara, Senecio spp. Crotolaria spp. and Heliotropium spp.),
mycotoxins (e.g. sporidesmin) and drugs (e.g. carbon tetrachloride and phenanthridium).
Mechanism of action:
 Three factors contribute to the development of photosensitization: presence of a photo
activating (photodynamic) substance in skin, exposure to UV light and lack of skin
pigment which enables more light to penetrate the skin.
 When photodynamic substance in the peripheral circulation exposed to ultraviolet light
leads to initiate chemical reaction in the skin and causes tissue injury, cellular membrane
damage and alters cell membrane permeability.
 Tissue destruction causes release of histamine from mast cells that initiates local
inflammatory reactions i.e. erythema, oedema, vesicles, intense pruritus and necrosis.
 The cells die in the photosensitization process and the affected skin eventually sloughs
off.
Clinical signs:
 Photosensitive animals are photophobic when exposed to sunlight.
 Animal feels discomfort and scratches or rubs lightky pigmented exposed areas of skin
like ears, eyelids, muzzle, face, back, udder and legs.
 Affected skin rapidly becomes reddened, painful and oedematous.
 If exposure to light ceases at this stage, the lesions soon resolve; if exposure is prolonged,
there is marked serum exudation, scab formation and skin necrosis.
 After 2-3 weeks, the necrotic skin becomes dry and the hair and skin slough leaving
ulcerated areas that may develop secondary bacterial infections.
 In cattle, exposure of the tongue may result in glossitis with ulceration and deep necrosis.
 In secondary photosensitization the affected animal shows depression, anorexia, weight
loss, and jaundice. Other signs of liver disease like abdominal distension, ascites and
diarrhoea may also be present.
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Post-mortem findings:
 PM lesions include superficial necrosis on the unpigmented skin. Extensive necrosis may
be found around eyes, muzzle, ears and other areas.
 The carcass may be emaciated and dehydrated and visible mucous membranes are
usually icteric.
 Liver may be enlarged, distended gall bladder and proliferation of bile ducts.
 Ascites may be present with gastroenteritis.
Diagnosis:
 Dermatitis limited to areas of non-pigmented skin indicated photosensitization.
 Identification of photosensitizing plants in the animals environment and food may help in
the diagnosis.
 Serum analysis for liver function enzymes and examination of blood, faeces and urine for
porphyrin should be considered.
 [Photosensitization differs from sunburn, in sunburn lightly pigmented skin slowly
becomes inflamed following exposure to ultraviolet rays].
Treatment and management:
 Treatment is only supportive & symptomatic.
 Primary photosensitization responds well to treatment, but success of secondary
photosensitization is usually doubtful.
 Removed Animal from photodynamic plants containing area and housed in shaded area
(away from sun light), provided shelter and fed inside.
 Corticosteroids, if given parenterally in the early stages, may be helpful.
 Antibacterial to prevent secondary skin infections.
 Hepatoprotectives, Saline purgatives,
 Fluid and electrolyte therapy in hepatogenous photosensitization.
6) LANTANA CAMARA POISONING
 Lantana camara is an ornamental plant.
 Among various varieties of Lantana camara, the red flowered variety is considerably
toxic.
 Lantana camara is one of the ten most toxic weeds in the world.
 Plant has pungent test, Animals generally eat this plant in drought conditions.
 Sheep is most susceptible species; however cattle, goats and camels are also susceptible
to lantana toxicity.
 Vernacular Names: G :Gandhati, E : Lantana, Wild sage
 Toxic Parts : Whole plant
 Toxic Principles: Lantadene A, B, C & D. Lantadene A is most toxic & considered as
hepatotoxic.
 Toxicity: Hepatotoxicity, Secondary photosensitization in grazing animals. It also causes
cholestasis.
 Clinical Signs:
 In lantana poisoning, animal becomes sluggish, faeces are soft and may contain
blood, and there is paralysis of limbs (in some cases). Death mostly occurs in a few
days due to extensive liver damage.
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 Post-mortem findings:
 Liver is icteric and greatly swollen, distended gall bladder and proliferation of bile ducts.
 Rumen contents are usually dry and undigested.
 Treatment:
 No specific antidote available, symptomatic.
 Kept animal in well shaded area, Give IV dextrose, Hepatoprotectives, activated charcoal
followed by saline purgatives,
 Antibacterial to prevent secondary skin infections, antihistaminics & fluid and
electrolyte therapy
7) SWEET CLOVER POISONING:
 Vernacular Names: E : Indian sweet clover
 Source: Sweet clover is of two types white and yellow.
 Melilotus alba is white and Melilotus officinalis is yellow.
 Toxic Parts: Contaminated hay and silage of whole plant
 Toxic Principle: Dicoumarol
 Mechanism of Action:
 The plant contain coumarine and is not toxic but when spoilage of sweet clover hay or
silage. Coumarin → Dicoumarol
 Dicoumarol contain hay or silage when feed to animal it prevent formation of
prothrombine lead to poor blood clotting and chance of excessive hemorrhage.
 Clinical signs:
 Coagulopathies, massive internal bleeding, GI haemorrhage. It may be evidence by
blood tinch vomition, saliva & faeces. Anemia, weakness, respiratory distress,
haemorrhage in and around brain, paralysis and death.
 Post Mortem Lesion:
 Hematoma formation, hemorrhage of various degree of digestive tract, Clotting of
blood is delayed. Poorly clot of blood in heart, blood vessels were observed.
 Treatment:
 Antidote is Vitamin-K1 (Synthetic Vitamin-K: Phytonadione) I/M or S/C. In cattle
dose: 1 mg/kg, b.i.d. for 2 days.
 Blood transfusion in emergency.
8) DATURA STRAMONIUM POISONING :
 Vernacular Names: G : Dhatura, E :Thorn apple, Jimson weed
 Atropine or scopolamine or tropane (alkaloid) found in solanaceae family plants.
 Sources: Datura stramonium (Jimson weed, thorn or mad apple)
 Atropa balladona → Atropine
 Solanum nigram & Solanum tuberosum
 Toxic Principles: Atropine, hyoscine, hyoscyamine and Scopolamine
 Toxicodynamic:
 Anticholinergic/ parasympatholytic in nature. It blocks muscarinic and nicotinic
receptors. Interact with muscarinic receptors not allowed to act Ach (Acetylcholine).
There for nerve impulse transmission not propogated and at high dose bind with

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autonomic ganglia and block nicotinic receptor at motor end plate and ganglion.
 Clinical signs:
 Depression, dry mouth extreme thirst, anorexia, dysphagia, ruminal atony,
constipation, occasionally blindness.
 Rabbits are resistant because atropinase present in liver which rapidly hydrolyse and
inactivate atropine.
 Tachycardia, restlessness, hypothermia, Insensible wandering. Relaxation of
sphincture, respiratory depression of the affected animal will give the appearance as
red, mad and crazy.
 Post mortem lesion:
 Congestion in meninges, haemorrhage in brain, presence of plant material in stomach,
marked congestion and oedema in lung.
 Diagnosis:
 Based on history, clinical sign, PM lesion and respond to therapy.
 Collect the urine of affected animal and drops of it putting in the one eye of cat. It will
cause mydriasis. Pupil will not constrict when exposed to light while untreated eye
pupil will constrict.
 Treatment:
 No any specific antidote available. Symptomatic care.
 Remove source of material, gastric lavage.
 Give parasympathomimetic agent like physostigmine.
 Give pentobarbital, Tranquilizer, Saline purgatives (no case atropine is given).
9) ABRUS PRECATORIUS POISONING :
 Vernacular Names: G: Chanothi, E: Indian Liquorice, Crab’s eye, Rosary Pea
 Abrus precatorious seeds are generally used to make beads in jewelleries.
 In cattle this poisoning is known as “sui or sutari” poisoning.
 Toxic Principles: Abrin, Abralin, Abrussic acid (similar to that of viper snake
venom)
 Toxicodynamic: Abrin which agglutinate RBCS. It is potent cytotoxin, inhibit the
protein synthesis in ribosomes.
 Seeds are toxic. One seed can kill a small sized dog.
 Clinical signs:
 Salivation, stiffness, incordination, muscular spasm, convulsion, affected animal die
within 2-4 days. It seed are taken orally by goat. It produces symptoms like loss of
appetite, bloody diarrhea, dysponea, loss of condition and recumbancy.
 Post-mortem lesion:
 Acute gastroenteritis, congestion of visceral organs and petechial hemorrhages
throughout the body.
 Treatment: saline purgative. Arecoline given to voided out unexposed material.
 Immunization by S/C administration of the anti-abrin serum antidotes
10) RICINUS COMMUNIS POISONING:
 Vernacular Names: G : Divela, E :Castor, S: Eranda
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 Toxic Principles: Ricin (Seed/ castor beans) & Ricinine (Leaves & fruits)
(Alkaloids).
 Toxicodynamic:
 Ricin inhibits the protein synthesis. It damage gut epithelium. Castor oil is not
poisonous but untreaed cake is toxic. Boiling of seed make them non toxic.
 Symptoms:
 Cow: Bloody diarrhea, colic, incoordination, tremors, salivation. If more
concentration of ricin than symptoms of GIT was observed. If ricinine is more than
CNS symptoms observed.
 Horse: Dullness, incoordination & profuse sweating. In severe case tetanic spasm,
diarrhoea without blood.
 Pig: Vomition & Diarrhoea
 Dog: Hemorrhage, gastroenteritis, cyanosis with fever, vomiting, convulsion and
death.
 Post mortem lesion:
 Fluidy/semifluidy contents of gut. Gastrointestinal hemorrhage. Trachea and bronchi
are filled with frothy oedematous fluid and swollen lymph node.
 Treatment: I/V fluid, emesis, gastritis lavage, GI demulcent, Broad spectrum
antibiotic. Vitamin-B complex, Prevent exudation.
 Antidote: Anti-ricin serum.
 In case oligouria give mannitol as a diuretics. Also give urinary alkalisors (sodium
bicarbonate) & Blood plasma expanders
11) STRYCHNOS NUX VOMICA POISONING:
 Vernacular Names: G : Jher kochlu, E : Snake wood/ Poison nut tree
 Toxic Principles: Strychnine (Seed), Brucine (Bark, leaves)
 Susceptible animal: Horse/Ruminants, poultry, Dog and cat by consumption of seeds.
 Mode of action:
 Spinal cord stimulant. Strychnine cause blockage of glycine (inhibitory
neurotransmitter) in CNS. Loss of inhibitory effect leading to uncontrolled excitation
of spinal cord.
 Clinical symptoms:
 Appear within 10 min to 2 hrs. Initially, nervousness, restlessness, muscle tremors,
convulsion, hyperirritability or intermittent tonic spasm in response to noise at
external stimuli. Touch & light also stimulate seizures, twitching are more prevalence,
spontaneous and continuous “tetanic seizures” & opisthotonus. Poisonous animal
remain conscious unless near to death. No vomition, body temperature is increase.
 Post mortem lesion: Non specific, except petenchial haemorrhage and find plant
material in stomach.
 Differential diagnosis from organophosphorus, tetanus toxin, carbon monoxide poisoning,
carbamate poisoning, 2,4-D zinc phosphide etc.
 Typical tetanic convulsion on external stimuli like touch.
 Treatment:
 No specific antidote available. Symptomatic rapidly treat.
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 Keep animal in cool and quite condition where no external stimuli like touch.
 If convulsion not started than remove plant material from stomach by gastric lavage. Give 2%
aqueous tannic acid or dilute HCl. OR 1:1000 potassium permanganate solution given (0.1%).
 Activated charcoal orally than lavage by saline purgatives.
 To control spasm give pentobarbitone 30mg/kg I/V in small animals. In large animals 7%
chloral hydrate I/V.
 Muscle relaxant, Diazepam also used as a tranquilizors.
 Artificial respiration may be given.
12) CALOTROPIS GIGANTEA POISONING:
 Vernacular Names: G :Akado, E :Swallow wart, Milk weed
 All parts of plants are toxic.
 Toxic Principles: Calotropin, Calotoxin, Calactin, Gigantin
 Toxicity sign: Cutenous and mucosal irritation, Acute Gastroenteritis, Abortions in pregnant
females and Cardiotoxicity.
 Irritation of skin and m.m., acute gastro intetritis and cardiotoxicity
 Treatment:
 Symptomatic and supportive.
13) GOSSYPIUM ARBOREUM / COTTON SEED POISONING:
 Vernacular Names: G : Rui, Kapas E : Cotton
 Toxic principle: Gossypol
 Seeds are toxic.
 Clinical signs: Gastroenteritis, anorexia, weakness, pulmonary oedema, dyspnoea in pigs and
horses. Myocardial degeneration and subsequent heart failure (in pre-ruminant calves). Cattle
exhibit anemia, haemolysis, dyspnoea, oedema of brisket, depression and death).
 Treatment:
 Remove the source of poisoning, antiarrhythmic drugs.
 Supplement the feed with iron (Fe).
14) PARTHENIUM HYSTEROPHORUS (CONGRESS GRASS) POISONING:
 Vernacular Names: G :Congress grass, E :Parthenium
 Toxic Principle: Parthenin
 All parts of plant are toxic.
 Mechanism of action: Produce primary photosensitization, liver damage and skin reactions.

 Clinical sign:
 Diarrhoea followed by skin lesions like itching, erythematous eruption, depigmentation.
 Treatment:
 Give antipruritics and antiseptics.
 Hepatotonics, animal immediately shift to normal fodder.

15) NERIUM INDICUM OR NERIUM OLEADER POISONING:

 Vernacular Names: G: Red Karen, E :Oleander [Thevetia peruviana is yellow Karen].
 Toxic Parts : Stem, Leaves
 Active principle: Neriodarine, oleandrine, neriene, olendeoside, nerioside.
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 Mechanism of action:
 Cardiotoxin interfere with sodium-potasium ATPase system.
 Induce Arrythmia and complete loss of myocardial contractility.
 Clinical sign: Two type of GIT & CVS.
 GIT : Anorexia, nausea, vomiting, colic and diarrhoea.
 CVS: Arrythmia, tachycardia followed by complete heart block.
 Treatment:
 Emetics, purgatives, activated charcoal.
 Sedatives, tranquilizers, Lidocaine
16) IPOMEA CARNEA POISONING:
 Vernacular Names: G :Naffatiyu, E :Morning glories
 Toxic Parts : Roots, Bark, Seed, Leaves
 Toxic Principles: Toxic saponin (in leaves)
 It also concentrate nitrate from the soil. It originally native to south America was introduced
in our country as an ornamental plant. It cause poisoning in calves, sheep and goats.
 Toxicity symptoms:
 Drastic purgation. hallucination, ataxia, staggering gait. Paralysis of limbs, hypotension and
death. Anaemia & lucopenia.
 Treatment:
 No specific treatment.
 Supportive therapy: Gastric lavage, saline purgative, fluid therapy.
17) NICOTINA TABACUM POISONING:
 Vernacular Names: G:Tamaku, Tambaku, E: Tobacco
 Toxic Parts : Leaves
 Toxic principle: Nicotine
 Toxicity sign: Excitement, respiratory paralysis, carcinogenic in chronic exposure, salivation,
hypertension, vomiting, diarrhea and coma.
 Mechanism of Toxicity: It initially stimulate than inhibit nicotinic cholinergic site in
automatic ganglia and myoneural junctions.
 Treatment: Symptomatic and supportive care

18) ALLIUM SEPA / ONION POISONING:

 Vernacular Names: G : Kanda, Dungadi, E :Onion
 Toxic principle: N-Propyl disulphide
 Mode of Toxicity: Haemolysis, Oxidant associated effects.
 Toxicity sign: Weakness, haemoglobinuria, jaundice, haemolytic anemia, characteristic onion
odour.
 Treatment: Symptomatic and supportive, Blood transfusion, Fluid Therapy

Veterinary Toxicology / Poisonous plants/ CVSc&AH, Anand/2019

POISONOUS PLANTS
(Toxicity of Plants)
Sorghum bicolor/ Sorghum vulgare

Vernacular Names: G :Jowar, E:Sorghum

Toxic Parts : Immature and fast growing plants, Leaves, Stems, Stalks
Toxic Principles: Cyanogenic glycosides, Hydrogen cyanide (HCN)
Toxicity: Excessive salivation, Lacrimation, Muscle tremor and Fasciculation,
Asphyxial convulsions, Death due to respiratory paralysis (Tissue anoxia).
Immature Sorghum

The acute onset, bright red m.m., bright cherry red

blood and bitter almond smell are indicative of cyanide
poisoning.
Sorghum
Lathyrus Spp.

Osteolathyrism

Garden sweet pea (Lathyrus odoratus)

Vernacular Names: garden sweet pea (L. odoratus) , Tiny pea (Lathyrus pusillus)
Toxic Parts : legume or seeds
Toxic Principles: β-N-(γ-L glutamyl)-amino propio nitrile (BAPN).
Toxicity: Weakening of the bones and blood vessel walls. Cattle are affected
showed lameness, pain and exostoses.
Lathyrus Spp.
Neurolathyrism

Lathyrus sativus- Indian pea Lathyrus cicera- Red pea

Vernacular Names: Indian pea (L. sativus) & Red pea (L. cicera).
Toxic Parts : legume or seeds
Toxic Principles: β-N- oxalyl L- α-β diaminopropionic acid (ODAP)
Toxicity: weakness of legs & muscles, weight shift from one leg to another, stiffness of
muscles, stilted gait, paralysis of legs, bladder and rectum muscles.
Death occurs due to respiratory failure. Horses are more susceptible
Pteridium aquilinum

Vernacular Names: E :Star grass, Common bracken, Bracken fern

Toxic Parts : Rhizomes, Fronds
Toxic Principles: Ptaquiloside, Thiaminase enzyme, Quercetin
Toxicity: Damages blood cells and destroys Thiamine (Vitamin B1), Carcinogenic
Photosensitization lesions on eye, nose, mouth, muzzle, face and skin
Photosensitization lesions on eyes, nose, mouth, muzzle, face and skin
Photosensitization lesions on skin
Lantana camara

Vernacular Names: G :Gandhati, E :Wild sage, Lantana weed

Toxic Parts : Whole plant
Toxic Principles: Lantadene
Toxicity: Hepatotoxicity, Secondary photosensitization.
Lantana camara
Lantana camara
Melilotus alba Melilotus officinalis
(White sweet clover) (Yellow sweet clover)

Vernacular Names: E : Indian sweet clover

Toxic Parts : Contaminated hay and silage of whole plant
Toxic Principles: Dicoumarol
Toxicity: Coagulopathies, massive internal hemorrhage, hematoma.
Datura stramonium

Vernacular Names: G :Dhatura E :Thorn apple, Jimson weed

Toxic Parts : Whole plant
Toxic Principles: Atropine, Hyoscyamine, hyoscine and Scopolamine
Toxicity: Severe mydriasis and painful photophobia, Hyperthermia and Tachycardia
(Parasympatholytic effects).
Abrus precatorius Sui or Sutari Poisoning

Vernacular Names: G: Chanothi, E: Indian Liquorice, Crab’s eye, Rosary Pea

Toxic Parts : Seeds
Toxic Principles: Abrin, Abralin, Abrussic acid
Toxicity: Hemolytic anemia, GIT irritation, Colic, Inhibits protein synthesis
Abrus precatorius
Ricinus communis

Vernacular Names: G : Diveli, E :Castor, S: Eranda

Toxic Parts : Seed
Toxic Principles: Ricin (Seed), Ricinine (Leaves & fruits)
Toxicity: Cathartic, Severe colic with bloody diarrhea.
Strychnos nux vomica

Vernacular Names: G:Jher kochlu, E:Snake wood/ Poison nut tree

Toxic Parts : Seed, bark, leaves
Toxic Principles: Strychnine (Seed), Brucine (Bark, leaves)
Toxicity: Spinal cord stimulant, muscle tremors, convulsion,
seizures, opisthotonus
Calotropis gigantea

Vernacular Names: G :Akado, E :Swallow wart, Milk weed

Toxic Parts : Whole plant
Toxic Principles: Calotropin, Calotoxin, Calactin, Gigantin
Toxicity: Cutenous and mucosal irritation, Acute Gastroenteritis,
Abortions in pregnant females and Cardiotoxicity.
Calotropis gigantea
Gossypium arboreum

Vernacular Names: G : Rui, Kapas E : Cotton

Toxic Parts : Seeds
Toxic Principles: Gossypol
Toxicity: Gastroenteritis, Diarrhoea, Labored and shallow breathing
Parthenium hysterophorus

Vernacular Names: G :Congress grass, E :Parthenium

Toxic Parts : Whole plant
Toxic Principles: Parthenin
Toxicity: Primary photosensitization, liver damage, diarrhoea
followed by skin lesions, depigmentation, itching, eruptions.
Nerium indicum
Nerium oleander

Red Karen
Vernacular Names: G :Karen, E :Oleander
Toxic Parts : Stem, Leaves
Toxic Principles: Nerioside, Oleandroside, Oleandrin, Neriene
Toxicity: Tachycardia, Arrhythmias, Colic, Diarrhoea, Seizures
Thevetia peruviana

Yellow Karen
Ipomoea carnea

Vernacular Names: G : Naffatiyu E : Morning glories

Toxic Parts : Roots, Bark, Seed, Leaves
Toxic Principles: Saponins, Scammonin (Jalapin), Turpethin, Pharbitisin
Toxicity: Drastic purgation, Hallucination, Ataxia, Staggering gait
Nicotina tabacum

Vernacular Names: G:Tamaku, Tambaku, E: Tobacco

Toxic Parts : Leaves
Toxic Principles: Nicotine
Toxicity: Excitement, Respiratory paralysis, Carcinogenic in
chronic exposure
Allium sepa

Vernacular Names: G : Kanda, Dungadi E :Onion

Toxic Parts : Whole plant
Toxic Principles: N-propyl disulphide
Toxicity: Weakness, haemoglobinuria, jaundice, haemolytic anemia
Medicinal Plants
Ocimum sanctum
Adhatoda vasica
Annona squamosa
(i) Synonyms: (E) Custard apple (H) Sitaphal (G)
Sitaphal
(ii) Active principles : Anonaine alkaloid
(ii) Parts used : Leaves, fruit, seed, root
(iv) Actions and uses: Antibacterial property,
Leaves made in to paste without adding water are
used in wound dressing.
Used in; Fruit: enriching blood, increasing
muscular strength, burning sensation, lessening
tendency to biliousness, retrieving vomiting.
Crushed leaves: tympany, bloat, foot and mouth
diseases, dewormer, dressing on wound with
maggots. Leaf juice: in broken horn.
Tinospora cordifolia
(i) Synonyms : (E) Gulancha tinospra, (H)
Gulanca, (G) Gulvel/Galo
(ii) Active principles : Alkaloids, starch.
(iii) Parts used : Stem
(iv)Actions & Uses : The stem is bitter, astringent,
thermogenic, anthelmintic, antispasmodic, anti-
inflammatory, antipyretic, antiemetic, digestive,
carminative, stomachic, cardiotonic, haematinic,
expectorant and aphrodisiac.
Used in vitiated condition of vata, burning
sensation, hyperdipsia, helmenthiasis, flatulence,
intermittent fevers, inflammations, gout, vomiting,
cardiac debility, skin diseases, leprosy, erysipelas,
anaemia, cough, asthma, general debility, jaundice,
seminal weakness, uropathy and splenopathy.
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TOXICITY CAUSED BY FOOD/FEED ADDITIVES AND PRESERVATIVES

 Food additives are non nutritive substances added intentionally to food generally in small
quantities to improve its appearance, texture and storage properties.
 Any substance intentionally added to food during production, processing, treatment,
packaging, transportation or storage.
 Salt has been used as a preservative for years.
 Food additives have to be tested for toxicity before they can be used and before humans
are exposed to them.
 Each food additive is assign a unique number to regulate its use and food safety. This
number is prefixed by “E” in European countries and without E in some other countries.
e.g. Benzoic acid is written as E210 on product label.
 This numbering is practiced in the international food trade.

Purpose of food additives

 To facilitate handling, distribution and preparation of food stuffs.
 To improve sensory & nutritive properties.
 To impart preservatives with antibacterial, antifungal or antioxidant properties
 To change physical characteristics, particularly for processing
 To change taste, colour, odour
 To preserve quality over extended period

Purpose of feed additives

 It favorably affects the characteristics of feed and animal products
 Colour of ornamental fish and birds
 Animal production, performance or welfare, particularly by affecting the gastro-
intestinal flora or digestibility of feeding stuffs or have a coccidiostatic effect
 Satisfy the nutritional needs of animals
 Environmental consequences of animal production

Classes of Food Additives

1) Anti-caking agents – Sodium aluminosilicate, calcium silicate
2) Anti-oxidants – Vitamin C, Propyl gallate, triethylcitrate
3) Colouring agents – Tartrazine, Amaranth
4) Emulsifiers – cholic acid, deoxycholic acid
5) Flavour agents – Methyl anthranilate, safrole
6) Sweeteners – Saccharin, sodium cyclamate, aspartame
7) Nutrient supplements- Vitamins and aminoacids
8) Preservatives – Benzoic acid, Sorbic acid, salicylic acid
9) Stabilisers and thickeners - Vegetable gums (Acacia & agar-agar)

Veterinary Toxicology / Toxicity of feed additives and preservatives /CVSc & AH, Anand/2019
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Classes of Feed Additives

1) Growth & performance enhancers
a) Ionophore antibiotics: Monensin, salinomycin and lasalocid
b) Non-Ionophore antibiotics: Tylosin and zinc bacitracin
2) Non protein nitrogen compounds- Urea, Ammonium compounds
3) Other: sodium chloride/common salt

Toxicity of Food/Feed Additives

 Tartrazine, a common colouring agent, may lead to urticaria in susceptible
individuals.
 Ascorbic acid is an irritant to skin and eyes and increase risk of urinary oxalate stone.
 Excessive urea causes ruminal alkalosis and toxicity due to ammonia release;
Excessive sodium chloride cause diarrhoea and cerebral oedema.
 Continuous and prolong administration of antibacterials through feed in farm animals
causes development of resistant strains of enteric bacteria.
 Saccharin at high doses in animals, lead to pathological changes (bladder tumors)
which were difficult to interpret as the kinetics are different at such high doses when
elimination becomes saturated.

Safety of Food/Feed Additives

 In general, food additives have proved to be safe and without chronic toxicity.
 Many were introduced when toxicity testing was relatively unsophisticated, and some
of these have been subsequently shown to be toxic.
 Thousands of food additives are in use worldwide and many have been introduced
with inadequate testing.
 The question of synergistic interactions between these compounds used as additives
has not been explored adequately.

Precautions to be taken while using feed additives in animal feed

 Use of feed additives requires safety precautions in order to minimize possible
adverse effect on animal and human health.
 Additives must be mixed in appropriate quantity and in a homogeneous way.
 Storage, production facilities and manufacturing equipment must be clean and in a
good state.
 The process flow within the manufacturing facility must be designed to minimize the
potential for contamination and carryover.
 Reasonable precautions must be taken against dust accumulation and other residual
materials in place of processing and storage.

Veterinary Toxicology / Toxicity of feed additives and preservatives /CVSc & AH, Anand/2019
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RADIATION HAZARDS

 Radiation toxicology is the study of adverse effects of radiations on living

organisms.
 Radiation is produced by disintegration of unstable naturally occurring or manmade
elements.
 Radiation have been utilized for many beneficial effects, but direct or indirect
exposure to ionizing radiation produces number of deleterious effects on animals.

Types of radiation:
 It is of two types: 1) Ionizing Radiation and 2) Non Ionizing Radiation

1) Ionizing Radiation
• It produces their effect by ionizing the biological molecules or atoms by knocking the
electrons out of their orbit.
• This process of electron removal from atoms by ionizing radiation produce two
electrically charged particles viz. negatively charged electron and positively charged
electron.
• Both of which are toxic and may cause damage to tissue.
• Ionizing radiation occurs as either particles (e.g. alpha, beta particles, positron,
neutron and proton) or electromagnetic rays (e.g. X-rays, gamma rays and UV rays)

2) Non- Ionizing Radiation

• Refers to any type of electromagnetic radiation that does not carry enough energy to
ionize atoms or molecules i.e. to completely remove an electron from atom or
molecule.
• Non-ionizing radiation is thought to be essentially harmless below the levels that
cause heating e.g. visible light, infrared, microwaves, radio waves & sun light.

Radiation units
 The effect of radiation depends on the amount received and the exposure time.
 The dose per mass of body tissue unit is the gray (Gy).
 1 Gy = 1 J/kg (Joule/kg)
 The older unit is RAD (Radiation Absorbed Dose)
 REM: Radiation equivalent Man

Factors affecting toxicity

 Mammalian cells are most sensitive during mitosis.
 Tissue with high rate of cell turnover are highly sensitive e.g. Intestinal epithelium
and hematopoietic system are highly sensitive.
 Young and old animal are more sensitive.
 Developing embryo and foetus are more sensitive compared to adult ones.

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Toxicity
• It can varies depend on the
• Type of radiation
• Magnitude of radiation dose
• Period of exposure
• A direct dose of > 5000 REM will be lethal to humans within 1 hour due to
CNS defect
• Age, sex, health status of the animal and degree of post irradiation care may
affect the toxicity.

Mechanism of action
• Mainly harmful due to biochemical changes in tissues that lead to physiological,
histological and genetic changes.
• Direct effects: Here, transfer of radiation energy directly to cell molecule/DNA.
• Beta rays
• Alpha rays
• X rays and gamma rays
• Indirect effects
• Ion pairs
• Formation of free radicals

Biological effects & clinical signs:

Two type of biological effects are there; 1) Non genetic effects and 2) Genetic effects

1) Non genetic effects

 It is due to radiation induced cell killings with the accompanying loss of function
for which it is responsible.
 Tissue with actively dividing cell tends to exhibit greater sensitivity to radiation.
 The severity of non genetic effects differ as per whether a person has received
whole body radiation or partial body radiation

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2) Genetic effects
• Damage to germ cell may result in genetic mutation which is expressed in next
generation
• Radiation induced hereditary defects may be dominant or recessive
• These genetic defects may lead to stillbirth, sex chromosomal abnormalities, major
congenital defects, tumors and leukemia.
PM Findings
 PM lesions may be on specific organ or system. Gastroenteritis, ulceration of
pharyngeal mucosa, pulmonary oedema, degenerative lesion in all organs,
hemorrhages and hematomas.
Diagnosis
• Based on history, clinical signs and P.M. lesions.
• Absolute lymphocyte count- most useful screening tool for radiation exposure
Treatment
• No specific treatment
• Only symptomatic and supportive treatment
• Antibiotics to treat secondary infection
• Fluid and electrolyte therapy
• Corticosteroids and antihistaminic creams for skin ulcer and inflammation.

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AIR POLLUTANTS
 Air pollution is mainly an urban problem. It originates from geographical, biological
and man-made sources.
 A number of gaseous agents cause toxicity.
 Primary pollutants: Carbon monoxide, carbon dioxide, sulphur dioxide, nitrogen
oxide, hydrogen sulphide and smoke cause toxic effects.
 Secondary pollutants includes ozone and peroxyacetyl nitrate.
 Five pollutants namely carbon monoxide (52%), sulphur dioxide (18%), hydrocarbons
(12%), particulate matters (10%) and nitrogen oxides (6%) accounts for almost 98%
of air pollution.
 Carbon monoxide is the most notorious and abundant pollutant present in the lower
atmosphere. It produced by incomplete combustion of hydrocarbon fuels mainly in
closed spaces.
 Carbon monoxide has high affinity to haemoglobin and forms carboxy-haemoglobin
and a decrease in the oxygen carrying capacity.
 Sulphur dioxide is a mild respiratory irritant and causes bronchoconstriction.

INDUSTRIAL TOXICANTS
 People who work in industries have the risk of exposure to chemicals.
 Mining has always been a hazardous occupation and miners suffer silicosis, while
asbestos workers suffer asbestosis and mesothelioma, and paper and printing workers
are prone to diseases of the skin.
 Exposure in the workplace may occur via any or all of the three major routes: by oral
ingestion, by inhalation and by absorption following skin contact.
 The most common routes of exposure are, however, via inhalation and skin contact.
 These routes of exposure apply to gases, vapours, aerosols, volatile solvents and other
liquids as well as to dusts and fibres.
 The toxic effects of industrial chemicals may be either chronic or acute.
 The acute inhalation of solvents in large quantities can cause asphyxiation,
unconsciousness or death.
 Inhalation of large quantities of very irritant substances, such as methyl isocyanate
may cause immediate bronchoconstriction and pulmonary oedema leading to death.
This was the toxicant responsible for Bhopal gas tragedy.
 In the work place exposure of the skin to some substances may cause local irritation
or contact dermatitis or other types of chronic skin disease.
 Some compounds may be absorbed through the skin and cause toxic effects in other
parts of the body. For example, the insecticide parathion causes fatal poisoning
following skin absorption.
 Some chemicals may act simply as irritants to the skin while others may act as
sensitizers.
 Skin sensitizers act through immunological mechanism to cause contact dermatitis
initially.
 The chemical may pass through the epidermis and react with proteins such as keratin,
to produce an antigen. This antigenic protein then initiates the production of
antibodies. Re-exposure to the substance will then initiate an allergic reaction.

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Asbestos
 Asbestos is a relatively inert substance but causes lung cancer (mesothelioma,
bronchial carcinoma) and asbestosis, a chronic lung disease.
 The fibres lodge in the lungs, are taken up by phagocytic cells which leak cell
contents and damage the surrounding tissue.
 Fibre size is a crucial factor in determining the toxicity.
Nickel
 Nickel and its salts are a well-known cause of contact dermatitis (nickel itch).
 This may result from occupational exposure and also from exposure to nickel in
jewellery.
Vinyl chloride
 High levels of exposure to vinyl chloride have occurred in manufacturing plants and
resulted in rare liver cancer developing some years later.
 Vinyl chloride also caused liver damage and effects on skin and bones.
Cadmium
 Cadmium is an element widely used in industry in various forms.
 Its toxic effects include kidney damage following oral or inhalation exposure, brittle
bones (Itai-Itai disease) and after chronic inhalation of cadmium fumes, lung irritation
and emphysema.

Aromatic amines
 A variety of aromatic amines are used in industry such as the production of rubber.
 A number of these are suspected or known to cause carcinogenicity such as 2-
naphthylamine.
 2-Naphthylamine can be detoxified by acetylation, therefore the slow acetylator status
is a factor and slow acetylators are more at risk from bladder cancer.
 Other aromatic amines used in industry are also carcinogenic or toxic in other ways
(jaundice, methaemoglobinaemia).

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RESIDUE TOXICOLOGY

WHAT IS RESIDUE?
 Residue is defined as parent compound (toxicants/drugs) or their metabolites that
may accumulate/deposit within the cells, tissues, organs or edible products (e.g. milk,
eggs, meat) of an animal.
 Residue also includes accumulation of elements like metals or other chemicals which
may be present in food due to natural circumstances or as a consequence of industrial
or agricultural activities
 Chemical residues may be found in animal tissues, milk or eggs following the
administration of veterinary drugs.
 Accidental exposure may also result in tissue residues.
 The total drug residue in the treated animal therefore consists of parent compound,
free metabolites and metabolites covalently bound to macromolecules.

TYPES OF RESIDUES
There are three types of residues.
1) Total residues
 It is determined by overall quantitative assessment of residual radioactivity after
administration of the labelled compound.
2) Extractable residues
 Fraction which can be extracted from biological tissues or fluids using various
solvents (water at varying pH, organic solvents) before and after denaturation of
macromolecules.
3) Non-extractable or bound residues
 The fraction of radioactivity that persists in tissue extracts after the treatment.

HAZARDS OF RESIDUE
Potential Hazards from Livestock Medicines
 Food safety can be compromised if livestock medicines or veterinary equipment are
misused or best practice is not adopted.
 Three main types of food safety hazards are associated with livestock medicines:
1) Chemical
2) Biological
3) Other/Physical
1) Chemical Hazards
 Drug residues can render a product (milk, meat) unsuitable or unsafe for its intended
use.
 Once a residue occurs it cannot be removed easily or at all.
 It is vital to be aware of and fully comply with the stated withdrawal dates for a
particular remedy.
 It is an offence not to observe the proper dose rate and withdrawal period stated on the
product label.
 It is illegal to sell animals or products before the withdrawal period for any animal
remedy administered has expired.
2) Biological Hazards
 Bacterial or parasitic resistance to drugs can pose an overall threat to human and
animal health.
 Resistance can occur if human or animal drugs are misused or overused.

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3) Other Hazards
 Producers should handle all veterinary medicines with care. Extra caution is required
for products where user contact with the medicine can readily occur. This includes
small animal dips, pour on medicines and certain vaccines.
 Unauthorised mixing of drugs together or administering certain drugs at the same time
could potentially cause harmful interactions for the animal. The stated withdrawal
periods may also be affected.
 Dirty needles can damage or blemish meat. Damaged or burred needles may also
damage meat and inflict pain to the animal. Do not inject animals in valuable meat
areas (e.g. loin, hind quarters)
 Careless storage or disposal of animal drugs can harm the environment. Particular
care is required with the disposal of animal waste.

WITHDRAWAL TIME
 The withdrawal time is the time from the end of treatment to the time it takes for the
residues of the drug to reduce below the safe concentration.
 Withdrawal times for the FDA approved drugs for use in food animals are only valid
for the specified species, dose, route and frequency of administration.
 They are also specific to the manufacturer’s product and formulation: thus, a drug
substance may have different withdrawal times when present in the differently
formulated drug products.
 The withdrawal period is the time required for the residue of toxicological
significance to reach a safe concentration.
 Withdrawal periods reflect the amount of time necessary for an animal to metabolize
an administered product and the amount of time necessary for the product
concentration level in the tissues to decrease to a safe, acceptable level.
Withdrawal periods for meat and milk
 Every approved drug for animal health has a withdrawal period printed on the product
label or package insert.
 Products carry meat withdrawal periods ranging from 0 to 60 days.
 Examples for meat range from: No withdrawal period with ceftiofur and 4-15 days
with different penicillin products. 28 days with pirlimycin.
 Animals treated with a product that has a withdrawal period of 45 days should be
withheld from sale or slaughter for at least 45 days.
 Withdrawal times are not the same for all drugs.
 Examples of withdrawal period for milk include:
Pirlimycin - 36 hours
Cloxacillin - 48 hours,
Amoxicillin - 60 hours,
Penicillin - 72 hours
 Milk produced during that period must be disposed off.

MRL (Maximum Residue Limit)

 MRL is the maximum amount of pesticide or drug residue that is legally permitted as
acceptable in food commodities and animal feeds.
 MRL must be proposed for the various edible tissues and produces in which the
residues of the substance concerned could occur.

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 The responsibility for keeping residues under the MRL lies with veterinary surgeons
and farmers, using licensed animal medicines.

Prevention of Residues
 It is the responsibility of many producers, veterinarians, professional and lay-person
associations and governmental agencies.
 Cure animal disease in a responsible manner in order to prevent accumulation of
harmful amounts of residues in the food safety.
 Antimicrobials should be used when indicated using antibiotics directed against the
causative agent.

Minimizing drug and toxic residues in animal products

The control systems for residue prevention should include the following measures:
 Identifying and tracking animals to which drugs were administered
 Maintaining a system of medication/treatment records
 Properly storing, labelling, and accounting of all drug products and medicated feeds.
 Obtaining and using veterinary prescription drugs only through a licensed veterinarian
 Veterinarians who practice food animal medicine have a great responsibility to ensure
that food of animal origin complies with pure food laws relating to their acceptable
levels of drug residues.
 Drugs not registered for animal use should not be used.

Veterinary Toxicology / Residue Toxicology /CVSc&AH, Anand/2019

FUNGAL & BACTERIAL TOXINS
Sr. Mycotoxins Sources Animal affected & Mechanism of Toxicity signs PM lesion Treatment
no. Imp. points Toxicity
1. Hepatotoxic Mycotoxins
a Aflatoxins Aspergillus Type: B1 & B2, G1 & Interact with N-  Acute toxicity: Liver is pale, Feed withdrawn,
flavus, G2 and M1 & M2. guanyl residues of Anorexia, Tremor, fibrosed and low fat and high
(Aflatoxicosis A. parasiticus Among all Aflatoxin nuclear DNA of Dypsonea ,Anemia firm, protein diet,
also called as B1 is most toxic. hepatocyte to  Hemorrhage, Bloody Microscopically therapy with
Turkey X  Ruminant are less inhibit synthesis centrilobillar multivitamins,
faeces
disease b/c susceptible than the of DNA, DNA  necrosis, bile 0.5% hydrated
first Chronic toxicity ( most
monogastric animals depended RNA common): duct proliferation sodium calcium
discovered in
turkey)
and poultry polymerase  Blindness, twitching of & veno- aluminosilicate as
(duckling). activity, messenger ear, grinding of teeth, occlution are the feed additive it act
[Note: B1 & B2-Blue RNA and protein  circling movement, main changes. as adsorbent,
fluorescence, G1 & synthesis.  frothing in mouth, Activated
G2- Green Aflatoxin 8, 9 photosensitive, charcoal, Vitamin
fluorescence and M1 epoxide is highly dermatitis, prolapse, E & Selenium.
& M2- excreted in reactive recumbency, convulsion,
milk]. metabolite. followed by death.
b Rubratoxins Penicillium Rubratoxin A & B. In hepatocyte bind Anorexia, depression, Necrotic foci on Remove
rubrum, B is more toxic, to cellular DNA & dehydration, colic, liver, contaminated feed,
Swine, goat, dog & RNA, Alter DNA, Horse shows profuse Hemorrhagic Symptomatic
P. horse are susceptible RNA polymerase bloody diarrhoea, enteritis, severe
purpurogenum function so inhibit incoordination & hemorrhagic
protein synthesis recumbency. necrotizing
and ATPase. hepatitis.

c Sporidesmin Sporodesmium Common in cattle and Potent hepatotoxic, Anorexia, jaundice, facial Swollen mottled Animal
bakeri Sheep damage liver and eczema, liver, thickened immediately
Ruminant graze on biliary epithelium photosensitization, bile duct wall. shifted to shaded
short pasture consume leading to bile duct dermatitis. In chronic case, area.
dead plant infested obstruction. So, liver become Hepatotonic,
with it get infection. phylloerythrin rough and antibiotics,
accumulation lead fibrosed. antihistaminic.
to
photosensitization.

VPT (Veterinary Toxicology), Vet College, Anand 37

FUNGAL & BACTERIAL TOXINS

2. Nepharotoxic Mycotoxins
a Ochratoxins Aspergillus Ochratoxin A is most Inhibit Anorexia, depression Enlarge, pale Remove
ochraceus, toxic. mitochondrial resp. abdominal pain, kidney, Enteritis, contaminated feed
Pigs & birds are most and oxidative polydipsia gastric ulcer, ,
Penicillium susceptible. phosphorylation polyurea, dehydration eodema, dilated, Activated
viridicatum and reduce ATP uremia. degenerated charcoal,
level, so damage to proximal renal Supportive
tubular cells and tubules. therapy
impair proximal
renal tubular
functions.
b Citrinin Penicillium Pigs are sensitive Cause nephrotoxic Watery diarrhea, Fatty infiltration Symptomatic
citrinum, effect increased feed in kidney &
consumption, decrease wt. liver,
P. viridicatum gain. Interstitial
nephritis

3. Oestrogenic Mycotoxin
a Zearalenone Fusarium Potent non-steroidal Enter to Porcine vulvovaginitis / Uterine and Withdrawn of
(F-2 toxin) roseum oestrogenic mycotoxin hypothalamus & Hyperesrogenic vaginal feed,
Pigs are most pituitary, react syndrome: Congestion & metaplasia Dehydrated alfa-
susceptible. with estrogenic edema of vulva & vagina, alfa meal (15%)
It also affects the receptor & cause Enlargement of vulva & reduces the
cattle, sheep and over-stimulation of uterus, uterine bleeding, absorption of
poultry. receptors. Abortion. mycotoxins,
PGF2α @5mg,
two day
4. Cytotoxic Mycotoxin
a Trichothece Fusarium spp., T-2 toxin most Penetrate cell lipid Acute: Vomiting, bloody Oral, esophageal Symptomatic
nes Trichothecium common, bilayers and inhibit diarrhea, lethargy, & ruminal
spp. Affect most of protein synthesis. hypothermia, shock erosion,
mammals Chronic: salivation, colic, hemorrhagic
infertility, poor wt. gain. enteritis.

VPT (Veterinary Toxicology), Vet College, Anand 38

FUNGAL & BACTERIAL TOXINS

5. Neurotoxic Mycotoxin
a Penitrem A Penicillium spp. Affect most of Not cleared, Dysponea, ataxia, Off fed, Sedatives,
mammals produce neurotoxic convulsion, tremors Symptomatic
effect.
6. Miscellaneous Mycotoxins
a Ergot Claviceps  Sclerotium is toxic Cause uterine & Gangrenous/ Gangrene of Off fed, saline
poisoning purpurea element. it is hard, vasoconstriction, chronic form: extremities, purgative,
(Parasitic black elongated body adrenergic Dry gangrene and slough Arterial spasm, sedative,
fungus) formed on grains & it blockade, of hooves, ears and tail. congestion, antibacterial,
contains substance – serotonin Nervous/acute ulceration and provide warm,
Ergot. antagonism, form: Hyper-irritability, necrosis of GIT. clean, stress free
 Active principle: medullary and excitability, muscular environment.
 Ergotamine, CNS stimulant incoordination, ataxia,
 Ergometrine, effect. convulsions and death.
Ergotoxin
BACTERIAL TOXINS
1 Botulinum Clostridium  Type: A to G Inhibit release of Paralysis of jaw, throat & CNS Polyvalent
toxin botulinum  A,B,C,F-Human Ach & produce limb muscles, haemorrhages & botulinum
botulism flaccid paralysis. constipation, urine congestion, antitoxin,
 B,C,D, E-animals retention, dysphagia, distended urinary Penicillin-G,
Resp. & cardiac paralysis, bladder. Supportive,
death
2 Tetanus Clostridium  Tetanospasmin, Inhibit release of Muscular stiffness & Non specific Tetanus antitoxin,
toxin tetani tetanolysin, glycine & GABA tremor, erected ear, Penicillin, animal
 Horse & human most causes excessive stiffness of tail, prolapsed kept at dark room
susceptible. spinal cord of third eyelid. Saw horse & quite place.
stimulation lead to stance appearance.
tetany.

VPT (Veterinary Toxicology), Vet College, Anand 39

1

TOXICITY CAUSED BY VENOMOUS BITES AND STINGS/ ZOOTOXINS

 Zootoxins are the toxin produced by lower animals e.g. snakes, scorpions, spider, wasp,
toads, fish, ticks, ants etc. Most of the zootoxins are composed of proteins (both low and
high molecular weight). They may be amines, lipids, steroids, amino-polysaccharides,
quinines, 5HT, glycosides etc.

 Venomous animals produce venom in a highly developed secretary gland or group of

cells and deliver the toxin (venom) during a stinging or biting act.

 Poisonous animal possesses a toxin within its tissue that can have deleterious effects
when ingested.

CLASSIFICATION OF POISONOUS ANIMALS

1) Poisonous reptiles e.g. snakes and lizards
2) Poisonous insects e.g. bees, hornets, wasps and ants.
3) Poisonous arachnids e.g. spiders, scorpions and ticks
4) Poisonous amphibians e.g. toads
5) Poisonous fishes e.g. tetrotoxic fish, ciguatera and scombroid fish

 Factor affecting toxicity :

o Species of the venomous animal
o Route of entry
o Location/site
o Quantity of venom injected
o Accumulation
o Absorption from the site, Distribution, Metabolism and Excretion (ADME) and
o Species of animals affected
 In general the zootoxins either affect the nervous system or the cardiovascular system.
The venom components selectively target important sites of the nervous system in either
agonistic or antagonistic manners. Toxins acting on the cardiovascular system affect the
hemostasis.
 Venoms often have profound effects upon blood coagulation, acting directly upon
important clotting factors either by inappropriate activation or through prevention of
activation.

1) SNAKE POISONING
 Snake bite in animals generally occurs while grazing or hunting.
 Most cases of poisoning reported in dogs and horses.
 Snake venom is a complex mixture consisting of amino acids, polypeptides,
glycopeptides and biogenic amines. The venom also contains an enzymatic portion and a
non-enzymatic portion. Toxicity due to snakebite may be of two types – neurotoxicity and
cardio or haemo toxicity. The enzymatic portion of the venom produces neurotoxicity. Of
the 3500 types of snakes available, only 400 types belonging to six families are toxic.

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 Factor affecting toxicity:

o Quantity of venom injected
o Proportion between the quantity of venom injected and the body size of the
animal to which the venom is injected
o Species of snake
o Location of the bite
o Species of animal involved, that horse is most susceptible, followed by sheep,
cattle, goat, dogs, pig and cats.
 Venoms of snakes contain necrotizing, anticoagulant, coagulant, neurotoxic, cardiotoxic
and haemolytic fractions.
 Cobra and krait venom is neurotoxic while viper and rattle venom is haemotoxic.
 Venomous snakes fall into two classes: 1) the elapines, which include the cobra, mamba,
and coral snakes; and 2) the viperines, (a) the true vipers (e.g., Russell’s viper) and (b)
the pit vipers (e.g., rattle snakes).
 There are 4 common poisonous snakes in India.
o Indian cobra (Nag),
o Indian krait (Kalotaro),
o Russel’s viper (Khadchitro) and
o Saw-scaled viper (Phoorso).

 Elapine snakes have short fangs and tend to hang on and ‘chew’ venom into their victims.
Their venom is neurotoxic and paralyzes the respiratory center.
 Viperine snakes have long, hinged, hollow fangs; they strike, inject venom (a voluntary
action), and withdraw.

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Clinical signs
 Severe local tissue damage and pain at bite site.
 Salvation, hyper excitability, mydriasis, asphyxia, gasping, recumbency, convulsions and
death in 2-4 hours. Regurgitation of ruminal contents, paralysis of the tongue, oesophagus
and larynx are noticed in ruminants.
Diagnosis:
 Diagnosis is based on sudden death, fang marks, local swelling and oozing of blood from
the site of bite. Typical pit viper bites are characterized by severe local tissue damage that
spreads from the bite site. The tissue becomes markedly discolored within a few minutes
and dark, bloody fluid may ooze from the fang wounds if not prevented by swelling.
Frequently, the epidermis sloughs when the overlying hair is clipped or merely parted.
Hair may hide the typical fang marks. Sometimes, only one fang mark or multiple
punctures are present. In elapine snakebites, pain and swelling are minimal; systemic
neurologic signs predominate.
Treatment
 Snake bite is an urgent emergency. In some cases, it is lethal in many it can cause
prolonged and disfiguring injury. Although the animal should receive veterinary care as
soon as possible, this should be done while keeping the animal as quiet as possible.
 Even if the snake is killed for identification purposes, caution must be exercised in
handling it after death. Envenomation is possible even after a poisonous snake has been
decapitated.
 Objectives of therapy are to neutralize the venom, prevent shock, and prevent secondary
infections; and sometimes to prevent the further spread of toxins, and remove the venom.
The use of alcohol to clean the wound is contraindicated because of its vasodilatory
effect, which would promote uptake and spread of venom.
 Includes administration of the specific anti-venom is the species of snake is known,
administration of polyvalent anti-venom if the species of snake is not known and
symptomatic.
 Broad-spectrum antibiotics should be given to prevent wound infection and other
secondary infections. Several potential pathogens, including Pseudomonas aeruginosa,
Clostridium spp., Corynebacterium spp. and staphylococci have been isolated from
rattlesnakes’ mouths. Antibiotics should be continued until all superficial lesions have
healed.
 Respiratory assistance (ventilator) may be needed for 48 - 72 hours for animals with coral
snake poisoning. The maintenance of a patent airway is critical. Large diameter tubing or
opened syringe cases are commonly placed in the nostrils of horses bitten on the face to
keep the airways open. Emergency tracheostomy may be required.
 Fluid therapy: Generally indicated in small animals. Hypotension is a common presenting
sign. Diuresis to facilitate excretion and renal damage has been reported to be useful in
man.
 Corticosteroids: Use is controversial. Useful in treating shock but increases in mortality
have been reported with their use. They can also alter results of laboratory tests that are
otherwise useful in monitoring an animal's progress. Generally used for prevention of
shock and hypotension. May not affect local swelling.
 Transfusions: Commonly indicated in dogs, if necessary, to treat anemia and hemorrhage.
 Tetanus antitoxin should always be given to the affected horse.
 Antihistamines have been reported to be contraindicated, but diphenhydramine
hydrochloride is frequently given along with antivenin to treat snakebite in humans.
Tranquilization in horses may be required.

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Therapies generally contraindicated

 Tourniquet - The use of tourniquets is controversial and usually they are avoided. When
used they are most effective in first 30 minutes. Tourniquets increase local tissue damage
due to hypoxia. The general location of snake bites (e.g., face) may prevent use.
Recommended only for animals in which the tissues below the tourniquet will be
sacrificed to save the animal's life.
 Incision and suction also controversial. Requires restraint of animal to be effective.
Minimal benefit with regards to the local removal of venom. Not recommended unless
pocket of venom will clearly be removable.
 Cryotherapy - Commonly associated with increased tissue damage. Not recommended.
 Surgical debridement - Use has not been substantiated. May result in serious scarring and
loss of function. May not prevent systemic signs. Not recommended early in course of
treatment for envenomation.

2) SCORPION POISONING
 There are approximately 1000 species of scorpions but only around 75 are clinically
important.

 The most potent venoms are low molecular weight proteins that affect the nervous
system.
 The nomenclature of scorpion toxins recognizes two general classes, alpha and beta-
toxins.
 Scorpion alpha-toxins induce a prolongation of the action potential of nerves and muscles
by slowing down the inactivation of the sodium channel with receptor affinity dependent
upon membrane potential, while beta-toxins bind to a receptor site distinct from that of
the alpha toxins with binding being independent of voltage.
Treatment:
 Specific antivenom available in some part of world.
 Cold compresses can be applied to relieve pain.
 Atropine can be indicated to control excessive parasympathetic manifestation.
 Calcium gluconate given to reduce muscle spasm.

3) SPIDER POISONING
 Spiders use their venom to paralyze prey while they eat victim’s body fluids.
 The venom of spiders is a complex mixture of neuroactive proteins and other chemicals.
 Toxic principle is proteins which include protease, hyaluronidase, sphingomyelinase D
and esterase. They have direct lytic effect on RBCs.
 The most venomous spiders in the world include Brown recluse spider, Hobo spider and
Black widow spider.

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 Some spider venoms can kill a mouse at a dose as low as 0.006 mg.
 The black widow species venom is made up of large proteins thought to affect the
transmission of calcium ions of nervous system cells.
 The initial sting of the bite is followed by muscle cramps, sweating and possibly
decreased blood pressure.
 There is no adequate treatment but the bite is seldom fatal.
 Spider venom is 10-15 times more potent than rattle snakes.
Signs
 The bite initially stings, and then any one of the two forms may take place.
o The cutaneous form begins as edema, progresses to an ulcerated wound.
o The viscera-cutaneous form, which is severe, produces hemolytic anemia,
hemoglobinuria, icterus and hyperthermia.
 Ninety percent of the cases heal in 1-3 weeks. Some may need skin grafting.
Mechanism of action
 Unidentified venom component is cytotoxic to endothelial cells. This triggers
intravascular coagulation and microthrombi formation within capillaries. Capillary
occlusion, hemorrhage, and necrosis occur.
 Polymononuclear leukocytes and complements play important roles in potentiating the
response to envenomation.
Treatment
 Specific black widow spider antivenin given in man and small animal by I/V route.
 Steroids may be used to protect against systemic effects.
 Hemolytic anemia can be managed by use of fluids and bicarbonate to minimize
hemoglobin deposition in renal tubules and by blood transfusion if anemia is severe
enough to justify.

4) WASP STING
 A sting from a wasp, like that of other large stinging insects such as bees, hornets and
yellow jackets, capable of triggering allergic reactions varying greatly in severity and
scope from a localized reaction limited to swelling of the regions where the bite occurred
to life-threatening systemic reactions in which the airway can swell and get closed.
 Stings by bees, wasps, hornets, and ants usually cause pain, redness, swelling, and
itching.

 The venom may contain histamine, serotonin, kinins and hyluronidase.

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6

 Allergic reactions are uncommon but may be serious. Allergic reactions may cause rash,
itching all over, wheezing, trouble breathing, and shock. In some cases, a red, swollen,
itchy patch develops instead of a blister. Isolated nerves may become inflamed, and
seizures may occur.
Treatment:
 Stingers should be removed as quickly as possible by scraping with a thin dull edge.
 An ice cube placed over the sting reduces the pain.
 A cream or ointment containing an antihistamine, an anesthetic, a corticosteroid, or a
combination of them is often useful.
 Severe allergic reactions are treated with epinephrine, intravenous fluids, and other drugs.
5) TOADS
 Toad venom, a defensive mechanism, is secreted by glands located dorsal and posterior to
the eyes and by other dermal structures, including warts.
 The venom, a thick, creamy white, highly irritating substance, can be expelled quickly by
the contraction of periglandular muscles in the skin.
 Its many components include bufagins, which have digitalis-like effects, catecholamines,
and serotonin. Bufo vulgaris is the commonly available toad.
 It inhibite Na+ K+ ATPase pump so excessive cardiac stimulation occur (digitalis-like).
 The parotid gland secretions of Bufo toads contain bufagins, bufotoxins, bufotenins, and
other compounds. Bufotoxins are conjugated bufagins. Bufagin's and bufotoxin's action
is described as digitalis-like, often resulting in ventricular fibrillation. Bufotenins have
oxytocic action and frequently a marked pressor action.
 Other compounds found in Bufo toxin are epinephrine, cholesterol, ergosterol and 5-
hydroxytryptamine (5-HT).

Clinical symptoms
 Signs vary according to the animal's age, concurrent disease, amount of toxin absorbed
and length of time since exposure. Signs of poisoning range from local effects to
convulsions and death
 There are three primary aspects to Bufo toxicosis:
o the cardiac glycoside-like effects of the bufagins;
o the pressor effects of the catecholamines and
o the hallucinogenic effects of the indole alkylamines.
Treatment
 There is no specific antidote available.
 The mouth should be washed well with plenty of water.
 Give activated charcoal and osmotic purgatives.
 Atropine may reduce the volume of saliva and the risk of aspiration.
 Give antihistaminics and sedatives.
 If bradyarrhythmias exist, atropine or dopamine should be considered; tachyarrhythmias
should be treated with lidocaine, phenytoin, propranolol, or procainamide hydrochloride.

6) FISH POISONING
 Tetrodotoxin is a bacteria-derived organic molecule assimilated into the tissues of the
pufferfish or into the modified salivary glands of the blue-ringed octopus.
 About 100 species of puffer fish use the powerful tetrodotoxin to discourage consumption
by predators.
 The puffer fish is the best known neurotoxic fish.
 Tetrodotoxinis found in all organs of the fish but is highest in liver, skin, and intestine.

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 Pufferfish may also have elevated levels of saxitoxin, a neurotoxin responsible for
paralysis in shellfish poisoning.
 Both saxitoxin and tetrodotoxin are heat stable and cooking does not reduce toxicity.
 Saxitoxin has a very different chemical structure to tetrodotoxin, but similar effects on
transport of cellular sodium; it produces similar neurological effects, but is less toxic that
tetrodotoxin.
 Tetrodotoxin causes paralysis by affecting sodium ion transport in both the central and
peripheral nervous system. so causes the membrane depolarization
 A low dose of tetrodotoxin produces tingling sensations and numbness around the mouth,
fingers, and toes.
 Higher doses produce nausea, vomiting, respiratory failure, difficulty in walking,
extensive paralysis and death.
 Ciguatera is fish borne poisoning of humans and pets caused by eating certain marine
fish that bioaccumulate a toxin called ciaguatoxin.
 Toxic signs are GIT distress, headache, ataxia and hallucination.
 Treatment involves only intestinal detoxification with gastric lavage and activated
charchol and artificial respiration.

7) TICK POISONING

 Tick paralysis is a paralytic disease in man, cattle, sheep and bison.

 Toxins are secreted by salivary glands of female ticks and type of toxin is neurotoxin.
 Ticks are not only carriers of a number of diseases but the saliva of some can cause
paralysis.
 The toxin causes paralysis of skeletal muscle by interfering with the release of Ach at
motor end plate.
 The first indication of tick bite is redness and swelling around the site of the bite.
 This is followed by neuromuscular weakness and difficulty in walking.
 Clinical sign observed after 3-7 days after attachment of ticks.
 If the tick is not removed eventual respiratory paralysis and death are noticed.
 Removal of the tick results in a quick recovery of function.
 Use ectoparasiticide to remove ticks.

8) ANTS POISONING
 Ants causes painful venomous sting.
 Formic acid is the primary constituents of ant venom.
 Toxicity is limited to the site of sting, causes haemolytic and cytotoxic action.
 Vesicles and pustules formation at site of sting.
 Wash the sing site with soap & water.
 Cold application and antihistaminic cream are helpful.

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