MALARIA CHEMOTHERAPY

Human malaria is caused by 4 species of

plasmodium
-Plasmodium Falciparum
-Plasmodium vivax
-Plasmodium Malariae
-Plasmodium Ovale
Serious complications and deaths are usually
caused by P. Falciparum.

P. Falciparum and P. Malariae have only

one cycle of liver cell invasion and
multiplication and liver cell invasion and
multiplication ceases spontaneously in
less than four weeks.
Treatment that eliminates erythrocytic
parasites will cure these infections.

P. vivax and P. Ovale infections cause dormant

hepatic stage, the hyponozites, and is not
eradicated by most and subsequent relapses
can therefore occur after therapy directed
against erythrocytic parasites.
Eradication of both erythrocytic and hepatic
parasites is required to cure these infections.

Radical cure involves elimination of both

hepatic and erythrocytic stages. There is
no single agent that can do this.
Causal prophylactic drugs are capable of
preventing erythrocytic infection.
All chemoprophylactic agents kill
erythrocytic parasites before they grow
sufficiently in number to cause clinical
disease.

CHLOROROQUINE
The use of Chloroquine for treatment of P.
Falciparum has been seriously
compromised by drug resistance. It
remains the drug of choice for the
treatment of sensitive P.falciparum and
other species of human malaria parasites.

CHEMISTRY
Chloroquine is a synthetic 4aminoquinoline.
It is formulated as phosphate salt for oral
use.

PHARMACOKINETICS
Rapidly and almost completely absorbed
from the G.I.T. It is rapidly distributed to
tissues.
Volume of distribution 100 to 1000 L/Kg.
It is slowly released from tissues and
metabolized.

It is mainly excreted in the urine with an

initial plasma half-life of 3 to 5 days but
has a longer terminal elimination half-life
of 1 to 2 months

ANTIMALARIAL ACTION
Blood schizonticide for all the four species.
Moderately effective against gametocytes
of P. vivax; P. ovale and P. malariae but
not those of P. falciparum.

MECHANISM OF ACTION
Probably acts by concentrating in the
parasite food vacuoles preventing the
polymerization of haemoglobin
breakdown product haem into
haemozoin and thus producing
parasite toxicity due to a build up free
haem.

RESISTANCE
Very common among strains of P. falciparum
and uncommon but increasing for P. vivax.
Resistance has been correlated with mutations
in a putative transporter
Choloroquine resistance can be reversed by
Verapamil; Desipramine and Chlorpheniramine
but clinical value of this has not been
established.

CLINICAL USES

Treatment of Mlaria.
Chemoprophylaxis.
Amoebic liver abscess- but not effective
against intestinal or other extrahepatic
amoebiasis.
Rheumatoid arthritis.

ADVERSE EFFECTS
Prurititis common in Africans.
Nausea; vomiting; abdominal pain;
headache; anorexia; malaise; blurring
vision and urticaria are uncommon.
Dosing after meals may reduce some of
these adverse effects

RARE REACTIONS
Include haemolysis in G6PD deficient
individuals..Impaired hearing; confusion;
psychosis; seizures; granulocytosis;
exfoliative dermatitis; bleaching of hair;
hypotension and ECG abnormalities (QRS
widening, T wave abnormalities ).

LONG TERM USE AS IN

RHEUMATOLOGY
Irreversible ototoxicity; retinopathy;
myopathy and neuropathy.
Large I/M or rapid I.V infusion of
chloroquine hydrochloride can result in
severe hypotension and respiratory and
cardiac arrest. Parenteral administration
should be avoided and if it must be given
then it must be infused slowly.

CONTRAINDICATIONS
Contraindicated in psoriasis or porphyria.
Should not be used in those with retinal or
visual field abnormalities or myopathy.
Should not be co-administered with
Kaolin; Calcium and Magnesium
containing antacids as well as all these
interfere with absorption of Chloroquine.
It is safe in pregnancy and in young
children.

AMODIAQUINE
Closely related to Chloroquine.
It has low cost; limited toxicities and in some
areas it is effective against Chloroquine resistant
strains of P. falciparum.
Recent re-evaluation has shown no serious
haematological toxicity from Amodiaquine and
some authorities now advocate its use a
replacement for chloroquine in areas with high
rates of resistance.

QUININE ANAD QUINIDINE

First line drug for falciparum malaria
especially severe disease though toxicity
may complicate therapy. Resistance to
quinine is uncommon.

CHEMISTRY
Quinine and Quinidine are Quinolinemethanols.
Quinine is an alkaloid purified from the
bark of the Cinchona tree. Quinidine is a
dextro-rotatory stereoisomer of Quinine
and is at least as effective in treatment of
severe falciparum malaria.

PHARMACOKINETICS
Quinine is rapidly absorbed from the G.I.T.
Widely distributed in body tissues.
Individuals with malaria develop higher
plasma levels of the drug than healthy
controls but toxicity is not increased
because of increased protein binding.

The plasma half-life is also higher in these

with severe malaria (T1/2 18 hrs) while in
healthy controls it is 11 hours.
Quinidine is less protein bound and has a
short T1/2.
Quinidine is primarily metabolized in the
liver and excreted in the urine

ANTIMALARIAL ACTION
Quinine is a highly effective blood
schizonticide against the four species.
It is gametocidal against P. vivax and P.
ovale but not P. falciparum.
It is not active against liver stage
parasites.
Resistance has been observed in South
East Asia.

CLINICAL USES

Parenteral treatment of severe

Falciparum malaria either Quinine
dihydrochloridr or Quinidine gluconate is
the treatment of severe Falciparum
malaria.Because of cardiac toxicity
Quinidine should be administered with
cardiac monitoring.

Oral treatment of Falciparum malaria

Quinine Sulphate for uncomplicated
falciparum malaria. It is commonly used
with a second drug (Doxycycline ) to
shorten Quinines duration of use (usually
to 3 days ).
Quinine is less effective than
Chloroquine against other human
malarias.

Malaria chemoprophylaxis:
A daily dose of 325 Mg is effective but is
toxic and hence not used.
Babesiosis:
Quinine is first line in combination with
Clindamycin in infection with Babesia
microti.

ADVERSE EFFECTS
In therapeutic dosage Quinine and
Quinidine commonly cause
(1)CINCHONISM ( tinnitus; headache;
dizziness; flushing and visual
disturbances ).
Prolonged therapy may cause- marked
visual and audotory abnormalities,
vomiting, diarrhoea and abnorminal pain.

(2) Hypersensitivity reactions ( rashes;

urticaria; angioedema and
bronchospasm).
(3)Haemolysis in G6PD deficiency,
leukopenia agranulocytosis and
thrombocytopenia).

(4)Hypoglycaemia due to stimulation of insulin

release A real problem in pregnancy where
the patient has increased sensitivity to insulin.
(5)Quinine stimulates uterine contractionI.V
infusion may cause thrombophlebitis.
(6)Black water fever.rare ..There is marked
haemolysis and haemoglobinuria. It may be
due to a hypersensitivity reaction to the drug.

MEFLOQUINE
CHEMISTRY:
Mefloquine hydrochloride is a synthetic 4Quinoline methanol

PHARMACOKINETICS
Well absorbed from G.I.T ( causes severe
local irritation if given parenterally ).
Highly protein bound; extensively
distributed to tissues
Terminal half life is 20 days..Mefloquine
and acid metabolites of the drug are
slowly excreted mainly in the faeces. The
drug may be detected in the blood for
months after completion of the therapy.

ANTIMALARIAL ACTION
Strong schizonticidal activity against P.
falciparum and P. vivaxNot active
against hepatic stages.

ADVERSE EFFECTS
When given weekly for chemoprophylaxis
adverse effects include nausea; vomiting;
dizziness, sleep and behaviour disturbances,
epigastric pain diarrhoea, abdominal pain
headache and rashSeizures---rare.
Leukopania and thrombocytopenia and
aminotransferase have been reported.
Dysrhythmias and bradycardia have also been
reported.

CONTRAINDICATIONS
If there is history of epilepsy, psychiatric
disorder; dysrhythmias, cardiac
conduction defects.
It should not be co-admnistered with
Quinine; Quinidine or Halofantrine.

PRIMAQUINE
Drug of choice for eradication of dormant
liver forms of P. vivax and P. ovale.

CHEMISTRY
Primaquine phosphate is a synthetic 8Aminoquinoline

PHARMACOKINETICS
Well absorbed from G.I.TWidely
distributed to tissues but only small
amount is bound to tissues.
Its plasma half-life is 3 to 8 hours.

It is rapidly metabolised and excreted in

the urine. The 3 major metabolites have
less antimalarial activity but more potential
for inducing haemolysis than the parent
compound.

ANTIMALARIAL ACTION
Primaquine is the only available agent for
the dormant hypnozoites stages of P.
vivax and P. ovaleIt is also gametocidal
against the four human malaria species
It has a very weak action on erythrocytic
stage parasites.

Mechanism of action is unknown

Resistance has been reported in some
areas and this is overcome by increasing
the dose.

CLINICAL USES
RADICAL CURE OF ACUTE VIVAX AND OVALE
MALARIA:

Chloroquine is included to eradicate the

erythrocytic forms while Primaquine
eradicates liver hypnozoites.

TERMINAL PROPHYLAXIS OF VIVAX AND OVALE

MALARIA:

Primaquine is used after the

completion of travel to an endemic
area

CHEMOPROPHYLAXIS OF MALARIA

.Not recommended.
Daily treatment with 0.5 Mg/Kg of base
provide good levels of protection against
Falciparum and vivax malaria. However
studies are limited and there are
potential toxicitiesPrimaquine is not
recommended routinely for prophylaxis.

GAMETOCIDAL ACTION:

A single dose ( 45 Mg base ) will render P.

falciparum gametocytes non- infective to
mosquitoes and disrupt transmission.

PNEUMOCYSTIS CARINII INFECTION:

A combination of Clindamycin and

Primaquine is an alternative regimen for
treatment of pneumocystisis.

ADVERSE EFFECTS
Nausea, epigastric pain, abdominal
cramps and headache.
Serious but rare side
effects..Leukopenia; agranulocytosis;
leukocytisis and cardiac arrhythmias.
Haemolysis and methaemoglobinamia in
G6PD deficient individuals.

INHIBITORS OF FOLATE
SYNTHESIS
PYRIMETHAMINE:
CHEMISTRY:
Is a 2,4 diaminopyridine related to
Trimethoprim

PHARMACOKINETICS

It is adequqtely absorbed from the G.I.t.

It is bound to plasma proteins.
Has an elimination half-life of 3 to 5 days.
It is extensively metabolized before
excretion.

PROGUANIL:
It is a biguanide and a pro-drug, its triazine
metabolite CYCLOGUANIL is active.

FANSIDAR:
Is affixed combination of Sulphonamide
Sulphadoxine ( 500 Mg per tablet) and
pyrimethamine ( 25 Mg per tablet ) .

METAKELFIN:Is a fixed combination of

Sulphametopyrazine and Pyrimethamine.

MALOPRIM:
Is a fixed combination of Dapsone and
Pyrimethamine.

ANTIMALARIAL ACTION
Pyrimethamine and Proguanil act slowly
agaist erythrocytic forms of all four human
malaria parasites.

PROGUANIL
Has some activity against hepatic forms.
Neither drug is adequately gametocidal or
effective against persistent liver stages of
P. vivax or P. ovale.
Sulphonamides and Sulphones are
weakly active against erythrocytic
schizonts but not active against liver
stages or gametocytes. They are effective
when combined with other drugs.

MECHANISM OF ACTION
Pyrimethamine and Proquanil inhibit
plasma dihydrofolate reductase.
Sulphonamides and Sulphone inhibit
dihydrofolote synthatase.
The fixed combinations provide a
sequential block.

CLINICAL USE

Chemoprophylaxis:
Combination- Chloroquine 500 Mg
weekly plus Proquanil ( 2000 Mg daily )
Treatment of Chloroquine resistant
Falciparum malaria.

Fansidar- but should not be used for

severe malaria as it is slower
acting..Can be used as an adjunct to
Quinine therapy to shorten the course of
Quinine.Not effective in vivax malaria
and its usefulness in ovale and malariae
has not been adequately studied.

Presumptive treatment of Falciparum

malaria.for travelers who develop fever
while traveling in malaria endemic
regionsAlternative presumptive
regimen are Quinine and Mefloquine.
Toxoplasmosis:Pyrimethamine in
combination with Sulphadiazine.

Pneumocystosis:.Trimethoprim plus
SulphamethoxazoleToxicities.Nausea,
vomiting; fever, rash; leukopenia, elevated
hepatic enzymes; azotemia, anemia and
thrombocytopenia.

ADVERSE EFFECTS
Mouth ulcers and alopecia have been
described with Proquanil.
Fansidar causes uncommon but severe
cutaneous reactions including erythema
multiforme, Stevens-Johnson syndrome
and toxic epidermal necrolysis. Severe
reactions appear to be much less common
with single dose therapy.

Maloprim is no longer recommended for

chemoprophylaxis because of its
unacceptably high rates of
agranulocytosis.
Fansidar may be used in pregnancy for
therapy and as an intermittent
chemotherapeutic agent.

ANTIBIOTICS
Tetracycline and Doxycycline are active
against erythrocytic schizonts of all human
malaria parasites. They are not active
against liver stages
Doxycycline is usually combined with
Quinidine or Quinine in the treatment of
Falciparum malaria thus allowing a shorter
and better tolerated course of Quinine.

DOXYCYCLINE ..SIDE EFFECTS

G.I.T. symptoms, candidal vaginitis and
photosensitivity.
Clindamycin. Azithromycin;
Fluoroquinolone.have antimalarial
activity and are studied as an alternative
therapeutic drugsFluoroquinolones have
antimalarial activity but efficacy is
suboptimal.

MECHANISM OF ACTION
The antibiotic may inhibit protein synthesis
or other functions in plasmodial
mitochochondrion and plastid.

HALOFANTRINE AND
LUMEFANTRINE
Halofantrine hydochloride is a
phenanthrene methanol related to Quinine
Halofantrine is effective against
erythrocytic stages of all four human
malaria species.
It is not effective against hepatic stages or
gematocytes.

PHARMACOKINETICS
Variable oral absorption but enhanced with
foodBut because of toxicity it should not
be taken with meals.
Plasma half-life is 4 days and the drug is
excreted mainly in the faeces.

MECHANISM OF ACTION
Not known.

ANTIMALARIAL ACTION
It is rapidly effective against most
Chloroquine resistant strains of P.
falciparum; but use is limited by irregular
absorption and cardiac toxicity and it
should not be used for chemoprophylaxis.

FOR TREATMENT OF P.
FALCIPARUM.Halofrantrine is given
orally in 500Mg doses at 6 hourly intervals
for 18 hours. The course is repeated in
one week for non-immune individuals.

ADVERSE EFFECTS
Abdominal pain, diarrhoea, vomiting,
cough rash, headache, pruritus and
elevated liver enzymes. It is embryotoxic
in animals; should not be given in
pregnancy.

ARTEMISININ( QINGHAOSU )
Derivatives Artesunate ( water soluble )
useful for oral, intravenous, I/M and rectal
route) and
Artemether ( lipid soluble; useful for oral
I/M and rectal administration )

PHARMACOKINETICS
They are rapidly absorbed; rapidly metabolized
to the active metabolite..Dihydro-artemisinin
with plasma half-life of 1 to 3 hours.
Artemisinin and analogues are rapidly acting
schizonticides agaist all human malaria
parasites but have no effect on hepatic stages.
The drugs are useful in multi-resistant P.
falciparum malaria and they are the only drugs
notably effectve against Quinine resistant
strains.

Two other analogues under study are

ARTEETHER and ARTELINIC acid.

ADVERSE EFFECTS
Nausea vomiting and diarrhoea.
Neurotoxicity has been seen in animals
treated with doses much higher than those
used for malaria.
LUMEFANRTINE has less cardiotoxicity
than Halofantrine and is available in
combination ARTEMETHER.