ANTICHOLINESTERASE ORGANOPHOSPHATES

PHARMACOLOGY PPT by Dr. Geraldine Corporal

 Irreversible inactivation of acetylcholinesterase, leading to
accumulation of acetylcholine (like myasthenia gravis).
OBJECTIVES  Tetraethyl pyrophosphate (TEPP) – Clemont (1845)
 Insecticides:
 Discuss anticholinesterase agents – its mechanism of action,  Parathion, Malathion
pharmacodynamics, and pharmacokinetics.  Sarin, Soman, Tabun, DFP – chemical warfare
 Discuss therapeutic uses of anticholinesterase agents.
 Formulate treatment plan for anticholinesterase toxicity.

ANTICHOLINESTERASE 3 CATEGORIES OF ORGANOPHOSPHATE POISONING

Muscarinic Nicotinic effects CNS effects
 Drugs that inhibit acetylcholinesterase. effects
 Acetylcholine accumulates – parasympathetic effects predominate. S – salivation Muscle fasciculations Anxiety
L – lacrimation Cramping Emotional liability
U – urination Weakness Restlessness
D – diarrhea Diaphragmatic failure Confusion
G – GI upset Ataxia
E - emesis Tremors
Seizures
Coma
Apnea

 Physostigmine (Eserine)
 Alkaloid from calabar or ordeal bean (Physostigma
venosum) in West Africa.
 Treatment for glaucoma – first therapeutic use by Laquer
(1877).
 Neostigmine
 Stimulant of GIT
 Treatment for myasthenia gravis (1931)

CASE

Ac, 50-year-old farmer with a history of alcohol abuse and depression is

brought to the emergency department semi-conscious. He has pinpoint
pupils, and has large amounts of secretions pouring from his mouth. His
heart rate is 50 bpm, bp 90/60 mmhg, and oxygen saturation 65%. His chest
has widespread crackles and rhonchi. Fine fasciculations are apparent in his
peri-orbital, chest, and leg muscles. He has been incontinent of urine and
faeces.

Pertinent points?

Primary considerations?

Other points in history to ask?

A bottle of Malathion was found beside him by the medic. His 7-year old
nephew saw him ingesting something from the bottle.

Diagnosis: organophosphate poisoning

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Neuromuscular junction Severe intoxication
 Fatigability/ generalized  Extreme salivations
weakness  Involuntary defecations/
 Involuntary twitchings urination
 Scattered fasciculations  Sweating
 Paralysis  Lacrimation
 Respiratory paralysis – most  Penile erection
serious, usual cause of death  Bradycardia/ hypotension
with cardiovascular
components

What can be given to treat AC the farmer?

Treatment for Anticholinesterase toxicity

Atropine Pralidoxime (2-PAM) / HI-6
 No effect on neuromuscular  Reverse neuromuscular
compromise. compromise
ANTICHOLINESTERASE PHARMACOLOGICAL PROPERTIES
 Initial: 2-4 mg IV  1-2 mg IV not <5 mins.
Stimulates Blocked by
 Muscarinic receptor  Atropine
 2 mg every 5-10 mins until Recurrence after 20-60 mins
 Nicotinic receptor (Muscarinic muscarinic symptoms – dose repeated
 CNS antagonist) disappear.
If they reappear or until signs
of atropine toxicity appears.
Eye GIT  Muscarinic antagonist, large
 Miosis  Increased gastric dose to reach CNS.
 Blocked accommodation contractions and secretions
reflex (focusing to near  Increased Esophageal tone
vision) and peristalsis DELAYED NEUROTOXICITY
 Decreased IOP (Facilitation of
outflow of aqueous humor)  Agent
Neuromuscular junctions Secretory glands  DFP
 Excitations and fasciculations  ↑Increased secretions of:  Mipafox (Fluorine-containing)
of muscular fibers.  Bronchial  Triorthocresyl phosphate
 Reverse paralysis of non-  Lacrimal  Manifestations
depolarizing muscle relaxant  Sweat
 Mild sensory disturbances
but not depolarizing muscle  Saliva
relaxant (succinylcholine).  Intestinal  Ataxia
 Weakness
 Muscle fatigue and twitching
↑ACh ↑ Epinephrine ↑HR  Reduced tendon reflexes
Bradycardia + Hypoxemia Severe Acetylcholinesterase  Tenderness to palpation
bronchoconstriction poisoning  Toxicity not due to inhibition of Acetylcholinesterase
= Hypoxemia  Linked to Neurotoxic esterase
 Recovery: requires several years, may be incomplete.
TOXICOLOGY OF ORGANOPHOSPHATE POISONING THERAPEUTIC USES OF ANTICHOLINESTERASE AGENTS
Paralytic Ileus: Atony of the Glaucoma
 Accidental intoxication; homicidal and suicidal purposes
Urinary bladder
 80% of pesticide-related hospitalizations
Neostigmine (Prostigmin – oral, ↑IOP leading to damage of optic
 200, 000 deaths per year (WHO) parenteral) disc resulting to irreversible
 Duration of toxic symptoms”  0.5 mg SC – peristaltic damage.
 Properties of compounds activity in 10-30 mins Anticholinesterase agents:
 Lipid solubility  15-30 mg PO – effects in 2-4 Effective in Primary (narrow-angle
 Stability of organophosphate-AChE bond hours and wide-angle glaucoma) and
 Time of death: <5 minutes to nearly 24 hours depending on the dose,  Contraindications: Secondary (aphakic glaucoma
route, agent, and other factors.  Intestinal and urinary following cataract extraction)
obstruction
Vapors/ aerosols Ingestion  Peritonitis
Ocular GI symptoms  Viability of bowel is
 Miosis  Anorexia doubtful
 Ocular pain  Nausea and vomiting  Inflammatory bowel
 Conjunctival congestion  Abdominal cramps disease
 Diminished vision  diarrhea
 Ciliary spasm
 Brow ache
Respiratory
 Chest tightness
 Wheezing
(bronchoconstriction with
bronchial secretions
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THERAPEUTIC USES OF ANTICHOLINESTERASE AGENTS:
Myasthenia Gravis
Edrophonium test
Neuromuscular disease Rapid injection of 2mg Edrophonium
caused by autoimmune chloride, followed by 45s later by
Abs against ACh receptor additional 8 mg if first dose is without
at the post-junctional end effect.
plate.
Positive response: Brief improvement in
Weakness and marked strength unaccompanied by lingual
fatigability of skeletal fasciculations (generally occurs in non-
muscle. myasthenic patients.
Treatments
Glucocorticoid:
Pyridostigmine, Promotes clinical improvement.
Neostigmine, and
Ambenomium: Thymectomy:
Preserve endogenous ACh Associated thymoma.
- ↑ response of Disease is not controlled by
myasthenic muscle to anticholinesterase and steroids.
repetitive nerve impulses.

Pyrolaxis in cholinesterase inhibitor poisoning

Persian Gulf war (1990)

Large scale of administration of Pyridostigmine in soldiers in anticipation
of nerve-agent attack.
30 mg q8 PO
Long term follow up: low incidence of Persian Gulf War syndrome
 Impaired cognition
 Ataxia
 Confusion
 Myoneuropathy
 Incontinence in soldiers given Pyridostigmine.
Pyridostigmine
FDA approved for prophylaxis against Soman – rapidly ages following
inhibition of cholinesterase.

THERAPEUTIC USES OF ANTICHOLINESTERASE AGENTS:

Alzheimer’s disease

Deficiency of intact cholinergic neurons.

Treatments
Tacrine Mild to moderate Alzheimer’s disease
Limitation due to hepatotoxicity.
Donezepil Side effects:
Nausea
Vomiting
Diarrhea
Rivastigmine Long-acting carbamoylating inhibitor
Galantamine

SUMMARY

 Anticholinesterase agents:
 Pyridostigmine
 Neostigmine
 Organophosphates
 They inhibit acetylcholinesterase, resulting to accumulation of
acetylcholine – predominance of parasympathetic effects.
 Therapeutic uses
 Treatment of paralytic ileus
 Atony of the urinary bladder
 Glaucoma
 Prophylaxis in cholinesterase inhibitor poisoning
 Alzheimer disease.
 Organophosphate poisoning treatment:
 Atropine (muscarinic antagonist)
 Pralidoxime (reverses neuromuscular compromise)
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