ORGANOPHOSPHATE POISONING

Anticholinesterases [Indirectly acting cholinergics] Reversible anticholinesterases

Carbamates
Physostigmine Neostigmine Pyridostigmine Edrophonium Ambenonium Demecarium Rivastigmine, Donepezil, Galantamine.

Acridine
Tacrine.

Irreversible Organophosphates

Carbamates

REVERSIBLE ANTICHOLINESTERASES-USES
MIOTIC

Glaucoma Reverse the effect of mydriatics Alternated with mydriatics-to break irido-corneal adhesions

REVERSIBLE ANTICHOLINESTERASES-USES
Postoperative paralytic ileus/urinary retension [Neostigmine] Postoperative decurarization [Neostigmine preceded by Atropine] Cobra bite [Neostigmine+Atropine] Belladona [Atropine] poisoning-Physostigmine Alzheimers disease-Tacrine, rivastgmine, donepezil, galantamine [cerebroselective]
Drug over dosage-e.g. TCA

Myasthenia gravis

Irreversible anticholinesterases
Organophosphates
Echothiophate used in glaucoma
Carbamates

Carbaryl
Propoxur

Parathion Malathion Diazinon Tabun Sarin Soman

Insecticides

Nerve gases

Entry into body

Transdermal Inhaled Ingested

Carbamylation and Phosphorylation

[Therapeutic] [Poisoning]

Reaction Very Slow Or irreversible

Organophosphorous compounds bind to acetylcholinesterase overabundance of acetylcholine in the synapse Enzyme+OP complex undergoes a conformational change (aging) renders the enzyme irreversibly resistant to reactivation.

OP Poisoning
Occupational Accidental Homicidal Suicidal Chemical warfare & terrorism

Paralysis

Types of toxicity
Acute cholinergic syndrome Intermediate syndrome [paralysis of proximal muscles] Delayed Neurotoxicity [OPIDN] In chemical terrorism & warfare

 Generally manifests in minutes to hours Evidence of cholinergic excess Parasympathetic-Sympathetic-Nicotinic

DUMBELLS=

SLUDGe =Salivation, Lacrimation, Urination, Defecation, Gastric Emptying. BBB= Bradycardia, Bronchorrhea, Bronchospasm.

Diarrhea , Diaphoresis Urination Miosis Bradycardia Emesis Lacrimation Lethargy Salivation

Management Acute toxicity

General supportive measures: Termination of exposure, copious washing , airway, respiration , oxygen, DIAZEPAM, tt shock Anticholinergics -Atropine i.v.[DOC] - Sufficent doses i.v. [For muscarinic effects]-till atropinization-maintained for 1-2 weeks Cholinesterase reactivators Pralidoxime - Sufficiently early i.v. [For Nicotinic effects]

Oximes-MOA
[Cholinesterase reactivators]

Pralidoxime[2-PAM] Obidoxime Diacetyl-monoxime[DAM]

Oxime phosphate diffuses

Oxime + Phosphorous

Oximes attach to anionic site

Oximes
Ineffective against carbamates-Anionic site is not free Contra indicated[carbamates]-intrinsic anti-ChE activity More effective at nicotinic Poor in muscarinic sites Not at all in CNS-does not cross BBB Not effective after phosphorylated enzyme under goes aging Atropine is the DOC-Oxime is secondary drug

Chronic OP poisoning
Fluorine compounds Polyneuritis and demyelination of nerves Sensory loss Motor loss LMN palsy Upper motor neurone paralysis Spasticity Mechanism not inhibition of ChE Takes years to recover

Nerve agents [Nerve gases]

These chemicals are liquid at room temperature, Phosphorus-containing organic chemicals (organophosphates) Weapons of mass destruction

Nerve gases
Miosis, profuse salivation, convulsions, involuntary urination and defecation and eventual death by asphyxiation Nerve agents can also be absorbed through the skin Or portal of entry into the body is the respiratory system Protection-full body suit in addition to a respirator.

Prophylaxis in battlefield
Soman [Irreversible] Pyridostigmine-prophylaxis [Reversible]

Oximes[Early] Frees enzyme

Ache Excess of Ach

Ache

Atropine Blocks receptors

Reversible Enzyme is freed Hydrolyzes excess of Ach

Binds to Cholinergic REC

Life threatening Cholinergic activity

CAUTION! The primary protection is protective clothing, masks, hoods etc Efficacy of pyridostigmine is dependent upon the rapid use of atropine and oxime after soman exposure Pyrido. should be stopped soon after exposure to nerve gas Pyridostigmine not effective if taken after or just before exposure

Nerve gases - Prophylaxis

Pyridostigmine bromide -pretreatment for exposure to the chemical nerve agent soman 30mg TID-several hours earlier Stopped immediately after gas exposure MOA-Reversible inhibition of a critical number of acetylcholinesterase active sites in the peripheral nervous system, protecting them from irreversible inhibition by Soman When the pyridostigmine-induced inhibition of the enzyme is subsequently reversed, there is a small residual amount of enzyme activity that is adequate to sustain life Not useful to give pyridostigmine either just before or during exposure to Soman

Gulf war syndrome

Approximately 250,000 of the 697,000 veterans who served in the 1991 Gulf War are afflicted with enduring chronic multi-symptom illness, A wide range of acute and chronic symptoms have included fatigue, loss of muscle control, headaches, dizziness and loss of balance, memory problems, muscle and joint pain, indigestion, skin problems, immune system problems, and birth defects. Nerve Gas?? Pyridostigmine??

Not a fatalistic attitude but a realistic wish

Chemical attacks will always be so severe that little can be done except to bury the dead History proves the opposite I WW[Mortality after exposure-1.7%] Tokyo subway Sarin [only 12 of 5500 who visited hospital died]

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