Pharmacology of cholinergic system Class 3 OP Poisoning

8/3/2019 Pharmacology of cholinergic system Class 3 OP Poisoning

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ORGANOPHOSPHATE

POISONING
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Anticholinesterases

[Indirectly acting cholinergics]

Reversible anticholinesterasesCarbamates Acridine

Tacrine.

Physostigmine Neostigmine

Pyridostigmine

Edrophonium

Ambenonium Demecarium

Rivastigmine,

Donepezil,

Galantamine. Irreversible

Organophosphates Carbamates


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REVERSIBLE

ANTICHOLINESTERASES-USES

MIOTIC

Glaucoma

Reverse the effect of mydriatics

Alternated with mydriatics-to

break irido-corneal adhesions


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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


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Irreversible anticholinesterases

Organophosphates Carbamates

Carbaryl

Echothiophate used in glaucoma Propoxur

Parathion

Malathion

Diazinon

Tabun

Sarin

Soman

Insecticides

Nerve gases


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Entry into body

Transdermal

Inhaled

Ingested


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Carbamylation [Therapeutic]andPhosphorylation [Poisoning]

ReactionVery Slow

Orirreversible


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Organophosphorous

compounds bind to acetylcholinesterase

overabundance ofacetylcholine in the synapse

Enzyme+OP complex undergoes a conformational

change (aging) renders the enzyme irreversibly

resistant to reactivation.


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OP Poisoning

Occupational

Accidental

Homicidal Suicidal

Chemical warfare & terrorism


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Paralysis


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Types of toxicity

Acute cholinergic syndrome

Intermediate syndrome [paralysis of proximal

muscles]

Delayed Neurotoxicity [OPIDN]

In chemical terrorism & warfare


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Generally manifests in minutes to hours

Evidence of cholinergic excess

Parasympathetic-Sympathetic-Nicotinic

SLUDGe =Salivation,

Lacrimation,

Urination,

Defecation,

Gastric Emptying.

BBB= Bradycardia,

Bronchorrhea,

Bronchospasm.

DUMBELLS= Diarrhea ,

Diaphoresis

Urination

Miosis

Bradycardia

EmesisLacrimation

Lethargy

Salivation


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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]


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Oximes-MOA

Oximes attachto anionic site

Oxime +Phosphorous

Oxime phosphatediffuses

Pralidoxime[2-PAM]ObidoximeDiacetyl-monoxime[DAM]

[Cholinesterase reactivators]


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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


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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


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Nerve agents [Nerve gases]

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


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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 bodyis the respiratory system

Protection-full body suit in

addition to a respirator.

P h l i i b l fi ld


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Pyridostigmine-prophylaxis[Reversible]Soman

[Irreversible]

Excess of Ach

Binds to Cholinergic REC

Life threatening Cholinergic activity

Ache AcheReversibleEnzyme is freedHydrolyzes excess

of AchAtropineBlocks receptors

Oximes[Early]Frees enzyme

CAUTION!The primary protection is protective clothing, masks, hoods etc Efficacy of pyridostigmine is dependent upon the rapid use of atropineand oxime after soman exposure

Pyrido. should be stopped soon after exposure to nerve gasPyridostigmine not effective if taken after or just before exposure

Prophylaxis in battlefield


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Nerve gases - Prophylaxis

Pyridostigmine bromide -pretreatment for exposure to the chemicalnerve 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 enzymeactivity that is adequate to sustain life

Not useful to give pyridostigmine either just before or during

exposure to Soman


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Gulf war syndrome

Approximately 250,000 of the 697,000veterans who served in the 1991 Gulf

War are afflicted with enduring chronic

multi-symptom illness,

A wide range of acute and chronicsymptoms 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??


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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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Pharmacology of cholinergic system Class 3 OP Poisoning

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