Anticholinesterases

[Indirectly acting cholinomimitics]

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Dr.U.P.Rathnakar
MD.DIH.PGDHM www.scribd.com

anti-ChE agents [Indirectly acting cholinomimitics]

Protect acetylcholine from hydrolysis Potentiate Ach in vivo and vitro Some of them have direct action on receptors

anti-ChE agents [Indirectly acting cholinomimitics]

Acetylcholinesterase (AChE) terminates the action of ACh. Inhibitors of AChE, or anti-ChE) agents, ACh to accumulate Produce effects equivalent to excessive stimulation of cholinergic receptors This is the basis of clinical use and adverse effects of antiChE. Since cholinergic neurotransmission is widely distributed across animal species, anti-ChE agents are also effective toxins (e.g., agricultural insecticides, pesticides, Also regrettably, chemical warfare nerve gases

Anticholinesterases [Indirectly acting cholinergics] Reversible anticholinesterases

Carbamates Acridine

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

Tacrine.

Irreversible anticholinesterases

Anticholinesterases [Indirectly acting cholinergics]

Irreversible anticholinesterases
Organophosphates

Carbamates

[Insecticides]

Echothiophate Parathion* Malathion* Diazinon* Tabun# Sarin# Soman#

Carbaryl* Propoxur*

Mechanisms of action of indirect (reversible) cholinergic agonists

Acetylcholinesterase

anti-ChE agents

Inactivation of acetylcholine

Acetylcholinesteras e

Carbamylation [Therapeutic] and Phosphorylation [Poisoning]

s ate ] m le rba rsib a e C

v [Re

Reaction Very Slow Or irreversible

ble] [Irreversi

OP

AChE inhibitors -Three groups

Edrophonium [& Tacrine]

Other Carbamates

Bind-Anionic site Termination by diffusion Short acting

Bind to both sites Termination hydrolysis Long acting

O.Phosphates Bind to esteratic site Termination very, very slow or not at all Irreversible [Aging]

AChE inhibitors Ph.actions

Similar to Ach or cholinergic agonists Lipid solubleMuscarinic action, Stimulate ganglion, less action on NMJ, cross BBB Lipid insoluble Nicotinic action, Stimulate ganglia, act on NMJ, do not cross BBB

AChE inhibitors Ph.actions

Ganglia

Stimulation High doses-blockade

AChE inhibitors Ph.actions

1. 2. 3.

CVS

Complex Muscarinic- Bradycardia Ganglionic- Tachycardia Medullary center- Stimulation followed by depression

AChE inhibitors Ph.actions

Sk.Muscles Repeated stimulation- Fasiculations High doses- Paralysis Neostigmine-Direct receptor action

AChE inhibitors -PK

Physostigmine
Well absorbed from GIT Penetrates cornea Crosses BBB

Neostigmine
Poorly absorbed from GIT Oral dose is 20-30 times i.v. dose Do not cross BBB

OP compounds
Absorbed from all sites including intact skin

Physostigmine
Natural alakloid Tertiary amine Lipid soluble Oral absorption+++ CNS actions++ Penetrates cornea No direct action on NM Rec Predominant autonomic effects Use-Glaucoma Oral dose-0.5-1mg.

Synthetic Quaternary amine Not lipid soluble Oral absorption-poor No CNS actions Does not penetrte Direct action on NM Rec++ + Predominant sk.mucle action Neostigmine Use-Myesthenia gravis 15-30mg

REVERSIBLE ANTICHOLINESTERASES-USES
MIOTIC
1. 2. 3.

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

Myesthenia gravis

Some ADEs of cholinergic drugs

Myasthenia gravis

Myasthenia gravis

Neuromuscular disorder characterized by weakness and fatigability of skeletal muscles. Decrease in the number of available NM receptors at NM junctions Due to an antibody-mediated autoimmune attack.

MG-treatment

Anticholinesterase Medications Thymectomy Immunosuppression-glucocorticoids Plasmapheresis Intravenous Immunoglobulin

Pharmacotherapy-MG [Anticholinesterases]
For diagnosis Edrophonium For treatment Pyridostigmine, neostigmine, and ambenonium

Pharmacotherapy-MG
[Tensilon]Edrophonium test [To aid diagnosis]: i.v.2 mg of edrophonium chloride45 seconds 8 mg if the first dose is without effect Brief improvement in strength Those on tt Decrease in strength indicates cholinergic crisis [Overdose of anticholinesterases in tt] Improvement signifies myasthenic crisis [Under dose of anticholinesterases in tt]

Pharmacotherapy-MG..

Pyridostigmine, neostigmine, and ambenonium Baseline recordings are made for grip strength, Oral pyridostigmine (3060 mg), neostigmine (7.515 mg), or ambenonium (2.55 mg). Measure response-If inadequate After an hour or longer in the basal state, the drug is readministered at 1.5 times the initial amount, This sequence is continued, with increasing increments of one-half the initial dose, until an optimal response is obtained.

Pharmacotherapy-MG..

The dose may vary from day to day; physical and emotional stress, infections, Menstruation usually necessitate an increase in the frequency or size of the dose. Patients can be taught to modify their dosage regimens according to their changing requirements. Pyridostigmine SR -180 mg-60 mg is released immediately and 120 mg over several hours; maintaining patients for 68-hour

P y ri Generalized weakness in the trunk, arms, d legs. and o st Eye blink test-ptosis after ig blinking for number of m minutes in e

Grip test-Significant weakening of grip after squeezing

Arm raise test Vital capacity

P y ri Generalized weakness in the trunk, arms, and legs. d o Eye blink test-ptosis after blinking for number of minutes st Grip test-Significant weakening iggrip after of squeezing m in Arm raise test e Vital parameters 1. 5 ti Repeat tests till baseline reached m Decide adequate response reached or not Not adequate e s

Return to baseline

Generalized weakness in the trunk, arms, and legs.

Eye blink test-ptosis after blinking for number of minutes

Grip test-Significant weakening of grip after squeezing

Arm raise test Vital parameters

Drug interactions in MG