class 2 pharmacology of cholinergic system

8/8/2019 Class 2 Pharmacology of Cholinergic System

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Anticholinesterases[Indirectly acting cholinomimitics]



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 anti-ChE.

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 ³nerve gases´



Organophosphates: Carbamates:

Echothiophate Carbaryl*

Parathion* Propoxur *

Malathion*

Diazinon*

Tabun#

Sarin#

Soman#

*Insecticides# Nerve gases-

chemical warfare

Irreversible anticholinesterases

Anticholinesterases

[Indirectly acting cholinergics]



Inactivation of acetylcholine

Acetylcholinesterase



Carbamylation [Therapeutic]

and

Phosphorylation [Poisoning]

Reaction

Very Slow

Or

irreversible



AChE inhibitors -Three groups

Edrophonium

Bind-Anionic

site

Termination bydiffusion

Short acting

Carbamates

Bind to both

sites

Terminationhydrolysis

Long acting

Oximes not

effective in

poisoning

O.Phosphates

Bind to

esteratic site

Terminationvery, very slow

or not at all

Oximes are

effective

[Before aging]



AChE inhibitors ±Ph.actions

Similar to agonists

Lipid soluble[Physo, O.P]- Muscarinic

actions, CNS actions, Stimulate ganglion

and less action at NMJ

Lipid insoluble[Neostigmine]-Prominent action at NMJ, stimulate

ganglion Less muscarinic, less CNS

effects



AChE inhibitors -PK

Physostigmine

absorbed from the GI tract, subcutaneous tissues,

and mucous membranes.

Conjunctival instillation of solutions of the drug

may result in systemic effects if measures (e.g.,

pressure on the inner canthus) are not taken toprevent absorption from the nasal mucosa.

Crosses BBB



AChE inhibitors -PK

Neostigmine and pyridostigmine

Absorbed poorly after oral administration,

Larger doses are needed than by the parenteral

route

Organophosphorus anti-ChE-Highly lipid soluble

Absorbed from all sites

More toxic

Children lack enzymes for metabolism

Very toxic



NeostigminePhysostigmine

Natural alakloid

Tertiary amine

Lipid soluble

Oral absorption+++CNS actions++

Penetrates cornea

No direct action on NM

RecPredominant

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

Use-Myesthenia gravis

15-30mg



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]

P

ostoperative decurarization [Neostigminepreceded by Atropine]

Cobra bite [Neostigmine+Atropine]

Belladona [Atropine] poisoning-P

hysostigmine Alzheimer¶s disease-Tacrine, rivastgmine,

donepezil, galantamine [cerebroselective] Drug over dosage-e.g. TCA

Myesthenia gravis



Some ADEs of cholinergic drugs



Myasthenia gravis

Neuromuscular disorder characterized

by weakness and fatigability of skeletal

muscles.

Decrease in the number of available

acetylcholine receptors at NM junctions

Due to an antibody-mediated

autoimmune attack.



MG-treatment

Anticholinesterase Medications

Thymectomy Immunosuppression

Plasmapheresis Intravenous Immunoglobulin



Pharmacotherapy-MG

For diagnosis

Edrophonium

For treatment Pyridostigmine, neostigmine, and

ambenonium



Pharmacotherapy-MG

Edrophonium test:

i.v.2 mg of edrophonium chloride45

seconds 8 mg if the first dose is withouteffect Brief improvement in strength

D

ecrease in strength indicates cholinergiccrisis [ 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 (30±60 mg), neostigmine

(7.5±15 mg), or ambenonium (2.5±5 mg).

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 inthe 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 6±8-hour



Generalized

weakness in the trunk,

arms, and legs.

Eye blink test-ptosisafter blinking for

number of minutes

Grip test-Significant

weakening of grip after

squeezing

Arm raise test

Vital parameters

Pyridostigmine

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

Generalized

weakness in the trunk,

arms, and legs.

Eye blink test-ptosisafter blinking for

number of minutes

Grip test-Significant

weakening of grip after

squeezing

Arm raise test

Vital parameters

Pyridostigmine 1.5 times

Return

to

baseline

Repeat tests till baseline reached

Decide adequate response reached

or notNot adequate



Drug interactions in MG

class 2 pharmacology of cholinergic system

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