CHOLINERGIC DRUGSDr Indrajit BanerjeeAssistant ProfessorMBBS, M.DDepartment of PharmacologyDr. D Y Patil Medical CollegeMauritius

Learning Objectives

• Neurotransmitters of Cholinergic system

• Sites of acetylcholine release, synthesis and fate of acetylcholine

• Cholinergic receptors, agonist and antagonists

• Physiological actions of acetylcholine

• Classification of directly acting cholinergic drugs, uses, adverse effects of acetylcholine and acetylcholine substitutes

• Mushroom poisoning

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•Acetylcholine [Ach] an choline

ester, is a neurotransmitter of

parasympathetic system. Nerves

which synthesize, stores &

release Ach are known as

‘Cholinergic”

CHOLINERGIC SYSTEM

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•GANGLIA- All pre-ganglionic fibers of ANS.[Both in sympathetic & parasympathetic ganglia.]•POST GANGLIONIC PARASYMPATHETHIC nerve endings

SITES OF ACTYLCHOLINE RELEASE:

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•SWEAT GLANDS: Sympathetic

postganglionic nerve endings

supplying sweat glands

•SKELETAL MUSCLES- Somatic

nerve endings supplying skeletal

muscles

SITES OF ACTYLCHOLINE RELEASE:

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•ADRENAL MEDULLA

•CNS- brain & spinal cord.

SITES OF ACTYLCHOLINE RELEASE:

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ACETYLCHOLINE (Ach)

• Is major neurotransmitter autonomic & somatic site

• Hemicholinium block choline uptake in axoplasm

• Transport of Ach into synaptic vesicle is blocked vesamicol

• Botulinum toxin inhibit Ach release relieve spasm in spastic disorder, facial wrinkles

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Termination of action of Ach

• A specific Acetylcholineesterase present in all cholinergic sites hydrolyses ester bond choline in µs (very fast)

• Location: All cholinergic sites, RBC, Gray matter

• Nonspecific Butrylcholinesterase (Pseudo) present in plasma hydrolyses Ach slowly

• Location: Plasma, Liver, Intestine, White matter

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Cholinergic receptor

• Muscarine alkaloid mimic the effect of parasympathetic nerve discharge but not in autonomic ganglia

• Nicotinic alkaloid stimulate autonomic ganglia, neuromuscular junction but not other autonomic effector cells

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Muscarinic receptor sub types

Receptor/ Location

Transducer mechanism

Agonist Antagonist

M1-CNS,nerves, Gastric parietal cells

IP3/DAG- cytosolic Ca++

Oxotremorine Pirenzepine

M2-Heart cAMP-k+ channel regulation

Methacholine Tripitamine

M3-gland,smooth muscle,endothelium

IP3/DAG- cytosolic Ca++

Bethanechol Darifenacin

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Nicotinic sub types

NM

Neuromuscular junction

Opening of cation (Na+ K+) channels

Agonist-

PTMA

Antagonist-

Tubocurarine

NN

Autonomic ganglia

Opening of cation (Na+ K+) channels

DMPP Trimethaphan

PTMA-Phenyltrimethylammonium

DMPP-Dimethylphenylpiperazinium

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Cholinergic Drugs

Choline esters

•Acetylcholine

•Bethanechol

•Carbachol

•Methacholine

Alkaloid

•Muscarine

•Arecoline

•Pilocarpine

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Acetylcholine (Prototype)

• Orally destroyed, given iv destroyed by pseudocholinesterase in plasma & at the site of action by cholinesterase

• Nonspecific in action

• Not used therapeutically

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Physiology of Ach & action in vitro

preparation

Eye-(M3)

• Sphincter muscle of iris-contraction(miosis)

• Ciliary muscle-contraction for near vision

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Heart M2

• SA node-Hyperpolarization rate of impulse generation (-ve chronotropic)

• Atria –K+channel open(hyperpolrization),cAMP, refractory period (-ve inotropic)Contractility

• AV node- conduction velocity(-ve dromotropic)

• Ventricle-small decrease in contractile strength

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Blood vessels (M3)• Vasodilatation is primarily mediated through

endothelium derived relaxing factor(EDRF) which is nitric oxide

• In vivo parasympathetic stimulation effects appears as fall in BP and flushing esp in blush area of face which has cholinergic innervation

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Smooth muscle (M3)• Tone and peristalsis in GI tract-

• Sphincters relax – abdominal cramps & evacuation of bowels

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Bronchial smooth constrict-

bronchoconstriction

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Detrusor muscle contract while bladder

trigone & sphincter relax-Voiding of urine

urinary bladder.htm

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Glands

•Glands- sweating, salivation, lacrimation

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Skeletal muscle(NM)

• Ach to muscle end plate causes contraction of fibre

• High dose can cause twitching & fasciculations

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Ach substitute

• Effective orally, more selective in their action

• Methacholine –

Less susceptible to acetylcholinesterase, totally resistant to pseudocholinesterase

• Carbachol, Bethanechol resistant to hydrolysis of both true and pseudocholinesterase

• Bethanechol(M3)have negligible effects on CVS (M2), no nicotinic action

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Adverse effects

• Extension of pharmacological action

• Flushing, salivation, sweating, bradycardia, bronchospasm, hypotension

Uses• Post-operative paralytic ileus, Urinary

retention, abdominal distension

• Bethanechol is preferred drug due to specific action & wider margin of safety

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Cholinomimetic AlkaloidPilocarpine-

• Alkaloid obtained from the leaves of Pilocarpusmicrophyllus

• Systemic administration produce toxic effects, it can be given orally (5-10 mg)

USES:

• Topical preparation for eye-0.5-4%,uses as miotic in reversing angle closure glaucoma(contraction of circular muscle of iris),break the adhesions of iris with lens or cornea by alternating use with mydriatics

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Cont…..• T/t for open angle glaucoma-contraction of

ciliary muscle of iris increases outflow facility• ADR-

• Painful spasm of accommodation & brow pain frequent side effects

• Systemic effects-nausea, diarrhoea, sweating & bronchospasm

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ARECOLINE

• Found in Betal nut

• Areca catechu

• Has Muscarinic & Nicotinic action

• Tried in dementia

• Not used therapeutically

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Muscarine

• Not used therapeutically

• Can cause Mushroom Poisoning

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MUSHROOM POISONING

• Amanita muscaria, Inocybe, A.phalloides

• TYPES:• Muscarine Type-(Early Mushroom

Poisoning)• Inocybe species• Nausea, Vomiting , Diarrhoea, Bradycardia,

Salivation, Sweating, Bronchospasm, hypotension

• Treated by Atropine IV

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• Hallucinogenic Type:

• Caused by Amanita muscaria

• Due to muscimol and other isoxazolecompounds.

• Produces central effects

• Activates aminoacid receptor in Brain

• Block muscarinic receptor

• No specific tratment

• Atropine is C/I

Another type Psilocybe mexicana whose active

psilocybine is a tryptaminergic

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CONT…

• LATE MUSHROOM POISONING:

• A. phalloides

• Occurs due to pepide toxins

• Causes inhibition of RNA & Protein synthesis

• Causes gastrointestinal, hepatic & renal damage

• Treated with thioctic acid

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