CholinergicsDr.Elza Emmannual

Nervous system Central nervous system (CNS) Peripheral nervous system

1. Autonomic nervous system

2. Somatic system, innervating skeletal muscle

Autonomic nervous system

Most organs receive both sympathetic and parasympathetic innervation

Functionally antagonistic

Sympathetic /adrenergic system

Parasympathetic/cholinergic system

Sites where the Ach acts as neurotransmitter NMJ All ganglia Postganglionic parasympathetic nerves Postganglionic sympathetic nerves of

sweat glands Adrenal medulla

Sympathetic Parasympathetic

origin thoracolumbar craniosacral

distribution wide Head, neck, sacral region

ganglia Away from organ

Close to organ

Pre:Postganglionic Fibre ratio

1:20-1:100 1:1-1:2

neurotransmitter

Nor adrenaline(NA)

Acetyl Choline(Ach)

function Fight & Flight response

Rest & digest response

Autonomic nerve

CNS

PreganglionicNerve fibre Postganglionic

Nerve fibre

Ganglia

Effector organ

Steps in neurotransmission Synthesis Storage Release Receptor action Termination

CHOLINERGIC TRANSMISSION

Choline +Acetyl

CoA

ACh

AChVAT

Choline acetyl transferase

Ca 2+

ACh

Choline

Acetate

SNAP

VAMPNicotinicreceptor

Muscarin

i

c

receptor Choline esterase

Choline Transporter

Choline Transporter

Choline +Acetyl

CoA

ACh

AChVAT

Choline acetyl transferase

Ca 2+

ACh

Choline

Acetate

SNAP

VAMPNicotinicreceptor

Muscarin

i

c

receptor Choline esterase

Hemicholinium

Vescamicol

Botulinum toxin A

Botulinum toxin B & Beta bangarotoxin

Black widow spider toxin

Tetradotoxin

Saxitoxin

Toxins ActionLocal anaesthetics,tetradotoxins(Puffer fish),saxitoxins(Gaunyaulax)(shell fish consumed red algal blooms)

Block voltage-gated sodium channels

Hemicholiniums Block uptake of choline

Vesamicol Inhibits VATΩ conotoxin(marine snails) Blocks nerve terminal calcium

channels

Alpha Latrotoxin(Black widow spider venom)

Explosive transmitter release

Alpha Bengarotoxin(cobra venom) Nm receptor antagonist

Beta bengarotoxin(Krait venom) Inhibits release of acetylcholineBatrocotoxin(South African frog) Selective increase in permeability of

sodium channels Scorpion toxin Persistant depolarisation by

inactivation of Sodium channels

Cholinergic Receptors

Muscarinic receptorsM1, M2, M3,M4,M5

Nicotinic receptors NM, NN

Receptor

Site Action Nature Agonist Antagonist

M1

CNS

GangliaGastric parital cells

CNS Learning & MemoryGastric glands gastric secretion

G protein coupled (Gq)

Oxotremorine

Pirenzepine

HeartPresynaptic

SA node heart rateAV node velocity of conductionAtria & Ventricles contractility

Gi coupled Methacholine

Methoctramine

M2

Smooth muscle including iris & ciliary musclesGlandsEndothelial cells

Visceral smooth muscle Contraction except urinary& intestinal sphinctorsExocrine glands SecretionVascular endothelium: release NO vasodilationCiliary muscle contractionIris constriction of pupil

Gq coupled Bethenechol

Darifenacin

M3

Ganglia Autonomic ganglia & Adrenal medulla Catecholamine release

Ion channel DMPP Trimethaphan

NN

NMJ Neuromuscular junction Contraction of skeletal muscle

Ion channel PTMA dTC ,Alpha BangarotoxinNM

Actions of ACh CVSHEART↓ HR AV node - ↓ conduction Atria - ↓contraction

BLOOD VESSELS Vasodilation

M2

M3

Smooth muscle

↑contraction

GIT - Tone & peristalisis in GIT ↑, Sphincters relax Abdominal cramps & evacuation of bowel

Ureter peristalsis↑, Detrusor contracts, Bladder trigone & sphincter relax: Voiding

Bronchospasm Eye

Contraction of circular muscles of iris MIOSIS Contraction of ciliary muscles ↑outflow of aqueous

humur↓ IOP

M3

M3

GLANDS Secretion from all glands ↑ Salivation , Sweating, lacrimation,

Gastric & Tracheobronchial secretion

M3

NICOTINICAUTONOMIC GANGLIASympathetic + Para sympathetic

stimulation

SKELETAL MUSCLESContraction of muscle

NN

NM

Cholinergic drugs classificationDIRECTLY ACTING Choline Esters

Cholinomimetic Alkaloids

INDIRECTLY ACTINGAnti choline esterases

Acetyl CholineMethacholine

CarbacholBethanechol

Pilocarpine

MuscarineArecoline

Anti choline esterasesReversible

Irreversible

CarbamatesPhysostigmineNeostigmine

PyridostigmineEdrophoniumRivastigmine

DonepezilGalantamine

Acridine

Tacrine

Organophosphates

MalathionParathion

DyflosEchothiophate

DiazinonNerve gases

CarbamatesPropoxyfurCarbaryl

Choline ester

SusceptibilityTo cholineesterase

Muscarinic action

Nicotinicaction

Acetylcholine ++++ +++ +++

Methacholine + ++++ None

Carbachol Negligible ++ +++

Bethanechol Negligible ++ None

Uses To reverse postoperative atony of

bladder To expel gases from intestines prior to

radiological examination To revert postoperative paralytic ileus of

gut To treat salivary gland malfunction

Pilocarpine Sourceleaves of Pilocarpus Microphyllus Crosses BBB Too toxic for systemic use

USES1)3rd line drug - open angle glaucoma2)To counteract mydriatics3)Prevent adhesions in iridocyclitis by altering with mydriatics

Muscarine

Amanita phalloides Amanita muscaria

Mycetism-Mushroom poisoningTreatment-Atropine 1-2mg IM every 30 minutes

Arecoline Chief alkaloid of areca or betel nut

Anticholine esterasesDrugs that inhibit choline

esterase enzyme prevent the hydrolysis of Ach potentiates Ach action

Classification

Anti choline esterasesReversible

Irreversible

CarbamatesPhysostigmineNeostigmine

PyridostigmineEdrophoniumRivastigmine

DonepezilGalantamine

Acridine

Tacrine

Organophosphates

MalathionParathion

DyflosEchothiophate

DiazinonNerve gases

CarbamatesPropoxyfurCarbaryl

Mechanism of actionCholine esterase has 2 sites anionic

site & esteratic site

Carbamates bind to both A & E

A E

A E

Carbamylated enzyme react

slowly so hydrolysis of Ach is inhibited

OP bind to esteratic site only

Phosphoylated enzyme react very slowly irreversibly inhibit Ach degradation

Phosphorylated enzyme undergoes “aging” become totally resistant to hydrolysis

A E

ActionsLIPID SOLUBLE – ( Physostigmine & OP) Marked Muscarinic & CNS effects

LIPID INSOLUBLE – ( Neostigmine) Effect on Skeletal muscle & stimulate

ganglia

Dont penetrate CNS & have no central effects

Fasciculation & twitching

USES1) Glaucoma ↑ tone of ciliary muscle outflow facility is ↑ Pilocarpine Physostigmine 2) To reverse the effects of mydriatics3) MYASTHENIA GRAVIS

Neostigmine

Edrophonium(for diagnosis

4)Post operative paralytic ileus/ urinary retentionNeostigmine5)Post operative decurarizationAtropine (Block Muscarinic action)

followed by Neostigmine6)Cobra biteNeostigmine + Atropine7) Belladona(Atropine) poisoningPhysostigmine8)Alzheimers diseaseTacrine , Donepezil , Rivastigmine

OP poisoning lacrimation, salivation, sweating ,

miosis, blurring of vision, breathlessness, colic, involuntary defecation & urination

cardiac arrhythmias Muscle fasciculationsconvulsions, coma & death (

RESPIRATORY FAILURE)

Agricultural & household insecticide

TREATMENTTermination of further exposure to

poison – fresh air, wash the skin with soap & water, gastric lavage

Maintain patent airway

Supportive measures Maintain BP, Hydration , control of convculsions diazepam

SPECIFIC ANTIDOTES1. ATROPINE

Highly effective in counteracting muscarinic symptoms

Doesn’t reverse peripheral muscle paralysis

(Nicotinic)

2) OXIMES (Pralidoxime)

OP

A E

A EOP

OXIME

Its oxime end reacts with Phosphorous atom attached to anionic site: Oxime Phosphonate diffuses away leaving reactivated Ach Esterase

Not effective in Carbamate poisoning because anionic site is not free

CI Carbamate poisoning

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