cholinergics
TRANSCRIPT
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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