Pharmacology of

CHOLINERGIC SYSTEM

Dr.U.P.Rathnakar
MD.DIH.PGDHM

http://www.scribd.com

www.pharmacologyfordummies.blogspot.com
Cholinergic system
 Biosynthesis and metabolism of Ach
 Cholinergic Rec.-Locations
 Effect of transmitter on receptors
 Cholinergic agonists
 Classification
 Uses
 ADEs
 NN
NN NN

α 1α 2
NM
β1β2β3

M123
Cholinergic Transmission
 Steps in Cholinergic transmission
• Impulse conduction
• Arrival of impulse
• Synthesis Storage & release
of transmitter

• Combination of
• transmitter
with P.J. receptors

• Postjunctional activity:
 Excitatory[EPSP] or
 Inhibitory[IPSP]

• Termination of
neurotransmitter action
[Diffusion, destruction, reuptak
Pharmacology of cholinergic system
 Ach and Cholinomimetics
 Anticholinesterases
 Antimuscarinics
 Skeletal muscle relaxants
 Acetylcholine (ACh):
Ach is synthesized in the cholinergic nerve endings.

ATP
+ Acetate = Acetyl CoEn-A
+ CoEn-A + Choline acetyl transferase
Choline

Acetylcholine + CoEn-A
Synthesis and Release of Acetylcholine
[Cholinergic transmission]
 Cholinergic receptors:

 Muscarinic (M) – M1,M2,M3,M4&M5

 Nicotinic ( N ) – NM & NN.

M – G-protein coupled receptor.

N - Ion channel receptor.
Location of cholinergic receptors:

 M1 : Gastric glands, Autonomic ganglia & CNS.

 M2 : SA node, AV node, Atrium, Ventricle,

 M3 : Visceral smooth muscle, Iris, Ciliary

muscle, Exocrine glands, Vascular endothelium.
 M4 & M5 : Brain
 NM : Neuromuscular junction.
 NN : Autonomic ganglia, Adrenal gland.
Metabolism of ACh:
ACh is metabolized by
acetylcholinesterase.

1.Acetylcholinesterase (True) :
Cholinergic sites, RBC,
Gray matter.
2.Pseudocholinesterase:
Plasma, Liver, Intestine, +

White matter.

Acetylcholinesterase
 Cholinesterases
True Pseudo

 Acetylcholinesterase   Butyrylcholinesterase
 Cholinergic sites, RBC  Liver, plasma
 Fast  Slow
 Sensitive –  Sensitive-OP
Physostigmine
 Termination of Ach  Hydrolysis of ingested
action esters
 Pseudocholinesterase
deficiency and Sch
Pharmacological actions of AcH
[Effects of Parasympathetic system]

SIT
REST
DIGEST
 Actions of ACh:
ORGAN RESPONSE
EYE
Iris Miosis
Ciliary muscle Contraction for near vision
HEART
SA Node -ve chronotropy
Atria -ve inotropy
AV Node -ve dromotropy[conduction]
Ventricle Small decrease in contractile strength
BLOOD VESSELS
Arteries Dilation[ERDF], constriction-direct, high dose
Veins --------”””””””----------
LUNG
Bronchial muscle Constriction
Bronchial glands Secretion
GIT
Motility Increase
Spincters Relax
Secretion Stimulation
URINARY BLADDER SIT
Detrusor Contraction
Trigone & Spincter Relaxation REST
GLANDS
Sweat, salivary,lacrimal, nasopharyngeal Secretion
DIGEST
Actions of ACh: (Muscarinic)

Heart [Cardiac glycosides, antiarrhythmic agents,]

 Decrease in heart rate.
 Decrease in contractile strength.
 Decrease in conduction velocity.
 Increase in refractory period.
Blood Vessels
 Vasodilatation due to release of EDRF (Endothelium
dependent relaxing factor) which is ‘NO’.
Actions of ACh: (Muscarinic)……..

Smooth muscle
 Contraction

Glands
 Secretions are increased.

Eye
 Miosis.
 Spasm of accommodation.
 Decrease in intraocular tension.
Actions of ACh: (Nicotinic)……

Autonomic ganglia
 Sympathetic and Parasympathetic ganglia are
stimulated.

Skeletal muscles
 Twitching and fasciculations.
Cholinergic Drugs
[Cholinomimitics]
Cholinergic Agonists

Choline esters
 Acetylcholine
 Methacholine
 Carbachol
 Bethanechol

Alkaloids
 Pilocarpine
 Muscarine
 Arecoline
 Properties of Choline Esters

Uses
1. Ach-too short acting & non
selective
2. Methacholine-PSVT-Obsolete
Pilocarpine:
[Pilocarpine is too toxic for systemic use]

Actions: Mainly muscarinic

[Initial]---- Fall of BP [Peripheral] This action
exception to
[Persistent]--- Rise in BP[Ganglionic] pilocarpine

Therapeutic uses:
Opthalmic use: ( Eye drops)
 Open angle glaucoma.
 To counteract mydriasis.
 In iridocyclitis to break adhesions
between iris and lens.
 Anticholinesterases
[Indirectly acting cholinergics]
Reversible anticholinesterases
Carbamates Acridine
Tacrine.
 Physostigmine
 Neostigmine
 Pyridostigmine
 Edrophonium
 Ambenonium
 Demecarium
 Rivastigmine,
 Donepezil,
 Galantamine.
Irreversible anticholinesterases
 Irreversible anticholinesterases
Organophosphates: Carbamates:
Carbaryl*
Propoxur*
 Echothiophate
 Parathion*
 Malathion*
 Diazinon* *Insecticides
 Tabun# # Nerve gases-
 Sarin# chemical warfare
 Soman#
 Mechanisms of action of indirect (reversible)
cholinergic agonists

Acetylcholinesterase

anti-ChE agents
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 to
prevent absorption from the nasal mucosa.

• Crosses BBB
Physostigmine Neostigmine
• Natural alakloid • Synthetic
• Tertiary amine • Quaternary amine
• Lipid soluble • Not lipid soluble
• Oral absorption++ • Oral absorption-poor
+ • No CNS actions
• CNS actions++ • Does not penetrte
• Penetrates cornea • Direct action on NM
• No direct action Rec+++
on NM Rec • Predominant sk.mucle
• Predominant action
autonomic effects • Use-Myesthenia gravis
• Use-Glaucoma
 REVERSIBLE
ANTICHOLINESTERASES-USES
– Postoperative paralytic ileus/urinary retension
[Neostigmine]
Glaucoma[Physostigmine]
– Postoperative decurarization [Neostigmine preceded by
Atropine]
– Cobra bite [Neostigmine+Atropine]
– Belladona [Atropine] poisoning-Physostigmine
– 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
 Organophosphorous poisoning
Insecticide poisoning
 Atropine-DOC-Muscarinic symptoms
 Activators-Oximes[Pralidoxime, Obidoxime]

Acetylcholinesterase
AchE-Reactivators

O.P.Compounds Atropine
[Anticholinesterases]