CHOLINOMIMETICS

Dr.a.m
 Cholinergic system
• Cholinergic neuron : neurons that release Ach as its 1ry neurotransmitter

• Autonomic : preganglionic , postganglionic parasympathetic N. , few

postganglionc sympathetic N.

• Somatic : motor neurons supplying the skeletal muscles

• C.N.S
 Chemical structure of Ach
• Ester of acetic acid & choline
• Ester : RCOOH + ROH = RCOOR + H2O
• Acetic acid : CH3COOH
• Choline : quaternary ammonium containing hydroxyl group
• Amines :
H H CH3

+
H O C N CH3

H H CH3

Choline
 Neurotransmission at cholinergic
neurons (6)
1) Synthesis :
• Entry of choline ; 2ry active symport with sodium, ( ACH cannot diffuse through
Mem.),
Rate limiting step.
• Choline acetyl transferase
2) Storage : in presynaptic vesicles
3) Release : AP→open voltage gated Ca+ Ch. →fusion of synaptic vesicle
with cell membrane→release Ach in synaptic space
* this can be blocked by botulinum toxin.
4) Binding to the receptor.
5) Degradation of Ach.
6) Recycling of Choline.
Degradation of Ach )5
1) 4ry N binds to the anionic site.
2) React with OH at esteratic site.
3) AchE become acetylated &
choline split off.
4) Acetylated enz. Hydrolise back
to the active formation in mS.
• 1 AchE molecule can
metabolize 10,000 Ach each
second.
 Choline Esterases
1) True choline esterase; Acetyl choline esterase:
present in all cholinergic sites and in RBCs
Hydrolyze Ach very fast (µs)
Essential for life
termination of Ach action
2) Pseudo choline esterase; butyryl choline esterase :
present in plasma and in liver
hydrolysis of Ach is much slower
hydrolysis of ingested esters
 Cholinergic receptors

Cholinergi
c
receptors
Muscarini
Nicotinic
c .Ligand gated ion ch
G protein coupled

M1 M2 M3 Nm Nn
 M
M1 • Heart • Gq , stimulatory
• Gq , stimulatory • smooth Ms • Sites:
• presynaptic • Glands
• Sites : • Smooth Ms :
• C.N.S : BG – • GIT
Hippocampus –
• Detrusor
cortex – CTZ
• Iris & cilliary
• Gastric glands : body
increase acid • Vascular
secretion indirectly M3 endothelium : ↑ NO
through H release.

M2
• Gi, inhibitory.
 Cholinomimetic Drugs

Cholinergic
drugs

Direct Acting Indirect acting

Cholinergic Anticholie
receptors esterases

Natural
Choline esters Reversible Irreversible
alkaloids
 A) Choline Esters
• Acetic Acid choline Esters :
• Acetyl Choline
• Methacholine ; extra methyl group at β carbon → weak nicotinic action
• Carbamic Acid choline esters :
• Carbachol
• Bethanecol ; extra methyl
• Quinuclidine derivative of Ach : selective for M3
• Cevimeline
• aceclidine
 Natural Alkaloids
• Muscarine
• Pilocarpine :
1. 3ry amine , uncharged .
2. can cross BBB.
3. Uses :
• Ophthalmology : preferred in glaucoma , …..
• Secretagogues : xerostomia after head and neck irradiation , sjögren’s
syndrome
• Hair tonics
 Reversible Anti Choline
Esterases
1. Simple Alcohols : Edrophonium

• Contain 4ry N
• Bind AchE only at anionic site
• Short duration of action (10 min)
• Used mainly in Tensilon test
2. Carbamates :
• Physostigmine: natural 3ry amine – penetrate cornea → eye drops – cross
BBB→ antidote of atropine
• Neostigmine: synthetic 4ry ammonium – can directly stimulate Nm receptor –
duration of action about 2h.
• Pyridostigmine : long acting neostigmine analogue- used in myasthenia
gravis.
• Donepezil, Rivastigmine,..: 3ry N neostigmine analogues – used in Alzheimer
Ds.
 Irreversibe Anti choline
esterases
• Organophosphate compounds
• Irreversibly inhibit true & pseudo choline esterase by forming strong
covalent bond with the esteratic site.
• The phosphorylated enzyme may also undergo “aging” by the loss of one
of the alkyl groups and become totally resistant to hydrolysis.
• Organophosphates are lipid soluble , absorbed from all sites.
• Ecothiophate has a 4ry N →water soluble .
 Indications
1. Nm receptor :
A. Terminate action of neuromuscular blockers : SC neostigmine preceded by
atropine.
B. Treatment of Myasthenia gravis.
2. M receptors :
• Toxicity of atropine/atropine like drugs : SC physostigmine
3. M1 : Alzheimer’s disease.
4. M3 :
4. M3 :
A. EYE :
• Terminate action of mydriatic cycloplegic : pilocarpine or physiostigmin
Ecothiophate if atropine was used
• Glucoma

B. Glands : oral pilocarpine or cevimeline in xerostomia

C. Blood vessels : pilocarpine in hair tonics, vasodilate scalp bl. Vessels.

D. Visceral smooth ms. :

• Postoperative non-obstructive urinary retention or paralytic ileus ; SC neostigmine
• Prokinetic agent in GERD ; Bethanecol

5. Irreversible AchE inhibitors : Antihelminthic, Insecticides.

 contraindications
1) Bronchial asthma & COPD

2) Peptic ulcer

3) Myocardial infarction and hypotensive states

4) Urinary & intestinal obstruction

5) Arrhythmia
Side effects