Cholinergic Receptors their function and Mechanism of action

2. CHOLINERGIC RECEPTORS
DR NAJM UL HASSAN KHAN
PhD (Pharmaceutical Chemistry)
MARYUM KHALID

3. INTRODUCTION
• Cholinergic nerves found in peripheral and CNS and release acetylcholine.
• 2 distinct receptors for ACh (Nicotinic and Muscarinic) that differ in composition, location and
pharmacological action having agonist and antagonist.
• ACh was 1st identified by Henry Hallet Dale for action on heart tissue in 1914.
• Otto Loewi conformed ACh as neurotransmitter in 1921 and gave it name as “vagusstoff”
because it was released from vagus nerve.
• Both received 1936 Nobel Prize in Physiology or Medicine for their work.

4. ACETYLCHOLINE

5. MUSCARINIC RECEPTORS
• These are receptor sites where muscarine bind eliciting same
qualitative effects as ACh. Muscarine is a toxic compound
found in mushrooms.
• These are Gprotein coupled receptors also known as
metabotropic receptors.
• Majorly 5 types of muscarinic recptors found in various organs
M1, M2, M3, M4 and M5.
• M1,3,5 showed stimulatory pathway while M2 and 4 showed
inhibitory pathway.

6. LOCATION AND FUNCTIONS OF MUSCARINIC
RECEPTORS
Recept
or
G
protein
Tissue location Cellular response Function
M1 Gq CNS, Salivary and gastric
glands, autonomic ganglion
PLC activation, Ca+2
increase, PKC activation
↑cognitive function,seizure
activity, secretions
M2 Gi/Go Heart, blood vessels, on
presynaptic membranes of
autonomic ganglion
Inhibition of adenyl cyclase
and Ca+2 channels, increase
activation of K+ channels
Dec. heart rate, ganglion
transmission.
Neuronal inhibition
M3 Gq CNS, smooth muscles, glands Same as M1 ↑secretions, smooth muscle
contraction, inhibits dopamine
release.
M4 Gi/Go CNS Same as M2 Analgesia, facilitates dopamine
release
M5 Gq Low levels in CNS and
periphery
Same as M1 Facilitates dopamine release,
mediates dilation of cerebral
arteries

7. ACTION OF M RECEPTORS
• STIMULATORY ACTION • INHIBITORY ACTION

8. NICOTINIC RECEPTORS
• The nicotinic acetylcholine receptors are receptor sites acted upon by nicotine eliciting the same
qualitative effects as acetyl choline.
• These are the 1st ACh receptor and 1st neurotransmitter receptor to be fully characterized.
• These receptors are ligand gated ion channels, also called as ionotropic channels. The receptor
creates a transmembrane channel(gate) and acetylcholine acts as gatekeeper by binding with the
receptor to modulate passage of K+ and Na+.
• They are pentameric transmembrane protein made up of 2α,ꞵ,ꞵ,ꞵ subunits . The 5 subunits are
arranged around a central pore that serves as ion channel.
• There are two subtypes of nicotinic receptors: Nm and Nn receptors.

9. LOCATION AND FUNCTION
Receptor Location Membrane
response
Molecular
mechanism
Agonists Antagonists
Nm Neuromuscular
junction
Excitatory , end
plate
depolarization,
contraction of
muscle
Increased Na+
and K+
permeability
ACH,nicotine Atracurium ,
Vecuronium,
pancuronium.
Nn Autonomic
ganglion,
adrenal medulla
Excitatory post
synaptic
potential,
propagates
action potential
Increased Na+
and K+
permeability
ACH, nicotine,
dimethylphenyl
piperazinum
mecamylamine

10. CHOLINOMIMETICS
• The agents that bind to acetylcholine receptors and stimulate the parasympathetic nervous system.
• Actions of cholinomimetics:
• They dilate nearly all blood vessels and cause smooth muscle relaxation.
• In high dose may decrease heart rate and atrioventricular conduction velocity and cause varying degree of
heart block, may decrease strength of atrial contractions.
• In therapeutic doses usually only vasodilation occurs and heart rate and contractility may increase.
• Stimulate gastrointestinal smooth muscles and increase peristalsis and decreasing bowel transit time.
• Contract smooth detrusor muscle of urinary bladder but relax trigonal sphincter thus causing urination.
• Stimulates iris causing miosis, decrease intraocular pressure in glaucoma.
• On glands show stimulation so excessive salivation, bronchorrhoea inc gastric and pancreatic secretions and
copious sweating.

11. SAR OF CHOLINOMIMETICS
Acyloxy group:
Higher homologues of methyl group= less active
Ester of aromatic of higher mol. Weight acids= anticholinergic activity
Replacement of ester group with ether or ketone = chemically stable and potent
Ethylene bridge:
Chain length inc= dec. activity
Acetyl ꞵ methyl choline= muscarinic receptor
Acetyl α methyl choline= nicotinic receptor
Quaternary ammonium group:
Essential for activity
Replacement of methyl by larger compounds= inactive compounds

12. CLASSIFICATION OF CHOLINERGIC
AGONISTS
DIRECT ACTING
AGONIST:
Acetylcholine chloride
Bethanechol
Carbachol
Nicotine
Pilocarpine
ANTICHOLINESTRAS
E(REVERSIBLE)
Neostigmine
Physostigmine
Rivastigmine
Pyridostigmine
Edrophonium
Donepezil
Galantamine
Ambenonium
ANTICHOLINESTRAS
E(IRREVERSIBLE)
Ecothiophate
Parathion
Malathion

13. SYNTHESIS OF ACETYLCHOLINE CHLORIDE
• It is prototypical muscarinic and nicotinic agonist but a poor therapeutic agent because of its low
chemical and enzymatic stability with low availability dur to poor absorption.
• It is a cardiac depressant and vasodilator
• Used in ocular surgery, causes miosis in seconds, instilled directly in anterior chamber.
Properties:
White crystalline powder, hygroscopic, soluble in water and alcohol.
Dose: topically used as 1% solution.

14. ANTICHOLINESTRASES
• Acetylcholinesterase AChE is a serine dependent isoenzyme capable of hydrolyzing ACh to
choline and acetic acid.
• On hydrolysis the acetyl group of ACh is transferred to serine –OH group. Spontaneous
hydrolysis of serine acetyl group occurs rapidly.
• They are indirect acting cholinomimetics.
• Duration is for few minutes to few hours.

15. • USES:
• Mysthenia gravis
• Intestinal distention
• Agricultural insectidies
• Nerve gas warfare agent
• Physostigmine for antagonize toxic CNS affects antimuscarinic agents, tca antidepressants, h1
antihistamines and benzodiazepens. Also for alzheimers diseases. In eye for treatment of
glaucoma.

16. NEOSTIGMINE
• It is a quaternary amine so no CNS activity.
• Employed for the treatment of genitourinary, gastrointestinal and neuromuscular disease.
• Myasthenia gravis prophylaxis, reversal of neuromuscular blockage, prophylaxis of postoperative
abdominal distension.
• Properties:
• It exists as white, odourless, crystalline powder with a bitter taste, freely soluble in water, alcohol, and
insoluble in ether. Its solutions are neutral to litmus.
• Dosage forms: neostigmine bromide tablets I.P., Neostigmine methyl sulphate injection I.P.,
Neostigmine tablets B.P

17. SYNTHESIS OF NEOSTIGMINE

18. ANTICHOLINERGIC AGENTS
• They are mostly antimuscarinic that are competitive antagonists that act only on cholinergic
receptors
• Therapeutically used as skeletal muscle relaxant adjuvants with anesthesia, intubation and
orthopedic procedures
• Side effects are decreased gastric secretion, dry mouth, drying of mucous membrane, general
mydriasis, loss of accommodation, urinary retention, decreased sweating, bronchial and biliary
dilation and tachycardia.

19. CLASSIFICATION OF ANTICHOLINERGICS
Antimuscarinic agents
• Atropine
• Benztropine
• Cyclopentolate
• Ipratropium
• Scopolamine
• Tiotropium
• Tropicamide
• Oxybutinin
Antinicotinic agents
• Nicotine
• Pancuronium
• Rocuronium
• Ciscuronium
• Succinylcholine

20. ANTIMUSCARINIC AGENTS
• COMPETITIVE ANTAGONISTS
• Uses:
• Topically to dilate pupil and paralyse accommodation
• Pre-anaesthetic medicine, to inhibit excessive salivary and mucous secretions
• Antisecretory effect is also sought in treatment of hay fever and rhinitis
• In bronchial asthma and peptic ulcers
• In treatment of parkinsons disease.

21. CLASSIFICATION OF ANTIMUSCARINIC
TERTIARY ANTIMUSCARINIC
• Can penetrate cell membranes
• Nonionized, penetrate cornea and cause
mydriasis and cycloplegia
• No nicotinic receptor affinity
• E.g, atropine sulphate, cyclopentolate,
tropicamide
QUATERNARY
ANTIMUSCARINIC
• Can't pass BBB lack CNS action
• Ionized,Poorly penetrate eye
• Greater affinity for nicotinic receptor
• e.g, anisotropine, ipratropium

22. ATROPINE
• It is a white crystalline powder or colourless crystals, freely soluble in alcohol and well soluble in
water.
• The greater molar potency of atropine helps it to block several moles of acetylcholine.
• The circled portion of the atropine molecule depicts the segment resembling acetylcholine
• The most potent compounds were those that possessed two lipophilic ring substituents on the carbon
alpha to carbonyl of ester moiety for antimuscarinic activity
• Atropine has all the actions and uses of antimuscarinic drugs.
• Dose:
• In bradycardia: adult: 500 μg every 3–5 min totally 3 mg.

23. ATROPINE SYNTHESIS

24. ANTINICOTINIC AGENTS
• HISTORY:
• The neuromuscular blocking effects of extracts of curare were first reported as early as 1510, when
explorers of the amazon river region of South America found natives using these plant extracts as arrow
poisons.
• In 1856, however, Bernard demonstrated that curare extracts prevented skeletal muscle contractions by an
effect at the neuromuscular junction, rather than the nerve innervating the muscle or the muscle itself.
• In 1935, King isolated a pure alkaloid, which he named d-tubocurarine, from a tube curare of unknown
botanical origin. The word “tube” refers to the container in which the south american natives transported
their plant extract.

25. • Nicotine:
• Dose dependent
• At high dose bp falls and
activity in GIT and bladder
musculature ceases.
• Colorless, odourless, on
air/light exposure turns slightly
brown, soluble in alcohol, oils,
ether and cholorform.
GANGLIONIC
BLOCKERS

26. NEUROMUSCULAR BLOCKING AGENTS
• SUCCINYLCHOLINE:
• D
DIMER OF
ACETYLCHOLINE

27. • Rapid onset of action
• Useful when rapid endotracheal intubation is required during induction of anesthesia
• Also used in electroconvulsant shock treatment.
• Muscle relaxant
• Properties= white crystalline powder, hygroscopic and odourless, freely soluble in water and normal saline
• ADR:
• Hyperthermia
• Hyperkalemia so dangerous in burn patients and pt. with major tissue damage cz K+ has been rapidly lost from
within cells.
• Postoperative muscle pain
• Cardiac arrythmias

28. REFRENCES
• FOYES PRINCIPLES OF MEDICINAL CHEMISTRY
• MEDICINAL CHEMISTRY BY D. SRIRAM
• TEXTBOOK OF MEDICINAL CHEMISTRY BY V. ALGARSMY
• LIPPINCOTTS ILLUSTRATED REVIEW: PHARMACOLOGY
• AN INTRODUCTION TO MEDICINAL CHEMISTRY 5TH EDITION GRAHAM. L.
PATRICK