1. Cholinergic (Cholinoceptor Activating) Drugs-1
Dept. of Pharmacology
Faculty of Medicine & Health Sciences
AIMST

2. Cholinergic Drugs-1-Lecture Outline
Cholinoceptors(Review)
Types
Muscarinic
Nicotinic
Characteristics
Typical Locations
Cholinergic Drugs
Classification
Direct Acting
Choline Esters
Cholinomimetic Alkaloids

3. Cholinergic Drugs-1-Lecture Outline(contd.)
Cholinergic Drugs (contd.)
Indirect Acting (Anticholinesterase Agents)
Reversible
Irreversible
ACh-Pharmacological Actions
Choline Esters
Properties
Therapeutic Uses
Cholinomimetic Alkaloids
Cholinomimetic Drugs
Contraindications

4. Cholinergic Receptors(Cholinoceptors)-Types & Characteristics
Acetylcholine Receptors (Cholinoceptors)
Main subdivision is into muscarinic (mAChR) and nicotinic (nAChR) subtypes
In smooth muscle, cardiac muscle and glands the cholinergic receptors are of the muscarinic (mAChR) type (i.e. stimulated by muscarine, an alkaloid from Amanita muscaria mushrooms)

5. Cholinergic Receptors(Cholinoceptors)-Types & Characteristics
Acetylcholine Receptors (Cholinoceptors)
In striated (skeletal) muscle and autonomic ganglia (sympathetic and parasympathetic) the cholinergic receptors are nicotinic (nAChR) (i.e. stimulated by nicotine)
mAChR’s are G-protein coupled receptors, causing:
Activation of phospholipase C
Inhibition of adenylate cyclase
Activation of potassium channels
Inhibition of calcium channels

6. Cholinergic Receptors(Cholinoceptors)-Types & Characteristics
Muscarinic Acetylcholine Receptors(mAChR’s)
Five types occur, viz.:
M1-receptors (neural)- Selectively blocked by pirenzepine
M2-receptors (cardiac)- Decrease cardiac contractility and heart rate; selectively blocked by gallamine
M3-receptors (glandular)- causing secretion, visceral smooth muscle contraction, vascular relaxation
M4-receptors & M5-receptors- largely confined to CNS; functional role not well understood

7. Autonomic Nervous System(ANS)- Cholinergic Receptors
M1-receptors -
M1, M3 and M5 receptor subtypes have stimulatory effect on the target tissue
M2 and M4 subtypes are inhibitory

8. Cholinergic Muscarinic Receptors

9. Cholinergic Receptors(Cholinoceptors)-Types & Characteristics
Nicotinic Acetylcholine Receptors(nAChR’s)
Two types occur, viz.:
NM receptors (muscle type)- located at skeletal muscle neuromuscular junction, Na+, K+ depolarizing ion channel, blocked by d-tubocurarine
NG receptors (neuronal type)- located at postganglionic cell body, Na+, K+ depolarizing ion channel, blocked by hexamethonium

10. Cholinergic (Cholinoceptor Activating) Drugs
Cholinergic Drugs(Cholinomimetics/ Parasympathomimetics)
Drugs producing actions similar to that of Acetylcholine (ACh)
Two modes of action:
May directly interact with cholinergic receptors
Increase availability of ACh at receptor sites

11. Cholinergic (Cholinoceptor Activating) Drugs-Classification
Cholinergic Drugs
Direct-acting drugs (bind to & activate muscarinic or nicotinic receptors)
Choline esters
Acetylcholine
Bethanechol
Carbachol
Methacholine
Cholinomimetic Alkaloids
Pilocarpine
Muscarine
Nicotine
Lobeline
Arecoline
Oxotremorine

12. Cholinergic (Cholinoceptor Activating) Drugs-Classification
Cholinergic Drugs (contd.)
Indirect-acting drugs (↑ ACh/Cholinesterase inhibitors/Anticholinesterases)
Reversible (water soluble)
Edrophonium
Physostigmine
Neostigmine
Pyridostigmine
Ambenonium
Demecarium
Eptastigmine
Rivastigmine
Donepezil

13. Cholinergic (Cholinoceptor Activating) Drugs-Classification
Cholinergic Drugs (contd.)
Indirect-acting drugs (↑ ACh/ Cholinesterase inhibitors)
Irreversible (lipid soluble)
Organophosphates (e.g., Echothiophate, Diisopropylfluorophosphate, Malathion, Parathion, Diazinon, Soman, Sarin, Tabun, etc.)
Carbamates (e.g., Carbaryl, Propoxur)
Clinically – seen in poisoning , suicide in the A&E Dept.

14. Acetylcholine (ACh)- Actions
Muscarinic
Heart
SA Node
Hyperpolarization of SA nodal cells
Decreased rate of impulse generation (Bradycardia, negative chronotropy)
Atria
Decrease in contractile strength(negative inotropy)
Atrioventricular Node
Decrease in conduction velocity (negative dromotropy)
Ventricles
Small decrease in contractile strength

15. Acetylcholine (ACh)- Actions
Muscarinic
Blood vessels
Very few blood vessels receive cholinergic innervation
Muscarinic receptors present on vascular endothelial cells
Arteries
Dilation (via EDRF(NO))
Veins

16. Acetylcholine (ACh)- Actions
Muscarinic
Lung
Bronchial muscle
Contraction (Bronchoconstriction)
Bronchial glands
Stimulation of secretion
Gastrointestinal tract (evacuation of bowel)
Motility
Increase
Sphincters
Relaxation
Secretion
Stimulation (e.g.,double vagotomy for DU in the past)

17. Acetylcholine (ACh)- Actions
Muscarinic
Urinary bladder (voiding of bladder)
Detrusor
Contraction
Trigone & sphincter
Relaxation
Ureter
Increased peristalsis
Glands
Sweat/salivary/lacrimal/nasopharyngeal
Increased secretions

18. Acetylcholine (ACh)- Actions
Muscarinic
Eye
Sphincter (circular) muscle of iris
Contraction (miosis)
Ciliary muscle
Contraction for near vision
Spasm of accomodation
Increased aqueous outflow
Reduction in intraocular tension

19. Acetylcholine (ACh)- Actions
Nicotinic
Autonomic ganglia
Both parasympathetic & sympathetic ganglia stimulated
High dose ACh after atropine administration leads to
Tachycardia
Rise in BP
Skeletal muscles
Iontophoretic application of ACh to motor endplate leads to skeletal muscle contraction

20. Choline Esters-Properties
Susceptibility to Cholinesterase
Muscarinic Action
Nicotinic Action
Acetylcholine chloride
++++
+++
Methacholine chloride +
None
Carbachol chloride
Negligible ++
Bethanechol chloride

21. Choline Esters-Properties
Bethanechol
Not destroyed by cholinesterase (both true & pseudo)
Has mainly muscarinic actions (well antagonized by atropine)
Negligible CVS effects
Acts chiefly on the bladder & bowels
Preferable to carbachol because of this partial selectivity
Carbachol
More potent than bethanechol & methacholine
Muscarinic effects not adequately antagonized by atropine

22. Choline Esters-Properties
Carbachol(contd.)
Stimulates autonomic ganglia & skeletal muscles
Actions are most pronounced on the bladder & bowels
Used to stimulate bladder & intestines after surgery
Methacholine
Effective orally (though its absorption upon oral administration is variable)
3 times more resistant to hydrolysis by true cholinesterase w.r.t. ACh
Totally resistant to hydrolysis by pseudocholinesterase
Longer duration of action than ACh

23. Choline Esters- Uses
Acetylcholine not used because of its transient & non-selective action
Others rarely used nowadays
Bethanechol has been used in
Postoperative paralytic ileus & gastric atony
Postoperative/postpartum nonobstructive urinary retention
Neurogenic bladder atony
Congenital megacolon, and
Gastroesophageal reflux
Methacholine was occasionally used to terminate paroxysmal supraventricular tachycardia (PSVT)

24. Cholinomimetic Alkaloids
Pilocarpine(Tertiary amine)
Obtained from leaves of Pilocarpus microphyllus
Prominent muscarinic actions
Causes marked sweating, salivation & increases other secretions
Applied to the eye, it penetrates cornea and promptly causes miosis, ciliary muscle contraction and fall in intraocular tension
Initial therapy (pilocarpine + physostigmine) in acute angle-closure glaucoma
Used as 0.5-4% drops to treat chronic simple glaucoma

25. Cholinomimetic Alkaloids
Muscarine
Occurs in poisonous mushrooms (Amanita muscaria & Inocybe spp.)
Quaternary amine
Has only muscarinic actions
Not used therapeutically
Nicotine
Derived from the plant Nicotiana tabacum
Tertiary amine
Has only nicotinic actions
Lobeline
Plant derivative similar to nicotine

26. Cholinomimetic Drugs-Contraindications
Bronchial Asthma
Cholinergic drugs can precipitate an asthmatic attack in susceptible individuals as they can cause bronchoconstriction
Peptic Ulcer
Enhance gastric acid production and hence can aggravate symptoms of acid peptic disease

27. Cholinergic Drugs-1(Summary)
Two types of cholinergic receptors (muscarinic & nicotinic)
Muscarinic receptors-smooth muscles/cardiac muscle/glands/CNS
Nicotinic receptors-skeletal muscles/ganglia/ CNS
Cholinergic Drugs(Direct & Indirect-acting)
ACh actions on various organ systems
Choline esters & cholinomimetic alkaloids

28. THANK YOU !