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

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

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

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)

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

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

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

Cholinergic Muscarinic Receptors

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

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

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

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

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.

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

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

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)

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

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

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

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

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

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

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)

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

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

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

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

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