6-cholinergic agonists

Cholinergic agonists/ Cholinomimetic agents

Dr. Kyi Kyi ThaBasic Medical SciencesKulliyyah of Pharmacy

IIUM

Cholinergic/ Cholinergic/ Parasympathetic systemParasympathetic system

CholinergicCholinergic 1. all preganglionic neurons1. all preganglionic neurons 2. the anatomically 2. the anatomically

parasympathetic postganglionic parasympathetic postganglionic neuronsneurons

3. the anatomically sympathetic 3. the anatomically sympathetic postganglionic neurons that postganglionic neurons that innervate sweat glandsinnervate sweat glands

4. the anatomically sympathetic 4. the anatomically sympathetic neurons that end on blood vessels neurons that end on blood vessels in skeletal muscles and produce in skeletal muscles and produce vasodilatation when stimulated vasodilatation when stimulated (sympathetic vasodilator nerves)(sympathetic vasodilator nerves)

Neurotransmitters : Neurotransmitters : AcetylcholineAcetylcholineReceptors : Receptors : Muscarinic (M1 to 5, Muscarinic (M1 to 5,

cardiac, glandular smooth muscles, cardiac, glandular smooth muscles, exocrine glands) & Nicotinic exocrine glands) & Nicotinic receptors (skeletal muscle, receptors (skeletal muscle, ganglion, CNS)ganglion, CNS)

Physiological effectsPhysiological effects

Cholinergic agonistsCholinergic agonists

Acetylcholine receptorsAcetylcholine receptors

Cholinergic Cholinergic agonists/Cholinomimetic/agonists/Cholinomimetic/

Parasympathomimetic agentsParasympathomimetic agents

Cholinergic agonists

Direct acting Indirect acting

Muscarinic acetylcholine receptor agonists

Nicotinic acetylcholine Receptor agonists

(Ganglia)Anticholinesterases

Muscarinic agonistsMuscarinic agonists

Direct acting parasympathomimetic drugsDirect acting parasympathomimetic drugs- Mimic the effects of acetylcholine by Mimic the effects of acetylcholine by

binding directly to muscarinic receptors. binding directly to muscarinic receptors.

(1)(1) ACh and synthetic choline esters - ACh and synthetic choline esters - Acetylcholine, Methancholine, Carbachol, Acetylcholine, Methancholine, Carbachol, BethanecholBethanechol

(2)(2) Naturally occurring cholinomimetic Naturally occurring cholinomimetic alkaloidsalkaloids

Muscarine, Pilocarpine, Arecoline.Muscarine, Pilocarpine, Arecoline.

(3) Synthetic drugs: Cevimeline, Varenicline.(3) Synthetic drugs: Cevimeline, Varenicline.

Parasympathomimetic Parasympathomimetic agentsagents

Structures of muscarinic Structures of muscarinic agonistsagonists

The key features of The key features of ACh molecule ACh molecule (choline ester of (choline ester of acetic acid) acetic acid) important for its important for its activity are activity are quaternary quaternary ammonium group and ammonium group and ester group.ester group.

Pharmacological actions of Pharmacological actions of muscarinic agonistsmuscarinic agonists

MOA: activate muscarinic ACh MOA: activate muscarinic ACh receptors.receptors.

Selectivity – muscarinic/ nicotinic Selectivity – muscarinic/ nicotinic actionsactions

(ACh –both muscarinic & nicotinic (ACh –both muscarinic & nicotinic actions. Bethanechol- little/no actions. Bethanechol- little/no nicotinic action.)nicotinic action.)

Pharmacological actions of Pharmacological actions of muscarinic agonistsmuscarinic agonists

1. CVS: mimic effects of vagal stimulation.1. CVS: mimic effects of vagal stimulation. a decrease in cardiac rate (-ve chronotropic a decrease in cardiac rate (-ve chronotropic

effect), a decrease in rate of conduction in effect), a decrease in rate of conduction in SA and AV nodes (-ve dromotropic), SA and AV nodes (-ve dromotropic), decrease in force of cardiac contraction (-ve decrease in force of cardiac contraction (-ve inotropic), vasodilatation (endothelial inotropic), vasodilatation (endothelial mediated, M3 receptor, activation of NO mediated, M3 receptor, activation of NO synthetase & formation of NO and increase synthetase & formation of NO and increase cGMP to relax vascular smooth muscles).cGMP to relax vascular smooth muscles).

i.v injection can cause fall in B.P.i.v injection can cause fall in B.P.

Pharmacological actions of Pharmacological actions of muscarinic agonistsmuscarinic agonists

2. GIT: increases salivary secretions, 2. GIT: increases salivary secretions, stimulates intestinal secretions and motility.stimulates intestinal secretions and motility.

3. Resp: bronchoconstriction, bronchial 3. Resp: bronchoconstriction, bronchial secretions are also stimulated.secretions are also stimulated.

4. Genitourinary: detrusor muscle 4. Genitourinary: detrusor muscle contraction, increased voiding pressure, contraction, increased voiding pressure, relax internal sphincter causing micturition, relax internal sphincter causing micturition, ureter peristalsis.ureter peristalsis.

5. Eye: stimulating ciliary muscle contraction 5. Eye: stimulating ciliary muscle contraction for near vision, constriction of pupillae for near vision, constriction of pupillae sphincter muscle causing miosis (marked sphincter muscle causing miosis (marked constriction of pupil), increase lacrimal constriction of pupil), increase lacrimal gland secretion.gland secretion.

PharmacokineticsPharmacokinetics Bethanechol - orally, subcutaneous inj, Pilocarpine Bethanechol - orally, subcutaneous inj, Pilocarpine

eye drop (topical)eye drop (topical) Quaternary ammonium compound: Acetylcholine, Quaternary ammonium compound: Acetylcholine,

Bethanechol - cannot penetrate membranes, limited Bethanechol - cannot penetrate membranes, limited absorption.absorption.

Tertiary amine- Pilocarpine- can cross conjunctival Tertiary amine- Pilocarpine- can cross conjunctival membrane, can enter CNS.membrane, can enter CNS.

ACh is rapidly hydrolyzed by ACE, has extremely ACh is rapidly hydrolyzed by ACE, has extremely short duration of action.short duration of action.

Many of agonists at muscarinic ACh receptors are Many of agonists at muscarinic ACh receptors are less susceptible than ACh to hydrolysis by less susceptible than ACh to hydrolysis by acetylcholinesterase- more prolong duration of acetylcholinesterase- more prolong duration of action. (e.g. Bethanechol= 1 hr, Pilocarpine= 1 day)action. (e.g. Bethanechol= 1 hr, Pilocarpine= 1 day)

Therapeutic usesTherapeutic uses 1. 1. OphalmologicalOphalmological: Pilocarpine, Carbachol- to : Pilocarpine, Carbachol- to

decrease intraocular pressure in chronic open decrease intraocular pressure in chronic open angle glaucoma.angle glaucoma.

2. 2. GI disordersGI disorders : postoperative abdominal : postoperative abdominal distension/gastric atony (Bethanechol)distension/gastric atony (Bethanechol)

3. 3. Urinary bladder disordersUrinary bladder disorders: to stimulate : to stimulate atonic bladder, postoperative/postpartum atonic bladder, postoperative/postpartum nonobstructive urinary retention nonobstructive urinary retention (Bethanechol)(Bethanechol)

4. Xerostomia: Pilocarpine, Cevimeline 4. Xerostomia: Pilocarpine, Cevimeline 5. treatment of cognitive impairment 5. treatment of cognitive impairment

associated with Alzheimer’s disease, associated with Alzheimer’s disease, dementia. (clinical trial drugs- M1 agonists -dementia. (clinical trial drugs- M1 agonists -Taclifensine)Taclifensine)

6. ACh: intraocular (cataract surgery, 6. ACh: intraocular (cataract surgery, diagnostic coronary angiography)diagnostic coronary angiography)

Actions of Pilocarpine on Actions of Pilocarpine on eyeeye

Topical eye drops- rapid miosis & Topical eye drops- rapid miosis & contraction of ciliary muscle.contraction of ciliary muscle.

To reduce IOP of both closed and To reduce IOP of both closed and open- angle glaucoma.open- angle glaucoma.

Adverse effectsAdverse effects1. exaggeration of the 1. exaggeration of the

parasympathomimetic parasympathomimetic effects: sweating, effects: sweating, salivation, flushing, salivation, flushing, decreased BP, nausea, decreased BP, nausea, abdominal pain, diarrhoea, abdominal pain, diarrhoea, bronchospasmbronchospasm

2. The toxic potential 2. The toxic potential depends on their depends on their absorption, access to CNS absorption, access to CNS and metabolism.and metabolism.

ToxicologyToxicology : Mushroom : Mushroom Poisonining (muscarine).Poisonining (muscarine).

Nicotinic receptor Nicotinic receptor agonistsagonists

Nicotine (chewing gum, transdermal Pathches) is Clinically used to stop smoking.

Other synthetic drugsOther synthetic drugs

CevimelineCevimeline Synthetic direct-acting muscarinic agonistSynthetic direct-acting muscarinic agonist OralOral Uses: treatment of dry mouth, ? dry eyesUses: treatment of dry mouth, ? dry eyes Caution in patients with asthma and Caution in patients with asthma and

cardiac arrhythmia. cardiac arrhythmia. VareniclineVarenicline Partial agonist at nicotinic receptor in Partial agonist at nicotinic receptor in

brain.brain. Used in smoking cessation.Used in smoking cessation.

ReferencesReferences

1. Rang & Dale’s Pharmacology 1. Rang & Dale’s Pharmacology (2007).(2007).

2. Goodman & Gilman (2006) The 2. Goodman & Gilman (2006) The Pharmacological Basis of therapeutics.Pharmacological Basis of therapeutics.

3. Katzung. B. G (2001) Basic & 3. Katzung. B. G (2001) Basic & Clinical Pharmacology.Clinical Pharmacology.

4. Mary J. Myck (2000) Lippincott’s 4. Mary J. Myck (2000) Lippincott’s illustrated Reviews: Pharmacology. illustrated Reviews: Pharmacology.

5. Brenner & Stevens (2010) 5. Brenner & Stevens (2010) Pharmacology.Pharmacology.