Pharmacology of Cholinergic Agonists Dr. Thomas Abraham PHAR 417: Fall 2004

Cholinergic Agonists Parasympathomimetic, cholinoceptor agonists. Have predominant actions on: autonomic effector organs innervated by postganglionic parasympathetic nerves. cells containing cholinergic receptors. Cholinergic agonists primarily divided into: acetylcholine and synthetic choline esters cholinomimetic natural alkaloids and analogs Cholinergic agonists also activate Nicotinic receptors found in the ganglia, neuromuscular junction and CNS

Cholinergic Agonists ACETYLCHOLINE AND CHOLINE ESTERS Ø ACETYLCHOLINE -         endogenous neurotransmitter; no selectivity for muscarinic vs. nicotinic receptors   -         rapid metabolism by acetylcholinesterase, butyrylcholinesterase; short half-life -         limited therapeutic or diagnostic value

Cholinergic Agonists Ø DERIVATIVES OF CHOLINE ESTERS   Ø      DERIVATIVES OF CHOLINE ESTERS resistant to AChE metabolism. Susceptibility to cholinesterase metabolism: Acetylcholine >>> Methacholine >> Carbachol > Bethanechol mainly muscarinic receptor agonists but Carbachol has significant nicotinic receptor activity. Selectivity for cholinergic receptors: Acetylcholine Non-selective Methacholine Predominantly muscarinic (****) Bethanechol Predominantly muscarinic (**) Carbachol Muscarinic (**) and Nicotinic (***)

Cholinergic Agonists Ø      Activation of specific muscarinic receptors in various organs elicits physiological response: 1.      Decreased heart rate (negative chronotropy), decreased conduction velocity, decreased atrial contractility (negative inotropy).   2.      Vasodilation of arteries and arterioles: indirectly by the release of nitric oxide from endothelial cells. 3.      Gastrointestinal: increased intestinal smooth muscle contraction, motility; relaxation of sphincters, nausea, flatulence, defecation. 4.      Urinary tract: increased detrusor muscle contraction, decreased trigone, sphincter muscle tone, decreased bladder volume. 5.      Increased bronchial constriction, increased salivation, lacrimation, miosis, increased accommodation for near vision.

Cholinergic Agonists Vasodilation of arteries by Muscarinic Agonists Endothelium Vascular Sm. Muscle These experiments show that endothelial cells on arteries and veins contain muscarinic receptors which when activated would lead to relaxation of vascular smooth muscle and vasodilation.

Cholinergic Agonists Ø      Multiple muscarinic receptors regulate the various physiological effects of endogenous acetylcholine or synthetic analogs: M1 receptor M2 receptor M3 receptor M4 receptor G-protein coupling   Second messenger system Receptor Location Gq/11   Activation of PLC – Ca2+, PKC Brain, sympathetic ganglia, glands, Smooth muscle Gi/o   Inhibition of adenylate cyclase, K+ current activation Heart, brain, Gq/11   Activation of PLC – Ca2+, PKC Smooth muscle, glands, brain Gi/o   Inhibition of adenylate cyclase, K+ current activation Brain

Cholinergic Agonists Signal transduction systems of Muscarinic receptors Coupling of muscarinic receptors to phosphoinositide hydrolysis: results in initiating various calcium-dependent processes e.g. smooth muscle contraction, secretion of saliva, mucous, release of digestive enzymes, etc

Cholinergic Agonists II. Coupling of muscarinic receptors to effectors via Go/i M2 receptor activation results in decreased heart rate and decreased neurotransmitter release from cholinergic nerves.

Cholinergic Agonists Therapeutic Uses of Choline esters To produce miosis during ocular surgery and decrease intraocular pressure: acetylcholine (Miochol®), carbachol (Isopto Carbachol®).    Airway hyperactivity test: methacholine (Provocholine®). Urinary incontinence and increase GI motility: bethanechol (Urecholine®). Cautions and contraindications   Ø      Use with caution in patients with asthma, hyperthyroidism, coronary insufficiency, peptic ulcer disease.  Ø      Toxicity evidenced by hypotension, bradycardia, GI cramps, belching, lack of visual accommodation, headaches, salivation.

Cholinergic Agonists CHOLINOMIMETIC NATURAL ALKALOIDS   Ø      More selective for muscarinic vs. nicotinic receptors. Ø      Muscarine from amanita, inocybe, clitocybe sp. of mushrooms; pilocarpine from pilocarpus plant; arecholine from betel nut.

Cholinergic Agonists Mushrooms of Amanita species contain muscarine which if ingested can cause intoxication “There are many old mushroom pickers and many bold mushroom pickers but there are no old, bold mushroom pickers”

Cholinergic Agonists Ø      Systemic administration produces less selective muscarinic effects than local application: 1.      Cardiovascular system – small doses of muscarine (i.v.) decrease heart rate and blood pressure while pilocarpine can have direct muscarinic effects and indirect (ganglionic) effects.     2.      Smooth muscle effects – pupillary constriction by pilocarpine (miosis), initial increase followed by decreased intraocular pressure, decreased accommodation of lens (for far vision); muscarine increases bronchial and GI muscle contraction while muscarine and pilocarpine promote urination.   3.      Exocrine glands – muscarine and pilocarpine result in sweating, nausea, vomiting, salivation, lacrimation. Ø      Therapeutic uses of pilocarpine for the reduction of intraocular pressure in open-angle glaucoma; supplied as ophthalmic solution and sustained release delivery system (Occusert Pilo-20®).

Cholinergic Agonists Drainage of Aqueous Humor through the Eye Aqueous humor is produced by the ciliary body to maintain shape of the eyeball. Poor drainage through the canal of Schlemm results in elevated intraocular pressure. Muscarinic agonists cause contraction of the ciliary mucles to relax the trabecular network to allow more fluid movement through the canal. Increasing the thickness of Drainage of Aqueous Humor through the Eye Closed angle the lens also allows for more movement of aqueous fluid to the anterior chamber. Constriction of the sphincter muscles of the iris also allows proper fluid drainage by pulling away the iris from the closed angle.