Presentation on theme: "Pharmacology of Cholinergic Agonists"— Presentation transcript:
1 Pharmacology of Cholinergic Agonists Dr. Thomas AbrahamPHAR 417: Fall 2004
2 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 esterscholinomimetic natural alkaloids and analogsCholinergic agonists also activate Nicotinic receptors found in the ganglia, neuromuscular junction and CNS
3 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
4 Cholinergic Agonists Ø DERIVATIVES OF CHOLINE ESTERS Ø DERIVATIVES OF CHOLINE ESTERSresistant to AChE metabolism.Susceptibility to cholinesterase metabolism:Acetylcholine >>> Methacholine >> Carbachol > Bethanecholmainly muscarinic receptor agonists but Carbachol hassignificant nicotinic receptor activity.Selectivity for cholinergic receptors:Acetylcholine Non-selectiveMethacholine Predominantly muscarinic (****)Bethanechol Predominantly muscarinic (**)Carbachol Muscarinic (**) and Nicotinic (***)
5 Cholinergic AgonistsØ Activation of specific muscarinic receptors in various organs elicits physiological response:1. Decreased heart rate (negative chronotropy), decreased conductionvelocity, decreased atrial contractility (negative inotropy).2. Vasodilation of arteries and arterioles: indirectly by the release ofnitric 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, decreasedtrigone, sphincter muscle tone, decreased bladder volume.5. Increased bronchial constriction, increased salivation, lacrimation,miosis, increased accommodation for near vision.
6 Cholinergic Agonists Vasodilation of arteries by Muscarinic Agonists EndotheliumVascular Sm.MuscleThese 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.
7 Cholinergic AgonistsØ Multiple muscarinic receptors regulate the various physiologicaleffects of endogenous acetylcholine or synthetic analogs:M1 receptor M2 receptor M3 receptor M4 receptorG-protein couplingSecond messengersystemReceptor LocationGq/11Activation of PLC – Ca2+, PKCBrain, sympathetic ganglia, glands,Smooth muscleGi/oInhibition of adenylate cyclase, K+ current activationHeart, brain,Gq/11Activation of PLC – Ca2+, PKCSmooth muscle, glands, brainGi/oInhibition of adenylate cyclase, K+ current activationBrain
8 Cholinergic AgonistsSignal transduction systems of Muscarinic receptorsCoupling 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
9 Cholinergic AgonistsII. Coupling of muscarinic receptors to effectors via Go/iM2 receptor activation results in decreased heart rate and decreased neurotransmitter release from cholinergic nerves.
10 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 contraindicationsØ 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.
11 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.
12 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”
13 Cholinergic AgonistsØ Systemic administration produces less selective muscarinic effects thanlocal application:1. Cardiovascular system – small doses of muscarine (i.v.) decreaseheart 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 pressurein open-angle glaucoma; supplied as ophthalmic solution and sustained release delivery system (Occusert Pilo-20®).
14 Cholinergic Agonists Drainage of Aqueous Humor through the Eye Aqueous humor is producedby the ciliary body to maintainshape 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 ofDrainage of Aqueous Humor through the EyeClosed anglethe 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.