1Cholinergic drugs (1)cholinergic stimulantsRichard D. YeProfessorDepartment of PharmacologyCollege of MedicineTel. 996-5087, COMRB 4143E-mail: [email protected] of cholinergic stimulantsDirect-actingReceptor agonistsCholine estersACETYLCHOLINEBETHANECOLAlkaloidsPILOCARPINECholinesterase inhibitorsCarbamatesPHYSOSTIGMINENEOSTIGMINEPYRIDOSTIGMINEEDROPHONIUMPhosphatesISOFLUROPHATEAntidotePRALIDOXIMINEIndirect-acting2Chemical structures of selecteddirect-acting cholinergic agonistsTertiary amineQuaternary ammonium Muscarinic agonistsDrugsReceptor specificityHydrolysis by AchEmAChR nAchRAcetylcholineCarbacholBethanecholMuscarinePilocarpineMethacholine+++ ++++++++ +++( − )+++ + ++++++++++( − ) ( − )( − ) ( − )( − ) ( − )Muscarinic antagonistsAtropine, scopolamine, and pirenzepine (relatively selective for M1 mAChR)3Choline esters: Absorption, metabolism, distribution- Absorption: polarity dependent (poorly distributed into CNS due to quaternary ammonium), intravenous, subcutaneous and intramuscular use for local effects- Metabolism: Highly dependent on the susceptibility to acetylcholinesterase (AChE)Compound Susceptibility (AChE) MuscarinicEffectAcetylcholine chloride High (++++) High (limited by AChE)Methacholine chloride Low (+) Highest (++++)Carbachol chloride Negligible Medium (++)Bethanechol chloride Negligible Medium (++)Pilocarpine, a cholinomimetic alkaloid• Chewing pilocarpus causes salivation. It also induces sweating.Amazon• Used clinically for treating dry mouth (xerostomia) after radiation therapy of head and neck tumor; also for treatment of glaucoma.4LensPupillary dilator muscle (α1)Pupillary constrictor muscle (M3)Secretion of acqueous humor (β)(M3)Cholinergic effects: Adrenergic effects:• Contraction of pupillary constrictor muscle-- miosis• Contraction of ciliary muscle - bulge of lens-- near vision, ↑ outflow of acqueous humor • Contraction of pupillary dilator muscle-- mydriasis• Stimulation of ciliary epithelium-- ↑ production of aqueous humor Trabecular meshwork(opened by pilocarpine)Organ effects of cholinergic agonists• Eyes: contraction of ciliary muscle and smooth muscle of the iris sphincter (miosis) – aqueous humor outflow, drainage of the anterior chamber• Cardiovascular: Bradycardia (possibly preceded by tachycardia), vasodilation (all vascular beds including pulmonary and coronary – M3) and hypotension, reduction of the contraction strength (atrial and ventricular cells, IK+ , ICa2+ diastolic depolarization , NO-inhibitable ATP), negative chronotropic effect (inhibition of adrenergic activation). • Respiratory: Bronchoconstriction, mucus secretion5Organ effects of cholinergic agonists•GI -increases in tone, amplitude of contractions, and peristaltic activity of the stomach and intestines; enhances secretory activity of the gastrointestinal tract.• Urinary bladder - increase ureteral peristalsis, contract the detrusor muscle of the urinary bladder, increase the maximal voluntary voiding pressure, and decrease the capacity of the bladder.• Other effects – Increased secretion from all glands that receive parasymphatetic enervation (salivary, lacrimal, tracheobronchial, digestive and exocrine sweat glands)Adverse effect of pilocarpine• Although the clinical use of pilocarpine is mostly based on its action at the M3 muscarinic receptor, pilocarpine is in fact a non-selective muscarinic receptor agonist and its side effects are mostly associated with this property. • Excessive sweating, excessive salivation, increased bronchial mucus secretion, diarrhea.• Bronchospasm, bradycardia, vasodilation, miosis (when used chronically as eye drops). • Reduces blood-brain barrier function. When pilocarpineenters the brain, it can induce chronic epilepsy (used in rodent experiments).6Oxotremorine: Extremely potent muscarinic agonist, synthetic, enters CNSLobeline: Plant derivative, nicotinic but with lower potency than nicotine.Dimethylphenylpiparazinium (DMPP) : Potent synthetic nicotinic stimulant; selectively activate ganglionic nicotinic receptors.Other direct-acting cholinergic agonistsCarbachol: Also known as carbamylcholine, is a synthetic cholinergic agonist acting on both muscarinic and nicotinic receptors. It is not susceptible to AChE, making it longer lasting than acetylcholine (2-5 min onset, 4-8 h duration, 24 h duration by intraocular administration). Used primarily for treatment of glaucoma. Bethanecol: A β-methylated carbachol, its action is selective for muscarinic receptors. Bethanechol can be administered orally or subcutaneously for treatment of urinary retention resulting from general anesthetic diabetic neuropathy of the bladder. It is also used for treating gastrointestinal atony (lack of muscular tone). Unlike carbachol and pilocarpine which are used for treating glaucoma through activation of the M3 muscarinicreceptor, in vitro study showed that bethanecol does not activate the M3 receptor. Indirect cholinergic stimulants(cholinesterase inhibitors, anticholinesterases)Acetylcholinesterase (AChE)• Bound to the basement membrane in the synaptic cleft at cholinergic synapses• Also present as a soluble form in cholinergic nerve terminals; function unknown• Binds Ach, forming a transient intermediate which then becomes acetylated AChEand choline; spontaneous and rapid deacylation follows, regenerating the enzymeButyrylcholinesterase (BChE, pseudocholinesterase)• Widely present, including a presence in soluble form in the plasma• Not particularly associated with cholinergic synapases• Broader substrate specificity than AChE; hydrolyses butyrylcholine more efficiently than acetylcholine; function remains largely unknown• Together with AChE, keeps acetylcholine concentration in plasma nearly undetectable7Reversible cholinesterase inhibitors(compared to acetylcholine)Ester of carbamic acidQuaternary ammoniumIrreversible cholinesterase inhibitorsDashed line: bond that is hydrolyzed in binding to the enzyme.Shaded esters: points of detoxification of the molecule (metabolized) in mammals and birds but not in insects.8Cholinesterase inhibitors – mechanisms of actionHis447Glu334Ser203H.P. Rang et al. Pharmacology, 5thEd.Drugs in this class are carbamyl esters instead of acetyl esters that bind to the anionic site (Glu), same as with acetylcholine. The carbamyl group is transferred to Ser. However the carbamylatedenzyme is much slower to hydrolyze, thereby reducing the recovery