Chapter 5: Cholinergic Drugs Prof,R.D.Ye 2012-09-29
Chapter 5: Cholinergic Drugs Prof. R.D. Ye 2012-09-29
Classes of cholinergic agonists Direct-acting Indirect-acting Receptor agonists Cholinesterase inhibitors Carbamates Choline esters PHYSOSTIGMINE Phosphates NEOSTIGMINE ISOFLUROPHATE ACETYLCHOLINE Alkaloids PYRIDOSTIGMINE Antidote BETHANECOL PILOCARPINE EDROPHONIUM PRALIDOXIMINE
Classes of cholinergic agonists Direct-acting Receptor agonists Choline esters ACETYLCHOLINE BETHANECOL Alkaloids PILOCARPINE Cholinesterase inhibitors Carbamates PHYSOSTIGMINE NEOSTIGMINE PYRIDOSTIGMINE EDROPHONIUM Phosphates ISOFLUROPHATE Antidote PRALIDOXIMINE Indirect-acting
Chemical structures of selected direct-acting cholinergic agonists 0 CH3 Quaternary ammonium HC-C-O-CH2-CH2-N*一 CHa CH3 Action chiefly muscarinic Acetylcholine HO 0 CH3 Hg H3C-C-O-CH-CH2-N*一 CH3 HgC CH2 -+N-( CH3 CH3 CHg CH3 Methacholine Muscarine (acetyl-B-methylcholine) 0 HaC-CH2 CH2 N-CH3 HN-0-0-cH-ch-N≤ CHa CHg CH3 Carbachol (carbamoylcholine) Pilocarpine 0 CHa CH3 Tertiary amine H2N-C-O-CH-CH2-N一 CH3 CHa Bethanechol (carbamoyl-B-methylcholine)
Chemical structures of selected direct-acting cholinergic agonists Tertiary amine Quaternary ammonium
Muscarinic agonists Receptor specificity Drugs mAChR nAchR Hydrolysis by AchE Acetylcholine +++ +++ +++ Carbachol ++ ++ (-) Methacholine +++ + Bethanechol +++ (-) (-) Muscarine +++ (-) (-) Pilocarpine + (-) (-) Muscarinic antagonists Atropine,scopolamine,and pirenzepine(relatively selective for M1 mAChR)
Muscarinic agonists Drugs Receptor specificity mAChR nAchR Hydrolysis by AchE Acetylcholine Carbachol Bethanechol Muscarine Pilocarpine Methacholine Muscarinic antagonists Atropine, scopolamine, and pirenzepine (relatively selective for M1 mAChR)
Choline 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) Muscarinic Effect Acetylcholine chloride High (++++ High(limited by AChE) Methacholine chloride Low (+ Highest (++++ Carbachol chloride Negligible Medium (++ Bethanechol chloride Negligible Medium (++
Choline 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) Muscarinic Effect Acetylcholine 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 0c88切 South America Used clinically for treating dry mouth(xerostomia)after radiation therapy of head and neck tumor;also for treatment of glaucoma
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
Cholinergic effects: Adrenergic effects: Contraction of pupillary constrictor muscle Contraction of pupillary dilator muscle --miosis --mydriasis Contraction of ciliary muscle-bulge of lens Stimulation of ciliary epithelium --near vision,T outflow of acqueous humor --1 production of aqueous humor Pupillary dilator muscle (a1) Pupillary constrictor muscle(M3) Cornea Iris Pathway for aqueous humour Canal of Schlemm Trabecular meshwork (opened by pilocarpine) Lens Ciliary muscle (M3) Ciliary body Suspensory ligaments Secretion of acqueous humor(B) Fig.6.5 The anterior chamber of the eye,showing the pathway for secretion and drainage of the aqueous humor
Lens Pupillary dilator muscle () Pupillary constrictor muscle (M3) Secretion of acqueous humor () (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 e Eyes:contraction of ciliary muscle and smooth muscle of the iris sphincter(miosis)-aqueous humor outflow, drainage of the anterior chamber e 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+Icadiastolic depolarization,1NO- inhibitable ATP),negative chronotropic effect (inhibition of adrenergic activation). Respiratory:Bronchoconstriction,mucus secretion
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 , NOinhibitable ATP), negative chronotropic effect (inhibition of adrenergic activation). • Respiratory: Bronchoconstriction, mucus secretion
Organ 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 parasympatetic enervation(salivary,lacrimal, tracheobronchial,digestive and exocrine sweat glands)
Organ 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 parasympatetic 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. o 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 pilocarpine enters the brain,it can induce chronic epilepsy (used in rodent experiments)
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 pilocarpine enters the brain, it can induce chronic epilepsy (used in rodent experiments)
