神经系统药理魏尔清（传出药理概论 拟胆碱药课件

Part 2 Parasympathomimetics,Cholinoceptor agonists: M, N Anticholinesterase inhibitors,A Muscarinic receptor agonists,A Muscarinic receptor agonists,1. Choline Esters (胆碱酯类) Acetylcholine 乙酰胆碱 Carbachol 卡巴胆碱 Methacholine 醋甲胆碱 Bethanechol chloride 氯贝胆碱 2. Natural Alkaloids (生物碱类) Pilocarpine 毛果芸香碱（匹罗卡品） Muscarine 毒蕈碱,Pilocarpine 毛果芸香碱（匹罗卡品）,Pilocarpine 毛果芸香碱,A Muscarinic receptor agonists,1. Pharmacological effects （1）Eyes Miosis（缩瞳）: contraction of sphincter muscle of iris Lowing intraocular pressure（降低眼内压）: enlarging angle of anterior chamber, increasing drainage of aquous humor Spasm of accommodation（调节痉挛）: contraction of ciliary muscle, contraction for near vision,A Muscarinic receptor agonists,Iris, cilliary muscles, and Schelemm canal,（2） Promoting secretion of exocrine glands（外分泌腺体） especially in sweat, salivary and tear glands,A Muscarinic receptor agonists,2. Clinical uses （1）Ophthamological uses Glaucoma: narrow- or wide-angles Iritis: miotics/mydriatics,BOX Glaucoma Acute congestive glaucoma（narrow-angle） Chronic simple glaucoma（wide-angle）,A Muscarinic receptor agonists,（2）Systemic use Dry mouth: radiotherapy Antidote for atropine poisoning,A Muscarinic receptor agonists,3. Adverse effects （1）Local (eye): pain, tears （2）Systemic: secretion of exocrine glands, treated with atropine,A Muscarinic receptor agonists,B Anticholinesterases,1. Reversible anticholinesterases 2. Irreversible anticholinesterases,anionic site esteratic site Acetylcholinesterase is the mechanism of terminating ACh effects,B-1 Reversible anticholinesterases,Action of acetylcholinesterase,Acetylcholinese: structure for interaction with substrate,B-1 Reversible anticholinesterases,Neostigmine 新斯的明,Neostigmine 新斯的明,1. Pharmacological effects binding to AChE, but slowly hydrolysis inhibiting AChE activity Properties of Effects stronger effect on skeletal muscles AChE(-), ACh release, stimulating NM receptor effective on GI tract and urinary bladder more polar and can not enter CNS relatively ineffective on CVS, glands, eye,B-1 Reversible anticholinesterases,Effect of neostigmine on AChE,Action of neostigmine on acetylcholinesterase,2. Clinical uses (1) Myasthenia gravis（重症肌无力）: symptomatic treatment, overdose: cholinergic crisis (2) Paralytic ileus and bladder（手术后肠道及膀胱麻痹）: post operative abdominal distension and urinary retention (3) Antidote for nondepolarizing skeletal muscle relaxants poisoning（解除非除极化型肌松药中毒） (4) Paroxysmal superventricular tachycardia（阵发性室上性心动过速）,B-1 Reversible anticholinesterases,3. Adverse effects （1）Cholinergic effects: muscarinic and nicotinic effects, treated with atropine (muscarinic) （2）Contraindications： mechanical ileus（机械性肠梗阻） urinary obstruction（尿路阻塞） bronchial asthma（支气管哮喘） poisoning of depolarizing skeletal muscle relaxants （除极化型肌松药中毒）,B -1 Reversible anticholinesterases,Other reversible anticholinesterases Pyridostigmine (吡斯的明): myasthenia gravis, paralytic ileus and bladder Physostigmine (毒扁豆碱): glaucoma Edrophonium chloride (依酚氯铵)：myasthenia gravis Galantarmine (加兰他敏)：myasthenia gravis,B-1 Reversible anticholinesterases,Anticholinesterases improving memory Tacrine (他克林)：improving memory / hepatic toxicity Donepezil (多奈哌齐) and rivastigmine (利凡斯的明): improving menory; used in mild/moderate Alzheimer patients Huperzine (哈伯因，石杉碱甲)：myasthenia gravis, improving memory,B-1 Reversible anticholinesterases,B-2 Irreversible Anticholinesterases and Cholinesterase reactivators,1. Organophosphates（有机磷酸酯类） (1) Toxicology Irreversible binding to esteric site of AChE by covalent attachmentphosphorylated AChE aging ACh accumulated in the synaptic sites, and caused toxic effects,Irreversibly binding to esteric site of AChE by covalent attachmentphosphorylated AChE,(2) Toxic symptoms Acute intoxication Muscarinic symptoms eye, exocrine glands, respiration, GI tract, urinary tract, CVS Nicotinic symptoms NN: elevation of BP, increase of HR; NM: tremor of skeletal muscles Central symptoms excitation, convulsion; depression (advanced phase),B-2 Irreversible Anticholinesterases and Cholinesterase reactivators,Chronic intoxication usually occupational poisoning plasma ChE activity weakness, restlessness, anxiety, tremor, miosis, ,B-2 Irreversible Anticholinesterases and Cholinesterase reactivators,(3) Detoxication Elimination of poison; Supportive therapy Antidotes Atropineantagonizing muscarinic effects; early, larger dose, and repeated use Cholinesterase reactivatorsreactivation of phosphorylated AChE; moderate-severe patients, early use, combined with atropine,B-2 Irreversible Anticholinesterases and Cholinesterase reactivators,2. Cholinesterase reactivators,Pyraloxime methoiodide 碘解磷定, PAM,Recognizing and binding to AChE,oxime group Conjugated with organo-phosphates,B-2 Irreversible Anticholinesterases and Cholinesterase reactivators,(1) Pharmacological effects a. Recognizing and binding to AChE, conjugating with organophosphate by oxime group (肟基) b. Conjugation with free organophasphates c. Rapid reactivation of AChE of neuromuscular junctions,B-2 Irreversible Anticholinesterases and Cholinesterase reactivators,1,2,(2) Clinical uses a. Moderate-severe patients b. Early use, ineffective for aging phosphorylated AChE c. More effective on tremor d. Combination with larger dose of atropine,B-2 Irreversible Anticholinesterases and Cholinesterase reactivators,(3) Adverse effects a. Central reactions: i.v. 500 mg/min b. Iodine toxic effects c. overdose: inhibiting AChE,B-2 Irreversible Anti