作用于胆碱受体的药物(传出神经药理)PPT课件

第十七章 作用于胆碱受体的药物,1,I.Definition Drugs can combine with cholinoceptor and act like ACh.II.Classfication1. M-cholinoceptor agonists胆碱酯类：acetylcholine（乙酰胆碱）, methacholine（醋甲胆碱）,carbachol（卡巴胆碱）,bethanechol（贝胆碱）拟胆碱生物碱：Pilocarpine（毛果芸香碱 ）,arecoline（槟榔碱）,musarine（毒蕈碱） 2. N-cholinoceptor agonists nicotine（尼古丁，烟碱）,2,Acetylcholine（乙酰胆碱）,1. Muscarinic effect (M-effect) :iV small dosage decrease heart rate and contractilitydilation（扩张） of blood vessels, decline of blood pressure constriction（收缩） of bronchial muscle, gastrointestinal,urinary tract,uterus smooth muscle（子宫平滑肌）and pupil（瞳孔） increase the secretion of gland (sweat, salivary, lacrimal, nasopharyngeal) SLUD response-Salivation,Lacrimation, Urination, Defecation（流涎、流泪、大小便失禁）,3,2. Nicotinic effects (N-effect): Larger dosage activates N1 a. produce and activate all the autonomic ganglia（神经节） b. resembles simultaneous discharge of both the parasympathetic and sympathetic nervous systems activates N2 a.constriction of skeletal muscle b.activates N1 receptor of pheochrome（ 嗜铬细胞瘤）cells of adrenal medulla（肾上腺髓质）- release adr. 3. Therapeutic use None-action are too transient,4,Pilocarpine （匹鲁卡品，即毛果芸香碱）,1. Pharmacological effects：stimulates M-receptor (1) Eye a.miosis（缩瞳） b.Decrease intraocular pressure c.cyclospasm（调节痉挛） (2)Glands increase secretion of sweat gland, salivary gland（唾液腺）,5,6,M受体激动药和阻断药对眼的作用示意图,7,房水循环,8,2. Clinical Uses a.Glaucoma（青光眼：闭角型青光眼、开角型青光眼） b.Iritis（虹膜炎：与扩瞳药交替应用）,9,I. Definition & classification,cholinoceptor blocking drugs （胆碱受体阻断药）的概念分类1.按受体 M-cholinoceptor blocking drugsM1,M2,M3 N-cholinoceptor blocking drugs N1,N2 2.按用途 平滑肌解痉药，神经节阻断药，骨骼肌松弛药和中枢性抗胆碱药,第二节 M胆碱受体阻断药,10,. M-cholinoceptor blocking drugs,Atropoine and related alkaloid（生物碱）,阿托品类生物碱及其来源,11,Atropine（阿托品）, An alkaloid that affects the nervous system,1.Mechanism of ActionCompetitive antagonism（对抗） of ACh to muscarinic receptorsNot distinguish among M1, M2, M3 Most sensitive tissues: salivary, bronchial and sweat glandsLess sensitive: gastric parietal cells（壁细胞）(gastric acid secretion)Intermediate: smooth muscle effectors and the heart,12,2. Pharmacological Effects Inhibition the secretion of gland a.salivary gland(dry mouth) b.sweat gland(dry skin) c.bronchial secretary gland d.large dosage-inhibits the secretary function of the stomach Visual a.mydriasis（散瞳） b.cycloplegia（睫状肌麻痹）-cant focus for near vision c.increases intraocular（眼内的） pressure,13,M-R阻断药,M-R激动药,14,Relaxation of visceral（内脏的）smooth muscle a. stomach intestine (reduced tone and motility) b. bronchial muscle, detrusor（逼尿肌） of bladder, urinary tract c. biliary tract gallbladder（胆囊） and bile ducts（胆管） - mild antispasmodic action d. uterus（子宫） - very weak effectHeart a.small dosage: decreases heart rate ( M1-R blocker) b.large dosage: increases the heart rate (M2-R blocker) c.influence is most noticeable in the people whom vagal（迷走神经） tone is considerable.,15,Dilate（扩张）blood vessels and improve（改善）microcirculation a.therapeutic dosage -no significant effect b.large dosage-dilates cutaneous（皮肤的） blood vessels(face and neck)improve microcirculation,recover the blood supply to the important organs, relieve anoxia（缺氧症）of the tissues.CNS stimulating effect a.therapeutic doses ( 0.51.0mg ) - mild excitation b.toxic doses- restlessness, irritability, disorientation, hallucination（幻觉）, delirium（谵妄） c.continual larger doses-CNS depression-circulatory collapse and respiratory failure,16,3. Clinical Uses Relaxation of smooth muscle spasm（痉挛） -visceral（内脏的）colic pain（绞痛） a.gastric and intestinal colic pain b.bladder irritating symptoms c.gallbladder colic pain(less effect) d.renal colic pain(less effect)Inhibition of the secretary gland secretion a.preanaesthetic medication for controlling the side effect of aether（乙醚） b.adjunctive therapy for peptic ulcers,17,Ophthalmology（眼科学） a.examining optic fundus（底） b.examining retina（视网膜） c.prevent adhesion formation in uveitis（葡萄膜炎）and iritis(relax the iris and ciliary body) Cardiovascular（心脏血管的）disorder -severe arrhythmia(bradycardia（心动过缓）: SA block, A-V block)Anti-shock（抗休克） -infectious shockOrganophosphate intoxication,18,4. Side Effects depending on the dose of drug employed; may have: dry mouth（口干）, blurred vision（视物模糊）, tachycardia（心动过速）, dryness of skin（皮肤干燥）, flush（面色潮红）, dizziness（头昏）, difficulty in urination（排尿困难）, constipation（便秘）5. Toxic effects hyperthermia（高热）, restlessness（烦躁）, delirium（谵妄）, hallucination（幻觉）,coma（昏迷） etc.,19,6. Contraindications（禁忌症） glaucoma（青光眼） pyloric obstruction（幽门梗阻） prostatic hypertrophy（前列腺肥大）7. Use with caution（慎用） myocardial infarction（心肌梗塞）, tachycardia（心动过速） elderly,20,Anisodamine （山莨菪碱，654-2）,peripheral anticholinergic effect（外周抗胆碱作用） Uses - colic pain (gastrointestinal tract) - infectious shock（感染中毒性休克）,21,Scopolamine （东莨菪碱）,like atropine, but with central sedative（镇静）effect1.Uses preanaesthetic（麻醉前）medication -sedation & inhibit secretion motion (travel) sickness2.Side effects: similar to atropine,22,Synthetic mydriatic,几种扩瞳药滴眼作用的比较,药物,浓度(%),扩瞳作用高峰(min) 消退(d),调节麻痹作用高峰(min) 消退(d),硫酸阿托品 1.0 30-40 7-10 1-3 7-12,后马托品 1.0-2.0 40-60 1-2 0.5-1 1-2,托比卡胺 0.5-1.0 20-40 0.25 0.5 0.25,环喷托酯 0.5 30-50 1 1 0.25-1,尤卡托品 2.0-5.0 30 1/12-1/4 - -,23,Synthetic spasmolytic agents,Propantheline bromide（溴丙胺太林）,inhibits gastrointestinal tract contraction and inhibits gastric acid secretion.Uses peptic ulcer as an adjuvant（辅佐剂） gastric spasm pregnant vomiting（妊娠呕吐） bed-wetting（遗尿症）,24,抗胆碱酯酶药和胆碱酯酶复活药,第三节,25,Cholinesterase（胆碱酯酶，AChE）,acetylcholinesterase（乙酰胆碱酯酶）也称真性胆碱酯酶：主要存在于胆碱能神经末梢突触间隙。Pseudocholinesterase（假性胆碱酯 酶）：主要存在于血液及肝脏中。,26,27,新斯的明抑制胆碱酯酶过程示意图,28,Neostigmine（新斯的明）,1. Pharmacological effects cholinesterase inhibitor very strong effect on skeletal muscle -direct activating N2 receptors -release ACh at the motor nerve endings（运动神经） strong stimulating effect on gastrointestinal tract（胃肠道平滑肌） and gallbladder smooth muscle（胆囊平滑肌）,I.易逆性抗胆碱酯酶药,29,2. Clinical Uses myasthenia gravis （重症肌无力） Postoperative ileus（术后肠梗阻） and urinary retention（尿潴留） Paroxysmal supraventricular tachycardia（阵发性室上性心动过速） Overdosage of muscle relaxants Atropine intoxication,30,3. Side Effectslarge dosage-nausea（恶心）, vomiting（呕吐）, abdominal pain（腹痛）,HR , fibrillation of muscle fibers（肌束颤动）, “cholinergic crisis”（胆碱能危机）4. Contraindications Mechanical intestinal obstruction (ileus) （机械性肠梗阻）urinary obstruction（尿路阻塞）bronchial asthma（支气管哮喘）,31,Pyridostigmine（吡斯的明）,1.Similar and weaker than neostigmine 2.Duration is longer3.Clinical Uses myasthenia gravis postoperative intestinal distention and urinary retention less side effects,32,Physostigmine(毒扁豆碱，又称Eserine）,Clinical Uses glaucoma（青光眼） awakening of traditional Chinese herb anesthesia （中药麻醉的催醒） atropine intoxication,33,病例讨论,34,35,36,.难逆性抗胆碱酯酶药,Organophosphates (有机磷酸酯类，OPs ）,1.Classification Organophosphorus -dipterex（敌百虫）,rogor（乐果）,DDVP, Parathion（对硫磷）, Malathion（马拉硫磷） -used as an insecticide. -rapidly absorbed skin, respiratory,GI etc. Nerve gases -tabun（塔崩）, sarin（沙林）, soman（梭曼）,37,有机磷酸酯类抑制胆碱酯酶过程示意图,38,2. Mechanism of Organophosphate Intoxication With exposure to Ops anticholinesterase agents, the enzyme (AChE) is phosphorylated（使磷酸化）and becomes unable to function. Acetylcholine build-up,which causes interfer-ence with nerve impulse transmission at nerve endings.,39,3. Acute intoxicationMuscarinic receptors -pupil,vision,gland,respiration,gastrointestinal tract, bladder,etc.Nicotinic receptors -heart rate,blood pressure -neuromuscular junctioncentral nervous system -excitementinhibition Cholinesterase Aging (Once aging occurs, re-activation of the enzyme is virtually impossible.),Acute cholinergic crisis（急性胆碱能危象）,40,4.Chronic Intoxication Reduction of AChE, headache, dizziness, fatigue（疲劳）, sometimes muscle fasciculation, miosis（瞳孔缩小）.5.Treatment of Acute Intoxication Terminate exposure Maintain airway Atropine cholinesterase reactivator other treatment,41,Atropine (阿托品 ）,“及早、足量、反复”-阿托品化（大、红、快、干、净）Atropine blocks acetylcholine receptors(M-R) and halts the cholinergic stimulation；Very large doses of atropine are usually required； The patient should be kept atropinelized（阿托品化）by giving atropine every hour.,42,. Cholinesterase Reactivator（胆碱酯酶复活药）,Compounds called oximes（肟）can cause dephosphorylation（脱磷酸）. Oximes have the general structure R-CH=N-OH （肟基）. Reactivate acetylcholinesterase and is effective in restoring skeletal muscle function. But seems less effective at reversing muscarinic or central signs.,43,44,Pralidoxime iodide (碘解磷定，派姆，PAM ）,1. Pharmacological effects Dephosphorylation Phosphorylated cholinesterase + PAM-phosphorylated PAM + reactivated AChE Direct and minor effect PAM + organophosphate- phosphorylated PAM,45,2.Improve the symptoms stop muscle fasciculation（肌束颤动） improve CNS symptoms -awake the patients -stop convulsion（躁动不安） 3.Side Effects General malaise（不适）,blurred vision（视力模糊）,dizziness,nausea（恶心）,Vomiting, tachycardia（心动过速）,46,Pralidoxime chloride,PAM-Cl (氯解磷定）,Similar to PAM, but reactivating enzyme effect more stronger.Can be used im. or iv.,47,病例讨论,某男，24岁。因20min前口服敌敌畏15mL而入院治疗。体检：嗜睡状，大汗淋漓，呕吐数次。全身皮肤湿冷，无肌肉震颤。双侧瞳孔直径23mm对光反射存在。体温、呼吸及血压基本正常。双肺呼吸音粗。化验：WBC 14.2109/L，中性93，余未见异常。诊断为急性有机磷农药中毒。入院后，用2%碳酸氢钠溶液洗胃，静脉注射阿托品10mg次，共3次。另静脉注射山莨菪碱10mg，解磷定1g，并给青霉素、庆大霉素及输液治疗之后，瞳孔直径为56mm，P 72/min，律齐，皮肤干燥，颜面微红。不久痊愈出院。,48,讨论：（1）对口服有机磷中毒的病人洗胃时应注意哪些问题？如果该患者为敌百虫口服中毒是否仍可用碱性溶液洗胃？ （2）如何正确使用阿托品？ （3）为什么在使用M-R阻断剂时，合用解磷定治疗？,49,Benactyzine（贝那替秦，又名胃复康）,Uses peptic ulcer gastritis（胃炎）, gastric spasm（胃痉挛） bladder irritating symptoms（膀胱刺激症） sedative effect - treat peptic ulcer with anxiety,50,M1 cholinoceptor blocking drugs,Pirenzepine（哌仑西平）,blocks gastric parietal M1 receptor oral absorp-tion is poor, should be taken before meal.,51,. N-cholinoceptor Blocking Drugs,N1-cholinoceptor blocking drugs,also called Ganglionic blocking drugs（神经节阻断药）,competitively blockade at both sympathetic and parasympathetic autonomic ganglia; Dually innervated organs. Uses:seldom used now hypertension hypertension emergency,mecamylamine（美卡拉明，美加明）,52,N2-choli