1、第八章 肌松藥的臨床應(yīng)用1第八章 肌松藥的臨床應(yīng)用1目的與要求掌握:肌松藥的應(yīng)用原則以及殘留肌松作用的判斷熟悉：肌松藥的不良反應(yīng),影響肌松藥作用的因素 肌松藥的麻醉期間的應(yīng)用了解：神經(jīng)肌肉傳遞功能監(jiān)測(cè)2目的與要求掌握:肌松藥的應(yīng)用原則以及殘留肌松作用的判斷2KeyHypnosisAnalgesiaAmnesia Relaxation3KeyHypnosis3History In 1942 Griffith and Johnson suggested that d-tubocurarine (dTc)Succinylcholine, introduced by Thesleff and Fold

2、es et al in 1952In 1967 Baird and Reid first reported pancuroniumin the early 1980s of two new muscle relaxants of intermediate duration atracurium and vecuronium The early 1990s witnessed pipecuronium, doxacurium, mivacurium and rocuroniumAn atracurium isomer, cisatracurium introduced in 1996 4Hist

3、ory In 1942 Griffith and JClinical UseTracheal intubation OperationICUCure of spasticity5Clinical UseTracheal intubatioMolecular Features Neuromuscular blocking drugs are quaternary ammonium compoundsNearly all muscle relaxants contain two positive charges 6Molecular Features NeuromusculMuscle relax

4、ants are generally quite water-soluble The water solubility of relaxants inhibits uptake into hepatocytes Metabolism and/or excretion in the liver is usually not a major pathway of elimination The muscle relaxants are easily excreted by glomerular filtration in the urine 7Muscle relaxants are genera

5、llyClassDepolarizing drugsuccinylcholine Imbretil（己氨膽堿、氨酰膽堿）8ClassDepolarizing drug8PHARMACOLOGY OF SUCCINYLCHOLINE Rapid hydrolysis by pseudocholinesterase假膽堿酯酶Factors lowering pseudocholinesterase concentrationliver diseasePregnancyBurnsoral contraceptivesmonoamine oxidase inhibitorscytotoxic drug

6、sneoplastic diseaseanticholinesterase drugs膽堿酯酶抑制劑9PHARMACOLOGY Cardiovascular Effects stimulates nicotinic receptors on both sympathetic and parasympathetic ganglia and muscarinic receptors in the sinus node of the heart In low doses, both negative inotropic and chronotropic（負(fù)性變力、變頻 ）responses may

7、occur. These can be attenuated by prior administration of atropine With large doses, positive responses. cardiac arrhythmias 10Cardiovascular Effects stimulaSinus Bradycardia with high sympathetic tone, such as children in adults and appears more commonly after a second dose of the drug is given app

8、roximately 5 minutes after the firstprevented by thiopental, atropine, ganglion-blocking drugs, and nondepolarizing muscle relaxants 11Sinus Bradycardia 11Nodal (Junctional) Rhythms suppressing the sinus mechanism and allowing the emergence of the atrioventricular node as the pacemaker prevented by

9、prior administration of dTc 12Nodal (Junctional) Rhythms 12Ventricular Arrhythmias lowers the threshold of the ventricle to catecholamine-induced arrhythmias Circulating catecholamine concentrations increase 4-fold and potassium increases by one-third Other stimuli, such as endotracheal intubation,

10、hypoxia, hypercarbia, and surgery, are probably additive to the effect of succinylcholine 13Ventricular Arrhythmias 13Complications Hyperkalemia Burns Trauma Closed Head Injury Intra-Abdominal Infections Renal Failure Metabolic Acidosis 14Complications Hyperkalemia 14Increased Intraocular Pressure I

11、ncreased Intragastric Pressure PregnancyAscitesBowel obstructionHiatus herniaIntracranial Pressure Muscle Pains 15Increased Intraocular PressureNondepolarizing drugSteroidal CompoundsPancuronium, Pipecuronium, Vecuronium, Rocuronium and Rapacuronium 無(wú)組胺釋放作用,主要經(jīng)腎排泄，可松弛迷走神經(jīng)松弛迷走神經(jīng)中度Pancuronium, Rapacur

12、onium輕度Rocuronium無(wú) Pipecuronium, Vecuronium16Nondepolarizing drug16親脂/親水的水平?jīng)Q定肝臟攝取親脂性強(qiáng)Vecuronium, Rocuronium and Rapacuronium 中短效、效能低、作用快、肝臟攝取代謝比例大， Vecuronium3040%經(jīng)肝去乙?；x親脂性弱Pancuronium長(zhǎng)效、效能高、作用慢、肝臟攝取代謝比例小，1520%經(jīng)肝代謝17親脂/親水的水平?jīng)Q定肝臟攝取17Benzylisoquinolinium（芐基異喹啉 ） Compoundsd-Tubocurarine, Metocurine，

13、Doxacurium， Atracurium， Cisatracurium and Mivacurium有組胺釋放作用，可經(jīng)腎排泄，不松弛迷走神經(jīng)組胺釋放作用顯著 d-Tubocurarine中度 Metocurine甲筒箭毒輕度 Atracurium， Mivacurium無(wú) Doxacurium， Cisatracurium給予組胺受體(H1和H2受體)阻滯藥 18Benzylisoquinolinium（芐基異喹啉 ） Classification by Duration of Action Long-Acting Relaxants Relaxants of Intermediate

14、Duration Short-Acting Relaxants 19Classification by Duration of Long-Acting Relaxantsd-Tubocurarine, Metocurine，Doxacurium， Pancuronium，Pipecuronium，Gallamine36min起作用1.52倍ED95劑量插管80120min肌顫搐恢復(fù)25%需謹(jǐn)慎拮抗絕大部分經(jīng)腎以原型排泄20Long-Acting Relaxantsd-TubocurRelaxants of Intermediate DurationVecuronium, Rocuronium，

15、Atracurium，Cisatracurium22.5min起效維持3060min4590min95%肌顫搐恢復(fù)Vecuronium, Rocuronium經(jīng)肝、腎雙通道排泄Atracurium, Cisatracurium Hofmann效應(yīng)21Relaxants of Intermediate DuraShort-Acting RelaxantsMivacurium2min起效維持1220min2535min95%肌顫搐恢復(fù)血漿假性膽堿酯酶催化水解22Short-Acting RelaxantsMivacuriRapacuronium1min起效維持1520min2550min95%肌顫

16、搐恢復(fù)經(jīng)膽汁、腎排泄代謝產(chǎn)物仍有活性可有蓄積作用23Rapacuronium23Pharmacokinetics and Pharmacodynamics 24Pharmacokinetics and Pharmacod25252626Dosage for Tracheal Intubation dosage in the range of two to three times the ED95 is usually given within 1 to 3 minutes If the trachea has already been intubated without a relaxant

17、or with succinylcholine and the purpose is simply to produce surgical relaxation, a dose slightly less than the ED95 27Dosage for Tracheal IntubationMaintenance Dosage Supplemental (maintenance) doses of nondepolarizers range from 20 to 30 percent of the initial dose in the case of long-acting drugs

18、 to 35 to 50 percent of the initial dose in the case of intermediate- and short-acting relaxants 28Maintenance Dosage SupplementaControl of Depth of Neuromuscular Blockade to maintain 90 to 95 percent block of the twitch (one twitch visible on TOF stimulation) Infusion dosage is usually decreased by

19、 about 30 to 50 percent in the presence of potent inhaled anesthetics Relaxation is generally inadequate for most situations if all four responses are clearly visible or palpable during TOF monitoring29Control of Depth of If one or two responses are visible or palpable, relaxation should be sufficie

20、nt for abdominal surgery under adequate depth of anesthesiaIf only one twitch is faintly visible or palpable, relaxation should be deep enough to permit intubation of the trachea under already-established general anesthesia 30If one or two responses are viDosage for Priming a small subparalyzing dos

21、e of the nondepolarizer (about 20% of the ED95 or about 10% of the intubating dose) be given 2 to 4 minutes before giving a second large dose for tracheal intubation. This procedure, termed priming31Dosage for Priming a small subhas been shown to accelerate the onset of block of most nondepolarizing

22、 relaxants by about 30 to 60 secondswith the result that intubation can be performed within approximately 90 seconds following the second dose Rocuronium and Rapacuronium起效快不需預(yù)給量5倍ED95劑量以上的初始量后不需預(yù)給量32has been shown to accelerate tPancuronium Dosage (mg/kg)Clinical Duration (min)ED950.06-0.07Intubati

23、on (at t = + 23 min)0.08-0.1260-120Relaxation (N2O/O2)0.05-0.0630-60Relaxation (Vapor)0.0330-60Maintenance0.01-0.01530-4033Pancuronium Dosage (mg/kg)Cli stimulation of the sympathetic nervous system usually cause an increase in heart rate, blood pressure, and cardiac outputPancuronium is cleared lar

24、gely by the kidney A small amount (1020%) is deacetylated at the 3-position in the liver 34 stimulation of the sympathetiPipecuronium Dosage (mg/kg)Clinical Duration (min)ED950.04-0.05Intubation (at t = + 23 min)0.08-0.1280-120Relaxation (N2O/O2)0.04-0.0640-60Relaxation (Vapor)0.2-0.340-60Maintenanc

25、e0.005-0.0130-4535Pipecuronium Dosage (mg/kg)Clpipecuronium does not block autonomic ganglia, nor does it release histamine The major excretory pathway is the kidney Only a very small amount of the drug (5%) may be deacetylated at the 3-position 36pipecuronium does not block auVecuronium Dosage (mg/

26、kg)Clinical Duration (min)ED950.5Intubation (at t = + 1.53 min)0.1-0.245-90Relaxation (N2O/O2)0.0525-40Relaxation (Vapor)0.03-0.0425-40Maintenance0.01-0.0215-30Infusion0.8-2.0 mg/kg/min37Vecuronium Dosage (mg/kg)Clinmore facile tracheal intubation with nondepolarizers easier administration by infusi

27、on for maintenance of blockade during surgery faster and more complete antagonism of residual blockade at the end of the case lack of cardiovascular responses throughout a wide clinical dose range from one to eight times the ED95the liver is the principal organ of elimination for vecuronium 38more f

28、acile tracheal intubatioRocuronium Dosage (mg/kg)Clinical Duration (min)ED950.3-0.4Intubation (at t = +6090 s)0.6-1.035-75Relaxation (N2O/O2)0.3-0.430-40Relaxation (Vapor)0.2-0.330-40Maintenance0.1-0.1515-25Infusion8-12 mg/kg/min39Rocuronium Dosage (mg/kg)Clinfaster onset It is seven to eight times

29、less potent than vecuronium rocuronium produces pain on injection Rocuronium is eliminated primarily by the liver, with a small fraction (10%) eliminated in the urine 40faster onset 40Rapacuronium Dosage (mg/kg)Clinical Duration (min)ED951.0-1.3Intubation (at t = +6090 s)1.5-2.515-35Relaxation (N2O/

30、O2)1.0-1.515-20Relaxation (Vapor) 0.6-1.015-20Maintenance 0.2-0.515-20Infusiona 129 mg/kg/minaCumulation and slowed recovery tend to develop.41Rapacuronium Dosage (mg/kg)Clow potency (ED90 1.15 mg/kg), a fast onset， and short-to-intermediate durationlittle cardiovascular effect The dose of 3 mg/kg w

31、as associated with an increase of plasma histamine Renal excretion amounts to 22 percent of an administered dose it is possible that its principal route of elimination may be via the liver 42low potency (ED90 1.15 mg/kg),Atracurium Dosage (mg/kg)Clinical Duration (min)ED950.23Intubation (at t = +23

32、min)0.5-0.630-45Relaxation (N2O/O2)0.3-0.430-45Relaxation (Vapor)0.2-0.330-45Maintenance0.1-0.1515-20Infusion4-12mg/kg/min43Atracurium Dosage (mg/kg)ClinHofmann elimination doses of more than 0.5 mg/kg (more than two times ED95 ) cause the release of histamine at high dosage44Hofmann elimination 44C

33、isatracurium Dosage (mg/kg)Clinical Duration (min)ED950.05Intubation (at t = +1.53 min)0.15-0.240-75Relaxation (N2O/O2)0.0530-45Relaxation (Vapor)0.03-0.0430-45Maintenance0.01-0.0215-20Infusion1-2 mg/kg/min45Cisatracurium Dosage (mg/kg)CCisatracurium is about four times more potent than atracurium a

34、nd has minimal cardiovascular side effects intermediate duration of action Hofmann elimination 46Cisatracurium is about four tiMivacurium Dosage (mg/kg)Clinical Duration (min)ED950.07-0.08Intubation (at t = +2.03.0 min)0.2-0.2515-20Relaxation (N2O/O2)0.110-15Relaxation (Vapor)0.0810-15Maintenance0.0

35、5-0.15-10Infusion3-15 (average 6) mg/kg/min47Mivacurium Dosage (mg/kg)Clinhydrolyzed by plasma cholinesteraseThe short duration of action enables maintenance of relaxation by continuous infusion rapid injection of doses of 0.2 to 0.25 mg/kg cause histamine release 48hydrolyzed by plasma cholinest非去極

36、化肌松藥的復(fù)合應(yīng)用 前后復(fù)合應(yīng)用 長(zhǎng)時(shí)效肌松藥后加用中時(shí)效或短時(shí)效肌松藥,前者使后者的作用時(shí)效延長(zhǎng)短時(shí)效肌松藥后加用長(zhǎng)時(shí)效或中時(shí)效肌松藥，前者將使后者的作用時(shí)效縮短 49非去極化肌松藥的復(fù)合應(yīng)用 前后復(fù)合應(yīng)用 49同時(shí)復(fù)合應(yīng)用化學(xué)結(jié)構(gòu)為同一類的兩肌松藥復(fù)合應(yīng)用其作用相加不是同一類的兩肌松藥復(fù)合應(yīng)用其作用協(xié)同 50同時(shí)復(fù)合應(yīng)用50影響肌松藥的藥代動(dòng)力學(xué)因素 增加肌松藥與蛋白的結(jié)合量,可增加其在體內(nèi)分布容積，延緩其由腎排泄增加細(xì)胞外液量可增加肌松藥在體內(nèi)分布容積肝疾病引起體液潴留可增加肌松藥分布容積，肝臟功能下降可引起經(jīng)肝臟代謝消除延緩，作用時(shí)效延長(zhǎng)。腎功能衰竭病人不宜應(yīng)用經(jīng)腎排泄的肌松藥51影響

37、肌松藥的藥代動(dòng)力學(xué)因素 增加肌松藥與蛋白的結(jié)合量,可增影響肌松藥的藥效動(dòng)力學(xué)因素 水、電解質(zhì)和酸堿平衡 呼吸性酸中毒增加氯筒箭毒堿和泮庫(kù)溴銨的肌松作用,且使其作用不易為新斯的明拮抗代謝性酸中毒抑制新斯的明拮抗上述兩肌松藥低鉀血癥和高鈉血癥可增強(qiáng)非去極化肌松藥的作用低鈣血癥和高鎂血癥減少乙酰膽堿釋放，增強(qiáng)非去極化肌松藥作用 52影響肌松藥的藥效動(dòng)力學(xué)因素 水、電解質(zhì)和酸堿平衡 52低溫 低溫可以減少肌肉的血流量,也可降低血漿蛋白結(jié)合肌肉松弛藥的能力，使藥物不易從神經(jīng)肌肉接頭部位轉(zhuǎn)運(yùn)至肝腎等器官代謝和排泄低溫也影響肝臟和腎的血流量，降低代謝酶的活性低溫還可影響乙酰膽堿的合成、釋放，并能影響神經(jīng)肌肉

38、接頭部位的敏感性 53低溫 53年齡 新生兒體液量相對(duì)較大,分布容積增加，消除半衰延長(zhǎng)，因此追加次數(shù)應(yīng)減少老年人體液量減少和腎排泄減慢，肌松藥用量應(yīng)減少神經(jīng)肌肉疾病重癥肌無(wú)力病人用藥應(yīng)十分謹(jǐn)慎肌無(wú)力綜合征病人對(duì)去極化肌松藥和非去極化肌松藥都十分敏感肌強(qiáng)直綜合征病人易發(fā)生術(shù)后呼吸抑制54年齡 54假性膽堿酯酶異常 肝疾病、饑餓、妊娠末期及產(chǎn)褥期,此酶量減少或活性降低有機(jī)磷、六甲溴銨、新斯的明、單胺氧化酶抑制劑和某些抗癌藥均可抑制該酶活性非典型性假性膽堿酯酶是由于遺傳上的缺陷引起酶性質(zhì)異常55假性膽堿酯酶異常 55藥物相互作用 吸入全麻藥 吸入麻醉藥增強(qiáng)非去極化肌松藥作用的順序是,最強(qiáng)為異氟烷、恩

39、氟烷和地氟烷，其次是氟烷，最弱為氧化亞氮吸入麻醉藥增強(qiáng)長(zhǎng)時(shí)效非去極化肌松藥如氯筒箭毒堿、泮庫(kù)溴銨和哌庫(kù)溴銨的作用比較明顯，1/2-1/3 56藥物相互作用 吸入全麻藥 56吸入麻醉藥對(duì)中時(shí)效非去極化肌松藥如維庫(kù)溴銨和阿曲庫(kù)銨的增強(qiáng)作用較弱,僅減少其藥量的1/4吸入全麻藥對(duì)去極化肌松藥的影響相對(duì)較弱，其中以異氟烷的作用最強(qiáng)恩氟烷和異氟烷可促使琥珀膽堿較早演變?yōu)镮I相阻滯 57吸入麻醉藥對(duì)中時(shí)效非去極化肌松藥如維庫(kù)溴銨和阿曲庫(kù)銨的增強(qiáng)作局麻藥大劑量局麻藥本身就可阻滯神經(jīng)肌肉接頭較小劑量的局麻藥能增強(qiáng)非去極化肌松藥和去極化肌松藥作用 58局麻藥58機(jī)制局麻藥作用于接頭前膜,減少乙酞膽堿囊胞的含量直接

40、作用于接頭后膜阻斷鈉通道，從而降低接頭后膜對(duì)乙酞膽堿的敏感性可直接作用于肌纖維膜的離子通道，降低肌肉的收縮能力抑制血漿假性膽堿酯酶的活性，使琥珀膽堿和米庫(kù)氯銨的分解減慢，時(shí)效延長(zhǎng)59機(jī)制59抗心律失常藥奎尼丁具有局部麻醉作用,可與非去極化肌松藥和去極化肌松藥產(chǎn)生協(xié)同作用，增強(qiáng)肌松藥的強(qiáng)度和作用時(shí)效 -受體阻滯藥、鈣通道阻滯藥有可能影響神經(jīng)肌肉接頭的離子傳導(dǎo)而增強(qiáng)肌松藥作用60抗心律失常藥60抗生素 多粘菌素的神經(jīng)肌肉接頭阻滯作用是所有抗生素中最強(qiáng)者,其效應(yīng)逆轉(zhuǎn)困難，鈣離子和新斯的明對(duì)其拮抗的效應(yīng)均很差氨基甙類抗生素中以新霉素和鏈霉素抑制神經(jīng)肌肉傳遞的功能最強(qiáng)，還有妥布霉素、慶大霉素，丁胺卡那霉

41、素，均可增強(qiáng)非去極化肌松藥和去極化肌松藥作用61抗生素 61機(jī)制有接頭前和接頭后雙重效應(yīng)。作用于接頭前膜有類似鎂離子作用,影響乙酞膽堿的釋放。作用于接頭后有膜穩(wěn)定作用。該類藥物的神經(jīng)肌肉接頭阻滯作用可被鈣離子和抗膽堿酯酶藥部分拮抗林可霉素和氯霉素增強(qiáng)非去極化肌松藥的效應(yīng)，而對(duì)去極化肌松藥的效應(yīng)影響很小。其作用機(jī)制同樣涉及接頭前和接頭后雙重作用，并可部分被鈣和新斯的明拮抗62機(jī)制有接頭前和接頭后雙重效應(yīng)。作用于接頭前膜有類似鎂離子作用抗驚厥藥及精神藥 苯妥英鈉與泮庫(kù)溴銨、氯二甲箭毒和維庫(kù)溴銨合用時(shí),可影響后者的肌肉松弛效應(yīng)，但對(duì)氯筒箭毒堿及阿曲庫(kù)按無(wú)影響鋰離子可取代體內(nèi)的鉀離子和鈉離子，產(chǎn)生低鉀

42、血癥和增強(qiáng)非去極化阻滯。對(duì)用鋰治療的躁狂抑郁癥病人，泮庫(kù)溴銨和琥珀膽堿的效應(yīng)增強(qiáng)63抗驚厥藥及精神藥 63肌松藥的拮抗 機(jī)制使乙酰膽堿在神經(jīng)肌肉接頭部位的濃度相對(duì)提高,使更多的膽堿受體從與肌松藥結(jié)合狀態(tài)中解離出來(lái)而使神經(jīng)肌肉接頭恢復(fù)正常增加乙酰膽堿濃度或延長(zhǎng)乙酰膽堿作用時(shí)間，均能拮抗非去極化肌松藥的作用 64肌松藥的拮抗 機(jī)制64抗膽堿酯酶藥新斯的明、吡啶斯的明和依酚氯銨使較多的乙酰膽堿在神經(jīng)肌肉接頭部位積聚,與非去極化肌松藥競(jìng)爭(zhēng)受體。新斯的明還可作用于接頭前膜增加乙酰膽堿釋放量，且可直接興奮膽堿受體鉀通道阻滯劑4-氨基吡啶延長(zhǎng)突觸前神經(jīng)的去極化作用，增加神經(jīng)內(nèi)Ca2+，從而增加乙酰膽堿釋放量

43、和延長(zhǎng)乙酰膽堿釋放時(shí)間為消除抗膽堿酯酶藥所引起的毒蕈堿樣不良反應(yīng)，常需伍用抗膽堿藥，如阿托品或格隆溴銨65抗膽堿酯酶藥新斯的明、吡啶斯的明和依酚氯銨使較多的乙酰膽堿在時(shí)機(jī)肌松藥應(yīng)用達(dá)其維持效果后有微弱呼吸動(dòng)作TOF ratio to more than 0.7 單次肌顫搐刺激恢復(fù)25%以上66時(shí)機(jī)66劑量neostigmine0.02mg/kg-0.04mg/kg 阿托品0.01mg/kg-0.02mg/kg格隆溴銨7g/kg與新斯的明0. 0350. 07mg/kg合用可減少心率變化所引起的危險(xiǎn),這適用于心肌缺血和心臟瓣膜疾病病人 67劑量67影響抗膽堿酯酶藥的作用酸堿和電解質(zhì)失衡呼吸性酸中毒不僅加強(qiáng)非去極化肌松藥的阻滯作用,且影響抗膽堿酯酶藥的作用。當(dāng)動(dòng)脈血二氧化碳分壓（PaCO2）超過(guò)50mmHg時(shí)，抗膽堿酯酶藥幾乎不可能拮抗殘余肌松代謝性堿中毒、低鉀血癥和高鎂血癥時(shí)，殘余肌松也同樣難以為抗膽堿酯酶藥所逆轉(zhuǎn) 68影響抗膽堿酯酶藥的作用68低溫肌松藥難以從神經(jīng)肌肉接頭部移出抗膽堿酯酶藥也難以進(jìn)人