1、CLINICAL PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTSJerrold H.Levy,MDProfessor of AnesthesiologyEmory University School of Medicine Division of Cardiothoracic Anesthesiology and Critical CareEmory HealthcareAtlanta,GeorgiaHISTORY OF NEUROMUSCULAR BLOCKING AGENTS AND CLINICAL DEVELOPMENTHISTORY1494
2、-Tales of travelers killed by poison darts1551-Ourari”or“cururu”meaning“bird killer”1812-Curarized cat kept alive by artificial respiration1912-Curare used to prevent fractures during ECT1941-Initial use by Griffith,Culler,and Rovenstine1951-Succinylcholine chloride first used in StockholmINTRODUCTI
3、ON OF NEW DRUGS1494-1942 Curare1947-1951 Succinylcholine chloride,Gallamine,Metocurine,Decamethonium1960sAlcuronium1970sPancuronium bromide,Fazadinium1980sVecuronium bromide,Atracurium besylate1990Pipecuronium bromide1991Doxacurium chloride1992Mivacurium chloride1994Rocuronium bromide2019Rapacuroniu
4、m bromideSTRUCTURAL CLASSES OF NONDEPOL.ARIZING RELAXANTS Steroids:Rocuronium bromide,Vecuronium bromide,Pancuronium bromide,Pipecuronium bromide Naturally occurring benzylisoquinolines:curare,metocurine Benzylisoquinoliniums:Atracurium besylate,Mivacurium chloride,Doxacurium chlorideTHE IDEAL RELAX
5、ANT Nondepolarizing Rapid onset Dose-dependent duration No side-effects Elimination independent of organ function No active or toxic metabolitesONSET OF PARALYSIS IS AFFECTED BY:Dose(relative to ED95)Potency(number of molecules)Keo(chemistry/blood flow)Clearance AgeWSustained 5-second head liftWAbil
6、ity to appose incisors(clench teeth)WNegative inspiratory force 40 cm H2OWAbility to open eyes wide for 5 secondsWHand-grip strengthWSustained arm/leg liftWQuality of speaking voiceWTongue protrusionAssessing Postoperative Neuromuscular FunctionCLINICAL ASSESSMENTKopman AF,et al.Anesthesiology,2019:
7、86;765Ali HH,et al.Br J Anaesth.1975;47:570Assessing Postoperative Neuromuscular FunctionTrain-of-Four(TOF)Fade RatioPeak Exp.Flow RateInspiratory ForceVital CapacityTOF RatioAssessing Postoperative Neuromuscular FunctionTHE ORIGIN OF THE GOLD STANDARDNEW DATA SUGGEST THAT A TOF OF 0.90 MAY BE NEEDE
8、D TO ENSURE NORMAL FUNCTIONAssessing Postoperative Neuromuscular FunctionWKopman:A TOF 0.90 compatible with normal clinical tests(Anesthesiology.2019;86:765)WEriksson:Pharyngeal function normal at TOF 0.90(Anesthesiology.2019;87:1035)Assessing Postoperative Neuromuscular FunctionWPatients are often
9、returned to the PACU with residual paralysis1WThe TOF ratio of 0.70 may be inadequate for discharge of an ambulatory patient1WTOF ratios 0.40 are difficult to assess clinically21Viby-Mogensen J,et al.Anesthesiology.1979;50:5392Kopman AF,et al.Anesthesiology.1994;81:1394Assessing Postoperative Neurom
10、uscular FunctionWRecovery is inadequate if fade is detected1,2WClinical trials are needed to demonstrate measurement techniques for TOF ratios of 0.902W VagolyticWPartially block cardiac muscarinic receptors involved in heart rate slowing,resulting in increased heart rate:Wrapacuronium pancuronium r
11、ocuronium vecuroniumW Generally do not promote histamine releaseWException:rapacuroniumW Organ-dependent eliminationWKidneys and liverNeuromuscular Blockers:Chemical Structure&Key CharacteristicsAminosteroidsSavage DS,et al.Br J Anaesth.1980;52 Suppl 1:3SDurant NN,et al.J Pharm Pharmacol.1979:31(12)
12、:831Marshall IG,et al.Br J Anaesth.1980;52 Suppl 1:11SWAbsence of vagolytic effectWthese drugs do not block cardiac-vagal(muscarinic)receptorsWHistamine releaseWdTc atracurium mivacurium cisatracuriumWcan cause rare bronchospasm,decreased blood pressure,increase of heart rateWGenerally organ-indepen
13、dent elimination1Wesp:atracurium,cisatracurium,mivacuriumWNoncumulative2Neuromuscular Blockers:Chemical Structure&Key CharacteristicsBenzylisoquinolines1Stenlake JB,et al.Br J Anaesth.1983;55;3S2Ali HH,et al.Br J Anaesth.1983;55:107SDURATION OF ACTION OF NEUROMUSCULAR BLOCKING AGENTS Ultra-Short:Suc
14、cinylcholine chloride Short:Mivacurium chloride Intermediate:Rocuronium bromide,Vecuronium bromide,Atracurium besylate Long:Pancuronium bromide,curare,metocurine,Pipecuronium bromide,Doxacurium chlorideCARDIOVASCULAR PROFILE OF NEUROMUSCULAR BLOCKING AGENTSHemodynamics,histamine release,and other as
15、pectsHISTAMINE RELEASING POTENTIALSignificantInsignificantTubocurarine+Rocuronium bromide Metocurine+Vecuronium bromide Atracurium besylate+Pancuronium bromide Mivacurium chloride+Pipecuronium bromide Succinylcholine chloride+Doxacurium chloride Muscle RelaxantsPancuronium Vagolytic:increases heart
16、rate,may require beta blockade Easy to use Intermediate duration of action Slower onset Not reversed at end of caseMuscle RelaxantsVecuronium No effects on HR,BP Requires reconstitution Reliable and controllable duration of action Slower onset Stable hemodynamics/no histamine releaseMuscle Relaxants
17、Rocuronium No effects on HR,BP Easy to use,liquid,no refrigeration Reliable and controllable duration of action Fast onset Stable hemodynamics/no histamine releaseEffects of Rocuronium on Heart RateEffects of Rocuronium on Mean Arterial PressureEffects of Rocuronium on Histamine ReleaseMuscle Relaxa
18、ntsRapacuronium Minimal effects on HR,BP Controllable duration of action Fast onset Stable hemodynamics/minimal histamine release Potential for bronchospasm led to its removal in 2019COSTS OF NEUROMUSCULAR BLOCKING AGENTS AND SELECTION CRITERIAW Cost of care acquisition costW The real,substantial sa
19、vings accrue from use of intermediate-and short-acting drugs because:WInexpensive,long-acting drugs are associated with prolonged postoperative recovery 1WFast recovery means shorter risk periods of residual blockade.This translates into fewer postoperative complications,as shown in the Berg study2W
20、Postoperative complications are very expensiveAvoiding these is where the real cost savings accrueNeuromuscular Agents:Costs of Care 1Ballantyne JC,et al.Anesth Analg.2019;85:4762Berg H,et al.Acta Anaesthesiol Scand.2019;41:1095WCardiovascular stabilityWNondepolarizing vs depolarizing WOrgan-independent eliminationWClinically significant active or toxic metabolitesWPredictability of durationWCumulative effectsWReversibilityWTime to onsetWStability of solutionWCostRationale for Selection of NMBAs:谢谢！供娄浪颓蓝辣袄驹靴锯澜互慌仲写绎衰斡染圾明将呆则孰盆瘸砒腥悉漠堑脊髓灰质炎(讲课2019)脊髓灰质炎(讲课2019)
