神經(jīng)肌肉阻斷劑課件

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 DEVELOPMENTHISTORY1

2、494- 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

3、 StockholmINTRODUCTION OF NEW DRUGS1494 - 1942 Curare1947 - 1951 Succinylcholine chloride, Gallamine, Metocurine, Decamethonium1960sAlcuronium1970sPancuronium bromide, Fazadinium1980sVecuronium bromide, Atracurium besylate1990Pipecuronium bromide1991Doxacurium chloride1992Mivacurium chloride1994Rocu

4、ronium bromide1999Rapacuronium bromideSTRUCTURAL CLASSES OF NONDEPOL.ARIZING RELAXANTSSteroids: Rocuronium bromide, Vecuronium bromide, Pancuronium bromide, Pipecuronium bromideNaturally occurring benzylisoquinolines: curare, metocurineBenzylisoquinoliniums: Atracurium besylate, Mivacurium chloride,

5、 Doxacurium chlorideTHE IDEAL RELAXANTNondepolarizingRapid onsetDose-dependent durationNo side-effectsElimination independent of organ functionNo active or toxic metabolitesONSET OF PARALYSIS IS AFFECTED BY:Dose (relative to ED95)Potency (number of molecules)Keo (chemistry/blood flow)ClearanceAgeAli

6、 HH, et al. Br J Anaesth. 1975;47:570Assessing Postoperative Neuromuscular FunctionTrain-of-Four (TOF) Fade Ratio9997100100%959110090%948810080%92829770%*95709160%100100100Control =100Peak Exp. Flow RateInspiratory ForceVital CapacityTOF RatioAssessing Postoperative Neuromuscular FunctionAli HH, et

7、al. Br J Anaesth. 1975;47:570THE ORIGIN OF THE GOLD STANDARD* Historically regarded as the Gold Standard NEW DATA SUGGEST THAT A TOF OF 0.90 MAY BE NEEDED TO ENSURE NORMAL FUNCTIONAssessing Postoperative Neuromuscular FunctionKopman: A TOF 0.90 compatible with normal clinical tests (Anesthesiology.

8、1997;86:765)Eriksson: Pharyngeal function normal at TOF 0.90 (Anesthesiology. 1997;87:1035)Absence of vagolytic effectthese drugs do not block cardiac-vagal (muscarinic) receptorsHistamine releasedTc atracurium mivacurium cisatracuriumcan cause rare bronchospasm, decreased blood pressure, increase o

9、f heart rateGenerally organ-independent elimination1esp: atracurium, cisatracurium, mivacuriumNoncumulative2Neuromuscular Blockers:Chemical Structure & Key CharacteristicsBenzylisoquinolines1Stenlake JB, et al. Br J Anaesth. 1983;55;3S2Ali HH, et al. Br J Anaesth. 1983;55:107SUltra- ShortShortClinic

10、al duration(injection to T25)6 - 812 - 2030 - 456030succinyl-cholinemivacuriumcisatracuriumdoxacuriumAssumes bolus dose = 2x ED951Anectine (succinylcholine chloride) Package Insert2Mivacron (mivacurium chloride) Package Insert3Nimbex (cisatracurium besylate) Package Insert4Nuromax (doxacurium chlori

11、de) Package Insert1234DURATION OF ACTION OF NEUROMUSCULAR BLOCKING AGENTSUltra-Short: Succinylcholine chlorideShort: Mivacurium chlorideIntermediate: Rocuronium bromide, Vecuronium bromide, Atracurium besylateLong: Pancuronium bromide, curare, metocurine, Pipecuronium bromide, Doxacurium chlorideCAR

12、DIOVASCULAR PROFILE OF NEUROMUSCULAR BLOCKING AGENTSHemodynamics, histamine release, and other aspectsMuscle RelaxantsPancuroniumVagolytic: increases heart rate, may require beta blockadeEasy to useIntermediate duration of actionSlower onsetNot reversed at end of caseMuscle RelaxantsVecuroniumNo eff

13、ects on HR, BPRequires reconstitutionReliable and controllable duration of actionSlower onsetStable hemodynamics/no histamine releaseMuscle RelaxantsRocuroniumNo effects on HR, BPEasy to use, liquid, no refrigerationReliable and controllable duration of actionFast onsetStable hemodynamics/no histami

14、ne releaseEffects of Rocuronium on Heart RateTime (minutes)1009080706050400.01.02.03.04.05.06.0Heart Rate (beats/min)Levy et al. Anesth Analg 1994;78,318-321.600 mcg/kg900 mcg/kg1200 mcg/kgEffects of Rocuronium on Mean Arterial PressureTime (minutes)10090807060500.01.02.03.04.05.06.0Mean Arterial Pr

15、essure (mmHg)600 mcg/kg900 mcg/kg1200 mcg/kgLevy et al. Anesth Analg 1994;78,318-321.Effects of Rocuronium on Histamine ReleaseTime (minutes)0.01.02.03.04.05.0Plasma Histamine (ng/ml)Levy et al. Anesth Analg 1994;78,318-321.600 mcg/kg900 mcg/kg1200 mcg/kg3.02.52.01.51.00.50.0Muscle RelaxantsRapacuro

16、niumMinimal effects on HR, BPControllable duration of actionFast onsetStable hemodynamics/minimal histamine releasePotential for bronchospasm led to its removal in 2001COSTS OF NEUROMUSCULAR BLOCKING AGENTS AND SELECTION CRITERIACost of care acquisition costThe real, substantial savings accrue from

17、use of intermediate- and short-acting drugs because:Inexpensive, long-acting drugs are associated with prolonged postoperative recovery 1Fast recovery means shorter risk periods of residual blockade. This translates into fewer postoperative complications, as shown in the Berg study2Postoperative complications are very expensiveAvoiding these is where the real cost savings accrueNeuromuscular Agents:Costs of Care 1Ballantyne JC, et al. Anesth Analg. 1997; 85:4762Berg H, et al. Acta Anaesthesiol Sca