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1、,CLINICAL PHARMACOLOGY OF NEUROMUSCULAR BLOCKING AGENTS,Jerrold H. Levy, MD Professor of Anesthesiology Emory University School of Medicine Division of Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia,HISTORY OF NEUROMUSCULAR BLOCKING AGENTS AND CLINICAL DEVELOPMENT,
2、HISTORY,1494 - Tales of travelers killed by poison darts 1551 - Ourari” or “cururu” meaning “bird killer” 1812 - Curarized cat kept alive by artificial respiration 1912 - Curare used to prevent fractures during ECT 1941 - Initial use by Griffith, Culler, and Rovenstine 1951 - Succinylcholine chlorid
3、e first used in Stockholm,INTRODUCTION OF NEW DRUGS,1494 - 1942 Curare 1947 - 1951 Succinylcholine chloride, Gallamine, Metocurine, Decamethonium 1960s Alcuronium 1970s Pancuronium bromide, Fazadinium 1980s Vecuronium bromide, Atracurium besylate 1990 Pipecuronium bromide 1991 Doxacurium chloride 19
4、92 Mivacurium chloride 1994 Rocuronium bromide 1999 Rapacuronium bromide,STRUCTURAL CLASSES OF NONDEPOL.ARIZING RELAXANTS,Steroids: Rocuronium bromide, Vecuronium bromide, Pancuronium bromide, Pipecuronium bromide Naturally occurring benzylisoquinolines: curare, metocurine Benzylisoquinoliniums: Atr
5、acurium besylate, Mivacurium chloride, Doxacurium chloride,THE IDEAL RELAXANT,Nondepolarizing Rapid onset Dose-dependent duration No side-effects Elimination independent of organ function No active or toxic metabolites,ONSET OF PARALYSIS IS AFFECTED BY:,Dose (relative to ED95) Potency (number of mol
6、ecules) Keo (chemistry/blood flow) Clearance Age,Neuromuscular Blocking Agents and Patient Evaluation,Assessing Postoperative Neuromuscular Function,Sustained 5-second head lift Ability to appose incisors (clench teeth) Negative inspiratory force 40 cm H2O Ability to open eyes wide for 5 seconds Han
7、d-grip strength Sustained arm/leg lift Quality of speaking voice Tongue protrusion,Assessing Postoperative Neuromuscular Function,CLINICAL ASSESSMENT,Kopman AF, et al. Anesthesiology, 1997:86;765,Ali HH, et al. Br J Anaesth. 1975;47:570,Assessing Postoperative Neuromuscular Function,Train-of-Four (T
8、OF) Fade Ratio,99,97,100,100%,95,91,100,90%,94,88,100,80%,92,82,97,70%*,95,70,91,60%,100,100,100,Control =100,Peak Exp. Flow Rate,Inspiratory Force,Vital Capacity,TOF Ratio,Assessing Postoperative Neuromuscular Function,Ali HH, et al. Br J Anaesth. 1975;47:570,THE ORIGIN OF THE GOLD STANDARD,* Histo
9、rically regarded as the Gold Standard,NEW DATA SUGGEST THAT A TOF OF 0.90 MAY BE NEEDED TO ENSURE NORMAL FUNCTION,Assessing Postoperative Neuromuscular Function,Kopman: A TOF 0.90 compatible with normal clinical tests (Anesthesiology. 1997;86:765) Eriksson: Pharyngeal function normal at TOF 0.90 (An
10、esthesiology. 1997;87:1035),Assessing Postoperative Neuromuscular Function,Patients are often returned to the PACU with residual paralysis1 The TOF ratio of 0.70 may be inadequate for discharge of an ambulatory patient1 TOF ratios 0.40 are difficult to assess clinically2,ASSESSING TOF FADE RATIO,1Vi
11、by-Mogensen J, et al. Anesthesiology. 1979;50:539 2Kopman AF, et al. Anesthesiology. 1994;81:1394,Assessing Postoperative Neuromuscular Function,Recovery is inadequate if fade is detected1,2 Clinical trials are needed to demonstrate measurement techniques for TOF ratios of 0.902,1Eriksson, LI, et al
12、. Anesthesiology. 1997;87:1035 2Bevan, DR, et al. Anesthesiology. 1988;69:272,TOF FADE RATIO: CONCLUSION,Vagolytic Partially block cardiac muscarinic receptors involved in heart rate slowing, resulting in increased heart rate: rapacuronium pancuronium rocuronium vecuronium Generally do not promote h
13、istamine release Exception: rapacuronium Organ-dependent elimination Kidneys and liver,Neuromuscular Blockers: Chemical Structure & Key Characteristics,Aminosteroids,Savage DS, et al. Br J Anaesth. 1980;52 Suppl 1:3S Durant NN, et al. J Pharm Pharmacol. 1979:31(12):831 Marshall IG, et al. Br J Anaes
14、th. 1980;52 Suppl 1:11S,Absence of vagolytic effect these drugs do not block cardiac-vagal (muscarinic) receptors Histamine release dTc atracurium mivacurium cisatracurium can cause rare bronchospasm, decreased blood pressure, increase of heart rate Generally organ-independent elimination1 esp: atra
15、curium, cisatracurium, mivacurium Noncumulative2,Neuromuscular Blockers: Chemical Structure & Key Characteristics,Benzylisoquinolines,1Stenlake JB, et al. Br J Anaesth. 1983;55;3S 2Ali HH, et al. Br J Anaesth. 1983;55:107S,Ultra- Short,Short,Clinical duration (injection to T25),6 - 8,12 - 20,30 - 45
16、,60,15,25 - 30,50 - 70,90 -180,Classification of Neuromuscular Blockers by Duration of Action (Minutes),Long,Intermediate,Recovery time (injection to T95),Recovery index (T25 to T75),Examples,2 - 3,6,10 -15,30,succinyl- choline,mivacurium,cisatracurium,doxacurium,Assumes bolus dose = 2x ED95,1Anecti
17、ne (succinylcholine chloride) Package Insert 2Mivacron (mivacurium chloride) Package Insert 3Nimbex (cisatracurium besylate) Package Insert 4Nuromax (doxacurium chloride) Package Insert,1,2,3,4,DURATION OF ACTION OF NEUROMUSCULAR BLOCKING AGENTS,Ultra-Short: Succinylcholine chloride Short: Mivacuriu
18、m chloride Intermediate: Rocuronium bromide, Vecuronium bromide, Atracurium besylate Long: Pancuronium bromide, curare, metocurine, Pipecuronium bromide, Doxacurium chloride,CARDIOVASCULAR PROFILE OF NEUROMUSCULAR BLOCKING AGENTS,Hemodynamics, histamine release, and other aspects,HISTAMINE RELEASING
19、 POTENTIAL,Significant Insignificant Tubocurarine + + + Rocuronium bromide Metocurine + Vecuronium bromide Atracurium besylate + Pancuronium bromide Mivacurium chloride + Pipecuronium bromide Succinylcholine chloride + Doxacurium chloride ,Muscle Relaxants,Pancuronium Vagolytic: increases heart rate
20、, may require beta blockade Easy to use Intermediate duration of action Slower onset Not reversed at end of case,Muscle Relaxants,Vecuronium No effects on HR, BP Requires reconstitution Reliable and controllable duration of action Slower onset Stable hemodynamics/no histamine release,Muscle Relaxant
21、s,Rocuronium No effects on HR, BP Easy to use, liquid, no refrigeration Reliable and controllable duration of action Fast onset Stable hemodynamics/no histamine release,Effects of Rocuronium on Heart Rate,Levy et al. Anesth Analg 1994;78,318-321.,Effects of Rocuronium on Mean Arterial Pressure,Time
22、(minutes),100,90,80,70,60,50,0.0,1.0,2.0,3.0,4.0,5.0,6.0,Mean Arterial Pressure (mmHg),Levy et al. Anesth Analg 1994;78,318-321.,Effects of Rocuronium on Histamine Release,Time (minutes),0.0,1.0,2.0,3.0,4.0,5.0,Plasma Histamine (ng/ml),Levy et al. Anesth Analg 1994;78,318-321.,3.0,2.5,2.0,1.5,1.0,0.
23、5,0.0,Muscle Relaxants,Rapacuronium Minimal effects on HR, BP Controllable duration of action Fast onset Stable hemodynamics/minimal histamine release Potential for bronchospasm led to its removal in 2001,COSTS OF NEUROMUSCULAR BLOCKING AGENTS AND SELECTION CRITERIA,Cost of care acquisition cost The
24、 real, substantial savings accrue from use of intermediate- and short-acting drugs because: Inexpensive, long-acting drugs are associated with prolonged postoperative recovery 1 Fast recovery means shorter risk periods of residual blockade. This translates into fewer postoperative complications, as
25、shown in the Berg study2 Postoperative complications are very expensive Avoiding these is where the real cost savings accrue,Neuromuscular Agents: Costs of Care,1Ballantyne JC, et al. Anesth Analg. 1997; 85:476 2Berg H, et al. Acta Anaesthesiol Scand. 1997;41:1095,Cardiovascular stability Nondepolarizing vs depolarizing Organ-independent elimination Clinically significant active or toxic metabolites Predictability of duration Cumulative effects Reversibility Time to onset Stability of solution Cost,Rationale for Selection of NMBAs:,
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