Chapter 13 – Pharmacology of Muscle Relaxants and Their Antagonists Mohamed Naguib, Cynthia A
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Chapter 13 – Pharmacology of Muscle Relaxants and Their Antagonists Mohamed Naguib, Cynthia A. Lien HISTORY AND CLINICAL USE In 1942 Griffith and Johnson[1] suggested that d-tubocurarine (dTc) is a safe drug to use during surgery to provide skeletal muscle relaxation. One year later, Cullen[2] described its use in 131 patients who had received general anesthesia for their surgery. In 1954, Beecher and Todd[3] reported a sixfold increase in mortality in patients receiving dTc versus those who had not received a relaxant. The increased mortality was due to a general lack of understanding of the pharmacology of neuromuscular blockers and their antagonism. The impact of residual neuromuscular blockade postoperatively was not appreciated, guidelines for monitoring muscle strength had not been established, and the importance of pharmacologically antagonizing residual blockade was not understood. Since then, the understanding of neuromuscular blocker pharmacology has improved, and relaxants have become an important component of many anesthetics and have facilitated the growth of surgery into new areas with the use of innovative techniques.[4] Succinylcholine, introduced by Thesleff[5] and by Foldes and colleagues in 1952,[4] changed anesthetic practice drastically. Its rapid onset of effect and ultrashort duration of action allowed for rapid tracheal intubation. In 1967, Baird and Reid first reported on clinical administration of the synthetic aminosteroid pancuronium.[6] Though similar to dTc, in terms of its duration of action, this compound had an improved cardiovascular side effect profile. It lacked ganglionic-blocking and histamine-releasing properties and was mildly vagolytic. The resulting increases in heart rate and blood pressure were considered significant improvements over its predecessors. Unlike dTc or any of the nondepolarizing neuromuscular blockers previously used, none of which were metabolized, pancuronium underwent some hepatic metabolism through deacetylation of the acetoxy groups. Development of the intermediate-acting neuromuscular blockers built on compound metabolism and resulted in the introduction of vecuronium,[7] an aminosteroid, and atracurium,[8][9] a benzylisoquinolinium, into practice in the 1980s. These relaxants had little or no dependence on the kidney for elimination. The lack of cardiovascular effects of vecuronium established a benchmark for safety to which newer relaxants are still held.[7] Degradation of atracurium by Hofmann elimination removed any important influence of biologic disorders such as advanced age or organ failure on the pattern of neuromuscular blockade. Mivacurium, the first short-acting nondepolarizing neuromuscular blocker, was introduced into clinical practice in the 1990s,[10] as was rocuronium,[11] an intermediate-acting nondepolarizing blocker with a rapid onset of effect. Mivacurium, like the intermediate- acting compounds, is extensively metabolized. It is, however, metabolized by butyrylcholinesterase, the same enzyme that is responsible for the metabolism of succinylcholine. In terms of facilitating rapid endotracheal intubation, rocuronium is the Page 1 Pharmacology of Muscle Relaxants and Their Antagonists first nondepolarizing neuromuscular blocker considered to be a replacement for succinylcholine. Other neuromuscular blockers have been introduced into clinical practice since the use of dTc was first advocated. These blockers include pipecuronium, doxacurium, cisatracurium, and rapacuronium. Although all do not remain in use, each represented an advance or improvement in at least one aspect over its predecessors. Still other neuromuscular blockers, TAAC3[12] and 430A,[13] are undergoing investigation. Neuromuscular blockers should be administered only to anesthetized individuals to provide relaxation of skeletal muscles. They should not be administered to stop patient movement because they have no analgesic or amnestic properties. Awareness during surgery[14] and in the intensive care unit (ICU)[15] has been described in multiple publications. Neuromuscular blockers are valuable adjuncts to general anesthetics and should be used as such. As stated by Cullen and Larson, "muscle relaxants given inappropriately may provide the surgeon with optimal [operating] conditions in ... a patient [who] is paralyzed but not anesthetized— a state that [is] wholly unacceptable for the patient."[16] Additionally, "muscle relaxants used to cover up deficiencies in total anesthetic management ... represent an ... inappropriate use of the valuable adjuncts to anesthesia." To administer relaxants for maintenance of neuromuscular blockade intraoperatively, the patient's depth of neuromuscular block must be monitored and the depth of anesthesia continuously assessed. The use of neuromuscular blockers in the operating room is quite common and has been important in the growth and development of anesthesia and surgery. As stated by Foldes and coauthors,[4] "... [the] first use of ... muscle relaxants ... not only revolutionized the practice of anesthesia but also started the modern era of surgery and made possible the explosive development of cardiothoracic, neurologic and organ transplant surgery." Certainly, neuromuscular blockers are now routinely used to facilitate endotracheal intubation and are commonly used to maintain neuromuscular blockade through any number of different surgical procedures. This chapter will review the pharmacology and clinical use of neuromuscular blockers, as well as anticholinesterases, in the operating room. Diseases of the neuromuscular system are also discussed as regards their influence on the actions of neuromuscular blockers. Finally, the economics of providing neuromuscular blockade is also considered. PRINCIPLES OF ACTION OF NEUROMUSCULAR BLOCKERS AT THE NEUROMUSCULAR JUNCTION (also see Chapter 22) Postjunctional Effects In adult mammalian skeletal muscle, the nicotinic acetylcholine receptor (nAChR) is a pentameric complex of two α-subunits in association with single β-, δ-, and ϵ- subunits (Fig. 13-1). These subunits are organized to form a transmembrane pore (a channel), as well as the extracellular binding pockets for acetylcholine and other agonists or antagonists.[17] Each of the two α-subunits has an acetylcholine-binding site. These sites are proteins located in pockets approximately 3.0 nm above the surface membrane at the [18] interfaces of the αH-ϵ and αL-δ subunits. αH and αL indicate the high- and low- affinity binding sites for dTc and probably result from a contribution from the different Page 2 Pharmacology of Muscle Relaxants and Their Antagonists [19][20] neighboring subunits. For instance, the binding affinity of dTc for the αH-ϵ site [18][20][21] is approximately 100- to 500-fold higher than that for the αL-δ site. Fetal nAChR contains a γ-subunit instead of the adult ϵ-subunit. Mature nAChR has a shorter burst duration and exhibits higher conductance of Na+, K+, and Ca2+ than fetal nAChR does.[17][22] Figure 13-1 Subunit composition of the nicotinic acetylcholine receptor (nAChR) in the end-plate surface of adult mammalian muscle. The adult AChR is an intrinsic membrane protein with five distinct subunits (α2βδϵ). Each subunit contains four helical domains labeled M1 to M4. The M2 domain forms the channel pore. The upper panel shows a single α-subunit with its N and C termini on the extracellular surface of the membrane lipid bilayer. Between the N and C termini, the α-subunit forms four helices (M1, M2, M3, and M4) that span the membrane bilayer. The lower panel shows the pentameric structure of the nAChR of adult mammalian muscle. The N termini of two subunits cooperate to form two distinct binding pockets for acetylcholine (ACh). These pockets occur at the ϵ-α and the δ-α subunit interface. The M2 membrane-spanning domain of each subunit lines the ion channel. The doubly liganded ion channel has permeability equal to that of Na+ and K+; Ca2+ contributes approximately 2.5% to the total permeability. (Redrawn from Naguib M, Flood P, McArdle JJ, et al: Advances in neurobiology of the neuromuscular junction: Implications for the anesthesiologist. Anesthesiology 96:202–231, 2002.) Functionally, the ion channel of the acetylcholine receptor is closed in the resting state. Simultaneous binding of two acetylcholine molecules to the α-subunits[23] initiates conformational changes that open the channel.[24][25][26] On the other hand, it is enough for one molecule of a nondepolarizing neuromuscular blocker (a competitive antagonist) to bind to one subunit to produce a block.[27] Paul and coworkers[28] found a correlation Page 3 Pharmacology of Muscle Relaxants and Their Antagonists between the ED50 (the dose that produces 50% depression of twitch tension) and the potency of nondepolarizing blockers at the adult nAChR. Depolarizing neuromuscular blockers such as succinylcholine produce prolonged depolarization of the end-plate region that results in (1) desensitization of nAChR, (2) inactivation of voltage-gated sodium channels at the neuromuscular junction, and (3) increases in potassium permeability in the surrounding membrane (see Chapter 22 for details).[27] The end result is failure of action potential generation, and block ensues. It should be noted that although acetylcholine produces depolarization, under physiologic conditions it results in muscle contraction because it has a very short (few milliseconds) duration of action.[27] Acetylcholine is rapidly hydrolyzed by acetylcholinesterase[29]