CLINICAL PHARMACOLOGY OF THE NEUROMUSCULAR BLOCKING AGENTS Ghassem E. Larijani, Irwin Gratz, Michael Silverberg, and AtholeG.Jacobi
ABSTRACf: Neuromuscular blocking agentsare among the most commonly used drugs during generalanesthesia. They competewith acetylcholine and interfere with the transmission of nerve impulses resulting in skeletal musclerelaxation. Basedon their mechanism of action, neuromuscular blocking agentsare classified as either depolarizing or nondepolarizing. Succinylcholine is a short-acting depolarizing agent. Commonlyused nondepolarizing agentsare curare (long-acting), pancuronium (long-acting), atracurium (intermediateacting), and vecuronium (intermediate-acting), Neuromuscular blocking agentsare used clinicallyto facilitate endotracheal intubation and to provide skeletalmusclerelaxation during surgery. This article provides an overview of the physiology of the neuromuscular transmission and summarizes our current knowledge on the use of these agentsduring generalanesthesia.
Dlep Ann Phannacother 1991;25:54-64.
as an arrow poison by South American Indians. Little was known about curare until 1850 when Claude Bernard demonstrated that curare's action at the neuromuscular junction (NMJ) was responsible for its skeletal muscle relaxant effect. Approximately a century later curare was used by Griffith and Johnson to provide muscle relaxation and to facilitate surgery. 1 Today neuromuscular blocking agents (NMBAs) are among the most commonly used drugs during general anesthesia and a whole body of information has appeared describing their pharmacological effects and proper clinical use. In this review we attempt to summarize the physiology of neuromuscular transmission and the clinical pharmacology of the most commonly used NMBAs.
CURARE WAS USED FOR CENTURIES
Physiology ofNeuromusculor Transmission The anatomy and physiology of the motor nerve-skeletal muscle is depicted in Figure I. The motor neurons run uninterrupted from the central nervous system (CNS) to the skeletal muscles. Each motor neuron consists of a cell body, several dendrites that lie in the spinal cord, and a relatively long axon. As the axon approaches the muscle it loses its myelin sheath and branches into many nerve fila-
GHASSEM E. LARUANI, Pharm.D., is an Associate Professor; IRWIN GRATZ, 0.0., is an Associate Professor; MICHAEL SILVERBERG, M.D., is an Instructor; and ATHOLE G. JACOBI, M.D., is a Professor, Departments of Anesthesiology and Pharmacology, Medical College of Pennsylvania, 3300 Henry Ave., Philadelphia, PA 19129. Reprints: Ghassem E. Larijani, Pharm.D. This work was supported in part by an educational grant from Organon Inc., West Orange, NJ.
54
•
DICP, The Annals ofPharmacotherapy •
ments, each of which innervates a muscle fiber. The nerve filament and the muscle fiber innervated are called a motor unit. The nerve and the muscle are separated by a junctional cleft of approximately 20 nm wide." In the axoplasm of the motor neuron, acetylcholine (ACH) is synthesized by the acetylation of choline. Choline is, in turn, actively transported into the axoplasm where it accepts an acetyl group from acetylcoenzyme A under the influence of cholineacetyltransferase. ACH is then transferred and stored in vesicles (Figure I). A nerve filament can have thousands of ACH vesicles, each containing apprximately 5000-10 000 ACH molecules. The release of ACH from these vesicles occurs through exocytosis and is quantal in nature (multiples of ACH vesicles). At rest, random release of a quantum or pocket of ACH (approximately one/sec) results in a miniature end-plate potential that is not adequate to produce an action potential and muscle contraction. Stimulation of the nerve, however, causes many ACH vesicles (200-400) to migrate to the surface of the nerve, undergo exocytosis, and discharge ACH molecules into the junctional cleft. 2,3 The discharged ACH molecules either activate the ACH receptors (ACH-R) or are hydrolyzed (deacetylated) by acetylcholinesterase to acetate and choline. Some choline is actively transported back into the axoplasm while the rest diffuses away. During the nerve stimulations calcium ions (Ca" +) also enter the axoplasm and are involved with the exocytotic release process of ACH. 3 Each ACH-R is a protein complex with a molecular weight of 250 000 daltons and is made of five subunits (two alpha, one beta, one gamma, and one delta). Each of the five subunits is linear and the five are arranged longitudinally so that they are capable of forming a channel or tube (Figure 1). The two alpha subunits contain the ACH recognition sites. The channel is closed unless ACH is simultaneously present on both alpha subunits. When two ACH molecules attach to the two alpha subunits the channel opens and allows inward movement of sodium (Na") and Ca" + and outward movement of potassium (K+) (Figure I). When there is sufficient ionic movements to shift the membrane potential from -90 to -50 millivolts, depolarization occurs resulting in the contraction of the muscle fiber. The current carried by two ACH molecules is, therefore, converted into a current carried by thousands of Na", Ca" +, and K+ ions, making the ACH-R a powerful amplifier with an off and on switch.i-'
1991 January, Volume 25
In the junctional cleft ACH is broken down within microseconds by acetylcholinesterase. The duration of depolarization by the two ACH molecules is longer (0.3 milliseconds) because of the relatively slow rate of unbinding from the ACH-R. There is evidence that the released ACH also works presynaptically to enhance the mobilization of ACH into the vesicles (positive-feedback)." The action of NMBAs at the NMJ may, therefore, be confined either to the ACH-R (alpha subunits) of postsynaptic membrane or to both post-and presynaptic receptors. 2
Classification ofNeuromuscular Blocking Agents NMBAs are either depolarizing (agonistic) or nondepolarizing (antagonistic) in nature. They are further subdivided, based on their duration of action, as short, intermediate, and long-acting. The only short-acting NMBA in clinical use is succinylcholine, which is also the only clinically used depolarizing agent. At present, there does not exist a short-acting NMBA with a nondepolarizing mechanism of action. Atracurium besylate and vecuronium bromide have an intermediate duration of action, and curare and pancuronium bromide are long-acting nondepolarizing agents. DEPOLARIZING AGENTS (AGONISTS)
Depolarizing agents initially mimic the effect of ACH on the postsynaptic ACH-R. Both ACH and succinylcholine can combine with the alpha subunits of ACH-R and depolarize the skeletal muscle fiber. After ACH unbinds and is hydrolyzed at the NMJ (within a few milliseconds), the muscle fiber will repolarize and become available for subsequent depolarization. Succinylcholine's effect, on the other hand, is terminated when it is diffused away from the NMJ; therefore, succinylcholine provides a much more sustained depolarization than ACH. This sustained polarization leads to inactivation of Na" channels in muscle membrane and hence prevents impulses from being gener-
ated in the muscle fiber. 2,4 The initial action of succinylcholine is to depolarize the postsynaptic membrane resulting in a brief period of excitation and transient muscular fasciculation followed by blockade of neuromuscular transmission and a flaccid paralysis. As long as there is a sufficient concentration of succinycholine to block the attachment of ACH to its receptors, further depolarization is prevented and paralysis ensues. NONDEPOLARIZING AGENTS (ANTAGONISTS)
Nondepolarizing NMBAs compete with ACH-R and reduce the probability of ACH molecules interacting with the two alpha subunits simultaneously; however, they do not totally prevent such an interaction. Two molecules of ACH are required to produce an effect but only a single molecule of the antagonist is adequate to prevent it. This competitive inhibition, therefore, is biased in favor of the antagonist. Increasing the concentration of ACH in the junctional cleft by the use of anticholinesterases will improve the probability of ACH combining with the alpha subunits and recovery will ensue.>' Because the competitive inhibition is in favor of the antagonist, a neuromuscular blockade produced by higher concentrations of the antagonist is more difficult to reverse than any produced by lower concentrations. Nondepolarizing NMBAs also have presynaptic effect and interfere with the mobilization of ACH.
Monitoring ofthe Neuromuscular Function To test the function of the NMJ, contraction of a muscle is measured after electrical stimulation of the motor nerve that innervates the muscle being evaluated. The contraction of an individual muscle fiber follows an all-or-none phenomena and approximately 75 percent of the ACH-R should be activated for contraction of the muscle fiber to occur.Y Clinically, when the whole muscle is being observed, the response of the muscle (contraction or twitch) has a sigmoidal relationship to the electrical current delivered to the nerve. A minimum current must be deliv-
Choline Carrier A"COAj§ChOline CAT COA
s:
iii Q) s: en
.s ~ ~
ACH
,r-@) Nucleus
!
..
ACHE ACH--.....
Acetate + Choline
ACH Receptor Figure I. Anatomy and physiology of motor neuron and acetylcholine receptor. A,COA = acetylcoenzyme A; ACH = acetylcholine; ACHE = acetylcholinesterase; Cat" = calcium ions; CAT = choline-acetyltransferase; COA = coenzyme A; K+ = potassium ions; Na" = sodium ions.
DICP, The Annals ofPharmacotherapy
•
1991 January, Volume 25 •
55
ered to observe any muscle contraction and as the stimulation current increases so does the muscle contraction proportionally until a plateaued response is reached. The plateaued response corresponds to contraction of all muscle fibers innervated by the nerve axon. When a further increase of the stimulation current causes no further increase in muscle contraction a "supramaximal stimulation" has been reached. For clinical purposes the motor neurons most accessible for stimulation are the ulnar nerve at the wrist and the facial nerve. Stimulation of the ulnar nerve at the wrist results in the adduction of the thumb and stimulation of the facial nerve results in twitching of the facial muscle. Ulnar nerve stimulation is commonly used to quantify the degree of muscle relaxation for research purposes. The response of the muscle to nerve stimulation is also dependent on the pattern of nerve stimulation. Various patterns of nerve stimulation, such as single, train-of-four (TOF), tetanic, post-tetanic, and double-burst stimulations, have been used by investigators to study the effect of NMBAs. Because of space constraints and the complexity of various stimulation patterns, only the significance of the TOF and tetanic stimulation will be briefly discussed here. For more information on various patterns of nerve stimulation readers should refer to a review by Ali. 7 TOF stimulation uses four stimuli delivered over 2 seconds (one stimulus every 0.5 sec) that can be repeated every 10-12 seconds if needed. In the absence of NMBAs, TOF stimulation results in four equal muscle contractions or twitches. When a fixed degree of muscle relaxation is produced by a depolarizing agent, the degree of muscle relaxation is equal after each successive stimulation in the TOF (e.g., 50 percent suppresion of the first, second, third, and fourth contraction or twitch). With the nondepolarizing agents, however, the magnitude of suppression will increase progressively with the second, third, and fourth contraction (e.g., the first contraction may be only 30 percent suppressed, while the second, third, and fourth contractions may be 40,50, and 60 percent depressed, respectively). The reason for this "fade" in the TOF is that nondepolarizing agents also work presynaptically and interfere with the mobilization of ACH resulting in less ACH release with each successive stimulation.v? Figure 2 depicts the pattern of contraction following TOF stimulation with depolarizing and nondepolarizing NMBAs. TOF stimulation is commonly used for both clinical and research purposes and serves two main functions. The first is to differentiate between depolarizing and nondepolarizing blocks; the second is to evaluate that recovery from muscle relaxation has occurred. Succinylcholine is classified as a depolarizing muscle relaxant but the depolarizing action of succinylcholine may not be the sole mechanism involved in producing neuromuscular relaxation, at least not with higher total doses. It is known that with high initial bolus doses (>3 mg/kg), after multiple boluses, or with a maintenance infusion (>90 min), the characteristics of the neuromuscular blockade produced by succinylcholine can change from depolarizing to nondepolarizing in nature (i.e., fade with the TOF stirnulationj.v" This is frequently referred to as phase II block, as compared with phase I block, which signifies a depolarizing block. Phase II block is longer-lasting and the patient may remain paralyzed for a couple of hours. TOF stimulation makes this distinction.
56 •
D/CP, The Annals ofPharmacotherapy •
Nondepolarizing Block
Depolarizing Block Onset of Block
Recovery
Figure 2. Train-of-four stimulation following nondepolarizing and depolarizing muscle relaxants.
It is essential when an NMBA is used to ensure that recovery is complete. The TOF can be used as the initial evaluation to make this determination. When a nondepolarizing blocker has been used, the absence of fade following a TOF indicates that adequate degree of recovery has occurred. Tetanic stimulation is more intense than TOF stimulation. The nerve is usually bombarded for a few seconds (50 Hz). The mechanism is the same as that described for the TOF but the absence of fade after a tetanus indicates that recovery is more complete and that the release of ACH has returned to normal. It should be remembered that the technique of neuromuscular monitoring is only an aid, not a substitute, for sound clinical observation and judgment of muscle relaxation or recovery.
Succinylcholine Succinylcholine is a short-acting depolarizing NMBA. Succinylcholine is made of two molecules of acetylcholine connected back-to-back through the acetate methyl group; therefore, succinylcholine is not hydrolyzed by acetylcholinesterase. Hydrolysis of succinylcholine is achieved by plasma cholinesterase (synthesized by the liver) at a rate much slower than that of ACH (half-life approximately 3-5 min). U.13 Approximately 70-80 percent of the administered succinylcholine is hydrolyzed prior to reaching the NMJ. 13 Because succinylcholine is metabolized primarily by plasma cholinesterase, its duration of action may increase in situations where the concentration of this enzyme is reduced, such as in liver disease, pregnancy, and in infants. 14.1S In addition, certain individuals have genetically abnormal plasma cholinesterase. 16.17 In these individuals succinylcholine will provide neuromuscular blockade that may last up to several hours. Patients in whom it is known that this genetic abnormality exists should obviously not receive succinylcholine. Tachyphylaxis to succinylcholine is also noted in some patients (manifested by a 20 percent or greater increase in the infusion rate needed to maintain 80-90 percent twitch suppression) with continuous infusion of greater than one hour.r-" The reason for the development oftachyphylaxis is not known, but may represent a change in the sensitivity of muscle fiber to the effect of succinylcholine. 9
/99/ January, Volume 25
Neuromuscular Blocking Agents PHARMACODYNAMICS
The most common use of succinylcholine is to provide rapid relaxation for endotracheal intubation. A typical intubating dose of succinylcholine (1-1.5 mglkg) will result in maximum supression of muscle twitch and provide goodto-excellent intubating conditions within 1-1.5 minutes. 8.18 Even in high doses, other NMBAs do not usually provide excellent intubating conditions in less than two minutes. 19-24 Succinylcholine is considered, therefore, to be the drug of choice when the trachea must be intubated quickly after the induction of anesthesia to prevent aspiration. Succinylcholine 1 mg/kg will provide surgical relaxation for approximately 5 minutes with full spontaneous recovery of muscle function in approximately 15 minutes. 8,18 Succinylcholine is, therefore, also the drug of choice when muscle relaxation is needed only for a short period of time. As with other NMBAs, the duration of action of this agent is dose-dependent. 11 During longer surgical cases anesthesiologists will usually use succinylcholine for intubation, wait until some degree of neuromuscular recovery is manifested, and then use a nondepolarizing agent for maintenance of relaxation. Administration of an intubating dose of succinylcholine may increase the plasma concentration of K" by as much as 0.5 mEq/L. 25.26 This results from the movement of K+ outside the cell during depolarization. In an otherwise healthy patient, the rise in K+ concentration is not usually clinically important. In burned patients and those with nervemuscle injury, succinylcholine may result in a much greater rise in the plasma concentration of K+ and predispose the patient to the cardiovascular effects of hyperkalemia. 26-28 Preoperative hyperkalemia may also be a relative contraindication for the use of succinylcholine. Muscle fasciculations and postoperative myalgias are also common with the use of succinylcholine.P-" Muscle fasciculations are, in fact, considered to be the earliest clinical sign of the onset of neuromuscular blockade following succinylcholine administration. Both muscle fasciculations and postoperative myalgias are thought to be direct effects of the depolarizing action of succinylcholine with muscle fasciculations resulting from the initial depolarization and
myalgias resulting from the prolonged depolarization (muscle fatigue). The administration of a small dose of a nondepolarizing agent given three minutes prior to the succinylcholine may attenuate or prevent the fasciculations and the postoperative myalgias. Bradycardia is the predominant cardiovascular adverse effect of succinylcholine, although it is most commonly seen with repeated doses." This bradycardic effect can vary in intensity and is short-lived. Succinylcholine may also increase intraocular pressure, intragastric pressure, and intracranial pressure. 16,31,32 PHARMACOKINETICS
Because of its rapid hydrolysis and the lack of an appropriate assay, very little is known about the pharmacokinetics of succinylcholine.
Curare (d-tubocurarine) Curare is the oldest NMBA in clinical use. It has one tertiary and one quaternary nitrogen atom. In the blood (pH 7.4), the tertiary nitrogen is protonated and curare is converted to a bisquaternary ammonium compound. PHARMACODYNAMICS
Much of the published information on curare is considerably old, so that little comparative data will be presented except in general terms. The mean dose of curare required to produce 95 percent suppression of muscle twitch (ED 9s ) in adult patients is approximately 0.5 mglkg 33 ,34 (i.e., this dose of curare causes at least 95 percent suppression of muscle twitch in half of the patients, and the remaining half will have less than 95 percent suppression). This doseresponse relationship appears to be the same regardless of the patient's age." When injecting a 0.5-mg/kg dose of curare intravenously over a few seconds, one sees maximal suppresion of muscle twitch within five mintus. 23,34 Curare, therefore, has slow onset of action when compared with succinylcholine, although its onset of action may not be much different from that of an intubating dose of pancuronium." A 0.5-0.6 mg/kg iv bolus dose of curare will usually have a clinical duration of 1.5 hours or more. 34,36 Furthermore, as with other nondepolarizing agents, vol-
Table 1. Comparative Pharmacokinetics of Muscle Relaxants
REF
41-49 41 50-55 56,57 50 51 52,55,56,58-63 56 59,63 60 61 64-69 65 64,66,67 68 11"
MUSCLE RELAXANT
Curare Pancuronium
Vecuronium
Atracurium
SURGICAL POPULATION
healthy adults renal failure healthy adults elderly renal failure cirrhosis healthy adults elderly renal failure cirrhosis cholestasis healthy adults elderly renal failure cirrhosis
11"11-1
(min)
ABSTRACf: Neuromuscular blocking agentsare among the most commonly used drugs during generalanesthesia. They competewith acetylcholine and interfere with the transmission of nerve impulses resulting in skeletal musclerelaxation. Basedon their mechanism of action, neuromuscular blocking agentsare classified as either depolarizing or nondepolarizing. Succinylcholine is a short-acting depolarizing agent. Commonlyused nondepolarizing agentsare curare (long-acting), pancuronium (long-acting), atracurium (intermediateacting), and vecuronium (intermediate-acting), Neuromuscular blocking agentsare used clinicallyto facilitate endotracheal intubation and to provide skeletalmusclerelaxation during surgery. This article provides an overview of the physiology of the neuromuscular transmission and summarizes our current knowledge on the use of these agentsduring generalanesthesia.
Dlep Ann Phannacother 1991;25:54-64.
as an arrow poison by South American Indians. Little was known about curare until 1850 when Claude Bernard demonstrated that curare's action at the neuromuscular junction (NMJ) was responsible for its skeletal muscle relaxant effect. Approximately a century later curare was used by Griffith and Johnson to provide muscle relaxation and to facilitate surgery. 1 Today neuromuscular blocking agents (NMBAs) are among the most commonly used drugs during general anesthesia and a whole body of information has appeared describing their pharmacological effects and proper clinical use. In this review we attempt to summarize the physiology of neuromuscular transmission and the clinical pharmacology of the most commonly used NMBAs.
CURARE WAS USED FOR CENTURIES
Physiology ofNeuromusculor Transmission The anatomy and physiology of the motor nerve-skeletal muscle is depicted in Figure I. The motor neurons run uninterrupted from the central nervous system (CNS) to the skeletal muscles. Each motor neuron consists of a cell body, several dendrites that lie in the spinal cord, and a relatively long axon. As the axon approaches the muscle it loses its myelin sheath and branches into many nerve fila-
GHASSEM E. LARUANI, Pharm.D., is an Associate Professor; IRWIN GRATZ, 0.0., is an Associate Professor; MICHAEL SILVERBERG, M.D., is an Instructor; and ATHOLE G. JACOBI, M.D., is a Professor, Departments of Anesthesiology and Pharmacology, Medical College of Pennsylvania, 3300 Henry Ave., Philadelphia, PA 19129. Reprints: Ghassem E. Larijani, Pharm.D. This work was supported in part by an educational grant from Organon Inc., West Orange, NJ.
54
•
DICP, The Annals ofPharmacotherapy •
ments, each of which innervates a muscle fiber. The nerve filament and the muscle fiber innervated are called a motor unit. The nerve and the muscle are separated by a junctional cleft of approximately 20 nm wide." In the axoplasm of the motor neuron, acetylcholine (ACH) is synthesized by the acetylation of choline. Choline is, in turn, actively transported into the axoplasm where it accepts an acetyl group from acetylcoenzyme A under the influence of cholineacetyltransferase. ACH is then transferred and stored in vesicles (Figure I). A nerve filament can have thousands of ACH vesicles, each containing apprximately 5000-10 000 ACH molecules. The release of ACH from these vesicles occurs through exocytosis and is quantal in nature (multiples of ACH vesicles). At rest, random release of a quantum or pocket of ACH (approximately one/sec) results in a miniature end-plate potential that is not adequate to produce an action potential and muscle contraction. Stimulation of the nerve, however, causes many ACH vesicles (200-400) to migrate to the surface of the nerve, undergo exocytosis, and discharge ACH molecules into the junctional cleft. 2,3 The discharged ACH molecules either activate the ACH receptors (ACH-R) or are hydrolyzed (deacetylated) by acetylcholinesterase to acetate and choline. Some choline is actively transported back into the axoplasm while the rest diffuses away. During the nerve stimulations calcium ions (Ca" +) also enter the axoplasm and are involved with the exocytotic release process of ACH. 3 Each ACH-R is a protein complex with a molecular weight of 250 000 daltons and is made of five subunits (two alpha, one beta, one gamma, and one delta). Each of the five subunits is linear and the five are arranged longitudinally so that they are capable of forming a channel or tube (Figure 1). The two alpha subunits contain the ACH recognition sites. The channel is closed unless ACH is simultaneously present on both alpha subunits. When two ACH molecules attach to the two alpha subunits the channel opens and allows inward movement of sodium (Na") and Ca" + and outward movement of potassium (K+) (Figure I). When there is sufficient ionic movements to shift the membrane potential from -90 to -50 millivolts, depolarization occurs resulting in the contraction of the muscle fiber. The current carried by two ACH molecules is, therefore, converted into a current carried by thousands of Na", Ca" +, and K+ ions, making the ACH-R a powerful amplifier with an off and on switch.i-'
1991 January, Volume 25
In the junctional cleft ACH is broken down within microseconds by acetylcholinesterase. The duration of depolarization by the two ACH molecules is longer (0.3 milliseconds) because of the relatively slow rate of unbinding from the ACH-R. There is evidence that the released ACH also works presynaptically to enhance the mobilization of ACH into the vesicles (positive-feedback)." The action of NMBAs at the NMJ may, therefore, be confined either to the ACH-R (alpha subunits) of postsynaptic membrane or to both post-and presynaptic receptors. 2
Classification ofNeuromuscular Blocking Agents NMBAs are either depolarizing (agonistic) or nondepolarizing (antagonistic) in nature. They are further subdivided, based on their duration of action, as short, intermediate, and long-acting. The only short-acting NMBA in clinical use is succinylcholine, which is also the only clinically used depolarizing agent. At present, there does not exist a short-acting NMBA with a nondepolarizing mechanism of action. Atracurium besylate and vecuronium bromide have an intermediate duration of action, and curare and pancuronium bromide are long-acting nondepolarizing agents. DEPOLARIZING AGENTS (AGONISTS)
Depolarizing agents initially mimic the effect of ACH on the postsynaptic ACH-R. Both ACH and succinylcholine can combine with the alpha subunits of ACH-R and depolarize the skeletal muscle fiber. After ACH unbinds and is hydrolyzed at the NMJ (within a few milliseconds), the muscle fiber will repolarize and become available for subsequent depolarization. Succinylcholine's effect, on the other hand, is terminated when it is diffused away from the NMJ; therefore, succinylcholine provides a much more sustained depolarization than ACH. This sustained polarization leads to inactivation of Na" channels in muscle membrane and hence prevents impulses from being gener-
ated in the muscle fiber. 2,4 The initial action of succinylcholine is to depolarize the postsynaptic membrane resulting in a brief period of excitation and transient muscular fasciculation followed by blockade of neuromuscular transmission and a flaccid paralysis. As long as there is a sufficient concentration of succinycholine to block the attachment of ACH to its receptors, further depolarization is prevented and paralysis ensues. NONDEPOLARIZING AGENTS (ANTAGONISTS)
Nondepolarizing NMBAs compete with ACH-R and reduce the probability of ACH molecules interacting with the two alpha subunits simultaneously; however, they do not totally prevent such an interaction. Two molecules of ACH are required to produce an effect but only a single molecule of the antagonist is adequate to prevent it. This competitive inhibition, therefore, is biased in favor of the antagonist. Increasing the concentration of ACH in the junctional cleft by the use of anticholinesterases will improve the probability of ACH combining with the alpha subunits and recovery will ensue.>' Because the competitive inhibition is in favor of the antagonist, a neuromuscular blockade produced by higher concentrations of the antagonist is more difficult to reverse than any produced by lower concentrations. Nondepolarizing NMBAs also have presynaptic effect and interfere with the mobilization of ACH.
Monitoring ofthe Neuromuscular Function To test the function of the NMJ, contraction of a muscle is measured after electrical stimulation of the motor nerve that innervates the muscle being evaluated. The contraction of an individual muscle fiber follows an all-or-none phenomena and approximately 75 percent of the ACH-R should be activated for contraction of the muscle fiber to occur.Y Clinically, when the whole muscle is being observed, the response of the muscle (contraction or twitch) has a sigmoidal relationship to the electrical current delivered to the nerve. A minimum current must be deliv-
Choline Carrier A"COAj§ChOline CAT COA
s:
iii Q) s: en
.s ~ ~
ACH
,r-@) Nucleus
!
..
ACHE ACH--.....
Acetate + Choline
ACH Receptor Figure I. Anatomy and physiology of motor neuron and acetylcholine receptor. A,COA = acetylcoenzyme A; ACH = acetylcholine; ACHE = acetylcholinesterase; Cat" = calcium ions; CAT = choline-acetyltransferase; COA = coenzyme A; K+ = potassium ions; Na" = sodium ions.
DICP, The Annals ofPharmacotherapy
•
1991 January, Volume 25 •
55
ered to observe any muscle contraction and as the stimulation current increases so does the muscle contraction proportionally until a plateaued response is reached. The plateaued response corresponds to contraction of all muscle fibers innervated by the nerve axon. When a further increase of the stimulation current causes no further increase in muscle contraction a "supramaximal stimulation" has been reached. For clinical purposes the motor neurons most accessible for stimulation are the ulnar nerve at the wrist and the facial nerve. Stimulation of the ulnar nerve at the wrist results in the adduction of the thumb and stimulation of the facial nerve results in twitching of the facial muscle. Ulnar nerve stimulation is commonly used to quantify the degree of muscle relaxation for research purposes. The response of the muscle to nerve stimulation is also dependent on the pattern of nerve stimulation. Various patterns of nerve stimulation, such as single, train-of-four (TOF), tetanic, post-tetanic, and double-burst stimulations, have been used by investigators to study the effect of NMBAs. Because of space constraints and the complexity of various stimulation patterns, only the significance of the TOF and tetanic stimulation will be briefly discussed here. For more information on various patterns of nerve stimulation readers should refer to a review by Ali. 7 TOF stimulation uses four stimuli delivered over 2 seconds (one stimulus every 0.5 sec) that can be repeated every 10-12 seconds if needed. In the absence of NMBAs, TOF stimulation results in four equal muscle contractions or twitches. When a fixed degree of muscle relaxation is produced by a depolarizing agent, the degree of muscle relaxation is equal after each successive stimulation in the TOF (e.g., 50 percent suppresion of the first, second, third, and fourth contraction or twitch). With the nondepolarizing agents, however, the magnitude of suppression will increase progressively with the second, third, and fourth contraction (e.g., the first contraction may be only 30 percent suppressed, while the second, third, and fourth contractions may be 40,50, and 60 percent depressed, respectively). The reason for this "fade" in the TOF is that nondepolarizing agents also work presynaptically and interfere with the mobilization of ACH resulting in less ACH release with each successive stimulation.v? Figure 2 depicts the pattern of contraction following TOF stimulation with depolarizing and nondepolarizing NMBAs. TOF stimulation is commonly used for both clinical and research purposes and serves two main functions. The first is to differentiate between depolarizing and nondepolarizing blocks; the second is to evaluate that recovery from muscle relaxation has occurred. Succinylcholine is classified as a depolarizing muscle relaxant but the depolarizing action of succinylcholine may not be the sole mechanism involved in producing neuromuscular relaxation, at least not with higher total doses. It is known that with high initial bolus doses (>3 mg/kg), after multiple boluses, or with a maintenance infusion (>90 min), the characteristics of the neuromuscular blockade produced by succinylcholine can change from depolarizing to nondepolarizing in nature (i.e., fade with the TOF stirnulationj.v" This is frequently referred to as phase II block, as compared with phase I block, which signifies a depolarizing block. Phase II block is longer-lasting and the patient may remain paralyzed for a couple of hours. TOF stimulation makes this distinction.
56 •
D/CP, The Annals ofPharmacotherapy •
Nondepolarizing Block
Depolarizing Block Onset of Block
Recovery
Figure 2. Train-of-four stimulation following nondepolarizing and depolarizing muscle relaxants.
It is essential when an NMBA is used to ensure that recovery is complete. The TOF can be used as the initial evaluation to make this determination. When a nondepolarizing blocker has been used, the absence of fade following a TOF indicates that adequate degree of recovery has occurred. Tetanic stimulation is more intense than TOF stimulation. The nerve is usually bombarded for a few seconds (50 Hz). The mechanism is the same as that described for the TOF but the absence of fade after a tetanus indicates that recovery is more complete and that the release of ACH has returned to normal. It should be remembered that the technique of neuromuscular monitoring is only an aid, not a substitute, for sound clinical observation and judgment of muscle relaxation or recovery.
Succinylcholine Succinylcholine is a short-acting depolarizing NMBA. Succinylcholine is made of two molecules of acetylcholine connected back-to-back through the acetate methyl group; therefore, succinylcholine is not hydrolyzed by acetylcholinesterase. Hydrolysis of succinylcholine is achieved by plasma cholinesterase (synthesized by the liver) at a rate much slower than that of ACH (half-life approximately 3-5 min). U.13 Approximately 70-80 percent of the administered succinylcholine is hydrolyzed prior to reaching the NMJ. 13 Because succinylcholine is metabolized primarily by plasma cholinesterase, its duration of action may increase in situations where the concentration of this enzyme is reduced, such as in liver disease, pregnancy, and in infants. 14.1S In addition, certain individuals have genetically abnormal plasma cholinesterase. 16.17 In these individuals succinylcholine will provide neuromuscular blockade that may last up to several hours. Patients in whom it is known that this genetic abnormality exists should obviously not receive succinylcholine. Tachyphylaxis to succinylcholine is also noted in some patients (manifested by a 20 percent or greater increase in the infusion rate needed to maintain 80-90 percent twitch suppression) with continuous infusion of greater than one hour.r-" The reason for the development oftachyphylaxis is not known, but may represent a change in the sensitivity of muscle fiber to the effect of succinylcholine. 9
/99/ January, Volume 25
Neuromuscular Blocking Agents PHARMACODYNAMICS
The most common use of succinylcholine is to provide rapid relaxation for endotracheal intubation. A typical intubating dose of succinylcholine (1-1.5 mglkg) will result in maximum supression of muscle twitch and provide goodto-excellent intubating conditions within 1-1.5 minutes. 8.18 Even in high doses, other NMBAs do not usually provide excellent intubating conditions in less than two minutes. 19-24 Succinylcholine is considered, therefore, to be the drug of choice when the trachea must be intubated quickly after the induction of anesthesia to prevent aspiration. Succinylcholine 1 mg/kg will provide surgical relaxation for approximately 5 minutes with full spontaneous recovery of muscle function in approximately 15 minutes. 8,18 Succinylcholine is, therefore, also the drug of choice when muscle relaxation is needed only for a short period of time. As with other NMBAs, the duration of action of this agent is dose-dependent. 11 During longer surgical cases anesthesiologists will usually use succinylcholine for intubation, wait until some degree of neuromuscular recovery is manifested, and then use a nondepolarizing agent for maintenance of relaxation. Administration of an intubating dose of succinylcholine may increase the plasma concentration of K" by as much as 0.5 mEq/L. 25.26 This results from the movement of K+ outside the cell during depolarization. In an otherwise healthy patient, the rise in K+ concentration is not usually clinically important. In burned patients and those with nervemuscle injury, succinylcholine may result in a much greater rise in the plasma concentration of K+ and predispose the patient to the cardiovascular effects of hyperkalemia. 26-28 Preoperative hyperkalemia may also be a relative contraindication for the use of succinylcholine. Muscle fasciculations and postoperative myalgias are also common with the use of succinylcholine.P-" Muscle fasciculations are, in fact, considered to be the earliest clinical sign of the onset of neuromuscular blockade following succinylcholine administration. Both muscle fasciculations and postoperative myalgias are thought to be direct effects of the depolarizing action of succinylcholine with muscle fasciculations resulting from the initial depolarization and
myalgias resulting from the prolonged depolarization (muscle fatigue). The administration of a small dose of a nondepolarizing agent given three minutes prior to the succinylcholine may attenuate or prevent the fasciculations and the postoperative myalgias. Bradycardia is the predominant cardiovascular adverse effect of succinylcholine, although it is most commonly seen with repeated doses." This bradycardic effect can vary in intensity and is short-lived. Succinylcholine may also increase intraocular pressure, intragastric pressure, and intracranial pressure. 16,31,32 PHARMACOKINETICS
Because of its rapid hydrolysis and the lack of an appropriate assay, very little is known about the pharmacokinetics of succinylcholine.
Curare (d-tubocurarine) Curare is the oldest NMBA in clinical use. It has one tertiary and one quaternary nitrogen atom. In the blood (pH 7.4), the tertiary nitrogen is protonated and curare is converted to a bisquaternary ammonium compound. PHARMACODYNAMICS
Much of the published information on curare is considerably old, so that little comparative data will be presented except in general terms. The mean dose of curare required to produce 95 percent suppression of muscle twitch (ED 9s ) in adult patients is approximately 0.5 mglkg 33 ,34 (i.e., this dose of curare causes at least 95 percent suppression of muscle twitch in half of the patients, and the remaining half will have less than 95 percent suppression). This doseresponse relationship appears to be the same regardless of the patient's age." When injecting a 0.5-mg/kg dose of curare intravenously over a few seconds, one sees maximal suppresion of muscle twitch within five mintus. 23,34 Curare, therefore, has slow onset of action when compared with succinylcholine, although its onset of action may not be much different from that of an intubating dose of pancuronium." A 0.5-0.6 mg/kg iv bolus dose of curare will usually have a clinical duration of 1.5 hours or more. 34,36 Furthermore, as with other nondepolarizing agents, vol-
Table 1. Comparative Pharmacokinetics of Muscle Relaxants
REF
41-49 41 50-55 56,57 50 51 52,55,56,58-63 56 59,63 60 61 64-69 65 64,66,67 68 11"
MUSCLE RELAXANT
Curare Pancuronium
Vecuronium
Atracurium
SURGICAL POPULATION
healthy adults renal failure healthy adults elderly renal failure cirrhosis healthy adults elderly renal failure cirrhosis cholestasis healthy adults elderly renal failure cirrhosis
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