DRUG DISPOSITION
Clin. Pharmacokinet. 22 (2): 94· 115. 1992 0312·5963/92/0002·0094/$11.00/0 © Adis International Limited. All rights reserved. CPK1
Clinical Pharmacokinetics of Neuromuscular Blocking Drugs Sandor Agoston, Ron H.G. Vandenbrom and J. Mark K.H. Wierda Research Group of the Institutes for Experimental Anesthesiology and Clinical Pharmacology, University of Groningen, Groningen, The Netherlands
Contents 94
96 96 99
101 104 106
108 108 10 III III 112
Summary
Summary I. Analytical Methods 2. Standard Nondepolarising Neuromuscular Blocking Agents 2. 1 Renal and Hepatic Failure 2.2 Pregnancy 3. New Nondepolarising Neuromuscular Blocking Agents 3.1 Vecuronium 3.2 Rocuronium 3.3 Pipecuronium 3.4 Atracurium 3.5 Mivacurium 3.6 Doxacurium 4. Conclusions
Neuromuscular blocking agents provide muscle relaxation for a great variety of surgical pro· cedures with light planes of general anaesthesia. Besides having a significant impact in the development of anaesthesia and surgery, these agents continue to play an important role as pharo macological tools in the elucidation of the physiological and pharmacological regulation of neuromuscular transmission and the morphofunctional organisation of the neuromuscular junction. In the daily practice of anaesthesia, muscle relaxants are considered to be safe drugs with predictable, straightforward pharmacological actions. However, the use of relaxants constitutes a deliberate encroachment on respiration, one of the most important physiological mechanisms. The pharmacokinetic behaviour of this class of agents is little influenced by age or anaesthetic agents; however, hepatic or renal disease may profoundly alter their excretion pattern, resulting in prolonged duration of neuromuscular blockade. Biotransformation plays an important role in the total elimination of recently introduced compounds. Consequently, knowledge of the disposition pharmacokinetics, excretion and biotransformation of this class of drugs is indispensable for their rational choice for various surgical procedures. In this review, the known pharmacokinetics of standard compounds (introduced before 1980) are briefly summarised and new information generated by the development of vecuronium,
Kinetics of Neuromuscular Blockers
95
rocuronium, pipecuronium (steroidal agents) and atracurium, mivacurium, doxacurium (benzylisoquinolinium esters) is discussed in more detail.
As pharmacological tools, the neuromuscular blocking agents play an important role elucidating the physiological and pharmacological regulation of neuromuscular transmission and the morphofunctional organisation of the neuromuscular junction. In 1851, Barnard took the first step towards our understanding of the neuromuscular transmission. Dale et al. (1936) reported the discovery of the role of acetylcholine in neuromuscular transmission. Curare has contributed to our present knowledge of the structure, organisation and function of the acetylcholine receptor and curare-like agents have increased our understanding of drugreceptor interactions and receptor conformation. Neuromuscular blocking agents had an impressive impact in the development of anaesthesia and surgery. When Griffith and Johnson introduced curare into clinical practice in 1942 they revolutionised anaesthetic use. The use of curare in the practice of anaesthesia both necessitated and enabled controlled ventilation during and after surgery and allowed adequate muscle relaxation under lighter, and therefore better tolerated, planes of general anaesthesia. Soon after, Gray and Holton (1946) developed the concept of the triad of anaesthesia, consisting of the provision of sleep, pain relief and muscular relaxation by relatively small doses of separate drugs. These developments extended the limits of operability, reduced anaesthesia-related morbidity and mortality and contributed to the explosive development of surgery. Without neuromuscular blocking agents, open heart or organ transplant surgery could not have developed. Anaesthetists are faced immediately with the consequences of the drugs they use, so it follows that, after the introduction of muscle relaxants into the clinical practice, they became interested in the physiology of the neuromuscular block and the pharmacology and pharmacokinetics ofneuromuscular blocking agents. Many important contribu-
tions to experimental and clinical pharmacology have come from anaesthetists. The structural characteristics of various neuromuscular blocking agents, including the charge distribution, nature of substituents at the onium centres and the interonium structure of the molecule, determine the interaction with acetylcholine receptors. These physicochemical features affect the transfer rate through biological membranes, affinity for nonspecific binding sites and receptors, biotransformation and excretion. In anaesthetic practice standard doses of muscle relaxants, i.e. the dose producing 95% depression of the indirectly evoked twitch tension of the adductor pollicis muscle (ED95) or 2 X ED95, are commonly used. Not infrequently, abnormal responses to these doses occur, i.e. greatly intensified or prolonged neuromuscular blockade, which are often attributed to individual patient differences in sensitivity to neuromuscular blocking agents. However, often these 'abnormal' responses could be prevented by considering the pharmacokinetics of neuromuscular blocking agents. The absorption, distribution to tissues and elimination by biotransformation and excretion are closely related to the effects of a drug and will determine the rate of onset, intensity and duration of pharmacological actions. Pharmacokinetics are important to anaesthetists, who are expected to bring the patient rapidly to an adequate level of anaesthesia during the surgical procedure and then recover the patient promptly to a safe level of consciousness with full vital functions. Neuromuscular blocking agents equilibrate rapidly between plasma and their sites of action. Consequently, it is relatively easy to define concentration-response relationships which in turn will permit the design of efficient dosage regimens for adequate anaesthesia or muscle paralysis with minimal side effects. Although developments in the field of the pharmacokinetics of the neuromuscular blocking agents
96
Clin. Pharmacokinet. 22 (2) 1992
have been comprehensively reviewed earlier (Ramzan et al. 1981c; Stan ski & Watkins 1982), during the past few years important advances have been made in our understanding of the relationship between pharmacokinetics and the structural properties important for drug design; new drugs and new, more reliable, analytical methods have become available. Besides a brief summary of the already reviewed human pharmacokinetic data, the above aspects form the main topics of this review.
1. Analytical Methods Pharmacokinetic studies with neuromuscular blocking agents have long been hampered by the lack of suitable analytical methods to determine the low drug concentrations encountered in normal clinical practice. Analytical methods for pharmacokinetic research must be sensitive, specific, selective, economical and preferably not too elaborate. Most pharmacokinetic studies in the past have used the modification by Kersten et al. (1973) of the original fluorometric method described by Cohen (1963). Further alterations to the method improved its selectivity, sensitivity and precision in all body fluids and tissues (Kosterink et al. 1990). This method combines the advantages of a sensitive fluorometric determination with a selective thin layer chromatographic (TLC) separation of the parent compounds from their breakdown products. Besides the combined fluorometric-TLC method, direct insertion probe chemical ionisation mass spectrometry (Castagnoli et al. 1986), a gas chromatographic method (GC) [Furuta et al. 1988] and a radioimmunoassay (Horowitz & Spector 1973) have been tried with variable success. However, the most promising analytical breakthrough seems to be the use of high performance liquid chromatography (HPLC) as described by Paanakker et al. (1987) and Simmonds (1985). Variants of the fluorometric assay are most commonly used. Although its sensitivity is less than that of the other methods, it is sufficient to follow low plasma concentrations for long enough (6 to 8h) to obtain meaningful pharmacokinetic data. Under routine clinical conditions, the lack of se-
lectivity can be partly overcome by submitting each sample to TLC analysis, so that semiquantitative data can be obtained on the occurrence and number of breakdown products. For further quantification of metabolites, compounds can be eluted from the thin layer plate and resubmitted to the fluorometric determination after ion-pair formation with rose bengal. This last step makes the method more elaborate, but provides low-cost quantitative information on the parent compound and metabolites in plasma, urine, bile and various tissue homogenates with detection limits ofO.Olmg/ L or 0.150mg using TLC. Mass spectrometry is extremely sensitive (detection limit 0.05 /-Lg/L), selective, elaborate and expensive. Only plasma concentrations of neuromuscular blocking agents have been determined and breakdown products have never been quantified. Capillary GC is similar, having very good to excellent sensitivity (detection limit 5.0 to 10.0 J.Lg/ L) and selectivity (Furuta et al. 1988) but high running costs. It is also very elaborate, with some steps taking as long as 16h. The most promising method. however, is reversed phase HPLC, recently described by Paanakker et al. (1987). It appears to be adaptable to various mono- and bisquaternary compounds in a variety of biological materials. The total costs (equipment and running costs) are similar to those of GC, but the analytical procedure is less elaborate. More importantly, its sensitivity (detection limit 5.0 /-LgfL) and selectivity are outstanding; therefore, it is recommended for both pharmacokinetic and forensic research.
2. Standard Nondepolarising Neuromuscular Blocking Agents Since the pharmacokinetic profile of neuromuscular blocking agents was reviewed by Ramzan et al. (1981), advances in intraoperative monitoring and postoperative patient care plus the introduction of new anaesthetic agents have greatly improved the surgical and anaesthetic management of high-risk patients. These developments also stimulated the search for new neuromuscular blocking agents and led to the introduction of 6
Kinetics of Neuromuscular Blockers
97
Table I. Pharmacokinetic parameters of classical nondepolarising muscle relaxants in anaesthetised patients. Where available. data from the elderly, children and patients with renal and hepatic dysfunction are listed Drug
Gallamine
Dose
tV20'
tv,~
(mg/kg)
(min)
(min)
2-6
6-16
128-250
Vc (ml/kg)
72-145
Vss (ml/kg)
202-290
CL
Reference
(ml/kg/ min) 1.0-1.6
Ramzan et al. (1980a,b); Westra et al. (1981)
renal
2
8.9
752
284
0.24
Ramzan et al. (1981 a)
hepatic
2-2.5
6-9
160-220
80-125
247-259
1.21-0.9
Ramzan et al. (1981 b);
0.3
2
216-360
40-66
340-350
1.0-1.3
Westra et al. (1981) Brotherton & Matteo (1981);
Metocurine
150
Matteo et al. (1982, 1985); Meijer et al. (1979) renal d- Tubocurarine
0.3 0.15-0.5
1.7-4.2
680 164-372
58 28-47
0.4 0.8-1.86
Brotherton & Matteo (1981) Martyn et al. (1982); Matteo et al. (1982, 1984, 1985); Meijer et al. (1979)
renal a Pancuronium
0.5 0.1-0.25
3-13
330 110-190
98 50-122
250 178-290
1.5 0.8-3.0
Miller et al. (1977) Duvaldestin et al. (1978a,b, 1982b); Evans et al. (1984); McLeod et al. (1976); Rupp et al. (1987); Somogyi et al. (1976); Sohn et al. (1986)
children (4y) elderly
0.1 0.08 b
renal
0.06-0.08
hepatic
0.08-0.25
Alcuronium
0.25-0.26
5
103
74
203
1.7
3
150-200
57
218
1.2
Duvaldestin et al. (1982b);
12-18c
Meistelman et al. (1986)
258-489 c
117-135
296
0.28-0.75
Rupp et al. (1987) McLeod et al. (1976);
208-224
120-173
425
1.45-1.47
Duvaldestin et al. (1978a);
197-218
122-180
312-357
1.2-1.4
Somogyi et al. (1977a) 5.6-23.7
Westra et al. (1981) 15
a
Data only partially based on actual drug level measurements.
b c
Pancuronium was infused at 2.5 /Lg/kg/min until 70 to 90% twitch depression was achieved.
Raaflaub & Frey (1972); Walker et al. (1980)
Calculated from absorption (k a) and elimination (ke) rate constants, where tv, = In2/(ka or k e). Abbreviations: tv," = distribution half-life; tv,~ = elimination half-life; Vc = volume of distribution of the central compartment; V 55 = volume of distribution at steady-state; CL = total plasma clearance.
new drugs: atracurium (Payne & Hughes 1981), vecuronium (Agoston et al. 1980), rocuronium (Org 9426) [Wierda et al. 1990b], mivacurium (Savarese et al. 1988), doxacurium (Basta et al. 1988) and pipecuronium (Agoston & Richardson 1985). These new agents are more variable in the duration of their neuromuscular blocking effects, ranging from short to long durations of action, reflecting contemporary clinical needs signalled as early as 1975 (Savarese & Kitz 1975). Atracurium and vecuronium are agents belonging to a subclass of com-
pounds with effects of intermediate duration. The other agents are now undergoing clinical investigation. Time course profiles for mivacurium (Savarese et al. 1988) and rocuronium (Wierda et al. 1990b) resemble those of vecuronium or atracurium. Doxacurium (Basta et al. 1988) and pipecuronium (Agoston & Richardson 1985) have a long duration of action comparable with that of pancuronium; however, both appear to be free of cardiovascular side effects. The pharmacokinetics of atracurium (Vanden-
Clin. Pharmacokinel. 22 (2) 11.)1.)2
98
brom et al. 1990; Ward & Weatherley 1986), vecuronium (Bencini et al. 1986a), pipecuronium (Caldwell et al. 1989), doxacurium (Dresner et al. 1990) and rocuronium (Wierda et al. 1991 a) have been reported. There is limited information on the pharmacokinetics of mivacurium (De Bros et al. 1987).
Table I lists the reported extreme pharmacokinetic values for patients administered the older agents (figs. 1 and 2) which are discussed briefly before a more detailed discussion of the newer agents. The studies varied in design, analytical technique, duration of blood sampling and methodology of data analysis; some used a biexponen-
Metocurine
Gallamine
CH
I CH2
I OH
Alcuronium
Fig. 1. Structural formulae of (a) gallamine, (b) metocurine, (c) d-tubocurarine and (d) alcuronium.
Kinetics of Neuromuscular Blockers
tial equation while others found a triexponential equation to be statistically preferable. The pharmacokinetic parameters in table I indicate no substantial differences between the standard agents. This is not surprising since neuromuscular blocking agents share important physicochemical properties. All have quaternary ammonium groups in relatively large bulky molecules which are highly ionised regardless of pH, limiting their distribution to extracellular water. Substantial differences in the disposition of these drugs are therefore unlikely. Differentiation may occur in disease states depending on the elimination and biotransformation patterns of the individual agents.
99
oI CH3
Compound
o
o
2.1 Renal and Hepatic Failure
II
Pancuronium
The effect of renal failure and hepatic or biliary tract disease is demonstrated by the altered pharmacokinetic variables also summarised in table I. Renal failure appears to have minimal effect on the volume of distribution (Vd) and distribution halflife (t'ha). However, a decrease in total plasma clearance (CL) with unchanged Vd, resulting in a prolonged elimination half-life (t'hfj), is a consistent finding. This has distinct implications for the clinical use of these agents in patients with renal failure. Neuromuscular effects of small and moderate doses will end when the drugs are redistributed to other tissues. In contrast, the effects of larger, paralysing doses are greatly influenced by renal elimination since the rate of recovery from neuromuscular blockade will be governed by the t'l213' which is prolonged in renal disease. A peculiar phenomenon associated with kidney disease in humans is an apparent resistance to the effects of neuromuscular blocking agents (Somogyi et a1. 1977a). Similar observations have since been reported with vecuronium (Bencini et a1. 1986b), atracurium (Hunter et al. 1984; Vandenbrom et a1. 1990) and in animal experiments with pipecuronium (Agoston et a1. 1988). The explanation for this phenomenon is not clear; a possible reason may be the release of endogenous substances, such as guanidine compounds, at sufficient concentrations to exert antagonistic activity or increase Yd.
Rl
- C -
II CH3
-
C - CH3
o
3-Deacetylpancuronium
II
-H
-
C - CH3
0
II
17 -Deacetylpancuronium
- 'C - CH3
-H
3.17 -Dideacetylpancuronium
-H
-H
Fig.2. Structural formulae ofpancuronium and its 3 possible metabolites.
Hepatocellular and obstructive liver disease may profoundly affect the pharmacokinetics of neuromuscular blocking agents. The nature and extent of these alterations, however, depend on the characteristics and dose of the individual drugs and on the degree of hepatic or biliary dysfunction. The pattern of elimination is also important. The pharmacokinetics of gallamine, which is almost 100% excreted by the kidneys in unchanged form (Agoston et a1. 1978), were unaffected by obstructive jaundice (Ramzan et a1. 1981 a; Westra et a1. 1981). In contrast, biliary obstruction prolonged the t'hfj of pancuronium (Westra et al. 1981) secondary to
Clin. Pharmacokinet. 22 (2) 1992
100
Table II. Percentages of administered doses of classical neuromuscular blocking agents excreted in the urine or bile or biotransformed within 24h after administration
Drug
Urine
Bile
Metabolites
References
Gallamine
95-98
Clin. Pharmacokinet. 22 (2): 94· 115. 1992 0312·5963/92/0002·0094/$11.00/0 © Adis International Limited. All rights reserved. CPK1
Clinical Pharmacokinetics of Neuromuscular Blocking Drugs Sandor Agoston, Ron H.G. Vandenbrom and J. Mark K.H. Wierda Research Group of the Institutes for Experimental Anesthesiology and Clinical Pharmacology, University of Groningen, Groningen, The Netherlands
Contents 94
96 96 99
101 104 106
108 108 10 III III 112
Summary
Summary I. Analytical Methods 2. Standard Nondepolarising Neuromuscular Blocking Agents 2. 1 Renal and Hepatic Failure 2.2 Pregnancy 3. New Nondepolarising Neuromuscular Blocking Agents 3.1 Vecuronium 3.2 Rocuronium 3.3 Pipecuronium 3.4 Atracurium 3.5 Mivacurium 3.6 Doxacurium 4. Conclusions
Neuromuscular blocking agents provide muscle relaxation for a great variety of surgical pro· cedures with light planes of general anaesthesia. Besides having a significant impact in the development of anaesthesia and surgery, these agents continue to play an important role as pharo macological tools in the elucidation of the physiological and pharmacological regulation of neuromuscular transmission and the morphofunctional organisation of the neuromuscular junction. In the daily practice of anaesthesia, muscle relaxants are considered to be safe drugs with predictable, straightforward pharmacological actions. However, the use of relaxants constitutes a deliberate encroachment on respiration, one of the most important physiological mechanisms. The pharmacokinetic behaviour of this class of agents is little influenced by age or anaesthetic agents; however, hepatic or renal disease may profoundly alter their excretion pattern, resulting in prolonged duration of neuromuscular blockade. Biotransformation plays an important role in the total elimination of recently introduced compounds. Consequently, knowledge of the disposition pharmacokinetics, excretion and biotransformation of this class of drugs is indispensable for their rational choice for various surgical procedures. In this review, the known pharmacokinetics of standard compounds (introduced before 1980) are briefly summarised and new information generated by the development of vecuronium,
Kinetics of Neuromuscular Blockers
95
rocuronium, pipecuronium (steroidal agents) and atracurium, mivacurium, doxacurium (benzylisoquinolinium esters) is discussed in more detail.
As pharmacological tools, the neuromuscular blocking agents play an important role elucidating the physiological and pharmacological regulation of neuromuscular transmission and the morphofunctional organisation of the neuromuscular junction. In 1851, Barnard took the first step towards our understanding of the neuromuscular transmission. Dale et al. (1936) reported the discovery of the role of acetylcholine in neuromuscular transmission. Curare has contributed to our present knowledge of the structure, organisation and function of the acetylcholine receptor and curare-like agents have increased our understanding of drugreceptor interactions and receptor conformation. Neuromuscular blocking agents had an impressive impact in the development of anaesthesia and surgery. When Griffith and Johnson introduced curare into clinical practice in 1942 they revolutionised anaesthetic use. The use of curare in the practice of anaesthesia both necessitated and enabled controlled ventilation during and after surgery and allowed adequate muscle relaxation under lighter, and therefore better tolerated, planes of general anaesthesia. Soon after, Gray and Holton (1946) developed the concept of the triad of anaesthesia, consisting of the provision of sleep, pain relief and muscular relaxation by relatively small doses of separate drugs. These developments extended the limits of operability, reduced anaesthesia-related morbidity and mortality and contributed to the explosive development of surgery. Without neuromuscular blocking agents, open heart or organ transplant surgery could not have developed. Anaesthetists are faced immediately with the consequences of the drugs they use, so it follows that, after the introduction of muscle relaxants into the clinical practice, they became interested in the physiology of the neuromuscular block and the pharmacology and pharmacokinetics ofneuromuscular blocking agents. Many important contribu-
tions to experimental and clinical pharmacology have come from anaesthetists. The structural characteristics of various neuromuscular blocking agents, including the charge distribution, nature of substituents at the onium centres and the interonium structure of the molecule, determine the interaction with acetylcholine receptors. These physicochemical features affect the transfer rate through biological membranes, affinity for nonspecific binding sites and receptors, biotransformation and excretion. In anaesthetic practice standard doses of muscle relaxants, i.e. the dose producing 95% depression of the indirectly evoked twitch tension of the adductor pollicis muscle (ED95) or 2 X ED95, are commonly used. Not infrequently, abnormal responses to these doses occur, i.e. greatly intensified or prolonged neuromuscular blockade, which are often attributed to individual patient differences in sensitivity to neuromuscular blocking agents. However, often these 'abnormal' responses could be prevented by considering the pharmacokinetics of neuromuscular blocking agents. The absorption, distribution to tissues and elimination by biotransformation and excretion are closely related to the effects of a drug and will determine the rate of onset, intensity and duration of pharmacological actions. Pharmacokinetics are important to anaesthetists, who are expected to bring the patient rapidly to an adequate level of anaesthesia during the surgical procedure and then recover the patient promptly to a safe level of consciousness with full vital functions. Neuromuscular blocking agents equilibrate rapidly between plasma and their sites of action. Consequently, it is relatively easy to define concentration-response relationships which in turn will permit the design of efficient dosage regimens for adequate anaesthesia or muscle paralysis with minimal side effects. Although developments in the field of the pharmacokinetics of the neuromuscular blocking agents
96
Clin. Pharmacokinet. 22 (2) 1992
have been comprehensively reviewed earlier (Ramzan et al. 1981c; Stan ski & Watkins 1982), during the past few years important advances have been made in our understanding of the relationship between pharmacokinetics and the structural properties important for drug design; new drugs and new, more reliable, analytical methods have become available. Besides a brief summary of the already reviewed human pharmacokinetic data, the above aspects form the main topics of this review.
1. Analytical Methods Pharmacokinetic studies with neuromuscular blocking agents have long been hampered by the lack of suitable analytical methods to determine the low drug concentrations encountered in normal clinical practice. Analytical methods for pharmacokinetic research must be sensitive, specific, selective, economical and preferably not too elaborate. Most pharmacokinetic studies in the past have used the modification by Kersten et al. (1973) of the original fluorometric method described by Cohen (1963). Further alterations to the method improved its selectivity, sensitivity and precision in all body fluids and tissues (Kosterink et al. 1990). This method combines the advantages of a sensitive fluorometric determination with a selective thin layer chromatographic (TLC) separation of the parent compounds from their breakdown products. Besides the combined fluorometric-TLC method, direct insertion probe chemical ionisation mass spectrometry (Castagnoli et al. 1986), a gas chromatographic method (GC) [Furuta et al. 1988] and a radioimmunoassay (Horowitz & Spector 1973) have been tried with variable success. However, the most promising analytical breakthrough seems to be the use of high performance liquid chromatography (HPLC) as described by Paanakker et al. (1987) and Simmonds (1985). Variants of the fluorometric assay are most commonly used. Although its sensitivity is less than that of the other methods, it is sufficient to follow low plasma concentrations for long enough (6 to 8h) to obtain meaningful pharmacokinetic data. Under routine clinical conditions, the lack of se-
lectivity can be partly overcome by submitting each sample to TLC analysis, so that semiquantitative data can be obtained on the occurrence and number of breakdown products. For further quantification of metabolites, compounds can be eluted from the thin layer plate and resubmitted to the fluorometric determination after ion-pair formation with rose bengal. This last step makes the method more elaborate, but provides low-cost quantitative information on the parent compound and metabolites in plasma, urine, bile and various tissue homogenates with detection limits ofO.Olmg/ L or 0.150mg using TLC. Mass spectrometry is extremely sensitive (detection limit 0.05 /-Lg/L), selective, elaborate and expensive. Only plasma concentrations of neuromuscular blocking agents have been determined and breakdown products have never been quantified. Capillary GC is similar, having very good to excellent sensitivity (detection limit 5.0 to 10.0 J.Lg/ L) and selectivity (Furuta et al. 1988) but high running costs. It is also very elaborate, with some steps taking as long as 16h. The most promising method. however, is reversed phase HPLC, recently described by Paanakker et al. (1987). It appears to be adaptable to various mono- and bisquaternary compounds in a variety of biological materials. The total costs (equipment and running costs) are similar to those of GC, but the analytical procedure is less elaborate. More importantly, its sensitivity (detection limit 5.0 /-LgfL) and selectivity are outstanding; therefore, it is recommended for both pharmacokinetic and forensic research.
2. Standard Nondepolarising Neuromuscular Blocking Agents Since the pharmacokinetic profile of neuromuscular blocking agents was reviewed by Ramzan et al. (1981), advances in intraoperative monitoring and postoperative patient care plus the introduction of new anaesthetic agents have greatly improved the surgical and anaesthetic management of high-risk patients. These developments also stimulated the search for new neuromuscular blocking agents and led to the introduction of 6
Kinetics of Neuromuscular Blockers
97
Table I. Pharmacokinetic parameters of classical nondepolarising muscle relaxants in anaesthetised patients. Where available. data from the elderly, children and patients with renal and hepatic dysfunction are listed Drug
Gallamine
Dose
tV20'
tv,~
(mg/kg)
(min)
(min)
2-6
6-16
128-250
Vc (ml/kg)
72-145
Vss (ml/kg)
202-290
CL
Reference
(ml/kg/ min) 1.0-1.6
Ramzan et al. (1980a,b); Westra et al. (1981)
renal
2
8.9
752
284
0.24
Ramzan et al. (1981 a)
hepatic
2-2.5
6-9
160-220
80-125
247-259
1.21-0.9
Ramzan et al. (1981 b);
0.3
2
216-360
40-66
340-350
1.0-1.3
Westra et al. (1981) Brotherton & Matteo (1981);
Metocurine
150
Matteo et al. (1982, 1985); Meijer et al. (1979) renal d- Tubocurarine
0.3 0.15-0.5
1.7-4.2
680 164-372
58 28-47
0.4 0.8-1.86
Brotherton & Matteo (1981) Martyn et al. (1982); Matteo et al. (1982, 1984, 1985); Meijer et al. (1979)
renal a Pancuronium
0.5 0.1-0.25
3-13
330 110-190
98 50-122
250 178-290
1.5 0.8-3.0
Miller et al. (1977) Duvaldestin et al. (1978a,b, 1982b); Evans et al. (1984); McLeod et al. (1976); Rupp et al. (1987); Somogyi et al. (1976); Sohn et al. (1986)
children (4y) elderly
0.1 0.08 b
renal
0.06-0.08
hepatic
0.08-0.25
Alcuronium
0.25-0.26
5
103
74
203
1.7
3
150-200
57
218
1.2
Duvaldestin et al. (1982b);
12-18c
Meistelman et al. (1986)
258-489 c
117-135
296
0.28-0.75
Rupp et al. (1987) McLeod et al. (1976);
208-224
120-173
425
1.45-1.47
Duvaldestin et al. (1978a);
197-218
122-180
312-357
1.2-1.4
Somogyi et al. (1977a) 5.6-23.7
Westra et al. (1981) 15
a
Data only partially based on actual drug level measurements.
b c
Pancuronium was infused at 2.5 /Lg/kg/min until 70 to 90% twitch depression was achieved.
Raaflaub & Frey (1972); Walker et al. (1980)
Calculated from absorption (k a) and elimination (ke) rate constants, where tv, = In2/(ka or k e). Abbreviations: tv," = distribution half-life; tv,~ = elimination half-life; Vc = volume of distribution of the central compartment; V 55 = volume of distribution at steady-state; CL = total plasma clearance.
new drugs: atracurium (Payne & Hughes 1981), vecuronium (Agoston et al. 1980), rocuronium (Org 9426) [Wierda et al. 1990b], mivacurium (Savarese et al. 1988), doxacurium (Basta et al. 1988) and pipecuronium (Agoston & Richardson 1985). These new agents are more variable in the duration of their neuromuscular blocking effects, ranging from short to long durations of action, reflecting contemporary clinical needs signalled as early as 1975 (Savarese & Kitz 1975). Atracurium and vecuronium are agents belonging to a subclass of com-
pounds with effects of intermediate duration. The other agents are now undergoing clinical investigation. Time course profiles for mivacurium (Savarese et al. 1988) and rocuronium (Wierda et al. 1990b) resemble those of vecuronium or atracurium. Doxacurium (Basta et al. 1988) and pipecuronium (Agoston & Richardson 1985) have a long duration of action comparable with that of pancuronium; however, both appear to be free of cardiovascular side effects. The pharmacokinetics of atracurium (Vanden-
Clin. Pharmacokinel. 22 (2) 11.)1.)2
98
brom et al. 1990; Ward & Weatherley 1986), vecuronium (Bencini et al. 1986a), pipecuronium (Caldwell et al. 1989), doxacurium (Dresner et al. 1990) and rocuronium (Wierda et al. 1991 a) have been reported. There is limited information on the pharmacokinetics of mivacurium (De Bros et al. 1987).
Table I lists the reported extreme pharmacokinetic values for patients administered the older agents (figs. 1 and 2) which are discussed briefly before a more detailed discussion of the newer agents. The studies varied in design, analytical technique, duration of blood sampling and methodology of data analysis; some used a biexponen-
Metocurine
Gallamine
CH
I CH2
I OH
Alcuronium
Fig. 1. Structural formulae of (a) gallamine, (b) metocurine, (c) d-tubocurarine and (d) alcuronium.
Kinetics of Neuromuscular Blockers
tial equation while others found a triexponential equation to be statistically preferable. The pharmacokinetic parameters in table I indicate no substantial differences between the standard agents. This is not surprising since neuromuscular blocking agents share important physicochemical properties. All have quaternary ammonium groups in relatively large bulky molecules which are highly ionised regardless of pH, limiting their distribution to extracellular water. Substantial differences in the disposition of these drugs are therefore unlikely. Differentiation may occur in disease states depending on the elimination and biotransformation patterns of the individual agents.
99
oI CH3
Compound
o
o
2.1 Renal and Hepatic Failure
II
Pancuronium
The effect of renal failure and hepatic or biliary tract disease is demonstrated by the altered pharmacokinetic variables also summarised in table I. Renal failure appears to have minimal effect on the volume of distribution (Vd) and distribution halflife (t'ha). However, a decrease in total plasma clearance (CL) with unchanged Vd, resulting in a prolonged elimination half-life (t'hfj), is a consistent finding. This has distinct implications for the clinical use of these agents in patients with renal failure. Neuromuscular effects of small and moderate doses will end when the drugs are redistributed to other tissues. In contrast, the effects of larger, paralysing doses are greatly influenced by renal elimination since the rate of recovery from neuromuscular blockade will be governed by the t'l213' which is prolonged in renal disease. A peculiar phenomenon associated with kidney disease in humans is an apparent resistance to the effects of neuromuscular blocking agents (Somogyi et a1. 1977a). Similar observations have since been reported with vecuronium (Bencini et a1. 1986b), atracurium (Hunter et al. 1984; Vandenbrom et a1. 1990) and in animal experiments with pipecuronium (Agoston et a1. 1988). The explanation for this phenomenon is not clear; a possible reason may be the release of endogenous substances, such as guanidine compounds, at sufficient concentrations to exert antagonistic activity or increase Yd.
Rl
- C -
II CH3
-
C - CH3
o
3-Deacetylpancuronium
II
-H
-
C - CH3
0
II
17 -Deacetylpancuronium
- 'C - CH3
-H
3.17 -Dideacetylpancuronium
-H
-H
Fig.2. Structural formulae ofpancuronium and its 3 possible metabolites.
Hepatocellular and obstructive liver disease may profoundly affect the pharmacokinetics of neuromuscular blocking agents. The nature and extent of these alterations, however, depend on the characteristics and dose of the individual drugs and on the degree of hepatic or biliary dysfunction. The pattern of elimination is also important. The pharmacokinetics of gallamine, which is almost 100% excreted by the kidneys in unchanged form (Agoston et a1. 1978), were unaffected by obstructive jaundice (Ramzan et a1. 1981 a; Westra et a1. 1981). In contrast, biliary obstruction prolonged the t'hfj of pancuronium (Westra et al. 1981) secondary to
Clin. Pharmacokinet. 22 (2) 1992
100
Table II. Percentages of administered doses of classical neuromuscular blocking agents excreted in the urine or bile or biotransformed within 24h after administration
Drug
Urine
Bile
Metabolites
References
Gallamine
95-98
