PHARMACOKINETICS OF COMPETITIVE MUSCLE RELAXANTS

Transcription

1 f. J. Anaesth. (1982), 54, 161 PHARMACOKINETICS OF COMPETITIVE MUSCLE RELAXANTS Pharmacokinetics refers to the rates of distribution, metabolism and excretion of a drug or its metabolites, or both. Pharmacodynamics, which in essence correlates the blood concentration of a drug with its effects, will be discussed elsewhere in this issue by Professor Hull. The emphasis of a pharmacokinetic approach is on the analysis of the rate and direction of a dynamic process and the dependency of that rate upon other simultaneous processes. The rates are usually expressions of mathematical relationships, and computers are widely used to generate these data. One of the problems with deriving a more accurate dosage regimen with muscle relaxants R. D. MILLER and more meaningful interpretation of the magnitude of neuromuscular blockade has been inaccessibility of muscle relaxant concentration at the active site. To help solve this problem, the technique of compartmental analysis has come into use. Feldman (1980), however, argues that making mathematical models to represent the complexities of the human body is seldom worthwhile. Perhaps confusion sometimes arises when one attempts to identify a compartment as an anatomical entity which it may not be. A compartment is denned kinetically as a pool in relationship to a drug concentration-time profile. For example, if a certain fraction of muscle relaxant were lost to some site per unit time, this site would represent a compartment regardless of whether it had anatomical or physiological significance. Thus, the amount of muscle relaxant in a compartment as a function of time can be assessed without knowing where that compartment is physically located. Some clinicians may be more comfortable with physiologically based models as have been used for the inhaled anaesthetics (Eger, 1964). As described by Stanski (personal communication), these models are limited because large numbers of RONALD D MILLER, M.D., Department of Anesthesia, University of California School of Medicine, Room S-436, San Francisco, California 94143, U.S.A /82/ S01.00 tissue samples are required for analysis of drug concentration. Furthermore, averages for organ size and blood flow must be assumed. A simpler approach is to characterize drug distribution and elimination using only the dose, plasma concentrations and time. Despite Feldman's (1980) reservations, a pharmacokinetic analysis is extremely important. For example, Katz (1971) has observed a variable response of patients to muscle relaxants. Much of the variability is just not inherent, but can be explained in part by pharmacokinetics. What diseases and physiological changes alter the rate at which the muscle relaxant leaves plasma and is eliminated? What diseases and physiological changes alter the sensitivity of the neuromuscular junction to muscle relaxants? If the answers to these questions were available, muscle relaxant dose could be more precise and much of the "variability" avoided. ANALYTICAL TECHNIQUES Until recently, pharmacokinetic data have not been available because analytical methods to measure muscle relaxant concentrations in blood and other body tissues were not available. However, assays for all non-depolarizing muscle relaxants and their antagonists have been developed. Horowitz and Spector (1973) developed a radioimmunoassay method for analysing tubocurarine that was later modified to measure metocurine concentrations in body tissues (Matteo and Khambatta, 1979). This technique had the advantage over the previously developed fluorimetric method because it had a greater sensitivity and did not require extractions from biological fluids. Sensitive and specific assays for neostigmine, pyridostigmine and edrophonium have been developed using high pressure liquid chromatography (De Ruyter, Cronnelly and Castagnoli, 1980). Pancuronium has proven to be a difficult compound to assay. Virtually all the pharmacokinetic studies of pancuronium have used the fluorimetric method Macmillan Publishers Ltd 1982

2 162 BRITISH JOURNAL OF ANAESTHESIA developed by Kersten, Meijer and Agoston (1973). This method can estimate concentrations greater than 1.5 jig ml" 1, but is not specific (Agoston et al., 1973), that is, the assay does not distinguish between unchanged pancuronium and its metabolites. Thus, when a pharmacokinetic analysis is performed, the investigators do not know the extent to which their plasma concentration reflects the metabolites rather than pancuronium itself. Paanakker and Van de Laar (in preparation) recently developed a high pressure liquid chromatography method to assay pancuronium. This technique is specific, but unfortunately is not especially sensitive. In the last few months in our laboratory, we have developed a mass spectrometry method for pancuronium and vecuronium (Org NC45), a new short-acting, non-depolarizing muscle relaxant. Although this technique is timeconsuming and tedious, it is specific in that it will distinguish pancuronium from its metabolites and is sensitive in that it will detect concentrations of ISOpgml" 1 or more. Although not directly clinically applicable, the reader should be aware of the problems and limitations of these assays without which a pharmacokinetic analysis would be impossible. GENERAL PHARMACOKINETICS Although various mathematical models have been used to characterize the pharmacokinetics of nondepolarizing muscle relaxants, four basic terms can be used to describe the data from these studies. The elimination half-life (T± f ) simply refers to that time necessary for the plasma concentration of muscle relaxant to decline by one-half during the elimination phase of pharamocokinetics.the distribution half-life (7^") refers to that time for the plasma concentration of muscle relaxant to decline by one-half during the distribution phase of pharmacokinetics. Although distribution and elimination are initially happening simultaneously, these two half-lives can be determined mathematically. The volume of distribution at steady state (V) is the sum of the volumes of the central and peripheral compartments. This term approximates the volume to which a muscle relaxant is distributed, although it does not refer to a specific anatomical entity. Clearance (Cl) refers to the volumes of plasrria from which the muscle relaxant is removed per unit time. Knowing the meaning of these terms will allow the reader to understand the clinical importance of just about any pharmacokinetic study of muscle relaxants B Time (mm) Time (mm) FIG. 1. Plasma concentration v. tune relationship of tubocuranne in patients with (B) and without (A) renal failure. The solid dark line represents the estimated mean population response for the dose and type of patient (from Sheiner et al., 1979) O = 0.5mgkg~'; A = 0.3mgkg~'.

3 PHARMACOKINETICS OF RELAXANTS 163 independent of how complicated the mathematics may appear to be. The rate of disappearance of muscle relaxant from blood is characterized by a rapid initial disappearance which is followed by a slower decay (fig. 1). Distribution to tissues is the major cause of the initial decrease, whereas the slower decay is a result of excretion primarily via the urine and bile (fig. 1). Because muscle relaxants are highly ionized, they do not cross all membranes and have a limited V". The initial volume of distribution usually ranges from 80 to 140mlkg"', which is not much larger than blood volume. V" usually ranges from 200 to 450mlkg" 1. This is in contrast to the lipid-soluble, unionized thiopentone which has a V* of about 2.0 litre kg" 1 SPECIFIC PHARMACOKINETIC CONCERNS Renal failure Generally, I would use that muscle relaxant which is the least dependent on renal excretion for its elimination when anaesthetizing patients with impaired or absence of renal function. Of the available muscle relaxants, suxamethonium is the only one not dependent on the kidney for its elimination. Although I commonly use suxamethonium in patients with renal failure, it obviously is not suitable for longer cases because of the development of a Phase II block. Of the nondepolarizing muscle relaxants, two short-acting muscle relaxants currently undergoing clinical trials are probably the least dependent on the kidney for their elimination. Only about 15-20% of an injected dose of vecuronium (Org NC 45) is eliminated in the urine (unpublished data). Thus the elimination half-life of even large doses (e.g. 0.28mgkg" 1 ) of vecuronium is only slightly prolonged in patients with no renal function (Fahey et al., 1981). Although not confirmed in man, in rats the major route of vecuronium's elimination appears to be the bile (unpublished data). Another new short-acting muscle relaxant, atracurium (Hunt, Hughes and Payne, 1980), may not depend on the kidney or liver for excretion because of Hoffman elimination, a form of spontaneous breakdown of the quaternary groups dependent on an alkaline ph. However, this route of metabolism of atracurium remains to be proven. Until these new short-acting muscle relaxants are available, suxamethonium appears to be the muscle relaxant of choice from a pharmacokinetic point of view in patients with renal failure. If one of the currently available non-depolarizing muscle relaxants is to be used, tubocurarine or fazadinium may be preferred to pancuronium, gallamine or metocurine. Meijer and others (1979) found tubocurarine to be less dependent on renal excretion than was metocurine. We believe tubocurarine is also less dependent on renal excretion than is pancuronium (Miller et al., 1977). Once again, this conclusion is tenuous because all studies with pancuronium were performed with the fluorimetric method which does not distinguish unchanged pancuronium from its metabolites. From a practical point of view, the neuromuscular response to nondepolarizing muscle relaxants is especially variable in patients with renal failure. For example, Somogyi, Shanks and Triggs (1977b) found a mean increase in duration of a pancuronium block of 81% in six patients with renal failure compared with patients with normal renal function. However, another four patients had a shortened neuromuscular block. This variability probably reflects the variable cardiovascular and general state of health of patients with renal function. The influence of renal failure also depends on the dose of muscle relaxant used. Even gallamine, which is practically 100% dependent on the kidney for elimination, has been given in small doses in patients undergoing bilateral nephrectomy without a prolonged block (White, de Weerd and Dawson, 1971). Obviously, with small doses, the block can be terminated by redistribution into inactive depots. Because these depots are small in volume, they rapidly become saturated and then primarily urinary excretion becomes the determining factor in the duration of neuromuscular blockade. This means that the margin of safety is enhanced if a drug which is not heavily dependent on the kidney for its elimination is used in patients with renal failure. Biliary or liver disease Pancuronium is the only non-depolarizing muscle relaxant which has been extensively studied in patients with biliary or liver disease from a pharmacokinetic point of view. Somogyi, Shanks and Triggs (1977a) found that the neuromuscular blockade and elimination half-life of pancuronium were prolonged in patients with extrahepatic biliary obstruction. Westra, Vermeer and others (1981) later confirmed these

4 164 BRITISH JOURNAL OF ANAESTHESIA observations and attributed the prolonged elimination half-life to an increased volume of distribution. In another study, Westra, Houwertjes and others (1981) also found that an increase in the plasma concentration of bile salts will inhibit hepatic uptake of both vecuronium (Org NC45) and pancuronium. Duvaldestin, Agoston and others (1978) found that, in patients with hepatic cirrhosis, the volume of distribution was increased and the elimination half-life of pancuronium prolonged. Because pancuronium is distributed to a larger volume in patients with cirrhosis, a larger dose of pancuronium may well be required to achieve a given neuromuscular blockade. However, once that neuromuscular blockade had been achieved, it should last longer because elimination is delayed. Monitoring and recording the degree of neuromuscular blockade would determine whether these pharmacokinetic predictions are correct. Age Many studies in animals clearly document that neuromuscular junctions degenerate (e.g. increasing degree of denervation) with age, which would alter this pharmacodynamic response to muscle relaxants. Other findings indicate that the pharmacokinetics of muscle relaxants and their antagonists should be altered by ageing (Miller, 1981). Ageing decreases renal function, which may lead to decreased drug elinination and hence increased blood concentrations. Renal perfusion decreases 1.5% per year after maturity; renal blood flow in a 65-year-old patient is half that of a younger patient. This decrease is reflected by a corresponding decrease in glomerular filtration rate and urea clearance. Drug metabolism may be decreased in the elderly because of decreased hepatic concentrations or because of reduced hepatic circulation. Plasma binding of drugs is often decreased in the elderly, thereby giving higher blood concentrations of free (active) drug. In addition to a reduction in overall weight, the elderly tend to have a decrease in the percentage of total body water and lean body mass and an increase in the percentage of fat. These conditions will decrease distribution volumes and distribution half-life of neuromuscular blocking drugs and their antagonists, which may result in a higher concentration of drug at the neuromuscular junction. Only one report examines the indications that ageing alters the pharmacokinetics and pharmacodynamics of neuromuscular blocking drugs. McLeod, Hull and Watson (1979) found that ageing decreased the clearance of pancuronium from plasma. Unfortunately, neuromuscular ' blockade per se was not monitored; therefore, a pharmacodynamic analysis could not be performed. Whether the decreased clearance from plasma altered (prolonged) the duration of neuromuscular blockade was not established. More < recently, Duvaldestin and colleagues (1980) } concluded that, because of this prolonged elimination half-life, elderly patients (75-86 yr) had a duration of neuromuscular blockade from pancuronium nearly twice as long as their younger counterparts (25-55 yr). At the other end of the age scale, only Fisher * and colleagues (1982) have attempted to perform a pharmacokinetic and dynamic analysis of nondepolarizing muscle relaxants, namely tubocurarine, in children. They concluded that neonates and infants have an increased sensitivity (lower blood concentration of tubocurarine to achieve a given neuromuscular blockade) to tubocurarine compared with adult patients. ~* However, because of a larger volume of, distribution in neonates and infants, the required initial dose does not vary from that of adults, but, because of a longer elimination half-life, the duration of tubocurarine neuromuscular blockade is probably prolonged. Hypothermia In cats, hypothermia was found to prolong both tubocurarine- (Ham, Miller and Benet, 1978) and pancuronium-induced neuromuscular blockade (Miller et al., 1978). Blockades induced by both ^ relaxants are prolonged because of delayed urinary and biliary excretion. With pancuronium, the block may be prolonged also because of decreased metabolism to inactive metabolites (Miller et al., 1978). More recently, Ham and colleagues (1982) found in man that hypothermia had little effect on the pharmacokinetics of tubocurarine. However, their temperature only ranged from a mean of 31.8 C to 35.8 C. A larger temperature range, as was used in the animal studies cited above, may have demonstrated a pharmacokinetic dependence on temperature. Despite the apparent lack of influence of

5 PHARMACOKINETICS OF RELAXANTS 165 hypothermia on the pharmacokinetics of tubocurarine in man, recovery time (25% to 75 O recovery of control twitch tension) was prolonged 82 0 by hypothermia as measured by twitch tension but not by the electromyograph. That mechanical recovery of neuromuscular blockade is prolonged by hypothermia and electrical recovery is not, suggests that neuromuscular transmission per se is not significantly affected by hypothermia, at least within the temperature range stated above. These results suggest that hypothermia affects the mechanical properties of the muscle itself. In fact, Ham and others (1982) had one patient who had marked prolongation of tubocurarine neuromuscular blockade which could not be fully antagonized by neostigmine and necessitated mechanical ventilation after operation until body temperature returned towards normal. They also found a tendency for the equilibrium between serum tubocurarine concentration and paralysis to be prolonged by hypothermia. This suggests that hypothermia reduces blood flow to the neuromuscular junction, delaying the onset of paralysis after administration of tubocurarine. However, other than the delayed half-time for equilibrium and differential effect on the twitch tension v. electromyograph, a decrease in body temperature to 31.9 C did not significantly alter the pharamacokinetics of tubocurarine. Cerebrosfnnalfluidand anaesthetic requirement Despite being ionized, non-depolarizing muscle relaxants administered i.v. do pass in the cerebrospinal fluid in amounts which may be clinically significant (Rao and Venkatakrishna- Bhatt, 1975; Matteo, Pua and Khambatta, 1977). Forbes, Cohen and Eger (1979) found that pancuronium administered i.v. reduced halothane anaesthetic requirement by 25%. Whether this was a central effect or was a result of abolition of muscle spindle afferent input was not clarified. The specific correlation between cerebrospinal fluid concentration and anaesthetic effect remains to be established. Placental transfer Despite being highly ionized, muscle relaxants clearly cross the placental barrier in small amounts (Poppers and Finster, 1971; Kivalo and Saarikoski, 1976; Duvaldestin, Demetriou et al., 1978). However, these small concentrations have not been shown to have any direct effect on the fetus. Duvaldestin, Demetriou and others (1978) found the cord vein to maternal concentration ratio of pancuronium averaged 0.22, which increased with a greater induction-delivery ratio. The mean cord arterial to cord venous ratio of pancuronium was 0.66 which they felt indicated fetal drug uptake. Nevertheless, all the Apgar scores of the babies were better than 9. Anaesthetics (table 1) Despite differing effects on renal and liver function, the choice of general anaesthetic has little or no influence on the pharmacokinetics of tubocurarine. Although this is the only muscle relaxant which has been studied, presumably this conclusion applies to other non-depolarizing muscle relaxants (Stanski et al., 1979, 1980). The ability of inhaled anaesthetics to augment a nondepolarizing neuromuscular blockade is a pharmacodynamic one that is, the blood concentration of muscle relaxants required to produce paralysis is decreased by inhaled TABLE I. Pharmacokinettcs of lubocurartne during nitrous oxide narcotic, halothane and enflurane anaesthesia (mean± SDJ (data takenfrom Stanski and others (1979,1980)). \Endtidal concentrations; K, = volume of central compartment; T^Keo = half time for equilibrium between plasma concentration and paralysis. See text for definition of other symbols Anaesthetic Nitrous oxidenarcotic HaJothane % %t Enfluranc %} No (min 6.2± ±2 4 48± ±2.6 7"/ (min) 119±66 104±56 84±69 101±48 (litre kg" 1 ) 0.10± ± ± ±0.07 V" a (litre kg-') (ml kg" 1 nun"') 0.30± ± ± ± ± ± ± ±0.3 T t Keo (min) 4.7 ± ±l ±2.5 49±18

6 166 BRITISH JOURNAL OF ANAESTHESIA anaesthetics compared with nitrous oxidenarcotic techniques. The only possible pharmacokinetic change was a longer equilibration halftime between plasma concentration and pharmacological effect with halothane v. nitrous oxide-narcotic anaesthetic. This probably is because of decreased muscle perfusion with halothane. Protein binding The extent to which non-depolarizing muscle relaxants bind to plasma proteins has been widely studied with little agreement. Between 30% and 50% of tubocurarine is bound to albumin and gamma globulin (Ghoneim et al., 1973; Meijer et al., 1979). While pancuronium was originally thought not to be extensively bound to plasma protein, Thompson (1976) found that 87% of pancuronium was bound to gamma globulin and albumin. If so, then only 13% of pancuronium would be unbound and active. The clinical significance of protein binding is unclear. Theoretically, increasing binding would effectively increase the volume of distribution thus reducing free drug available at the site of action. Increased binding might also reduce renal elimination of the drug, since only free drug is filtered at the glomerulus. Thompson (1976) hypothesized that the number of binding sites may remain constant as plasma protein concentration increases if proteins bind with their own binding sites. Furthermore, binding of muscle relaxants with previously mentioned other sites such as cartilage and chondroitin sulphate may be quantitatively and qualitatively as important as plasma protein binding (Olsen, Chan and Riker, 1975; Weitering et al., 1977). Thus, it is difficult to predict the effect of protein binding on muscle relaxant pharmacokinetics. However, protein binding overall should not be of significant clinical concern. Even in patients with renal and hepatic disease, which are diseases well known to have altered protein binding to other drugs, the protein binding of tubocurarine is not altered (Ghoneim et al., 1973). REFERENCES Agoston, S, Vcrmeer, G A, Kersten, V W., and Mci)er, D. K. F. (1973) The fate of pancuronium bromide in man Acta Anaesthesiol Scand, 17, 267. De Ruyter, M. G. M, Cronnelly, R. and Castagnoh, N. )r (1980). Reversed-phase ion-pair liquid chromatography of quaternary ammonium compounds. J Chromatogr., 183, 193 Duvaldesun, P, Agoston, S., Henzel, E., Kersten, V. W., and Desmonts, J M (1978) Pancuroruum pharmacokineucs in patients with liver cirrhosis. Br.J. Anaesth., 50, 1131 Berger, J L., Saada, ]., and Desmonts, J M (1980). Pancuronium' pharmacokinetics and pharmacodynanucs in the elderly Anesthesiology, 53, S284 Demetnou, M., Hanzel, D., and Desmonts, J M (1980). The placental transfer for pancuronium and its pharmacokinetics during Caesarcan section Acta Anaesthesiol. Scand, 22, 327 Eger, E I II (1964). Respiratory and circulatory factors in uptake and distribution of volatile anaesthetic agents Br J. Anaesth., 36, 155. Fahey, M R, Morris, R. B, Miller, R. D, Nguyen, T. L., and Upton, R A. (1981). Pharmacokineucs of Org NC45 (Norcuron) in patients with and without renal failure. Br. J Anaesth., 53, Feldman, S A. (1980). (Letter to the editor ) Sur. Anesth., 24, 266. Fisher, D. M., O'Keefe, C, Stanski, D. R, Cronnelly, R., Miller, R. D, and Gregory, G A. (1982). Pharmacokinetics and pharmacodynamics of d-tubocuranne children and adults. Anesthesiology (in press). Forbes, A. R., Cohen, N H, and Eger, E. I. II (1979) Pancuronium reduces halothane requirement in man. Anesthesiology, 58, 497. Ghoneim, M M., Kramer, S. E., Bannow,, R., Pahdya, M S, and Routh, J 1.(1973). Binding of d-tubocuranne to plasma in normal man and in patients with hepatic or renal disease. Anesthesiology, 39, 410. Ham, J, Miller, R. D., and Benet, L Z. (1978) Pharmacokineucs and pharmacodynamics of d-tubocuranne hypothermia in the cat. Anesthesiology, 49, 324. Stanski, D R, Newfield, P., and Miller, R. D (1982) Pharmacokinetics and dynamics of d-tubocuranne during hypothermia in man Anesthestology, (in press) Horowitz, P E., and Spector, S (1973). Determination of d- tubocurarine concentration by immunoassay J Pharmacol. Exp. Ther., 185, 94 Hunt, T M., Hughes, R., and Payne, J. P. (1980). Preliminary studies with atracunum in anaesthetized man. Br. J. Anaesth., 52, 238. Katz, R L. (1971) Clinical neuromuscular pharmacology of pancuronium Anesthesiology, 34, 550 Kersten, V. W., Meijer, D. K. F, and Agoston, S. (1973). Fluonmetnc and chromatographic determinauon of pancuronium bromide and its metabolites in biological matcnals. Clin. Chim. Acta, 44, 59. Kivalo, I., and Saankoski, S. (1976) Placental transfer of 14 C- dimethyltubocuranne during Caesarean secuon Br J Anasth, 48, 239. Matteo, R. S., and Khambatta, H J. (1979). Relation of serum metocunne concentration to neuromuscular blockade in man Anesthesiology, 57, S287 Pua, E. K, and Khambatta, H. J (1977). Cerebrospinal fluid levels of d-rubocuranne in man. Anesthesiology, 46, 396. McLeod, K., Hull, C. J, and Watson, M J. (1979). Effects of ageing on the pharmacokinetics of pancuroruum. Br. J Anaesth., 51, 435

7 v PHARMACOKINETICS OF RELAXANTS 167 Meijer, D K. F, Weitenng, J. G., Vermeer, G. A, and Scaf, A. H. J. (1979) Comparative pharmacokinencs of d-tubo- I curarine and metocurine in man. Anesthestology, 51, 402. Miller, R. D. (1981). Anesthesia for the elderly, in Anesthesia ^ (cd. R. D. Miller), p New York Churchill- Livingstone *- Agoston, S., Van der Pol, F., Booij, L H. D J., Cml, J F, and Ham, J. (1978). Hypothermia and the pharmacokineucs and pharamacodynamics of pancuronium in the cat. r J. Pharmacol. Exp. Ther., 207, 532 Matteo, R S., Benet, L. Z., and Sohn, Y. J. (1977). The pharmacokinetics of d-tubocuranne in the man with and without renal failure. J. Pharmacol. Exp. Ther., 202, 1. Olsen, G. D., Chan, E. M., and Riker, W. K. (1975) Binding i- of d-tubocurarine, di-(methyl 14 C) ether iodine and other amines to cartilage, chondroitin sulfate and human plasma protein. J Pharmacol. Exp. Ther., 195, 242 Poppers, P J., and Finster, M. (1971). The use of muscle relaxants in obstetrics, in Muscle Relaxants, p Amsterdam: Exerpta Medica. Rao, L. N., and Venkatakrishna-Bhatt, H (1975). Role of thiopentone, nitrous oxide and relaxant anaesthesia in. causing the syndrome of postoperative paralysis in man. Anaesthesut, 24, 73. Sheincr, L B, Stanski, D. R, Vozeh, S. Miller, R. D, and Ham, J. (1979). Simultaneous modelling of pharmacokinetics and pharmacodynamics: application to d- tubocuranne Cltn Pharmacol Ther., 25, 358. Somogyi, A. A., Shanks, C. A., and Tnggs, E. J. (1977a) Disposition kinetics of pancuronium bromide in patients with total biliary obstruction Br. J Anaesth., 49, 1103 *" (1977b). The effects of renal failure on the disposition and neuromuscular blocking action of pancuronium bromide. Eur. J. Cltn. Pharmacol., 12, 23. Stanski, D. R., Ham, J. Miller, R. D., and Sheincr, L B. (1979). Phannacokinetics and pharmacodynamics of d- tubocuranne during nitrous oxide-narcotic and halothane anesthesia in man. Anesthesiology, 51, 235. (1980) Time-dependent increase in ** sensitivity to d-tubocurarine during enflurane anesthesia in man. Anesthestology, 52, 483. Thompson, J M. (1976). Pancuronium binding by serum proteins Anaesthesia, 31, 219 Weitenng, J. G., Lammers, W, Meijer, D. K. F, and Mulder, G. J. (1977). Localization of d-tubocuranne in rat liver lysosomes. Arch. Pharmacol., 299, 277. Westra, P., Houwertjes, M. C, Wesseling, H, and Meijer, "^ D. K. F. (1981). Pile salts and neuromuscular blocking - agents. Br. J Anaesth., 53, 407. Vermeer, G. A., de Lange, A. R., Scaf, A. H. J., Meijer, D. K F., and Wesseling, H. (1981). Hepatic and renal disposition of pancuronium and gallamine in patients with extrahepatic cholestasis. Br. J. Anaesth., 53, 331. White, R. D., de Wcerd, J. H., and Dawson, B. (1971). Gallamine in anesthesia for patients with chronic renal -" failure unergoing bilateral nephrectomy. Anesth. Analg (Cleve.), 50, 11