" / would have everie man write what he knowes and no
BRITISH
JOURNAL
OF
more."—MONTAIGNE
ANAESTHESIA
VOLUME 68, No. 6
JUNE 1992
EDITORIAL NEUROMUSCULAR BLOCKING DRUGS AND RENAL FAILURE
action in renal failure is gallamine. The principal reason for this is that gallamine is metabolized to such a small extent that it relies almost solely on the kidney for elimination and therefore for termination of effect [6]. Theoretically, its action would be prolonged almost infinitely in patients with absent renal function, although in practice an approximately six-fold increase in terminal half-life has been reported [7]. Gallamine is generally regarded as being contraindicated in patients with impaired renal function. The other long established neuromuscular blocking agents are affected to a lesser extent. The plasma clearance of pancuronium is decreased approximately 33 % [8] to 50 % [9] of that of normal patients in the presence of renal failure. The elimination half-life of tubocurarine has been reported to be increased from 232 min in normal patients to 330 min in renal failure patients [10]. Alcuronium is also eliminated more slowly in patients with impaired renal function [11-13]. None of these neuromuscular blocking agents would seem, therefore, to be ideal for use in patients with impaired renal function. It is not only the elimination characteristics of a drug which dictate its usefulness in renal failure, but also many of its additional effects. Renal failure patients commonly have a number of other disease processes which might result from, or be the causative factor of, the renal failure. It is important, therefore, to choose a drug with as few undesirable side effects as possible. In the early 1980s, two new intermediate-acting, non-depolarizing neuromuscular blocking agents, atracurium and vecuronium, were introduced, and it rapidly became apparent that both were superior to any of the previously available neuromuscular blocking agents for use in renal failure. Atracurium has one notable advantage which sets it apart from all the other neuromuscular blocking agents, namely that it is spontaneously degraded in the body to metabolites which are devoid of neuromuscular blocking activity. There is one metabolite, laudanosine, which may produce cerebral excitation in laboratory animals. Because laudanosine is renally excreted, this metabolite, but not its parent drug, accumulates and much debate has centred around the possibility of significant adverse effects which might result from accumulation of laudanosine in renal failure. This debate is not yet concluded. The pharmacokinetics of atracurium are nevertheless unaffected by renal failure [14] and a dose of atracurium has the same duration of action in a renal failure patient as in a normal patient [14].
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 8, 2015
In patients who have impaired renal function, the use of many drugs poses problems in view of the reliance of most drugs on the kidney for final elimination. The neuromuscular blocking agents are no exception; all are ionized, water-soluble compounds and, as a result, would be expected to be filtered freely at the glomerulus and not to be reabsorbed. Thus one might expect them to rely principally upon intact renal function for termination of effect. Only the free molecules are filtered, not those bound to plasma proteins. However, the neuromuscular blocking drugs are not greatly bound to plasma proteins (up to about 50%) [1], and the rate of equilibration between bound and unbound forms is very rapid; it is unlikely, therefore, that plasma protein binding, or any changes in this binding, have any significant effect on the renal excretion of the neuromuscular blocking agents. If many of the older established texts in the specialty are consulted, it may be seen that caution was advised in all cases when using a neuromuscular blocking agent in a patient with impaired renal function. The principal reason advanced was the risk of postoperative "recurarization". The problem, as it was perceived at the time, was that the elimination of the neuromuscular blocking agent was considerably reduced in renal failure, to the extent that its action was extended significantly into the postoperative period. The argument then continued to suggest that as the effect of the antagonist began to wane there would be a reappearance of neuromuscular block [2]. Subsequent evidence has cast doubt on this reasoning by demonstrating that the anticholinesterases also rely upon the kidney to some extent for elimination, and that their duration of action is prolonged also in renal failure [3-5]. Nevertheless, difficulties or delays in antagonism of block, or postoperative weakness occurred. While it is true that the neuromuscular blocking agents are excreted renally, the kidney is not, of course, the only pathway for removal of active molecules from blood (and hence, by implication, from their site of action, the "active'biophase"). Redistribution plays an important role in the reduction of plasma concentrations, particularly in the early phase after administration of a bolus dose of the agent. Alternative routes of elimination exist for many of the agents, including in particular, hepatic metabolism and biliary excretion. All the neuromuscular blocking agents are subject, to a greater or lesser degree, to metabolic or degradative processes which result ultimately in a molecule which is pharmacologically inactive. The agent which comes foremost into every anaesthetist's mind with respect to prolongation of
546
amount. Administration of an anticholinesterase inhibits plasma cholinesterase in addition to acetylcholinesterase. It is likely, therefore, that the rate of destruction of mivacurium is reduced at the same time as pharmacological reversal progresses at the neuromuscular junction. It may transpire when mivacurium is in clinical use, therefore, that it is preferable to avoid anticholinesterases when antagonizing neuromuscular block. B. J. Pollard Manchester REFERENCES 1. Hunter JM. Resistance to non-depolarizing neuromuscular blocking agents. British Journal of Anaesthesia 1991; 67: 511-514. 2. Miller RD, Cullen DJ. Renal failure and postoperative respiratory failure: Recurarization? British Journal of Anaesthesia 1976; 48: 253-256. 3. Cronnelly R, Stanski DR, Miller RD. Renal function and the pharmacokinetics of neostigmine in anesthetized man. Anesthesiology 1979; 51: 222-226. 4. Cronnelly R, Stanski DR, Miller RD, Sheiner LB. Pyridostigmine kinetics with and without renal function. Clinical Pharmacology and Therapeutics 1980; 28: 78-81. 5. Morris RB, Cronnelly R, Miller RB. Pharmacokinetics of edrophonium in anephric and renal transplant patients. British Journal of Anaesthesia 1981; 53: 131-134. 6. Agoston S, Venneer GA, Kersten UW. A preliminary investigation of the renal and hepatic elimination of gallamine triethiodide in man. British Journal of Anaesthesia 1978; 50: 345-351. 7. Ramzan MI, Shanks CA, Triggs EJ. Gallamine disposition in surgical patients with chronic renal failure. British Journal of Clinical Pharmacology 1981; 12: 141-147. 8. McLeod K, Watson MJ, Rawlins MD. Pharmacokinetics of pancuronium in patients with normal and impaired renal function. British Journal of Anaesthesia 1976; 48: 341-345. 9. Somogyi AA, Shanks CA, Triggs EJ. The effect of renal failure on the disposition and neuromuscular blocking action of pancuronium bromide. European Journal of Clinical Pharmacology 1977; 12: 23-29. 10. Miller RD, Matteo RD, Benet LZ, Sohn YJ. The pharmacokinetics of d-tubocurarine in man with and without renal failure. Journal of Pharmacology and Experimental Therapeutics 1977; 202: 1-7. 11. Smith CL, Hunter JM, Jones RS. Prolonged paralyis following an infusion of alcuronium in a patient with renal dysfunction. Anaesthesia 1987; 42: 522-525. 12. Hofer R, Krenn J, Pfeiffer G, Steinbereithner K. Untersuchungen zer ausscheidung von diallyl-nor-toxiferin bei nierentransplantation. Anaesthesist 1969; 18: 304-308. 13. Cozanitis D , Haapanen E. Studies on muscle relaxants during haemodialysis. Acta Anaesthesiologica Scandinavica 1979; 23: 225-234. 14. Hunter JM, Jones RS, Utting JE. U»e of atracurium in patients with no renal function. British Journal of Anaesthesia 1982; 54: 1251-1258. 15. Bevan DR, Donati F, Gyasi H. Vecuronium in renal failure. Canadian Anaesthetists Society Journal 1984; 31: 491-496. 16. Segredo V, Matrhay MA, Sharma ML, Gruenke CD, Caldnutt JE, Miller RD. Prolonged neuromuscular blockade after long-term administration of vecuronium in two critically ill patients. Anesthesiology 1990; 72: 566-570. 17. Slater RM, Pollard BJ, Doran BRH. Prolonged neuromuscular blockade with vecuronium in renal failure. Anaesthesia 1988; 43: 250-251. 18. Meistelman C, Lienhart D , Leveque C. Pharmacology of vecuronium in patients with end stage renal failure. Anesthesiology 1983; 59: A293. 19. Caldwell JE, Heier T, Kim JB, Lynam DP, Farhey MR, Miller RD. Comparison of the neuromuscular block induced by mivacurium, suxamethonium or atracurium during nitrous oxide oxide-fentanyl anaesthesia. British Journal of Anaesthesia 1989; 63: 393-399.
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 8, 2015
Vecuronium is excreted renally, but also metabolized fairly rapidly. It is also taken up in various tissues of the body and has a large volume of distribution. Although the effect of renal failure on vecuronium is small, there is a gradual increase in duration of action with repeated doses, and this cumulation is presumed to be a result of gradual saturation of peripheral storage sites [15]. There is now no doubt that prolonged neuromuscular block may result from the use of an infusion or from larger doses of vecuronium in patients with severely impaired renal function [16, 17]. Indeed, it is possible to demonstrate a slight, yet significant increase in duration of action after a single dose in renal failure patients [18]. The possibility has been raised that it is accumulation of the 3-desacetyl metabolite more than the parent compound which contributes to this effect [16]. There are several new drugs undergoing assessment. Mivacurium represents a significant advance in that it has a shorter duration of effect than either atracurium or vecuronium [19,20]. This should make it of significant value for short surgical cases. Its action may be sufficiently brief that potentially it does not require antagonism. Mivacurium, in common with atracurium and vecuronium, has minimal cardiovascular side effects [21]. On these counts, it would seem to be of potential value in the renal patient. Mivacurium is metabolized by plasma cholinesterase [22] (not acetylcholinesterase) to substances which are devoid of neuromuscular action, and does not rely upon renal excretion for its inactivation. It is interesting to note that the rate of hydrolysis by plasma cholinesterase (which is in excess) depends upon the concentration of mivacurium in the plasma. Thus the greater the concentration of mivacurium, the more rapid its breakdown and, unlike the case with other neuromuscular blocking agents, increasing the dose has only a small effect upon the duration of action. Clearly, the breakdown of mivacurium would be affected by any factor which interferes with either the activity or the quantity of plasma cholinesterase (e.g. anticholinesterases). The destruction of mivacurium is reduced also (hence its duration of action is increased) in patients with atypical plasma cholinesterase [23]. Thus one might expect it not to be affected by renal impairment. Phillips and Hunter, in the May issue of this Journal [24], described a comparison of the characteristics of mivacurium in patients with no renal function with those of normal patients. They showed that the action of mivacurium was prolonged in the anephric patient, but not to any great extent. They suggested that there was probably no change in elimination directly as a result of the renal failure, but that there was a decrease in plasma cholinesterase activity, which is a common finding in renal failure. It would appear, therefore, that mivacurium is safe to use in renal failure patients, although a small prolongation of effect should be expected. A further observation was also made by Phillips and Hunter [24]. They noted that the use of an antichounesterase accelerated the recovery of a mivacurium neuromuscular block by only a small
BRITISH JOURNAL OF ANAESTHESIA
EDITORIAL 20. Ali HH, Savarese JJ, Embrce PB, Basta SJ, Stout RG, Bottros LH, Weakly JN. Clinical phannacology of mivacunum chloride (BW109OU) infusion: comparison with vecuronium and atracurium. British Journal of Anaesthesia 1988; 61: 541-546. 21. From RP, Pearson KS, Choi WW, Abou-Donia M, Sokod MD. Ncuromuscular and cardiovascular effects of mivacurium chloride (BM109OU) during nitrous oxidc-fentanylthiopentonc and nitrous oxide-halothane anaesthesia. British Journal of Anaesthesia 1990; 64: 193-198. 22. Cook DR, Stiller RL, Weakly JN, Cnakravorti S, Brandom
547 BW, Welch RM. In vitro metabolism of mivacurium chloride (BM109OU) and succinylcholine. Anesthesia and Analgesia 1989; 68: 425-456. 23. Ostergaard D, Jensen F, Jensen E, Viby-Mogensen J. Influence of plasma cholincsterase activity on recovery from mivacurium induced neuromuscular blockade. Acta Anaesthesiologica Scandinavica 1989; 33: A165. 24. Phillips BJ, Hunter JM. Use of mivacurium chloride by constant infusion in the anephric patient. British Journal of Anaesthesia 1992; 68: 492^98.
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 8, 2015
BRITISH
JOURNAL
OF
more."—MONTAIGNE
ANAESTHESIA
VOLUME 68, No. 6
JUNE 1992
EDITORIAL NEUROMUSCULAR BLOCKING DRUGS AND RENAL FAILURE
action in renal failure is gallamine. The principal reason for this is that gallamine is metabolized to such a small extent that it relies almost solely on the kidney for elimination and therefore for termination of effect [6]. Theoretically, its action would be prolonged almost infinitely in patients with absent renal function, although in practice an approximately six-fold increase in terminal half-life has been reported [7]. Gallamine is generally regarded as being contraindicated in patients with impaired renal function. The other long established neuromuscular blocking agents are affected to a lesser extent. The plasma clearance of pancuronium is decreased approximately 33 % [8] to 50 % [9] of that of normal patients in the presence of renal failure. The elimination half-life of tubocurarine has been reported to be increased from 232 min in normal patients to 330 min in renal failure patients [10]. Alcuronium is also eliminated more slowly in patients with impaired renal function [11-13]. None of these neuromuscular blocking agents would seem, therefore, to be ideal for use in patients with impaired renal function. It is not only the elimination characteristics of a drug which dictate its usefulness in renal failure, but also many of its additional effects. Renal failure patients commonly have a number of other disease processes which might result from, or be the causative factor of, the renal failure. It is important, therefore, to choose a drug with as few undesirable side effects as possible. In the early 1980s, two new intermediate-acting, non-depolarizing neuromuscular blocking agents, atracurium and vecuronium, were introduced, and it rapidly became apparent that both were superior to any of the previously available neuromuscular blocking agents for use in renal failure. Atracurium has one notable advantage which sets it apart from all the other neuromuscular blocking agents, namely that it is spontaneously degraded in the body to metabolites which are devoid of neuromuscular blocking activity. There is one metabolite, laudanosine, which may produce cerebral excitation in laboratory animals. Because laudanosine is renally excreted, this metabolite, but not its parent drug, accumulates and much debate has centred around the possibility of significant adverse effects which might result from accumulation of laudanosine in renal failure. This debate is not yet concluded. The pharmacokinetics of atracurium are nevertheless unaffected by renal failure [14] and a dose of atracurium has the same duration of action in a renal failure patient as in a normal patient [14].
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 8, 2015
In patients who have impaired renal function, the use of many drugs poses problems in view of the reliance of most drugs on the kidney for final elimination. The neuromuscular blocking agents are no exception; all are ionized, water-soluble compounds and, as a result, would be expected to be filtered freely at the glomerulus and not to be reabsorbed. Thus one might expect them to rely principally upon intact renal function for termination of effect. Only the free molecules are filtered, not those bound to plasma proteins. However, the neuromuscular blocking drugs are not greatly bound to plasma proteins (up to about 50%) [1], and the rate of equilibration between bound and unbound forms is very rapid; it is unlikely, therefore, that plasma protein binding, or any changes in this binding, have any significant effect on the renal excretion of the neuromuscular blocking agents. If many of the older established texts in the specialty are consulted, it may be seen that caution was advised in all cases when using a neuromuscular blocking agent in a patient with impaired renal function. The principal reason advanced was the risk of postoperative "recurarization". The problem, as it was perceived at the time, was that the elimination of the neuromuscular blocking agent was considerably reduced in renal failure, to the extent that its action was extended significantly into the postoperative period. The argument then continued to suggest that as the effect of the antagonist began to wane there would be a reappearance of neuromuscular block [2]. Subsequent evidence has cast doubt on this reasoning by demonstrating that the anticholinesterases also rely upon the kidney to some extent for elimination, and that their duration of action is prolonged also in renal failure [3-5]. Nevertheless, difficulties or delays in antagonism of block, or postoperative weakness occurred. While it is true that the neuromuscular blocking agents are excreted renally, the kidney is not, of course, the only pathway for removal of active molecules from blood (and hence, by implication, from their site of action, the "active'biophase"). Redistribution plays an important role in the reduction of plasma concentrations, particularly in the early phase after administration of a bolus dose of the agent. Alternative routes of elimination exist for many of the agents, including in particular, hepatic metabolism and biliary excretion. All the neuromuscular blocking agents are subject, to a greater or lesser degree, to metabolic or degradative processes which result ultimately in a molecule which is pharmacologically inactive. The agent which comes foremost into every anaesthetist's mind with respect to prolongation of
546
amount. Administration of an anticholinesterase inhibits plasma cholinesterase in addition to acetylcholinesterase. It is likely, therefore, that the rate of destruction of mivacurium is reduced at the same time as pharmacological reversal progresses at the neuromuscular junction. It may transpire when mivacurium is in clinical use, therefore, that it is preferable to avoid anticholinesterases when antagonizing neuromuscular block. B. J. Pollard Manchester REFERENCES 1. Hunter JM. Resistance to non-depolarizing neuromuscular blocking agents. British Journal of Anaesthesia 1991; 67: 511-514. 2. Miller RD, Cullen DJ. Renal failure and postoperative respiratory failure: Recurarization? British Journal of Anaesthesia 1976; 48: 253-256. 3. Cronnelly R, Stanski DR, Miller RD. Renal function and the pharmacokinetics of neostigmine in anesthetized man. Anesthesiology 1979; 51: 222-226. 4. Cronnelly R, Stanski DR, Miller RD, Sheiner LB. Pyridostigmine kinetics with and without renal function. Clinical Pharmacology and Therapeutics 1980; 28: 78-81. 5. Morris RB, Cronnelly R, Miller RB. Pharmacokinetics of edrophonium in anephric and renal transplant patients. British Journal of Anaesthesia 1981; 53: 131-134. 6. Agoston S, Venneer GA, Kersten UW. A preliminary investigation of the renal and hepatic elimination of gallamine triethiodide in man. British Journal of Anaesthesia 1978; 50: 345-351. 7. Ramzan MI, Shanks CA, Triggs EJ. Gallamine disposition in surgical patients with chronic renal failure. British Journal of Clinical Pharmacology 1981; 12: 141-147. 8. McLeod K, Watson MJ, Rawlins MD. Pharmacokinetics of pancuronium in patients with normal and impaired renal function. British Journal of Anaesthesia 1976; 48: 341-345. 9. Somogyi AA, Shanks CA, Triggs EJ. The effect of renal failure on the disposition and neuromuscular blocking action of pancuronium bromide. European Journal of Clinical Pharmacology 1977; 12: 23-29. 10. Miller RD, Matteo RD, Benet LZ, Sohn YJ. The pharmacokinetics of d-tubocurarine in man with and without renal failure. Journal of Pharmacology and Experimental Therapeutics 1977; 202: 1-7. 11. Smith CL, Hunter JM, Jones RS. Prolonged paralyis following an infusion of alcuronium in a patient with renal dysfunction. Anaesthesia 1987; 42: 522-525. 12. Hofer R, Krenn J, Pfeiffer G, Steinbereithner K. Untersuchungen zer ausscheidung von diallyl-nor-toxiferin bei nierentransplantation. Anaesthesist 1969; 18: 304-308. 13. Cozanitis D , Haapanen E. Studies on muscle relaxants during haemodialysis. Acta Anaesthesiologica Scandinavica 1979; 23: 225-234. 14. Hunter JM, Jones RS, Utting JE. U»e of atracurium in patients with no renal function. British Journal of Anaesthesia 1982; 54: 1251-1258. 15. Bevan DR, Donati F, Gyasi H. Vecuronium in renal failure. Canadian Anaesthetists Society Journal 1984; 31: 491-496. 16. Segredo V, Matrhay MA, Sharma ML, Gruenke CD, Caldnutt JE, Miller RD. Prolonged neuromuscular blockade after long-term administration of vecuronium in two critically ill patients. Anesthesiology 1990; 72: 566-570. 17. Slater RM, Pollard BJ, Doran BRH. Prolonged neuromuscular blockade with vecuronium in renal failure. Anaesthesia 1988; 43: 250-251. 18. Meistelman C, Lienhart D , Leveque C. Pharmacology of vecuronium in patients with end stage renal failure. Anesthesiology 1983; 59: A293. 19. Caldwell JE, Heier T, Kim JB, Lynam DP, Farhey MR, Miller RD. Comparison of the neuromuscular block induced by mivacurium, suxamethonium or atracurium during nitrous oxide oxide-fentanyl anaesthesia. British Journal of Anaesthesia 1989; 63: 393-399.
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 8, 2015
Vecuronium is excreted renally, but also metabolized fairly rapidly. It is also taken up in various tissues of the body and has a large volume of distribution. Although the effect of renal failure on vecuronium is small, there is a gradual increase in duration of action with repeated doses, and this cumulation is presumed to be a result of gradual saturation of peripheral storage sites [15]. There is now no doubt that prolonged neuromuscular block may result from the use of an infusion or from larger doses of vecuronium in patients with severely impaired renal function [16, 17]. Indeed, it is possible to demonstrate a slight, yet significant increase in duration of action after a single dose in renal failure patients [18]. The possibility has been raised that it is accumulation of the 3-desacetyl metabolite more than the parent compound which contributes to this effect [16]. There are several new drugs undergoing assessment. Mivacurium represents a significant advance in that it has a shorter duration of effect than either atracurium or vecuronium [19,20]. This should make it of significant value for short surgical cases. Its action may be sufficiently brief that potentially it does not require antagonism. Mivacurium, in common with atracurium and vecuronium, has minimal cardiovascular side effects [21]. On these counts, it would seem to be of potential value in the renal patient. Mivacurium is metabolized by plasma cholinesterase [22] (not acetylcholinesterase) to substances which are devoid of neuromuscular action, and does not rely upon renal excretion for its inactivation. It is interesting to note that the rate of hydrolysis by plasma cholinesterase (which is in excess) depends upon the concentration of mivacurium in the plasma. Thus the greater the concentration of mivacurium, the more rapid its breakdown and, unlike the case with other neuromuscular blocking agents, increasing the dose has only a small effect upon the duration of action. Clearly, the breakdown of mivacurium would be affected by any factor which interferes with either the activity or the quantity of plasma cholinesterase (e.g. anticholinesterases). The destruction of mivacurium is reduced also (hence its duration of action is increased) in patients with atypical plasma cholinesterase [23]. Thus one might expect it not to be affected by renal impairment. Phillips and Hunter, in the May issue of this Journal [24], described a comparison of the characteristics of mivacurium in patients with no renal function with those of normal patients. They showed that the action of mivacurium was prolonged in the anephric patient, but not to any great extent. They suggested that there was probably no change in elimination directly as a result of the renal failure, but that there was a decrease in plasma cholinesterase activity, which is a common finding in renal failure. It would appear, therefore, that mivacurium is safe to use in renal failure patients, although a small prolongation of effect should be expected. A further observation was also made by Phillips and Hunter [24]. They noted that the use of an antichounesterase accelerated the recovery of a mivacurium neuromuscular block by only a small
BRITISH JOURNAL OF ANAESTHESIA
EDITORIAL 20. Ali HH, Savarese JJ, Embrce PB, Basta SJ, Stout RG, Bottros LH, Weakly JN. Clinical phannacology of mivacunum chloride (BW109OU) infusion: comparison with vecuronium and atracurium. British Journal of Anaesthesia 1988; 61: 541-546. 21. From RP, Pearson KS, Choi WW, Abou-Donia M, Sokod MD. Ncuromuscular and cardiovascular effects of mivacurium chloride (BM109OU) during nitrous oxidc-fentanylthiopentonc and nitrous oxide-halothane anaesthesia. British Journal of Anaesthesia 1990; 64: 193-198. 22. Cook DR, Stiller RL, Weakly JN, Cnakravorti S, Brandom
547 BW, Welch RM. In vitro metabolism of mivacurium chloride (BM109OU) and succinylcholine. Anesthesia and Analgesia 1989; 68: 425-456. 23. Ostergaard D, Jensen F, Jensen E, Viby-Mogensen J. Influence of plasma cholincsterase activity on recovery from mivacurium induced neuromuscular blockade. Acta Anaesthesiologica Scandinavica 1989; 33: A165. 24. Phillips BJ, Hunter JM. Use of mivacurium chloride by constant infusion in the anephric patient. British Journal of Anaesthesia 1992; 68: 492^98.
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 8, 2015
