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CLEARANCE OF NEOSTIGMINE FROM THE CIRCULATION DURING THE ANTAGONISM OF NEUROMUSCULAR BLOCK
Br.J. Anaesth. (1978) 50, 1065
CLEARANCE OF NEOSTIGMINE FROM THE CIRCULATION DURING THE ANTAGONISM OF NEUROMUSCULAR BLOCK N. E. WILLIAMS, T. N. CALVEY AND K. CHAN SUMMARY
In the U.K., neostigmine methylsulphate is used invariably to antagonize non-depolarizing neuromuscular block, and the effect of the drug on neuromuscular function in these circumstances has been studied widely (MacFarlane et al., 1950; Katz, 1967; Rosner, Kepes and Foldes, 1971; Miller et al., 1974). By contrast, little is known of the distribution and elimination of neostigmine in man. In this study, we have investigated the clearance of neostigmine from the circulation during the antagonism of neuromuscular block induced by tubocurarine.
by the intermittent infusion of small volumes of heparinized saline. Residual neuromuscular block was antagonized with neostigmine methylsulphate 5 mg and atropine sulphate 1.2 mg. Blood samples were withdrawn after 2, 3, 4, 5, 7, 10, 15, 20, 30, 40, 50 and 60 min, and placed in tubes containing lithium heparin. As soon as was feasible, plasma was obtained by centrifugation and stored at — 20 °C. Neostigmine was extracted from plasma as an iodide complex, and its concentration was estimated by gas-liquid chromatography using a nitrogen detector (Chan et al., 1976).
METHODS
Five females who were undergoing plastic surgical procedures were studied. None was suffering from renal or hepatic disease. The ages of four patients were in the range 22-36 yr; one patient was aged 62 yr. Their body weights ranged from 63.1 to 72.6 kg. All were premedicated with nitrazepam 10 mg orally, given on the previous night, and diazepam 5-10 mg orally on the day of operation. Following the induction of anaesthesia with thiopentone 250400 mg, tubocurarine chloride 45 mg was administered. After tracheal intubation, anaesthesia was maintained with nitrous oxide 60-70% and halothane 0.5% in oxygen, utilizing IPPV. The duration of surgery was usually 60-90 min, and there was little or no fluid loss or replacement. At the end of the operation, an i.v. cannula was placed in a superficial vein. Its patency was maintained
—
2.5-
I o> S 2.0"
1.5-
0.5-
-i—n—i—
N. E. WILLIAMS, M.B., CH.B., F.F.A.RX.S. ; T. N. CALVEY,
B.SC, M.D., PH.D.; Whiston Hospital, Prescot, Lancashire, and Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3BX. K. CHAN, B.PHARM., M.SC, PH.D., School of Pharmacy, Liverpool
Polytechnic, Liverpool L3 3AF. 0007-0912/78/0050-1065 §01.00
2 5 10
-!
15 20
T 30
40
50
60
Time (min)
FIG. 1. Plasma concentration of neostigmine after i.v. injection. Each point and vertical bar represents the mean and standard error offiveobservations. © Macmillan Journals Ltd 1978
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 7, 2015
The plasma concentration of neostigmine was measured in five patients during the antagonism of neuromuscular block. The concentration of the drug decreased rapidly between 2 and 5 min after administration, and then more slowly. Detectable concentrations of neostigmine were present in plasma after 60 min. In the five patients the distribution half-life of neostigmine was less than 1 min; the elimination half-life ranged from 15.4 to 30.1 min.
1066
BRITISH JOURNAL OF ANAESTHESIA RESULTS
from 2.266 to 12.994 litre, although in one patient the volume was less than 1 litre (table II). TABLE II. Half-lives and apparent volume of distribution of neostigmine after i.v. injection
Patient
Distribution half-life (min)
Elimination half-life (min)
Total apparent volume of distribution (litre)
1 2 3 4 5
0.62 0.63 0.43 0.31 0.72
15.4 28.9 18.7 27.7 30.1
4.625 12.994 2.266 0.650 10.731
DISCUSSION
In this study, relatively great concentrations of neostigmine (0.84-6.25 fAg ml- 1 , or 3.7-27.5 ^mol litre"1) were present in plasma within 2 min. The initial plasma concentration invariably exceeded the concentrations which affect the amplitude of the endwhere Ct is the concentration of neostigmine in plate potential in the presence of tubocurarine plasma at time t and A, B, a and |8 are constants (Blaber and Christ, 1967). The plasma concentration (table I). Values for the distribution and elimination of neostigmine declined rapidly in the first few minutes after i.v. administration, and at 5 min was only 8% of its initial value. Nevertheless, in all the TABLE I. Relation between the plasma concentration of patients the block was antagonized adequately, and neostigmine and time. Plasma concentration at time t (C) = A e-" ( + B e"'3', where A, B, a and /? are constants there was no clinical evidence of the return of neuromuscular block. The absence of any clear Plasma concentration of neostigmine relationship between the pharmacodynamics of Patient (jig ml" 1 ) at time t neostigmine (Miller et al., 1974) and its pharmaco9.698 c- 1 - 126 ' +0.334 e-°- 0451 kinetics is consistent with the initial inhibition of 7.153 e - 1 1 0 9 ' +0.103 e-°- 024 ' junctional acetylcholinesterase by the high concentra1 618 03 54.806 e- - ' +0.214 e - ° " tions of neostigmine that are present transiently in 2 218 0 025 450.962 e- - ' + 0.136 e" - ' plasma. Thus the duration of action of the drug 8.109 e-°-968< +0.117 e-°- 023 ' reflects the relatively slow recovery in acetylcholinesterase activity and is almost entirely independent half-lives and the total apparent volume of distribu- of its removal from the circulation. tion were calculated in each patient from the expresIndividual differences in the concentration of sions : neostigmine at 2 min (which were not observed at subsequent times) may be related to incomplete and distribution half-life = 0.693/a uneven distribution of the drug in plasma, or to elimination half-life = 0.693/j3 variations in regional blood flow induced by halothane total apparent volume and tubocurarine. A similar phenomenon has been of distribution observed after the i.v. injection of other quaternary amines during general anaesthesia (Calvey et al., 1976). In all five subjects, the distribution half-life of Even compounds that are restricted almost wholly to neostigmine was invariably less than 1 min. In the circulation (for example, Evans blue) may not be contrast, the elimination half-life of the drug ranged distributed evenly in plasma for several minutes from 15.4 to 30.1 min (table II). The total apparent (Goldstein, Aronow and Kalman, 1974). Therefore, volume of distribution of neostigmine usually ranged the large initial variability may be a result of the
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 7, 2015
In all five patients, neostigmine was eliminated rapidly from the plasma during the antagonism of neuromuscular block. The concentration of the drug decreased from 2.42 + 0.99 (xgml- 1 to 0.19 + 0.03 y.g ml" 1 (mean + SEM) between 2 and 5 min and then declined more slowly (fig. 1). Detectable concentrations of neostigmine (0.027-0.037 fig ml"1) were present still in plasma after 60 min. There was a large variation in the concentration of neostigmine in plasma at 2 min (2.42 + 0.99 (xg ml" 1 ; range 0.846.25 (xg ml" 1 ), although marked inter-individual differences in the plasma concentrations of the drug were not observed subsequently (fig. 1). Thus, the concentration of neostigmine between 3 and 60 min was generally maintained within a relatively narrow range. The plasma concentration of neostigmine was invariably expressed as a biexponential equation of the form:
NEOSTIGMINE CLEARANCE AFTER NEUROMUSCULAR BLOCK
ACKNOWLEDGEMENTS
The financial assistance of the Muscular Dystrophy Group of Great Britain and the Peel Medical Research Trust is acknowledged. REFERENCES
Blaber, L. C , and Christ, D. D. (1967). The action of facilitatory drugs on the isolated tenuissimus muscle of the cat. Int. J. Neuropharmacol., 6,473. Calvey, T. N., Williams, N. E., Muir, K. T., and Barber, H. E. (1976). Plasma concentration of edrophonium in man. Clin. Pharmacol. Ther., 19,813. Chan, K.j Williams, N. E., Baty, J. D., and Calvey, T. N. (1976). A quantitative gas-liquid chromatographic method for the determination of neostigmine and pyridostigmine in human plasma. J. Chromatogr., 120, 349. Goldstein, A., Aronow, L., and Kalman, S. M. (1974). Principles of drug action; in The Basis of Pharmacology, p. 155. New York: John Wiley and Sons, Inc. Katz, R. L. (1967). Neuromuscular effects of d-tubocurarine, edrophonium and neostigmine in man. Anesthesiology, 28,327. MacFarlane, D. W., Unna, K. R., Pelikan, E. W., Cazort, R. J., Sadove, M. S., and Nelson, J. T. (1950). Evaluation of curarizing drugs in man. I l l : Antagonism to curarizing effects of d-tubocurarine and decamethylene-bis(trimethyl-ammonium bromide). J. Pharmacol. Exp. Ther., 99, 226.
Miller, R. D., Van Nyhuis, L. S., Eger, E. I., Vitez, T. S., and Way, W. L. (1974). Comparative times to peak effect and durations of action of neostigmine and pyridostigmine. Anesthesiology, 41,27. Rosner, V., Kepes, E. R., and Foldes, F. F. (1971). The effects of atropine and neostigmine on heart rate and rhythm. Br.J. Anaesth., 43, 1066. COEFFICIENT D'EPURATION PLASMATIQUE DE LA NEOSTIGMINE PENDANT L'ANTAGONISME D'UN BLOCAGE NEUROMUSCULAIRE RESUME
La concentration de neostigmine dans le plasma a ete mesuree sur cinq malades pendant l'antagonisme d'un blocage neuromusculaire. La concentration de ce medicament a baisse rapidement, entre 2 et 5 min apres son administration, et ensuite plus lentement. Des concentrations decelables de neostigmine etaient encore visibles dans le plasma apres 60 min. Sur les cinq malades, la demi-vie de la diffusion de la neostigmine a ete inferieure a 1 min alors que la demi-vie d'elimination a porte sur une plage de 15,4 a 30,1 min. CLEARANCE VON NEOSTIGMIN AUS DEM KREISLAUF WAHREND DER GEGENWIRKUNG DER NEUROMUSKULAREN BLOCKADE ZUSAMMENFASSUNG
Die Plasmakonzentration von Neostigmin wurde in fiinf Patienten wahrend der Gegenwirkung der neuromuskularen Blockade gemessen. Die Konzentration dieser Droge verringerte sich zwischen der 2 und 5 Min nach Verabreichung sehr schnell, dann langsamer. Im Plasma waren nach 60 Min noch Konzentrationen zu finden. In den fiinf Patienten dauerte die Verteilungshalbzeit von Neostigmin weniger als 1 min, die Ausscheidungshalbzeit betrug zwischen 15,4 und 30,1 Min. ELIMINACION DE LA NEOSTIGMINA FUERA DE LA CIRCULACION DURANTE EL ANTAGONISMO DEL BLOQUEO NEUROMUSCULAR SUMARIO
La concentraci6n de neostigmina en la plasma se midi6 en cinco pacientes durante el antagonismo del bloqueo neuromuscular. La concentraci6n de la droga disminuy6 rapidamente durante el periodo comprendido entre los 2 y 5 min posteriores a su administration, despues con mas lentitud. Se presentaron concentraciones detectables de neostigmina en la plasma al cabo de 60 min. En los cinco pacientes la distribution del perido de vida media de la neostigmina result6 inferior a 1 min; el periodo de vida media de la elimination vario entre 15,4 y 30,1 min.
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 7, 2015
circulation of the drug as a bolus immediately after its i.v. injection. In all five patients, the distribution half-life of neostigmine was invariably less than 1 min. The short distribution half-life may reflect partly the rapid transfer of neostigmine from plasma to interstitial fluid. The subsequent slower decline in concentration, with a half-life of 15-30 min, reflects the elimination of neostigmine from the body, and experimental evidence suggests that both hepatic metabolism and renal filtration and secretion may be involved in this process. Although trace amounts of neostigmine were detected still in plasma after 1 h, the elimination of the drug was extremely rapid; few, if any, drugs are known to have a shorter elimination half-life. In this study, the ages of four patients were in the range 22-36 yr, while one subject (patient 2) was aged 62 yr. There was no evidence that the pharmacokinetics of neostigmine were significantly different in the older patient; values for the distribution halflife, elimination half-life and total apparent volume of distribution were generally similar to those obtained in the younger patients.
1067
CLEARANCE OF NEOSTIGMINE FROM THE CIRCULATION DURING THE ANTAGONISM OF NEUROMUSCULAR BLOCK N. E. WILLIAMS, T. N. CALVEY AND K. CHAN SUMMARY
In the U.K., neostigmine methylsulphate is used invariably to antagonize non-depolarizing neuromuscular block, and the effect of the drug on neuromuscular function in these circumstances has been studied widely (MacFarlane et al., 1950; Katz, 1967; Rosner, Kepes and Foldes, 1971; Miller et al., 1974). By contrast, little is known of the distribution and elimination of neostigmine in man. In this study, we have investigated the clearance of neostigmine from the circulation during the antagonism of neuromuscular block induced by tubocurarine.
by the intermittent infusion of small volumes of heparinized saline. Residual neuromuscular block was antagonized with neostigmine methylsulphate 5 mg and atropine sulphate 1.2 mg. Blood samples were withdrawn after 2, 3, 4, 5, 7, 10, 15, 20, 30, 40, 50 and 60 min, and placed in tubes containing lithium heparin. As soon as was feasible, plasma was obtained by centrifugation and stored at — 20 °C. Neostigmine was extracted from plasma as an iodide complex, and its concentration was estimated by gas-liquid chromatography using a nitrogen detector (Chan et al., 1976).
METHODS
Five females who were undergoing plastic surgical procedures were studied. None was suffering from renal or hepatic disease. The ages of four patients were in the range 22-36 yr; one patient was aged 62 yr. Their body weights ranged from 63.1 to 72.6 kg. All were premedicated with nitrazepam 10 mg orally, given on the previous night, and diazepam 5-10 mg orally on the day of operation. Following the induction of anaesthesia with thiopentone 250400 mg, tubocurarine chloride 45 mg was administered. After tracheal intubation, anaesthesia was maintained with nitrous oxide 60-70% and halothane 0.5% in oxygen, utilizing IPPV. The duration of surgery was usually 60-90 min, and there was little or no fluid loss or replacement. At the end of the operation, an i.v. cannula was placed in a superficial vein. Its patency was maintained
—
2.5-
I o> S 2.0"
1.5-
0.5-
-i—n—i—
N. E. WILLIAMS, M.B., CH.B., F.F.A.RX.S. ; T. N. CALVEY,
B.SC, M.D., PH.D.; Whiston Hospital, Prescot, Lancashire, and Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3BX. K. CHAN, B.PHARM., M.SC, PH.D., School of Pharmacy, Liverpool
Polytechnic, Liverpool L3 3AF. 0007-0912/78/0050-1065 §01.00
2 5 10
-!
15 20
T 30
40
50
60
Time (min)
FIG. 1. Plasma concentration of neostigmine after i.v. injection. Each point and vertical bar represents the mean and standard error offiveobservations. © Macmillan Journals Ltd 1978
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 7, 2015
The plasma concentration of neostigmine was measured in five patients during the antagonism of neuromuscular block. The concentration of the drug decreased rapidly between 2 and 5 min after administration, and then more slowly. Detectable concentrations of neostigmine were present in plasma after 60 min. In the five patients the distribution half-life of neostigmine was less than 1 min; the elimination half-life ranged from 15.4 to 30.1 min.
1066
BRITISH JOURNAL OF ANAESTHESIA RESULTS
from 2.266 to 12.994 litre, although in one patient the volume was less than 1 litre (table II). TABLE II. Half-lives and apparent volume of distribution of neostigmine after i.v. injection
Patient
Distribution half-life (min)
Elimination half-life (min)
Total apparent volume of distribution (litre)
1 2 3 4 5
0.62 0.63 0.43 0.31 0.72
15.4 28.9 18.7 27.7 30.1
4.625 12.994 2.266 0.650 10.731
DISCUSSION
In this study, relatively great concentrations of neostigmine (0.84-6.25 fAg ml- 1 , or 3.7-27.5 ^mol litre"1) were present in plasma within 2 min. The initial plasma concentration invariably exceeded the concentrations which affect the amplitude of the endwhere Ct is the concentration of neostigmine in plate potential in the presence of tubocurarine plasma at time t and A, B, a and |8 are constants (Blaber and Christ, 1967). The plasma concentration (table I). Values for the distribution and elimination of neostigmine declined rapidly in the first few minutes after i.v. administration, and at 5 min was only 8% of its initial value. Nevertheless, in all the TABLE I. Relation between the plasma concentration of patients the block was antagonized adequately, and neostigmine and time. Plasma concentration at time t (C) = A e-" ( + B e"'3', where A, B, a and /? are constants there was no clinical evidence of the return of neuromuscular block. The absence of any clear Plasma concentration of neostigmine relationship between the pharmacodynamics of Patient (jig ml" 1 ) at time t neostigmine (Miller et al., 1974) and its pharmaco9.698 c- 1 - 126 ' +0.334 e-°- 0451 kinetics is consistent with the initial inhibition of 7.153 e - 1 1 0 9 ' +0.103 e-°- 024 ' junctional acetylcholinesterase by the high concentra1 618 03 54.806 e- - ' +0.214 e - ° " tions of neostigmine that are present transiently in 2 218 0 025 450.962 e- - ' + 0.136 e" - ' plasma. Thus the duration of action of the drug 8.109 e-°-968< +0.117 e-°- 023 ' reflects the relatively slow recovery in acetylcholinesterase activity and is almost entirely independent half-lives and the total apparent volume of distribu- of its removal from the circulation. tion were calculated in each patient from the expresIndividual differences in the concentration of sions : neostigmine at 2 min (which were not observed at subsequent times) may be related to incomplete and distribution half-life = 0.693/a uneven distribution of the drug in plasma, or to elimination half-life = 0.693/j3 variations in regional blood flow induced by halothane total apparent volume and tubocurarine. A similar phenomenon has been of distribution observed after the i.v. injection of other quaternary amines during general anaesthesia (Calvey et al., 1976). In all five subjects, the distribution half-life of Even compounds that are restricted almost wholly to neostigmine was invariably less than 1 min. In the circulation (for example, Evans blue) may not be contrast, the elimination half-life of the drug ranged distributed evenly in plasma for several minutes from 15.4 to 30.1 min (table II). The total apparent (Goldstein, Aronow and Kalman, 1974). Therefore, volume of distribution of neostigmine usually ranged the large initial variability may be a result of the
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 7, 2015
In all five patients, neostigmine was eliminated rapidly from the plasma during the antagonism of neuromuscular block. The concentration of the drug decreased from 2.42 + 0.99 (xgml- 1 to 0.19 + 0.03 y.g ml" 1 (mean + SEM) between 2 and 5 min and then declined more slowly (fig. 1). Detectable concentrations of neostigmine (0.027-0.037 fig ml"1) were present still in plasma after 60 min. There was a large variation in the concentration of neostigmine in plasma at 2 min (2.42 + 0.99 (xg ml" 1 ; range 0.846.25 (xg ml" 1 ), although marked inter-individual differences in the plasma concentrations of the drug were not observed subsequently (fig. 1). Thus, the concentration of neostigmine between 3 and 60 min was generally maintained within a relatively narrow range. The plasma concentration of neostigmine was invariably expressed as a biexponential equation of the form:
NEOSTIGMINE CLEARANCE AFTER NEUROMUSCULAR BLOCK
ACKNOWLEDGEMENTS
The financial assistance of the Muscular Dystrophy Group of Great Britain and the Peel Medical Research Trust is acknowledged. REFERENCES
Blaber, L. C , and Christ, D. D. (1967). The action of facilitatory drugs on the isolated tenuissimus muscle of the cat. Int. J. Neuropharmacol., 6,473. Calvey, T. N., Williams, N. E., Muir, K. T., and Barber, H. E. (1976). Plasma concentration of edrophonium in man. Clin. Pharmacol. Ther., 19,813. Chan, K.j Williams, N. E., Baty, J. D., and Calvey, T. N. (1976). A quantitative gas-liquid chromatographic method for the determination of neostigmine and pyridostigmine in human plasma. J. Chromatogr., 120, 349. Goldstein, A., Aronow, L., and Kalman, S. M. (1974). Principles of drug action; in The Basis of Pharmacology, p. 155. New York: John Wiley and Sons, Inc. Katz, R. L. (1967). Neuromuscular effects of d-tubocurarine, edrophonium and neostigmine in man. Anesthesiology, 28,327. MacFarlane, D. W., Unna, K. R., Pelikan, E. W., Cazort, R. J., Sadove, M. S., and Nelson, J. T. (1950). Evaluation of curarizing drugs in man. I l l : Antagonism to curarizing effects of d-tubocurarine and decamethylene-bis(trimethyl-ammonium bromide). J. Pharmacol. Exp. Ther., 99, 226.
Miller, R. D., Van Nyhuis, L. S., Eger, E. I., Vitez, T. S., and Way, W. L. (1974). Comparative times to peak effect and durations of action of neostigmine and pyridostigmine. Anesthesiology, 41,27. Rosner, V., Kepes, E. R., and Foldes, F. F. (1971). The effects of atropine and neostigmine on heart rate and rhythm. Br.J. Anaesth., 43, 1066. COEFFICIENT D'EPURATION PLASMATIQUE DE LA NEOSTIGMINE PENDANT L'ANTAGONISME D'UN BLOCAGE NEUROMUSCULAIRE RESUME
La concentration de neostigmine dans le plasma a ete mesuree sur cinq malades pendant l'antagonisme d'un blocage neuromusculaire. La concentration de ce medicament a baisse rapidement, entre 2 et 5 min apres son administration, et ensuite plus lentement. Des concentrations decelables de neostigmine etaient encore visibles dans le plasma apres 60 min. Sur les cinq malades, la demi-vie de la diffusion de la neostigmine a ete inferieure a 1 min alors que la demi-vie d'elimination a porte sur une plage de 15,4 a 30,1 min. CLEARANCE VON NEOSTIGMIN AUS DEM KREISLAUF WAHREND DER GEGENWIRKUNG DER NEUROMUSKULAREN BLOCKADE ZUSAMMENFASSUNG
Die Plasmakonzentration von Neostigmin wurde in fiinf Patienten wahrend der Gegenwirkung der neuromuskularen Blockade gemessen. Die Konzentration dieser Droge verringerte sich zwischen der 2 und 5 Min nach Verabreichung sehr schnell, dann langsamer. Im Plasma waren nach 60 Min noch Konzentrationen zu finden. In den fiinf Patienten dauerte die Verteilungshalbzeit von Neostigmin weniger als 1 min, die Ausscheidungshalbzeit betrug zwischen 15,4 und 30,1 Min. ELIMINACION DE LA NEOSTIGMINA FUERA DE LA CIRCULACION DURANTE EL ANTAGONISMO DEL BLOQUEO NEUROMUSCULAR SUMARIO
La concentraci6n de neostigmina en la plasma se midi6 en cinco pacientes durante el antagonismo del bloqueo neuromuscular. La concentraci6n de la droga disminuy6 rapidamente durante el periodo comprendido entre los 2 y 5 min posteriores a su administration, despues con mas lentitud. Se presentaron concentraciones detectables de neostigmina en la plasma al cabo de 60 min. En los cinco pacientes la distribution del perido de vida media de la neostigmina result6 inferior a 1 min; el periodo de vida media de la elimination vario entre 15,4 y 30,1 min.
Downloaded from http://bja.oxfordjournals.org/ at University of Bath Library & Learning Centre on June 7, 2015
circulation of the drug as a bolus immediately after its i.v. injection. In all five patients, the distribution half-life of neostigmine was invariably less than 1 min. The short distribution half-life may reflect partly the rapid transfer of neostigmine from plasma to interstitial fluid. The subsequent slower decline in concentration, with a half-life of 15-30 min, reflects the elimination of neostigmine from the body, and experimental evidence suggests that both hepatic metabolism and renal filtration and secretion may be involved in this process. Although trace amounts of neostigmine were detected still in plasma after 1 h, the elimination of the drug was extremely rapid; few, if any, drugs are known to have a shorter elimination half-life. In this study, the ages of four patients were in the range 22-36 yr, while one subject (patient 2) was aged 62 yr. There was no evidence that the pharmacokinetics of neostigmine were significantly different in the older patient; values for the distribution halflife, elimination half-life and total apparent volume of distribution were generally similar to those obtained in the younger patients.
1067