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PHARMACOKINETICS OF ATRACURIUM IN ACUTE HEPATIC FAILURE (WITH ACUTE RENAL FAILURE)
Br. J. Anaesth. (1983), 55,1169
PHARMACOKINETICS OF ATRACURIUM IN ACUTE HEPATIC FAILURE (WITH ACUTE RENAL FAILURE) S. W A R D AND E. A. M. N E I L L SUMMARY
In patients (ASA 1) undergoing minor surgery the pharmacokinetic profile of atracurium besylate is concise and reproducible (Ward et al., 1983). The relatively short elimination half-life of approximately 20 min can be explained as elimination extensively by Hofmann decomposition, a non-enzymic process which is temperature- and pH-dependent and which occurs in plasma even in vitro (Merrett, Thompson and Webb, 1983). Animal studies in the cat (Neill and Chappie, 1982) have shown that this elimination is also essentially independent of renal or hepatic function. To investigate this latter property of atracurium in man a study was designed to compare pharmacokinetic parameters after a single i.v. bolus in a group of patients with hepatic and renal failure with those for a group of normal patients. PATIENTS AND METHODS . Two groups of six patients were studied. The subjects in group I, in grade IV hepatic coma (Sherlock; 1975), were being ventilated for the respiratory failure resulting from this degree of fulminant liver failure. Subjects 1,2,3,4 and 5.were suffering from an overdose of paracetamol and subject 6 had undergone a liver transplant, which had failed, 13 days previously. The patients were in the Liver Unit at King's College Hospital and were, having charcoal column haemoperfusion and haemodialysis daily. Neither haemoperfusion nor haemodialysis was in operation during each investigation. Although each S. WARD, F.F.AJLC.S.. Anaesthetic Department, King's College Hospital, London SE5. E. A. M. NEILL, M.SC, Drug Metabolism Department, Wellcome Research Laboratories, Beckenham, Kent.
patient was primarily in hepatic failure, biochemical values (table I) showed them to be in renal failure also. The plasma pH of each was in the physiological range (approx 7.4 unit) with the exception of patient 6, in whom it was 7.25 unit. Each had an axillary temperature between 37 and 37.5°C. Subject 2 was investigated on two separate occasions with a 9-day interval. Atracurium was given as a bolus into a central vein and arterial blood samples were taken from an arteriovenous shunt. In group II the patients, undergoing routine minor surgery, had normal renal and hepatic function. Atracurium was administered as a bolus into a hand vein and sampling was from the superior vena cava. . The collection and analysis of samples was as described previously (Ward et al., 1983). Heparinized blood samples (10 ml) were withdrawn at 0, 2, 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120, 150, 180 min. The plasma from each was separated rapidly and stored at - 20 °C for extraction within 24 h. Unchanged atracurium concentrations were measured by high pressure liquid chromatography (Neill and Jones, 1983). Mean plasma concentrations against time for each patient were examined as a semi-log plot and fitted to a two-component exponential (C= Ae~" + Be~f) by the method of non-linear least squares analysis. From the macrokinetic parameters (A, a, B, P) values for Tf (distribution half-life), Tf (elimination half-life), Vt (first compartment volume), Cl (total clearance) and VTO (total distribution volume) were calculated (symbols are as described by Hull (1979)): © The Macmillan Press Ltd 1983
Downloaded from http://bja.oxfordjournals.org/ at University of Sussex on September 7, 2015
The pharmacokinetic profile of atracurium was wmim-H in six patients with acute hepatic and renal failure and compared with that in six normal patients after an i.v. bolus (mean dose 0.7mgkg~ l ). The plasma concentrations were measured by high pressure liquid chromatography and the data fitted to a twocompartment pharmacokinetic model. The results from the two groups were not significantly different, giving a mean plasma elimination half-life of 22 min in patients with severe hepatic and renal failure and a mean of 21 min in the normal group.
BRITISH JOURNAL OF ANAESTHESIA
1170
TABLE I. Biochemical valua for patina in hepatic (and renal) failurt (group I) Normal values
2a 127 4 24 19.7 301 43/12 46 32 262
127 3.4 18 17.2 359 27/13 49 30 119
134 3.6 25 23.8 400 20/13 49 24 319
133 4.1 15 8.3 460 40/12 47 28 94
127 4.1 17 11.9 605 52/12 48 33 168
126 3.8 19 32.9 708 24/1.2 66 35 421
117 6.1 13 43.4 706 22/12 46 23 667
160
154
284
175
140
236
181
3-13
388
3210
125
>5000
442
106
80
7-40
103
132
196
169
67
79
0-40
differences in elimination half-life (TiO and clearance, but significant increases in distribution halflife (TV") and distribution volumes. Mean values gave an elimination half-life of 22 min in group I and 21 min in group II.
Xd vl = A + B Cl = Xd AUC m
140 4.0 24 <5.0 <88 12/12 60 40 <17
Xd AUC.0
DISCUSSION
This study has demonstrated that the elimination half-life of atracurium was not altered significantly 7V=0.693/a by renal or hepatic failure. In renal failure (McLeod, 7}" = 0.693/0 Watson and Rawlins, 1976) and in hepatic failure, an increase in drug distribution volume is not unXd = dose usual. In the patients in group I, sdme of whom were oedematous, it can be seen that the total clearance of AUC = area under curve drug increased as the distribution volume increased. RESULTS With atracurium the elimination half-life was unIndividual pharmacokinetic values are shown for altered despite the changing distribution volumes group I (table II) and group II (table III). A com- and this can be achieved only if the clearance parison between group I and group II using the changes. unpaired t test (table IV) showed no significant Three patients in group I are of special interest. TABLE II. Pharmacokinetic valuet for group I. Sixpatitnts in acute hepatic(and rtnal) failurt
Wt(kg) Dose (mg kg"1)
7y(min) 7y(min) fl(Mgml"') CJ (ml min"1 kg"1) V^mlkg" 1 ) VWmlkg" 1 )
1
2
2a
3
4
5
6
70 0.70 3.5 24 10.3 1.5 6.7 59 236
65 0.70 2.0 19 11.2 3.6 5.6 47 151
65 0.62 3.0 18 6.5 1.7 8.2 75 216
62 0.64 3.3 20 4.1 2.6 6.8 97 194
58 0.69 2.5 23 3.8 2.0 8.6 118 281
72 0.83 3.7 22 12.7 3.8 4.4 50 140
73 0.82 2.6 30 6.7 3.0 5.2 85 228
Downloaded from http://bja.oxfordjournals.org/ at University of Sussex on September 7, 2015
Na (mmol litre ') K(mmol litre"1) HCO3 (mmol litre"1) Urea (mmol litre"1) Creatinine (jimo\ litre " l ) Prothrombin time (s) Total protein (g litre" •) Albumin (g litre"1) Bilirubin (total) (fimol litre"1) Alkaline phosphatase (K.A. unit litre"1) Aspartate transaminase (i.u. litre"1) Gamma glutamyltranf erase (i.u. litre"1)
PHARMACOKINETICS OF ATRACURIUM IN HEPATIC FAILURE
1171
and colleagues (1981) noted very little change in kinetics using gallamine in liver disease, but this drug is of little value in cases with concomitant renal 2 3 4 1 5 6 failure (Feldman, Cohen and Golling, 1969). Using Org NC45 in renal failure, Fahey and colleagues 81 Wt(kg) 89 80 63 51 98 0.68 0.63 0.63 0.74 0.88 0.92 (1981) stated that there was no significant difference Dose (mg kg "') 1.3 1.4 2.3 1.6 3.1 2.2 7y"(min) in elimination half-life compared with a normal Tj* (min) 22 20 20 18 22 25 group. However, in a study in cats (Westra, 1 17.0 22.0 6.5 10.3 16.0 19.0 AQigml' ) Houwertjes et al., 1981) it was shown that an in1 2.9 2.7 4.8 3.2 2.8 4.2 BOigml" ) 1 1 crease in bile salt concentration such as would occur 4.8 6.5 4.9 5.2 4.4 ') 5.7 a (ml min" kg" in hepatic failure inhibited the hepatic clearance of 34 25 69 49 47 40 V,(mlkg-') 178 142 186 130 162 156 pancuronium and Org NC 45. V^dnlkg In conclusion, a review of available literature and Patient 2 was examined on two separate occasions (2 the results of the present study support the view that and 2a) and demonstrated an increase in distribution the elimination half-life of atracurium is unaffected volume with a deterioration in renal and hepatic by both renal and hepatic failure. function, but no change in plasma half-life of the drug. Patient 5 was in high-output cardiac failure ACKNOWLEDGEMENTS (cardiac output of 17 litre min"1: thermal dilution) and a systemic arterial pressure of 80/50 min Hg and We wish to thank Dr Roger Williams, Director of the Liver Unit those could account for the very high apparent total at King's College Hospital, London, Miss D. Wright of the volume of distribution. Patient 6 had an increased Anaesthetic Department, King's College Hospital, Dr B. WeathWellcome Research Laboratories, for help with interpretaelimination half-life. This may be because his arteri- erley, tion of the data and Mr I. Pratt, Wellcome Research Laboratories al pH was 7.25 unit, thus decreasing the rate of l assistance. Hofmann decomposition. Blood pH could not be maintained within the physiological range because of the severity of his condition. REFERENCES Pancuronium is the non-depolarizing neuromus- Duvaldestin, P., Agoston, S., Henzel, E., Kersten, V. W., and cular blocking drug whose phannacokinetics have Desmonts, J. M. (1978). Pancuronium phannacokinetics in patients with liver cirrhosis. Br. J. Anaesth., 50,1131. been studied most extensively in patients with liver disease. In liver cirrhosis (Duvaldestin et al., 1978) Fahey, M. R., Morris, R. B., Miller, R. D.,Nguyen,T.-L.,and Upton, R. A. (1981). Phannacokinetics of Org NC45 (Norcuand extrahepatic biliary obstruction (Westra, Verron) in patients with and without renal failure. Br. J. Anaesth., meer et al., 1981) the increase in elimination half-life 54, 1049. was explained by an increase in distribution volume. Feldman, S. A., Cohen, E. N., and Golling, R. C. (1969). The excretion of ggllamini- in the dog. Anesthesiology, 30, 503. In this hospital, using pancuronium in fulminant hepatic failure, the increase in elimination half-life Hull, C. J. (1979). Symbols for compartmental models. Br. J. Anaesth., 51, 815. was attributed to a decrease in plasma clearance McLeod, K., Watson, M. J., and Rawlins, M. D. (1976). (Ward, Judge and Corall, 1982). Westra, Vermeer Phannacokinetics of pancuronium in patients with normal and TABLE HI. Pharmacokineric values for group U. Six patients in normal htpatic and rtnal function
Downloaded from http://bja.oxfordjournals.org/ at University of Sussex on September 7, 2015
impaired renal function. Br. J. Anaesth., 48, 341. TABLE IV. Comparison of values bttwttn group I (livtr and kidney Merrett, R. A., Thompson, C. J., and Webb, F. (1983). In vitro degradation of atracurium in human plasma. Br. J. Anaesth., failurt) and group U (normals) (mean ± SD). *Significant at 0.05 55,61. using unpairtd t test Neill, E. A. M., and Chappie, D. J. (1982). Metabolic studies in the cat with atracurium: a neuromuscular blocking agent Group I Group II designed for non-enzymatic inactivation at physiological pH. (n-7) (n-6) Xenobiotica, 12, 203. Jones, C. R. (1983). Determination of atracurium besylate Dose (mg kg •) 0.71 ± 0.08 0.75± 0.13 in human plasma. / . Chromatogr., 274,409. 7y*(min) 2.9 ± 0.6 2.0 ± 0.7* Sherlock, S. (1975). Diseases of the Liver and Biliary System, 5th Tf (min)1 22.0 ± 4.0 21.0 ± 2.0 edn, p.87. Oxford: Blackwell Ltd. AQigml' ) 7.9 ± 3.5 15.1 ± 5.7* Ward, S., Judge, S.,andCorrall,I. M.(1982). PharmacokineticB BOigml"1) 2.6 ± 0.9 3.4 ± 0.9 of pancuronium in liver failure. Br. J. Anaesth., 54,227P. Cl (ml min" 'kg"1) 6.5 ± 1.5 5.3 ± 0.8 Neill, E. A. M., Weatherley, B. C , and Corall, J. M. VKmlkg-1) 76.0 ±26.0 41.0 ±16.0* (1983). Pharmacokinetics of atracurium besylate in healthy V^dnlkg" 1 ) 207.0 ±49.0 159.0 ±21.0* patients (after a single i.v. bolus dose). Br.J. Anaesth., 55,113.
BRITISH JOURNAL OF ANAESTHESIA
1172 Westra, P., Houwertjes, M. C , Wesseling, H., and Meijer, D. K. F. (1981). Bile salts and neuromuscular blocking agents.
Br.J.Anaath. 53,407. Vermeer, G. A., de Lange, A. R., Scaf, A. H. J., Meijer, D. K. F.,andWesseling,H. (1981). Hepatic and renal disposition of pancuronium and gallamine in patients with extrahepatic cholestasis. Br. J. Aruusth., 53, 331. PHARMACOCINETIQUE DE L'ATRACURIUM DANS L'INSUFFISANCE HEPATOCELLULAIRE AIGUE (AVEC INSUFFISANCE RENALE AIGUE)
PHARMAKOKINETIK VON ATRACURIUM BEI AKUTEM LEBERVERSAGEN (MIT AKUTEM NffiRENVERSAGEN) ZUSAMMHNFASSUNG
Bei sechs Patienten mit akutem Leber- und Nierenversagen wurde das pharmakokinetische Profil von Atracurium untersucht und mit dem bei sechs Normalpersonen verglichcn. Es wurde ein i.v. - Bolus von durchschnittlich 0,7mgkg" 1 verabreicht. Die Plasma konzentrationen wurden mit Hochdruck Liquidchromatographie gemessen und die Daten nach einem Zwcikompartimente-Modell verarbeitet. Die Ergebnisse au> bciden Gruppen unterschieden sich nicht signif ikant und zeigten bei den Patienten mit schwerem Leber- und Nierenversagen eine mittlere Plasmaeliminations-Halbwertszeit von 22 Minuten, bei der Normalgruppe eine von 21 Minuten.
SUMAJUO
Se examino el perfil farmacocinetico del atracurio en seis pacientes que sufrian de defectos hepaticos y renales agudos y se companS con el de seis pacientes nonnales despues de una inyeccion de bolo i.v. (dosis promedia 0,7 mgkg"1). Se midieron las concentrariones en el plasma mediante cromatograf ia liquids de alta presion y los datos fueron puestos en un modelo farmacocinetico de dos comparnmientos. Los resultados en los dos grupos no diferian de manera significant con una media-vida promedia de diminadon del plasma de 22 min en los pacimtra con defectos hepaticos y renales severos y un promediode21 min en el grupo normal.
Downloaded from http://bja.oxfordjournals.org/ at University of Sussex on September 7, 2015
Nous avons etudie le profil pharmacocinetique de 1'atracurium chcz six enfants souffrant d'une insuffisance hcpalique et renale et nous l'avons compare a celui obtenu chcz six sujcts normaux apres injection i.v. directe (dose moyenne: 0,7 nig kg" 1 ). Les concentrations plasmatiques etaient mesurees par chromatographie liquide a haute pression (HPLC) et les resultats integres dans un modele pharmacocinetique a deux compartiments. Les resultats des deux groupes n'ctaient pas significativement differents, avee une demi-vie moyenne d'climination plasmatique de 22min chcz les patients ayant une insuffisance hepato-renale severe et de 21 min chcz les sujcts normaux.
FARMACOCINETICA DEL ATRACURIO EN DEFECTO HEPATICO AGUDO (CON DEFECTO RENAL AGUDO)
PHARMACOKINETICS OF ATRACURIUM IN ACUTE HEPATIC FAILURE (WITH ACUTE RENAL FAILURE) S. W A R D AND E. A. M. N E I L L SUMMARY
In patients (ASA 1) undergoing minor surgery the pharmacokinetic profile of atracurium besylate is concise and reproducible (Ward et al., 1983). The relatively short elimination half-life of approximately 20 min can be explained as elimination extensively by Hofmann decomposition, a non-enzymic process which is temperature- and pH-dependent and which occurs in plasma even in vitro (Merrett, Thompson and Webb, 1983). Animal studies in the cat (Neill and Chappie, 1982) have shown that this elimination is also essentially independent of renal or hepatic function. To investigate this latter property of atracurium in man a study was designed to compare pharmacokinetic parameters after a single i.v. bolus in a group of patients with hepatic and renal failure with those for a group of normal patients. PATIENTS AND METHODS . Two groups of six patients were studied. The subjects in group I, in grade IV hepatic coma (Sherlock; 1975), were being ventilated for the respiratory failure resulting from this degree of fulminant liver failure. Subjects 1,2,3,4 and 5.were suffering from an overdose of paracetamol and subject 6 had undergone a liver transplant, which had failed, 13 days previously. The patients were in the Liver Unit at King's College Hospital and were, having charcoal column haemoperfusion and haemodialysis daily. Neither haemoperfusion nor haemodialysis was in operation during each investigation. Although each S. WARD, F.F.AJLC.S.. Anaesthetic Department, King's College Hospital, London SE5. E. A. M. NEILL, M.SC, Drug Metabolism Department, Wellcome Research Laboratories, Beckenham, Kent.
patient was primarily in hepatic failure, biochemical values (table I) showed them to be in renal failure also. The plasma pH of each was in the physiological range (approx 7.4 unit) with the exception of patient 6, in whom it was 7.25 unit. Each had an axillary temperature between 37 and 37.5°C. Subject 2 was investigated on two separate occasions with a 9-day interval. Atracurium was given as a bolus into a central vein and arterial blood samples were taken from an arteriovenous shunt. In group II the patients, undergoing routine minor surgery, had normal renal and hepatic function. Atracurium was administered as a bolus into a hand vein and sampling was from the superior vena cava. . The collection and analysis of samples was as described previously (Ward et al., 1983). Heparinized blood samples (10 ml) were withdrawn at 0, 2, 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120, 150, 180 min. The plasma from each was separated rapidly and stored at - 20 °C for extraction within 24 h. Unchanged atracurium concentrations were measured by high pressure liquid chromatography (Neill and Jones, 1983). Mean plasma concentrations against time for each patient were examined as a semi-log plot and fitted to a two-component exponential (C= Ae~" + Be~f) by the method of non-linear least squares analysis. From the macrokinetic parameters (A, a, B, P) values for Tf (distribution half-life), Tf (elimination half-life), Vt (first compartment volume), Cl (total clearance) and VTO (total distribution volume) were calculated (symbols are as described by Hull (1979)): © The Macmillan Press Ltd 1983
Downloaded from http://bja.oxfordjournals.org/ at University of Sussex on September 7, 2015
The pharmacokinetic profile of atracurium was wmim-H in six patients with acute hepatic and renal failure and compared with that in six normal patients after an i.v. bolus (mean dose 0.7mgkg~ l ). The plasma concentrations were measured by high pressure liquid chromatography and the data fitted to a twocompartment pharmacokinetic model. The results from the two groups were not significantly different, giving a mean plasma elimination half-life of 22 min in patients with severe hepatic and renal failure and a mean of 21 min in the normal group.
BRITISH JOURNAL OF ANAESTHESIA
1170
TABLE I. Biochemical valua for patina in hepatic (and renal) failurt (group I) Normal values
2a 127 4 24 19.7 301 43/12 46 32 262
127 3.4 18 17.2 359 27/13 49 30 119
134 3.6 25 23.8 400 20/13 49 24 319
133 4.1 15 8.3 460 40/12 47 28 94
127 4.1 17 11.9 605 52/12 48 33 168
126 3.8 19 32.9 708 24/1.2 66 35 421
117 6.1 13 43.4 706 22/12 46 23 667
160
154
284
175
140
236
181
3-13
388
3210
125
>5000
442
106
80
7-40
103
132
196
169
67
79
0-40
differences in elimination half-life (TiO and clearance, but significant increases in distribution halflife (TV") and distribution volumes. Mean values gave an elimination half-life of 22 min in group I and 21 min in group II.
Xd vl = A + B Cl = Xd AUC m
140 4.0 24 <5.0 <88 12/12 60 40 <17
Xd AUC.0
DISCUSSION
This study has demonstrated that the elimination half-life of atracurium was not altered significantly 7V=0.693/a by renal or hepatic failure. In renal failure (McLeod, 7}" = 0.693/0 Watson and Rawlins, 1976) and in hepatic failure, an increase in drug distribution volume is not unXd = dose usual. In the patients in group I, sdme of whom were oedematous, it can be seen that the total clearance of AUC = area under curve drug increased as the distribution volume increased. RESULTS With atracurium the elimination half-life was unIndividual pharmacokinetic values are shown for altered despite the changing distribution volumes group I (table II) and group II (table III). A com- and this can be achieved only if the clearance parison between group I and group II using the changes. unpaired t test (table IV) showed no significant Three patients in group I are of special interest. TABLE II. Pharmacokinetic valuet for group I. Sixpatitnts in acute hepatic(and rtnal) failurt
Wt(kg) Dose (mg kg"1)
7y(min) 7y(min) fl(Mgml"') CJ (ml min"1 kg"1) V^mlkg" 1 ) VWmlkg" 1 )
1
2
2a
3
4
5
6
70 0.70 3.5 24 10.3 1.5 6.7 59 236
65 0.70 2.0 19 11.2 3.6 5.6 47 151
65 0.62 3.0 18 6.5 1.7 8.2 75 216
62 0.64 3.3 20 4.1 2.6 6.8 97 194
58 0.69 2.5 23 3.8 2.0 8.6 118 281
72 0.83 3.7 22 12.7 3.8 4.4 50 140
73 0.82 2.6 30 6.7 3.0 5.2 85 228
Downloaded from http://bja.oxfordjournals.org/ at University of Sussex on September 7, 2015
Na (mmol litre ') K(mmol litre"1) HCO3 (mmol litre"1) Urea (mmol litre"1) Creatinine (jimo\ litre " l ) Prothrombin time (s) Total protein (g litre" •) Albumin (g litre"1) Bilirubin (total) (fimol litre"1) Alkaline phosphatase (K.A. unit litre"1) Aspartate transaminase (i.u. litre"1) Gamma glutamyltranf erase (i.u. litre"1)
PHARMACOKINETICS OF ATRACURIUM IN HEPATIC FAILURE
1171
and colleagues (1981) noted very little change in kinetics using gallamine in liver disease, but this drug is of little value in cases with concomitant renal 2 3 4 1 5 6 failure (Feldman, Cohen and Golling, 1969). Using Org NC45 in renal failure, Fahey and colleagues 81 Wt(kg) 89 80 63 51 98 0.68 0.63 0.63 0.74 0.88 0.92 (1981) stated that there was no significant difference Dose (mg kg "') 1.3 1.4 2.3 1.6 3.1 2.2 7y"(min) in elimination half-life compared with a normal Tj* (min) 22 20 20 18 22 25 group. However, in a study in cats (Westra, 1 17.0 22.0 6.5 10.3 16.0 19.0 AQigml' ) Houwertjes et al., 1981) it was shown that an in1 2.9 2.7 4.8 3.2 2.8 4.2 BOigml" ) 1 1 crease in bile salt concentration such as would occur 4.8 6.5 4.9 5.2 4.4 ') 5.7 a (ml min" kg" in hepatic failure inhibited the hepatic clearance of 34 25 69 49 47 40 V,(mlkg-') 178 142 186 130 162 156 pancuronium and Org NC 45. V^dnlkg In conclusion, a review of available literature and Patient 2 was examined on two separate occasions (2 the results of the present study support the view that and 2a) and demonstrated an increase in distribution the elimination half-life of atracurium is unaffected volume with a deterioration in renal and hepatic by both renal and hepatic failure. function, but no change in plasma half-life of the drug. Patient 5 was in high-output cardiac failure ACKNOWLEDGEMENTS (cardiac output of 17 litre min"1: thermal dilution) and a systemic arterial pressure of 80/50 min Hg and We wish to thank Dr Roger Williams, Director of the Liver Unit those could account for the very high apparent total at King's College Hospital, London, Miss D. Wright of the volume of distribution. Patient 6 had an increased Anaesthetic Department, King's College Hospital, Dr B. WeathWellcome Research Laboratories, for help with interpretaelimination half-life. This may be because his arteri- erley, tion of the data and Mr I. Pratt, Wellcome Research Laboratories al pH was 7.25 unit, thus decreasing the rate of l assistance. Hofmann decomposition. Blood pH could not be maintained within the physiological range because of the severity of his condition. REFERENCES Pancuronium is the non-depolarizing neuromus- Duvaldestin, P., Agoston, S., Henzel, E., Kersten, V. W., and cular blocking drug whose phannacokinetics have Desmonts, J. M. (1978). Pancuronium phannacokinetics in patients with liver cirrhosis. Br. J. Anaesth., 50,1131. been studied most extensively in patients with liver disease. In liver cirrhosis (Duvaldestin et al., 1978) Fahey, M. R., Morris, R. B., Miller, R. D.,Nguyen,T.-L.,and Upton, R. A. (1981). Phannacokinetics of Org NC45 (Norcuand extrahepatic biliary obstruction (Westra, Verron) in patients with and without renal failure. Br. J. Anaesth., meer et al., 1981) the increase in elimination half-life 54, 1049. was explained by an increase in distribution volume. Feldman, S. A., Cohen, E. N., and Golling, R. C. (1969). The excretion of ggllamini- in the dog. Anesthesiology, 30, 503. In this hospital, using pancuronium in fulminant hepatic failure, the increase in elimination half-life Hull, C. J. (1979). Symbols for compartmental models. Br. J. Anaesth., 51, 815. was attributed to a decrease in plasma clearance McLeod, K., Watson, M. J., and Rawlins, M. D. (1976). (Ward, Judge and Corall, 1982). Westra, Vermeer Phannacokinetics of pancuronium in patients with normal and TABLE HI. Pharmacokineric values for group U. Six patients in normal htpatic and rtnal function
Downloaded from http://bja.oxfordjournals.org/ at University of Sussex on September 7, 2015
impaired renal function. Br. J. Anaesth., 48, 341. TABLE IV. Comparison of values bttwttn group I (livtr and kidney Merrett, R. A., Thompson, C. J., and Webb, F. (1983). In vitro degradation of atracurium in human plasma. Br. J. Anaesth., failurt) and group U (normals) (mean ± SD). *Significant at 0.05 55,61. using unpairtd t test Neill, E. A. M., and Chappie, D. J. (1982). Metabolic studies in the cat with atracurium: a neuromuscular blocking agent Group I Group II designed for non-enzymatic inactivation at physiological pH. (n-7) (n-6) Xenobiotica, 12, 203. Jones, C. R. (1983). Determination of atracurium besylate Dose (mg kg •) 0.71 ± 0.08 0.75± 0.13 in human plasma. / . Chromatogr., 274,409. 7y*(min) 2.9 ± 0.6 2.0 ± 0.7* Sherlock, S. (1975). Diseases of the Liver and Biliary System, 5th Tf (min)1 22.0 ± 4.0 21.0 ± 2.0 edn, p.87. Oxford: Blackwell Ltd. AQigml' ) 7.9 ± 3.5 15.1 ± 5.7* Ward, S., Judge, S.,andCorrall,I. M.(1982). PharmacokineticB BOigml"1) 2.6 ± 0.9 3.4 ± 0.9 of pancuronium in liver failure. Br. J. Anaesth., 54,227P. Cl (ml min" 'kg"1) 6.5 ± 1.5 5.3 ± 0.8 Neill, E. A. M., Weatherley, B. C , and Corall, J. M. VKmlkg-1) 76.0 ±26.0 41.0 ±16.0* (1983). Pharmacokinetics of atracurium besylate in healthy V^dnlkg" 1 ) 207.0 ±49.0 159.0 ±21.0* patients (after a single i.v. bolus dose). Br.J. Anaesth., 55,113.
BRITISH JOURNAL OF ANAESTHESIA
1172 Westra, P., Houwertjes, M. C , Wesseling, H., and Meijer, D. K. F. (1981). Bile salts and neuromuscular blocking agents.
Br.J.Anaath. 53,407. Vermeer, G. A., de Lange, A. R., Scaf, A. H. J., Meijer, D. K. F.,andWesseling,H. (1981). Hepatic and renal disposition of pancuronium and gallamine in patients with extrahepatic cholestasis. Br. J. Aruusth., 53, 331. PHARMACOCINETIQUE DE L'ATRACURIUM DANS L'INSUFFISANCE HEPATOCELLULAIRE AIGUE (AVEC INSUFFISANCE RENALE AIGUE)
PHARMAKOKINETIK VON ATRACURIUM BEI AKUTEM LEBERVERSAGEN (MIT AKUTEM NffiRENVERSAGEN) ZUSAMMHNFASSUNG
Bei sechs Patienten mit akutem Leber- und Nierenversagen wurde das pharmakokinetische Profil von Atracurium untersucht und mit dem bei sechs Normalpersonen verglichcn. Es wurde ein i.v. - Bolus von durchschnittlich 0,7mgkg" 1 verabreicht. Die Plasma konzentrationen wurden mit Hochdruck Liquidchromatographie gemessen und die Daten nach einem Zwcikompartimente-Modell verarbeitet. Die Ergebnisse au> bciden Gruppen unterschieden sich nicht signif ikant und zeigten bei den Patienten mit schwerem Leber- und Nierenversagen eine mittlere Plasmaeliminations-Halbwertszeit von 22 Minuten, bei der Normalgruppe eine von 21 Minuten.
SUMAJUO
Se examino el perfil farmacocinetico del atracurio en seis pacientes que sufrian de defectos hepaticos y renales agudos y se companS con el de seis pacientes nonnales despues de una inyeccion de bolo i.v. (dosis promedia 0,7 mgkg"1). Se midieron las concentrariones en el plasma mediante cromatograf ia liquids de alta presion y los datos fueron puestos en un modelo farmacocinetico de dos comparnmientos. Los resultados en los dos grupos no diferian de manera significant con una media-vida promedia de diminadon del plasma de 22 min en los pacimtra con defectos hepaticos y renales severos y un promediode21 min en el grupo normal.
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Nous avons etudie le profil pharmacocinetique de 1'atracurium chcz six enfants souffrant d'une insuffisance hcpalique et renale et nous l'avons compare a celui obtenu chcz six sujcts normaux apres injection i.v. directe (dose moyenne: 0,7 nig kg" 1 ). Les concentrations plasmatiques etaient mesurees par chromatographie liquide a haute pression (HPLC) et les resultats integres dans un modele pharmacocinetique a deux compartiments. Les resultats des deux groupes n'ctaient pas significativement differents, avee une demi-vie moyenne d'climination plasmatique de 22min chcz les patients ayant une insuffisance hepato-renale severe et de 21 min chcz les sujcts normaux.
FARMACOCINETICA DEL ATRACURIO EN DEFECTO HEPATICO AGUDO (CON DEFECTO RENAL AGUDO)