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PHARMACOKINETICS OF EDROPHONIUM IN ANEPHRIC AND RENAL TRANSPLANT PATIENTS
Br.J. Anaesth. (1981), 53, 1311
PHARMACOKINETICS OF EDROPHONIUM IN ANEPHRIC AND RENAL TRANSPLANT PATIENTS R. B. MORRIS, R. CRONNELLY, R. D. MILLER, D. R. STANSKI AND M. R. FAHEY SUMMARY
Impaired renal function decreases plasma clearance and increases the duration of action of tubocurarine and pancuronium (Pavulon) in anaesthetized patients (Miller et al., 1977; Somogyi, Shanks and Triggs, 1977). This probably does not represent a clinical problem since renal failure also decreases the plasma clearance of the commonly used antagonists, neostigmine and pyridostigmine (Cronnelly et al., 1979, 1980). Recently, edrophonium 0.5-1 .Omgkg"1, has been shown to produce sustained antagonism of non-depolarizing neuromuscular blockade (Bevan, 1979; Kopman, 1979; Morris et al., 1981). This study was designed to determine the influence of renal failure on the pharmacokinetics of edrophonium in anaesthetized patients. METHODS
Informed consent, approved by our Committee on Human Research, was obtained from 12 adult patients. Six of these patients were about to undergo transplant nephrectomy (anephric group), and the six remaining patients were about to receive a living related kidney transplant ROBERT B. MORRIS, MJ)., MARK R. FAHEY, MJJ. (Department of Anesthesia); ROY CRONNELLY, PH.D., M.D., RONALD D.
MILLER, M.D. (Department of Anesthesia and Pharmacology); University of California, San Francisco, California 94143, U.S.A. DONALD R. STANSKI, M.D., Department of Anesthesia and Medicine, Stanford Medical Center, Stanford, California, 94305, U.S.A. 0007-0912/81/121311-04 801.00
(LRKT). Approximately 1 h after the oral administration of diazepam (Valium) lOmg, anaesthesia was induced with thiopentone (Pentothal) 2-4mgkg~ 1 , and maintained with halothane 0.4-0.7% (end-tidal) and 60% nitrous oxide in oxygen, measured by mass spectrometry. Tubocurarine was administered as an i.v. bolus with repeated doses sufficient to maintain approximately a 90% depression of twitch tension. At the end of surgery, the neuromuscular blockade was antagonized with edrophonium l.Omgkg"1 combined with atropine 1.0 mg administered as a 2-min i.v. infusion. Venous blood samples were obtained 2,4, 6, 8,10,15, 30,45, 60, 90,120, 180, 210 and 240min after starting the infusion. Serum was stored at — 30°C until extracted and assayed by high pressure liquid chromatography (De Ruyter, Cronnelly and Castagnoli, 1980). Data were treated using a non-compartmental pharmacokinetic analysis (Benet and Galeazzi, 1979) and differences determined by a Tukey's Test (Snedecor, 1962). Data previously obtained (Morris et al., 1981) from four patients with normal renal function who received edrophonium lmgkg" 1 were analysed by non-compartmental pharmacokinetic analysis and included for comparison. RESULTS
The slope of the elimination phase for the anephric group is less than that of patients with normal renal function, resulting in significantly greater serum © Macmillan Publications Ltd 1981
Downloaded from http://bja.oxfordjournals.org/ at Cambridge University on August 17, 2015
The pharmacokinetics of edrophonium were determined in patients anaesthetized with nitrous oxide and halothane undergoing kidney transplant nephrectomy (n = 6) or transplantation of a live related donor kidney («— 6). Serum concentrations of edrophonium were assayed by high pressure liquid chromatography and pharmacokinetic variables computed using noh-compartmental analysis. Patients undergoing transplant nephrectomy had a significant increase in elimination half-life and a significant decrease (67%) in serum clearance when compared with kidney transplant recipients or patients with normal renal function. Pharmacokinetic indices for edrophonium in patients receiving a kidney transplant did not differ from those in patients with normal renal function. We conclude that absence of renal function decreases excretion of edrophonium to an extent similar to that of other acetylcholinesterase inhibitors, neostigmine and pyridostigmine.
BRITISH JOURNAL Of ANAESTHESIA
1312
Q.
Patients
Normal Anephric Transplant
Cl
(nun)
(litre kg" 1 )
(ml kg min"')
114.0±47 206.0±62* 86.5±23.9
0.87±0.22 0.68±0.13 0.92 + 0.16
8.2±2.7 2.7±1.4* 9.9±2.1
ACKNOWLEDGEMENTS
The authors thank Mr C. R. Pudwill for his excellent technical assistance and acknowledge Oscar Salvatieria jr, M.D., and Nicholas J. Feduska, MJJ., for their co-operation in surgery for
4 •
Downloaded from http://bja.oxfordjournals.org/ at Cambridge University on August 17, 2015
DISCUSSION concentrations of edrophonium in anephric patients after 4h (fig. 1). The data from patients When edrophonium is given in the absence of with normal renal function are taken from a renal function, plasma clearance is decreased and previous study (Morris et al., 1981). elimination half-life prolonged to an extent similar to that of neostigmine and pyridostigmine 2OOOOr (Cronnelly et al., 1979,1980). Plasma clearance of edrophonium is 8.2 ± 2.7 ml kg ~J min ~1 in normal patients and 2.7 ±1.4 ml kg"'min" 1 in patients 10000 • without renal function. Thus, approximately 67% of plasma clearance of edrophonium appears to be dependent on renal excretion, the remainder being dependent on non-renal mechanisms. If renal excretion occurred solely by glomerular filtration, renal clearance of 1-2 ml kg"'min" 1 would be expected (Melman and Morelli, 1978; Duchin and Sechrici, 1978). Larger values, such as o 1000 5.5 ml kg" l min" l reported here, suggest a tubular secretory process. Since edrophonium is not hydrolysed by cholinesterase, this cannot contribute to non-renal clearance. Hepatic metabolism and biliary excretion have been demonstrated in animals (Back and Calvey, 1972; Calvey and Back, 1973) and represent probable pathways for non-renal clearance of edrophonium in man. In the patients 100 80 120 160 200 240 receiving a living related kidney transplant, Tlme(mln) diuresis was induced before administration of FIG. 1. Serum concentration following 2-min i.v. infusion of edrophonium. Under these circumstances, the edrophonium l.Omgkg"' in anaesthetized patients without renal function and with normal renal function. Points represent pharmacokinetics of edrophonium did not differ from those in patients with normal renal function. means ±SD. Similar findings have been reported for tubocurarine (Miller et al., 1977), neostigmine Anephric patients had a significantly decreased (Cronnelly et al., 1979) and pyridostigmine plasma clearance and prolonged elimination half- (Cronnelly et al., 1980). life when compared with patients with normal Problems of prolonged neuromuscular blockade renal function and with those patients who had have occurred in patients with renal failure received a kidney transplant (table I). undergoing anaesthesia and surgery. Renal failure Pharmacokinetics of edrophonium in patients who has been thought to prolong tubocurarine activity had received a kidney transplant were not different more than the antagonist activity of neostigmine from those in patients with normal renal function and pyridostigmine (Miller and Cullen, 1976). If (table I). the plasma concentration is directly related to effect, antagonism by edrophonium should last longer than tubocurarine neuromuscular blockade TABLE I. Pharmacokinetics of edrophonium in antphric and renal in patients with renal failure. Consistent with this transplant patients (means ±SD). * Significant difference hypothesis are our observations of sustained (P<0.05)from normal and transplant. Tf= elimination halfof tubocurarine neuromuscular life, V*" = volume of distribution at steady state, Cl •= clearance antagonism blockade even in the presence of renal failure.
EDJIOPHONIUM PHARMACOKINETICS the parients undergoing renal transplant nephrectomy and living related renal transplantation. This work was supported in part by United States Public Health Service grants numbers GM 15571-12 and GM 26403-02. REFERENCES
LA PHARMACOCINETIQUE DE L'EDROPHONIUM CHEZ LES, PATIENTS SUBISSANT UNE NEPHRECTOMIE ET UNE GREFFE DU REIN RESUME
On a determine la pharmacocinetique de l'edrophonium sur des patients anesthesies au protoxyde d'azote et a liialothane subissant une nephrectomie avec greffe du rein (n => 6) ou une
greffe de rein provenantd'undonneurvivantapparente(n = 6). Les concentrations d'edrophonium dans le serum ont etc analysees par la chromatographic en phase liquide a haute pression et les variables pharmacocinetiques ont etc calculees a l'aide d'une analyse non compartimentee. Les patients subissant une nephrectomie avec greffe ont eu une augmentation significative de la demi-vie d'elimination et une diminution significative (67%) de l'epuration du serum par rapport aux receveurs de greffes de rein ou aux patients dont les reins fonctionnaient normalement. Les indices pharmacocinetiques de l'edrophonium dea patients subissant une greffe de rein n'ont r)as differe. de ceux del patients dont lei reins fonctionnaient normalement. Nous en avons conclu que l'absencc de fonction renalc diminue l'excretion de 1'edro.phonium a un point similaire a celui des autres inhibiteurs acetylcholjnesterases, de la neostigmine et de la pyridostigrnine. DIE PHARMAKOKINETIK VON EDROPHONIUM BEI NIERENLOSEN U N D NIERENTRANSPLANTATIONSPATIENTEN ZUSAMMBNFAKUNG
Es wurde die Pharmakokinetik von Edrophonium bci Patienten bestimmt, die mit Srickoxydul und Halothan anasthesiert wurden und sich einer Nierentransplantarionsnephrektomic (n = 6) bzw der Transplantation einer von einem verwandten Spender gestifteten Nierc (n = 6) unterzogen. Serumkonzentrarionen von Edrophonium wurden minels Hochdruck-Flussigkeitschromatographic ausgewertet und pharmakokinetische Variablen wurden mittels Analyse ohne Abteile ausgerechnet. Patienten, die sich einer Transplantatjonsncphrektomie unterzogen, zeigten cine bedeutende Steigerung der Efiminationshalbzeit und einen bedeutenden Abfall (67%) der Serumclearance im Vergleich zu Nierentransplantationspatienten oder Patienten mit normaler Nierenfunktion. Pharmakokinepsche Indizien fur Edrophonium bei Patienten, die eipe Nierentransplantation bekamen, unterschieden sich nicht von denen bei Patienten mit normaler Nierenfunkrion. Wir kamen zum Schluss, dass das Ausbleiben der Nierenfunktion die Absonderung von Edrophonium in ahnlichem Masse herabsetzt wie bei anderen Acetylcholincsterase-Inhibitoren, wie Neostigmin und Pyridosagmin. FARMACOCINETICAS DEL EDROFONIO EN PACIENTES NEFRITICOS Y DE TRANSPLANTE DE RINON SUMAR1O
Se determinaron las farmacocineticas del edrofonio en pacientes anestesiados con oxido nitroso y con halotano, sometidos a nefrectomia de transplante de riflon (n = 6) o a transplante de riflon vivo consanguinco (n = 6). Las concentraciones de edrofonio en el suero se evaluaron mediante cromatografia de liquido a alta presion y las las variables farmacocineticas se calcularon usando analisis sin compartimientos. Los pacientes sometidos a nefrectomia de transplante presentaron un incremento significativo en la vida media de la eliminaci6n y una significativa diiminuci6n (67%) en la clarificacion del suero, cuando se efectuo la comparacion con los receptores del transplante de riflon o con pacientes con funciones renales normales. Los indices farmacocineticos relativos al edrofonio, en pacientes sometidos a transplante de
Downloaded from http://bja.oxfordjournals.org/ at Cambridge University on August 17, 2015
Back, D. J., and Calvey, T. N. (1972). Excretion of 1 4 Cedrophonium and its metabolites in bile: role of the liver cell and the peribiliary vascular plexus. Br. J. Pharmacol., 44, 534. Benct, L. Z., and Galeazzi, R. L. (1979). Non-compartmental determination of the steady state volume of distribution. J. Pharm. Sci., 68/ 1071. Bevan, E>. R. (1979). Reversal of pancuronium with edrophonium. Anaesthesia, 34, 614. Calvey, T. N., and Back, D. J. (1973). Biliary excretion of '*Cedrophonium and its glucuronide metabolite in Gunn rats. Arch- Int. Pharmacodyn., 201, 147. Cronnelly, R., Stanski, D. R., Miller, R. D., and Sheiner, L. B. (1980). Pyridostigmine kinetics with and without renal function. Clin. Pharmacol. Ther., 28, 78. Sohn, V. J. (1979). Renal function and the pharmacokinetics of neostigmine in anesthetized man. Anesthesiology, 51, 30. De Ruyter, M. G. M., Cronnelly, R., and Castagnoli, N,. (1980). Rcversed-phase, ion-pair liquid chromatography of quaternary ammonium compounds. Determination of pyridostigmine, qeostigmine, and edrophonium in biological fluids. J. Chromatogr., 183, 193. Duchin, K. L., and Sechrici, R. W. (1978). Inter-relationship between renal hemodynamics, drug kinetics and drug action. Clin. Pharmacol., 3, 58. Kopman, A. F. (i979). Edrophonium antagonism of pancuronium-induced neuromuscular blockade in man. Anesthesiology, 51, 139. Mclman, K. L., and Morelli, H. F. (1978). Clinical Pharmacology, 2nd edn, p. 46. New York: Macmillan. Miller, R. D., and Cullen, D. S. (1976). Renal failure and postoperative respiratory failure: recurarizatior). Br.J. Anaesth., 48, 253. Matteo, R. S., Benet, L.Z., and Sohn, Y. J. (1977). The pharmacokinetics of d-tubocurarine in man with and without renal failure. J. Pharmacol. Exp. Ther., 202, 1. Morris, R. M., Cronnelly, R., Miller, R. D., Stanski, D. R., and Fahey, M. R.(1981). Pharmacokinetics of edrophonium and neostigmine when antagonizing d-tubocurarine neuromuscular blockade in man. Anesthesiology, 54, 399. Sncdecor, G. W. (1962). Statistical Methods,^. 251. Ames. la.: Iowa State University Press. Somogyi, A. A., Shanks, C. A., and Triggs, E. J. (1977). The effect of renal failure on the disposition and neuromuscular blocking action of pancuronium bromide. Europ. J. Clin. Pharmacol., 12, 23.
1313
1314
BRITISH JOURNAL OF ANAESTHESIA
riiion, no se diferenciaron de los de aquellos pacientes con funciones rcnales normales. Concluimos que la ausencia de las funciones renales disminuye la excrecion de edrofonio hasta un grado similar al de otros inhibidores de acetilcolinesterasas, ncostigmina y Rirodostigmjna.
Downloaded from http://bja.oxfordjournals.org/ at Cambridge University on August 17, 2015
PHARMACOKINETICS OF EDROPHONIUM IN ANEPHRIC AND RENAL TRANSPLANT PATIENTS R. B. MORRIS, R. CRONNELLY, R. D. MILLER, D. R. STANSKI AND M. R. FAHEY SUMMARY
Impaired renal function decreases plasma clearance and increases the duration of action of tubocurarine and pancuronium (Pavulon) in anaesthetized patients (Miller et al., 1977; Somogyi, Shanks and Triggs, 1977). This probably does not represent a clinical problem since renal failure also decreases the plasma clearance of the commonly used antagonists, neostigmine and pyridostigmine (Cronnelly et al., 1979, 1980). Recently, edrophonium 0.5-1 .Omgkg"1, has been shown to produce sustained antagonism of non-depolarizing neuromuscular blockade (Bevan, 1979; Kopman, 1979; Morris et al., 1981). This study was designed to determine the influence of renal failure on the pharmacokinetics of edrophonium in anaesthetized patients. METHODS
Informed consent, approved by our Committee on Human Research, was obtained from 12 adult patients. Six of these patients were about to undergo transplant nephrectomy (anephric group), and the six remaining patients were about to receive a living related kidney transplant ROBERT B. MORRIS, MJ)., MARK R. FAHEY, MJJ. (Department of Anesthesia); ROY CRONNELLY, PH.D., M.D., RONALD D.
MILLER, M.D. (Department of Anesthesia and Pharmacology); University of California, San Francisco, California 94143, U.S.A. DONALD R. STANSKI, M.D., Department of Anesthesia and Medicine, Stanford Medical Center, Stanford, California, 94305, U.S.A. 0007-0912/81/121311-04 801.00
(LRKT). Approximately 1 h after the oral administration of diazepam (Valium) lOmg, anaesthesia was induced with thiopentone (Pentothal) 2-4mgkg~ 1 , and maintained with halothane 0.4-0.7% (end-tidal) and 60% nitrous oxide in oxygen, measured by mass spectrometry. Tubocurarine was administered as an i.v. bolus with repeated doses sufficient to maintain approximately a 90% depression of twitch tension. At the end of surgery, the neuromuscular blockade was antagonized with edrophonium l.Omgkg"1 combined with atropine 1.0 mg administered as a 2-min i.v. infusion. Venous blood samples were obtained 2,4, 6, 8,10,15, 30,45, 60, 90,120, 180, 210 and 240min after starting the infusion. Serum was stored at — 30°C until extracted and assayed by high pressure liquid chromatography (De Ruyter, Cronnelly and Castagnoli, 1980). Data were treated using a non-compartmental pharmacokinetic analysis (Benet and Galeazzi, 1979) and differences determined by a Tukey's Test (Snedecor, 1962). Data previously obtained (Morris et al., 1981) from four patients with normal renal function who received edrophonium lmgkg" 1 were analysed by non-compartmental pharmacokinetic analysis and included for comparison. RESULTS
The slope of the elimination phase for the anephric group is less than that of patients with normal renal function, resulting in significantly greater serum © Macmillan Publications Ltd 1981
Downloaded from http://bja.oxfordjournals.org/ at Cambridge University on August 17, 2015
The pharmacokinetics of edrophonium were determined in patients anaesthetized with nitrous oxide and halothane undergoing kidney transplant nephrectomy (n = 6) or transplantation of a live related donor kidney («— 6). Serum concentrations of edrophonium were assayed by high pressure liquid chromatography and pharmacokinetic variables computed using noh-compartmental analysis. Patients undergoing transplant nephrectomy had a significant increase in elimination half-life and a significant decrease (67%) in serum clearance when compared with kidney transplant recipients or patients with normal renal function. Pharmacokinetic indices for edrophonium in patients receiving a kidney transplant did not differ from those in patients with normal renal function. We conclude that absence of renal function decreases excretion of edrophonium to an extent similar to that of other acetylcholinesterase inhibitors, neostigmine and pyridostigmine.
BRITISH JOURNAL Of ANAESTHESIA
1312
Q.
Patients
Normal Anephric Transplant
Cl
(nun)
(litre kg" 1 )
(ml kg min"')
114.0±47 206.0±62* 86.5±23.9
0.87±0.22 0.68±0.13 0.92 + 0.16
8.2±2.7 2.7±1.4* 9.9±2.1
ACKNOWLEDGEMENTS
The authors thank Mr C. R. Pudwill for his excellent technical assistance and acknowledge Oscar Salvatieria jr, M.D., and Nicholas J. Feduska, MJJ., for their co-operation in surgery for
4 •
Downloaded from http://bja.oxfordjournals.org/ at Cambridge University on August 17, 2015
DISCUSSION concentrations of edrophonium in anephric patients after 4h (fig. 1). The data from patients When edrophonium is given in the absence of with normal renal function are taken from a renal function, plasma clearance is decreased and previous study (Morris et al., 1981). elimination half-life prolonged to an extent similar to that of neostigmine and pyridostigmine 2OOOOr (Cronnelly et al., 1979,1980). Plasma clearance of edrophonium is 8.2 ± 2.7 ml kg ~J min ~1 in normal patients and 2.7 ±1.4 ml kg"'min" 1 in patients 10000 • without renal function. Thus, approximately 67% of plasma clearance of edrophonium appears to be dependent on renal excretion, the remainder being dependent on non-renal mechanisms. If renal excretion occurred solely by glomerular filtration, renal clearance of 1-2 ml kg"'min" 1 would be expected (Melman and Morelli, 1978; Duchin and Sechrici, 1978). Larger values, such as o 1000 5.5 ml kg" l min" l reported here, suggest a tubular secretory process. Since edrophonium is not hydrolysed by cholinesterase, this cannot contribute to non-renal clearance. Hepatic metabolism and biliary excretion have been demonstrated in animals (Back and Calvey, 1972; Calvey and Back, 1973) and represent probable pathways for non-renal clearance of edrophonium in man. In the patients 100 80 120 160 200 240 receiving a living related kidney transplant, Tlme(mln) diuresis was induced before administration of FIG. 1. Serum concentration following 2-min i.v. infusion of edrophonium. Under these circumstances, the edrophonium l.Omgkg"' in anaesthetized patients without renal function and with normal renal function. Points represent pharmacokinetics of edrophonium did not differ from those in patients with normal renal function. means ±SD. Similar findings have been reported for tubocurarine (Miller et al., 1977), neostigmine Anephric patients had a significantly decreased (Cronnelly et al., 1979) and pyridostigmine plasma clearance and prolonged elimination half- (Cronnelly et al., 1980). life when compared with patients with normal Problems of prolonged neuromuscular blockade renal function and with those patients who had have occurred in patients with renal failure received a kidney transplant (table I). undergoing anaesthesia and surgery. Renal failure Pharmacokinetics of edrophonium in patients who has been thought to prolong tubocurarine activity had received a kidney transplant were not different more than the antagonist activity of neostigmine from those in patients with normal renal function and pyridostigmine (Miller and Cullen, 1976). If (table I). the plasma concentration is directly related to effect, antagonism by edrophonium should last longer than tubocurarine neuromuscular blockade TABLE I. Pharmacokinetics of edrophonium in antphric and renal in patients with renal failure. Consistent with this transplant patients (means ±SD). * Significant difference hypothesis are our observations of sustained (P<0.05)from normal and transplant. Tf= elimination halfof tubocurarine neuromuscular life, V*" = volume of distribution at steady state, Cl •= clearance antagonism blockade even in the presence of renal failure.
EDJIOPHONIUM PHARMACOKINETICS the parients undergoing renal transplant nephrectomy and living related renal transplantation. This work was supported in part by United States Public Health Service grants numbers GM 15571-12 and GM 26403-02. REFERENCES
LA PHARMACOCINETIQUE DE L'EDROPHONIUM CHEZ LES, PATIENTS SUBISSANT UNE NEPHRECTOMIE ET UNE GREFFE DU REIN RESUME
On a determine la pharmacocinetique de l'edrophonium sur des patients anesthesies au protoxyde d'azote et a liialothane subissant une nephrectomie avec greffe du rein (n => 6) ou une
greffe de rein provenantd'undonneurvivantapparente(n = 6). Les concentrations d'edrophonium dans le serum ont etc analysees par la chromatographic en phase liquide a haute pression et les variables pharmacocinetiques ont etc calculees a l'aide d'une analyse non compartimentee. Les patients subissant une nephrectomie avec greffe ont eu une augmentation significative de la demi-vie d'elimination et une diminution significative (67%) de l'epuration du serum par rapport aux receveurs de greffes de rein ou aux patients dont les reins fonctionnaient normalement. Les indices pharmacocinetiques de l'edrophonium dea patients subissant une greffe de rein n'ont r)as differe. de ceux del patients dont lei reins fonctionnaient normalement. Nous en avons conclu que l'absencc de fonction renalc diminue l'excretion de 1'edro.phonium a un point similaire a celui des autres inhibiteurs acetylcholjnesterases, de la neostigmine et de la pyridostigrnine. DIE PHARMAKOKINETIK VON EDROPHONIUM BEI NIERENLOSEN U N D NIERENTRANSPLANTATIONSPATIENTEN ZUSAMMBNFAKUNG
Es wurde die Pharmakokinetik von Edrophonium bci Patienten bestimmt, die mit Srickoxydul und Halothan anasthesiert wurden und sich einer Nierentransplantarionsnephrektomic (n = 6) bzw der Transplantation einer von einem verwandten Spender gestifteten Nierc (n = 6) unterzogen. Serumkonzentrarionen von Edrophonium wurden minels Hochdruck-Flussigkeitschromatographic ausgewertet und pharmakokinetische Variablen wurden mittels Analyse ohne Abteile ausgerechnet. Patienten, die sich einer Transplantatjonsncphrektomie unterzogen, zeigten cine bedeutende Steigerung der Efiminationshalbzeit und einen bedeutenden Abfall (67%) der Serumclearance im Vergleich zu Nierentransplantationspatienten oder Patienten mit normaler Nierenfunktion. Pharmakokinepsche Indizien fur Edrophonium bei Patienten, die eipe Nierentransplantation bekamen, unterschieden sich nicht von denen bei Patienten mit normaler Nierenfunkrion. Wir kamen zum Schluss, dass das Ausbleiben der Nierenfunktion die Absonderung von Edrophonium in ahnlichem Masse herabsetzt wie bei anderen Acetylcholincsterase-Inhibitoren, wie Neostigmin und Pyridosagmin. FARMACOCINETICAS DEL EDROFONIO EN PACIENTES NEFRITICOS Y DE TRANSPLANTE DE RINON SUMAR1O
Se determinaron las farmacocineticas del edrofonio en pacientes anestesiados con oxido nitroso y con halotano, sometidos a nefrectomia de transplante de riflon (n = 6) o a transplante de riflon vivo consanguinco (n = 6). Las concentraciones de edrofonio en el suero se evaluaron mediante cromatografia de liquido a alta presion y las las variables farmacocineticas se calcularon usando analisis sin compartimientos. Los pacientes sometidos a nefrectomia de transplante presentaron un incremento significativo en la vida media de la eliminaci6n y una significativa diiminuci6n (67%) en la clarificacion del suero, cuando se efectuo la comparacion con los receptores del transplante de riflon o con pacientes con funciones renales normales. Los indices farmacocineticos relativos al edrofonio, en pacientes sometidos a transplante de
Downloaded from http://bja.oxfordjournals.org/ at Cambridge University on August 17, 2015
Back, D. J., and Calvey, T. N. (1972). Excretion of 1 4 Cedrophonium and its metabolites in bile: role of the liver cell and the peribiliary vascular plexus. Br. J. Pharmacol., 44, 534. Benct, L. Z., and Galeazzi, R. L. (1979). Non-compartmental determination of the steady state volume of distribution. J. Pharm. Sci., 68/ 1071. Bevan, E>. R. (1979). Reversal of pancuronium with edrophonium. Anaesthesia, 34, 614. Calvey, T. N., and Back, D. J. (1973). Biliary excretion of '*Cedrophonium and its glucuronide metabolite in Gunn rats. Arch- Int. Pharmacodyn., 201, 147. Cronnelly, R., Stanski, D. R., Miller, R. D., and Sheiner, L. B. (1980). Pyridostigmine kinetics with and without renal function. Clin. Pharmacol. Ther., 28, 78. Sohn, V. J. (1979). Renal function and the pharmacokinetics of neostigmine in anesthetized man. Anesthesiology, 51, 30. De Ruyter, M. G. M., Cronnelly, R., and Castagnoli, N,. (1980). Rcversed-phase, ion-pair liquid chromatography of quaternary ammonium compounds. Determination of pyridostigmine, qeostigmine, and edrophonium in biological fluids. J. Chromatogr., 183, 193. Duchin, K. L., and Sechrici, R. W. (1978). Inter-relationship between renal hemodynamics, drug kinetics and drug action. Clin. Pharmacol., 3, 58. Kopman, A. F. (i979). Edrophonium antagonism of pancuronium-induced neuromuscular blockade in man. Anesthesiology, 51, 139. Mclman, K. L., and Morelli, H. F. (1978). Clinical Pharmacology, 2nd edn, p. 46. New York: Macmillan. Miller, R. D., and Cullen, D. S. (1976). Renal failure and postoperative respiratory failure: recurarizatior). Br.J. Anaesth., 48, 253. Matteo, R. S., Benet, L.Z., and Sohn, Y. J. (1977). The pharmacokinetics of d-tubocurarine in man with and without renal failure. J. Pharmacol. Exp. Ther., 202, 1. Morris, R. M., Cronnelly, R., Miller, R. D., Stanski, D. R., and Fahey, M. R.(1981). Pharmacokinetics of edrophonium and neostigmine when antagonizing d-tubocurarine neuromuscular blockade in man. Anesthesiology, 54, 399. Sncdecor, G. W. (1962). Statistical Methods,^. 251. Ames. la.: Iowa State University Press. Somogyi, A. A., Shanks, C. A., and Triggs, E. J. (1977). The effect of renal failure on the disposition and neuromuscular blocking action of pancuronium bromide. Europ. J. Clin. Pharmacol., 12, 23.
1313
1314
BRITISH JOURNAL OF ANAESTHESIA
riiion, no se diferenciaron de los de aquellos pacientes con funciones rcnales normales. Concluimos que la ausencia de las funciones renales disminuye la excrecion de edrofonio hasta un grado similar al de otros inhibidores de acetilcolinesterasas, ncostigmina y Rirodostigmjna.
Downloaded from http://bja.oxfordjournals.org/ at Cambridge University on August 17, 2015