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PLASMA PROTEIN BINDING OF BUPIVACAINE AND ITS INTERACTION WITH OTHER DRUGS IN MAN
1030
BRITISH JOURNAL OF ANAESTHESIA
distribution, calculated on the basis of total blood concentrations, and is accompanied by an increase in the half-life of both total and free drug. Therefore, although initial free drug concentrations might not change to any great extent in the presence of a displacing agent, their persistence, and so the persistence of any pharmacological effects, could be prolonged. The above arguments are based on a change in total blood binding of the drug, that is binding to plasma and erythrocyte components. However, if displacement occurs only in the plasma and not on or in the erythrocytes, binding sites in the latter might take up some of the excess free drug (Tucker et al., 1970; Hahn et al., 1973) and any change in total blood drug concentrations would be buffered by this effect. This would have the effect of reducing the overall rate of drug elimination by the liver. G. T. TUCKER
Sheffield, England
REFERENCES
Borga, O., Azarnoff, D. L., Forschell, G. P., and Sjogrist, F. (1969). Plasma protein binding of tricyclic antidepressants in man. Biochem. Pharmacol., 18, 2135. Goodman, L. S., and Gilman, A. (1970). The Pharmacological Basis of Therapeutics, 4th edn., p. 717. London: Macmillan. Jensen, B. N., and Grynderup, V. (1966). Studies on the metabolism of phenytoin. Epilepsia, 7, 238. Reddin, P. C. (1967). Blood demerol studies. Arkansas Med. Soc. J., 63, 187. Spector, A. A., and Santos, E. C. (1973). Influence of free fatty acid concentration on dry binding to plasma albumin. Ann. N.Y. Acad. Sci., 226, 24. POSTOPERATIVE FLUID AND ELECTROLYTE REQUIREMENTS
L. E. MATHER
Downloaded from http://bja.oxfordjournals.org/ at Université Laval on June 28, 2015
Sir,—The paper by the Dallas group (Jenkins, Giesecke and Johnson, 1975) concerning perioperative fluid and electrolyte balance emphasizes the great difference between REFERENCES American and British practice in this field. There is scarcely Ghoneim, M. M., and Pandya, H. (1974). Plasma protein a paragraph in their paper with which I agree. However, binding of bupivacaine and its interaction with other perhaps I might be allowed to limit my comments to three drugs in man. Br.J. Anaesth., 46, 435. points. Hahn, I., Krieglstein, G., Kieglstein, J., and Tschentscher, First, the description of their regimens is interesting by K. (1973). Distribution of chlorpromazine in a simplified virtue of its ingenious and illogical complexity. However, blood influenced by various drugs. Naunyn. Schmiedebergs. it is irrelevant to British practice as one of the solutions used, Arch. Pharmacol, 278, 35. 5% dextrose in a balanced salt solution, is not commonly Hammer, W. M., and Sjoqvist, F. (1967). Plasma levels of available in this country. The amounts of fluid used, monomethylated tricyclic antidepressants during treat- although thankfully less than those recommended by the ment with imipramine-like compounds. Life Set., 6, 1895. same group 10 years ago, are still far in excess of that Mather, L. E., and Tucker, G. T. (1975). Meperidine considered safe by British anaesthetists and surgeons. It kinetics in man: intravenous injection in surgical patients must be remembered that a rapid infusion of only 1-2 litre and volunteers. Clin. Pharmacol. Ther., (in press). normal saline to fit, healthy adults who are not subject to the Smith, S. E., and Rawlins, M. D. (1973). Variability in profound fluid retention of surgery and anaesthesia show Human Drug Response. London: Butterworths. pulmonary changes which may lead to impairment of pulTucker, G. T., Boyes, R. N., Bridenbaugh, P. O., and monary gas exchange (Collins et al., 1973). Moore, D. C. (1970). Binding of anilide-type local Second, the rationale for giving 5% dextrose in water to anesthetics in human plasma. I: Relationships between reduce "renal work" is appealing until it is realized that binding, physicochemical properties, and anesthetic renal work, as assessed by oxygen consumption, is expended activity. Anesthesiology, 33, 287. in reabsorbing rather than excreting solute. Eighty per cent Mather, L. E. (1975). Pharmacokinetics of local of renal oxygen consumption is concerned with reabsorbing anaesthetic agents. Br. J. Anaesth., 47, 213. sodium. Thus, renal work can be reduced only by decreasing the amount of sodium presented to the proximal tubule, by Sir,—We would like to thank Drs Tucker and Mather for reducing G.F.R. or by using agents which decrease tubular their interest in our paper. We still think that we used sodium reabsorption. concentrations of displacing drugs that can occur during I would dispute that urine output during surgery their clinical use. Our references are the following: for is Third, guide to the adequacy of fluid replacement. It is diphenylhydantoin, Jensen and Grynderup (1966); quini- mya good experience that anaesthesia and surgery are always dine, Goodman and Gilman (1970); pethidine, Reddin associated severe oliguria unless diuretic agents or a (1967); and desipramine, Borga and colleagues (1969). fluid load with are given or unless renal perfusion is altered. Incidentally, the volume of the buffer compartment was not Even with a fluid load of more than 10 ml/kg, only half the significantly different from that of the plasma compartment administered is excreted (Fieber and Jones, 1967). at the end of dialysis. The difference between these refer- Thus, a urinefluid output of 50-100 ml/hr in the immediate ences and those cited by Tucker and Mather may be the perioperative period is suggestive of fluid overload rather result of different methods of analysis. The cause of the than normal renal function. decreased plasma binding of bupivacaine in patients who D. R. BEVAN received pethidine as a pre-medicant may be the pethidine London itself. However, if we accept Tucker's and Mather's figures of pethidine concentrations, one may speculate about other REFERENCES causes. For example, the stress of impending surgery may increase the circulating free fatty acids which may displace Collins, J. V., Cochrane, G. M., David, J., Benator, S. R., bupivacaine from its binding sites (Spector and Santos, and Clark, T. J. H. (1973). Some aspects of pulmonary 1973). The rest of Tucker's and Mather's letter explains in function after rapid saline infusion in healthy subjects. detail our statement that "Apart from accidental intraClin. Sci., 45, 407. vascular injection or gross overdosage a decrease in binding Fieber, W. W., and Jones, J. R. (1967). Operative fluid would release only a small absolute amount of drug." therapy. Anesth. Analg. (Cleve.), 46, 401. Jenkins, M. T., Giesecke, A. H., and Johnson, E. R. (1975). M. M. GHONEIM The postoperative patient and his fluid and electrolyte H. PANDYA requirements. Br. J. Anaesth., 47, 143. Iowa Seattle, U.S.A.
BRITISH JOURNAL OF ANAESTHESIA
distribution, calculated on the basis of total blood concentrations, and is accompanied by an increase in the half-life of both total and free drug. Therefore, although initial free drug concentrations might not change to any great extent in the presence of a displacing agent, their persistence, and so the persistence of any pharmacological effects, could be prolonged. The above arguments are based on a change in total blood binding of the drug, that is binding to plasma and erythrocyte components. However, if displacement occurs only in the plasma and not on or in the erythrocytes, binding sites in the latter might take up some of the excess free drug (Tucker et al., 1970; Hahn et al., 1973) and any change in total blood drug concentrations would be buffered by this effect. This would have the effect of reducing the overall rate of drug elimination by the liver. G. T. TUCKER
Sheffield, England
REFERENCES
Borga, O., Azarnoff, D. L., Forschell, G. P., and Sjogrist, F. (1969). Plasma protein binding of tricyclic antidepressants in man. Biochem. Pharmacol., 18, 2135. Goodman, L. S., and Gilman, A. (1970). The Pharmacological Basis of Therapeutics, 4th edn., p. 717. London: Macmillan. Jensen, B. N., and Grynderup, V. (1966). Studies on the metabolism of phenytoin. Epilepsia, 7, 238. Reddin, P. C. (1967). Blood demerol studies. Arkansas Med. Soc. J., 63, 187. Spector, A. A., and Santos, E. C. (1973). Influence of free fatty acid concentration on dry binding to plasma albumin. Ann. N.Y. Acad. Sci., 226, 24. POSTOPERATIVE FLUID AND ELECTROLYTE REQUIREMENTS
L. E. MATHER
Downloaded from http://bja.oxfordjournals.org/ at Université Laval on June 28, 2015
Sir,—The paper by the Dallas group (Jenkins, Giesecke and Johnson, 1975) concerning perioperative fluid and electrolyte balance emphasizes the great difference between REFERENCES American and British practice in this field. There is scarcely Ghoneim, M. M., and Pandya, H. (1974). Plasma protein a paragraph in their paper with which I agree. However, binding of bupivacaine and its interaction with other perhaps I might be allowed to limit my comments to three drugs in man. Br.J. Anaesth., 46, 435. points. Hahn, I., Krieglstein, G., Kieglstein, J., and Tschentscher, First, the description of their regimens is interesting by K. (1973). Distribution of chlorpromazine in a simplified virtue of its ingenious and illogical complexity. However, blood influenced by various drugs. Naunyn. Schmiedebergs. it is irrelevant to British practice as one of the solutions used, Arch. Pharmacol, 278, 35. 5% dextrose in a balanced salt solution, is not commonly Hammer, W. M., and Sjoqvist, F. (1967). Plasma levels of available in this country. The amounts of fluid used, monomethylated tricyclic antidepressants during treat- although thankfully less than those recommended by the ment with imipramine-like compounds. Life Set., 6, 1895. same group 10 years ago, are still far in excess of that Mather, L. E., and Tucker, G. T. (1975). Meperidine considered safe by British anaesthetists and surgeons. It kinetics in man: intravenous injection in surgical patients must be remembered that a rapid infusion of only 1-2 litre and volunteers. Clin. Pharmacol. Ther., (in press). normal saline to fit, healthy adults who are not subject to the Smith, S. E., and Rawlins, M. D. (1973). Variability in profound fluid retention of surgery and anaesthesia show Human Drug Response. London: Butterworths. pulmonary changes which may lead to impairment of pulTucker, G. T., Boyes, R. N., Bridenbaugh, P. O., and monary gas exchange (Collins et al., 1973). Moore, D. C. (1970). Binding of anilide-type local Second, the rationale for giving 5% dextrose in water to anesthetics in human plasma. I: Relationships between reduce "renal work" is appealing until it is realized that binding, physicochemical properties, and anesthetic renal work, as assessed by oxygen consumption, is expended activity. Anesthesiology, 33, 287. in reabsorbing rather than excreting solute. Eighty per cent Mather, L. E. (1975). Pharmacokinetics of local of renal oxygen consumption is concerned with reabsorbing anaesthetic agents. Br. J. Anaesth., 47, 213. sodium. Thus, renal work can be reduced only by decreasing the amount of sodium presented to the proximal tubule, by Sir,—We would like to thank Drs Tucker and Mather for reducing G.F.R. or by using agents which decrease tubular their interest in our paper. We still think that we used sodium reabsorption. concentrations of displacing drugs that can occur during I would dispute that urine output during surgery their clinical use. Our references are the following: for is Third, guide to the adequacy of fluid replacement. It is diphenylhydantoin, Jensen and Grynderup (1966); quini- mya good experience that anaesthesia and surgery are always dine, Goodman and Gilman (1970); pethidine, Reddin associated severe oliguria unless diuretic agents or a (1967); and desipramine, Borga and colleagues (1969). fluid load with are given or unless renal perfusion is altered. Incidentally, the volume of the buffer compartment was not Even with a fluid load of more than 10 ml/kg, only half the significantly different from that of the plasma compartment administered is excreted (Fieber and Jones, 1967). at the end of dialysis. The difference between these refer- Thus, a urinefluid output of 50-100 ml/hr in the immediate ences and those cited by Tucker and Mather may be the perioperative period is suggestive of fluid overload rather result of different methods of analysis. The cause of the than normal renal function. decreased plasma binding of bupivacaine in patients who D. R. BEVAN received pethidine as a pre-medicant may be the pethidine London itself. However, if we accept Tucker's and Mather's figures of pethidine concentrations, one may speculate about other REFERENCES causes. For example, the stress of impending surgery may increase the circulating free fatty acids which may displace Collins, J. V., Cochrane, G. M., David, J., Benator, S. R., bupivacaine from its binding sites (Spector and Santos, and Clark, T. J. H. (1973). Some aspects of pulmonary 1973). The rest of Tucker's and Mather's letter explains in function after rapid saline infusion in healthy subjects. detail our statement that "Apart from accidental intraClin. Sci., 45, 407. vascular injection or gross overdosage a decrease in binding Fieber, W. W., and Jones, J. R. (1967). Operative fluid would release only a small absolute amount of drug." therapy. Anesth. Analg. (Cleve.), 46, 401. Jenkins, M. T., Giesecke, A. H., and Johnson, E. R. (1975). M. M. GHONEIM The postoperative patient and his fluid and electrolyte H. PANDYA requirements. Br. J. Anaesth., 47, 143. Iowa Seattle, U.S.A.