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BETA-BLOCKERS IN PATIENTS WITH LIVER DISEASE
1357 advice to a wide audience on such imprecise documentation. The other reference12 clearly states that each dose consisted of 20 mg administered intravenously at a rate of 1 mg/min and that a maximum of three doses was given at intervals of 20 min, maximum cumulative dose 60 mg. However, even then life-threatening sinus bradycardia was found in 2 of 20
patients. Several other reports also support an intravenous dose of 20 mg Fogelman et ail. 13 used a fixed dose of 20 mg as being both "effective and safe"; Frishmanl4 concludes that the dose of sotalol is similar to that of oxprenolol; Tackels and Lauwers1S "never exceeded" 60 mg as three doses each of 20 mg; and Jadrogue and Jimenez gave a dose of 20-80 mg, but in patients with arrhythmias due to acute infarction found that even 20 mg produced an increase in pulmonary wedge pres-
sure. 16s A single dose of 10 mg of sotalol given intravenously to patients before they were moved from their homes to the hospital caused more bradycardia than did practolol 10 mg." The dose of practolol in acute myocardial infarction is better documented than that of sotalol, with full haemodynamics available for doses of 5 mg and 25 Mg. 18 Therefore, bearing in mind that the dose of sotalol is likely to be somewhat similar to practolol, and at the same time practolol may be somewhat less cardiodepressant, I would not recommend a dose exceeding 20 mg except in an expert coronary care unit with full hsemodynamic monitoring and facilities for coping with any untoward bradycardia.
Thus, mean blood concentrations of the drug are increased due to (a) and (b); and these changes have multiplicative rather than additive effects on the total area under the curve. 21 There is another aspect to beta-blocker therapy in liver disease which may be clinically relevant. Beta-blockade lowers cardiac output and increases peripheral arterial resistance. In monkeys dl-propranolol (unlike d-propranolol, which lacks a beta-blocking effect) increased hepatic arterial resistance by 57%22 and decreased hepatic blood flow by 31%." Beta-blockers therefore have an inherent tendency to reduce their own hepatic clearances-unhappily, those drugs with the highest intrinsic clearances (e.g., alprenolol and propranolol) are the ones that are most dependent on liver blood flow for their hepatic clearances. It is moreover these very compounds that are most vulnerable to the altered pharmacokinetics in liver disease as outlined above. This reduction of liver blood flow by the beta-blocker would only aggravate the situation. The already high blood concentrations of the drug together with a possible increase in its free and active fraction would enhance the pharmacodynamic response. This would in turn lead to an even greater reduction of liver blood flow, a further decrease in hepatic clearance, and soon.
MRC-UCT Ischæmic Heart Disease Research Unit,
Department of Medicine, University of Cape Town, and Hypertension Clinic, Groote Schuur Hospital, Cape Town, South Africa
(a) Increased systemic availability due both to a reduction in intrinsic clearance (and therefore first-pass extraction) and to bypassing of the first-pass effect by portasystemic and intrahepatic shunts. (b) Decreased systemic clearance due predominantly to a reduced intrinsic clearance and only secondarily -to a decreased liver blood flow. (c) Increased free (unbound) fraction of propranolol. 19
Beta-blockers with low intrinsic clearances (minimal firstextractions) and preferably cardioselective properties (to avoid liver blood flow changes) would appear to offer the most rational therapeutic prospect to patients with liver disease. pass
L. H. OPIE
Department of Pharmacology, University of Cape Town Medical School, Observatory, Cape 7925, South Africa
ASHLEY H. ROBINS
BETA-BLOCKERS IN PATIENTS WITH LIVER DISEASE
SIR,-Professor Opie (March 29, p. 693) cautions against the use of high hepatic clearance beta-blockers (e.g., alprenolol and propranolol) in patients with liver disease. Pharmacokinetic studies in cirrhotic patients after the oral administration of propranoloP9,2O and other drugs of high intrinsic clearance (substantial first-pass hepatic extraction) 21 have demonstrated the following: 12. Latour Y, Dumont G, Brosseau A, LeLorier J. Effects of sotalol in twenty patients with cardiac arrhythmias. Int J Clin Pharmacol Biopharm 1977; 15: 275-78. 13. Fogelman F, Lightman SL, Sillett RW, McNicol MW. Clinical assessment of sotalol as an anti-arrhythmic agent. In: Snart AG, ed. Advances in betaadrenergic blocking therapy. Sotalol, Vol. 3. Amsterdam: Excerpta Medica, 1974: 53-56. 14. Frishman W, Silverman R. Clinical pharmacology of the new beta-adrenergic blocking drugs. III. Comparative clinical experience and new therapeutic applications. Am Heart J 1979 98: 119-31. 15. Tackels R, Lauwers P. Treatment of chronic arrhythmias with sotalol. In: Snart AG, ed. Advances in beta-adrenergic blocking therapy. Sotalol. vol. 3. Amsterdam: Excerpta Medica, 1974; 48-52. 16. Jadraque LM, Jiménez DL. Sotalol in the treatment of cardiac arrhythmias. In: Snart AG, ed. Advances in beta-adrenergic blocking therapy. Sotalol. Vol. 3. Amsterdam: Excerpta Medica, 1974; 57-69. 17. Mulholland HC, Pantridge JF. Heart wave changes during movement of patients with acute myocardial infarction. Lancet 1974; i: 1244-47. 18. Jewitt DA. Antiarrhythmic drugs and their mechanisms of action. In: Oliver MF, ed. Modern trends in cardiology. vol. 3. London: Butterworths, 1975; 333-71. 19. Wood AJJ, Kornhauser DM, Wilkinson GR, Shand DG, Branch RA. The influence of cirrhosis on steady-state blood concentrations of unbound propranolol after oral administration. Clin Pharmacokin 1978; 3: 478-87. 20. Pessayre D, Lebrec D, Descatoire V, Peignoux M, Benhamou J. Mechanisms for reduced drug clearance in patients with cirrhosis. Gastroenterology
1978; 74: 566-71. 21. Neal EA, Meffin PJ, Gregory PB, Blaschke TF. Enhanced bioavailability and decreased clearance of analgesics in patients with cirrhosis. Gastroenterology 1979; 79: 96-102.
GLUCAGON FOR
&bgr;-BLOCKER POISONING SIR,-An editorial (April 12) and subsequent correspondence (May 10) discuss the treatment of p-blocker poisoning. You suggest that atropine and isoprenaline should be given first, followed by glucagon if there was an inadequate response. However, any delay in effective treatment may result in death. p-adrenergic agonists are often unsuccessfulm3 or there is an appreciable delay in restoring an adequate circulation.4,s Pacing may be ineffectual3.4 and is not always immediately available. Glucagon, in large doses, is effective in animals1.6,7 and, apparently, in man,1,2.5,8 even though other drugs were present. The effect is almost immediate, and the dosage regimen simple, but the use of diluent containing phenol should be avoided.*’* There are no reports of glucagon, AS, Evans GH, Shand DG. Regional hemodynamic effects of betaadrenergic blockade with propranolol in the unanesthetized primate. Amer Heart J 1973; 85: 97-102. 23. Nies AS, Evans GH, Shand DG. The hemodynamic effects of beta adrenergic blockade on the flow-dependent hepatic clearance of propranolol. J Phar-
22. Nies
macol Exp Ther 1973; 184: 716-20. EJ, Malindzak GS. Glucagon and isoproterenol in reversing propranolol toxicity. Arch Intern Med 1973; 132: 840-43 2. Ward DE, Jones B. Glucagon and beta-blocker toxicity. Br Med J 1976; ii: 1. Kosinski
151. 3. Khan A, Muscat-Baron JM. Fatal oxyprenolol poisoning. Br Med J 1977; i: 552. 4. Mattingly PC. Oxyprenolol overdose with survival. Br Med J 1977; i: 776. 5. Jacobsen D, Helgeland A, Koss A. Treatment of beta-blocker poisoning. Lancet 1980; i: 1031. 6. Glick G, Parmley WW, Wechsler AS, Sonnenblick EH. Glucagon. Circ Res
1968; 22: 789-99. 7. Lucchesi BR. Cardiac actions of glucagon. Circ Res 1968; 22: 777-87. 8. Illingworth RN. Glucagon for beta-blocker poisoning. Practitioner
223: 683-85.
1979;
patients. Several other reports also support an intravenous dose of 20 mg Fogelman et ail. 13 used a fixed dose of 20 mg as being both "effective and safe"; Frishmanl4 concludes that the dose of sotalol is similar to that of oxprenolol; Tackels and Lauwers1S "never exceeded" 60 mg as three doses each of 20 mg; and Jadrogue and Jimenez gave a dose of 20-80 mg, but in patients with arrhythmias due to acute infarction found that even 20 mg produced an increase in pulmonary wedge pres-
sure. 16s A single dose of 10 mg of sotalol given intravenously to patients before they were moved from their homes to the hospital caused more bradycardia than did practolol 10 mg." The dose of practolol in acute myocardial infarction is better documented than that of sotalol, with full haemodynamics available for doses of 5 mg and 25 Mg. 18 Therefore, bearing in mind that the dose of sotalol is likely to be somewhat similar to practolol, and at the same time practolol may be somewhat less cardiodepressant, I would not recommend a dose exceeding 20 mg except in an expert coronary care unit with full hsemodynamic monitoring and facilities for coping with any untoward bradycardia.
Thus, mean blood concentrations of the drug are increased due to (a) and (b); and these changes have multiplicative rather than additive effects on the total area under the curve. 21 There is another aspect to beta-blocker therapy in liver disease which may be clinically relevant. Beta-blockade lowers cardiac output and increases peripheral arterial resistance. In monkeys dl-propranolol (unlike d-propranolol, which lacks a beta-blocking effect) increased hepatic arterial resistance by 57%22 and decreased hepatic blood flow by 31%." Beta-blockers therefore have an inherent tendency to reduce their own hepatic clearances-unhappily, those drugs with the highest intrinsic clearances (e.g., alprenolol and propranolol) are the ones that are most dependent on liver blood flow for their hepatic clearances. It is moreover these very compounds that are most vulnerable to the altered pharmacokinetics in liver disease as outlined above. This reduction of liver blood flow by the beta-blocker would only aggravate the situation. The already high blood concentrations of the drug together with a possible increase in its free and active fraction would enhance the pharmacodynamic response. This would in turn lead to an even greater reduction of liver blood flow, a further decrease in hepatic clearance, and soon.
MRC-UCT Ischæmic Heart Disease Research Unit,
Department of Medicine, University of Cape Town, and Hypertension Clinic, Groote Schuur Hospital, Cape Town, South Africa
(a) Increased systemic availability due both to a reduction in intrinsic clearance (and therefore first-pass extraction) and to bypassing of the first-pass effect by portasystemic and intrahepatic shunts. (b) Decreased systemic clearance due predominantly to a reduced intrinsic clearance and only secondarily -to a decreased liver blood flow. (c) Increased free (unbound) fraction of propranolol. 19
Beta-blockers with low intrinsic clearances (minimal firstextractions) and preferably cardioselective properties (to avoid liver blood flow changes) would appear to offer the most rational therapeutic prospect to patients with liver disease. pass
L. H. OPIE
Department of Pharmacology, University of Cape Town Medical School, Observatory, Cape 7925, South Africa
ASHLEY H. ROBINS
BETA-BLOCKERS IN PATIENTS WITH LIVER DISEASE
SIR,-Professor Opie (March 29, p. 693) cautions against the use of high hepatic clearance beta-blockers (e.g., alprenolol and propranolol) in patients with liver disease. Pharmacokinetic studies in cirrhotic patients after the oral administration of propranoloP9,2O and other drugs of high intrinsic clearance (substantial first-pass hepatic extraction) 21 have demonstrated the following: 12. Latour Y, Dumont G, Brosseau A, LeLorier J. Effects of sotalol in twenty patients with cardiac arrhythmias. Int J Clin Pharmacol Biopharm 1977; 15: 275-78. 13. Fogelman F, Lightman SL, Sillett RW, McNicol MW. Clinical assessment of sotalol as an anti-arrhythmic agent. In: Snart AG, ed. Advances in betaadrenergic blocking therapy. Sotalol, Vol. 3. Amsterdam: Excerpta Medica, 1974: 53-56. 14. Frishman W, Silverman R. Clinical pharmacology of the new beta-adrenergic blocking drugs. III. Comparative clinical experience and new therapeutic applications. Am Heart J 1979 98: 119-31. 15. Tackels R, Lauwers P. Treatment of chronic arrhythmias with sotalol. In: Snart AG, ed. Advances in beta-adrenergic blocking therapy. Sotalol. vol. 3. Amsterdam: Excerpta Medica, 1974; 48-52. 16. Jadraque LM, Jiménez DL. Sotalol in the treatment of cardiac arrhythmias. In: Snart AG, ed. Advances in beta-adrenergic blocking therapy. Sotalol. Vol. 3. Amsterdam: Excerpta Medica, 1974; 57-69. 17. Mulholland HC, Pantridge JF. Heart wave changes during movement of patients with acute myocardial infarction. Lancet 1974; i: 1244-47. 18. Jewitt DA. Antiarrhythmic drugs and their mechanisms of action. In: Oliver MF, ed. Modern trends in cardiology. vol. 3. London: Butterworths, 1975; 333-71. 19. Wood AJJ, Kornhauser DM, Wilkinson GR, Shand DG, Branch RA. The influence of cirrhosis on steady-state blood concentrations of unbound propranolol after oral administration. Clin Pharmacokin 1978; 3: 478-87. 20. Pessayre D, Lebrec D, Descatoire V, Peignoux M, Benhamou J. Mechanisms for reduced drug clearance in patients with cirrhosis. Gastroenterology
1978; 74: 566-71. 21. Neal EA, Meffin PJ, Gregory PB, Blaschke TF. Enhanced bioavailability and decreased clearance of analgesics in patients with cirrhosis. Gastroenterology 1979; 79: 96-102.
GLUCAGON FOR
&bgr;-BLOCKER POISONING SIR,-An editorial (April 12) and subsequent correspondence (May 10) discuss the treatment of p-blocker poisoning. You suggest that atropine and isoprenaline should be given first, followed by glucagon if there was an inadequate response. However, any delay in effective treatment may result in death. p-adrenergic agonists are often unsuccessfulm3 or there is an appreciable delay in restoring an adequate circulation.4,s Pacing may be ineffectual3.4 and is not always immediately available. Glucagon, in large doses, is effective in animals1.6,7 and, apparently, in man,1,2.5,8 even though other drugs were present. The effect is almost immediate, and the dosage regimen simple, but the use of diluent containing phenol should be avoided.*’* There are no reports of glucagon, AS, Evans GH, Shand DG. Regional hemodynamic effects of betaadrenergic blockade with propranolol in the unanesthetized primate. Amer Heart J 1973; 85: 97-102. 23. Nies AS, Evans GH, Shand DG. The hemodynamic effects of beta adrenergic blockade on the flow-dependent hepatic clearance of propranolol. J Phar-
22. Nies
macol Exp Ther 1973; 184: 716-20. EJ, Malindzak GS. Glucagon and isoproterenol in reversing propranolol toxicity. Arch Intern Med 1973; 132: 840-43 2. Ward DE, Jones B. Glucagon and beta-blocker toxicity. Br Med J 1976; ii: 1. Kosinski
151. 3. Khan A, Muscat-Baron JM. Fatal oxyprenolol poisoning. Br Med J 1977; i: 552. 4. Mattingly PC. Oxyprenolol overdose with survival. Br Med J 1977; i: 776. 5. Jacobsen D, Helgeland A, Koss A. Treatment of beta-blocker poisoning. Lancet 1980; i: 1031. 6. Glick G, Parmley WW, Wechsler AS, Sonnenblick EH. Glucagon. Circ Res
1968; 22: 789-99. 7. Lucchesi BR. Cardiac actions of glucagon. Circ Res 1968; 22: 777-87. 8. Illingworth RN. Glucagon for beta-blocker poisoning. Practitioner
223: 683-85.
1979;