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Interaction between amiodarone and phenytoin
posterior leaflet8 Now a new cause has been found-namely, ASA. Clinical diaenosis of ASA in a natient with MVP is difticult, because a midsystolic click, which is the only auscultatory clue to the presence of ASA, is a common finding in MVP. The recent surge in the reported prevalence of ASA is certainly the result of increased use of echocardiography, both precordialiO and transesophageal,’ ’ and increased awareness of the entity. The true prevalence of interatria1 shunting in ASA might have been underestimated before the routine use of contrast echocardiography in conjunction with performance of the Valsalva maneuver~6.12,13
This “newly discovered” cause of stroke in patients with MVP also has an important therapeutic implication. The embolic risk here would make what would otherwise have been a simple anatomic curiosity a potentially serious anomaly. This has led some authors to propose surgical repair of ASA associated with systemic embolism, irrespective of its size, in order to prevent the risk of embolic recurrence and to avoid the need for lifelong anticoagulant therapy.i4 Teung 0. Cheng, MD Washington, D.C. 30 July 1990 1. Rahko PS, Xu QB. Increased prevalence of atria1 septal aneurysm in mitral valve prolapse. Am J Cardiol 1990:66:235-231. 2. Iliceto S, Papa A,Sorino M, Rizzon P. Combined atria1 septal aneurysm and mitral valve prolapse: detection by two-dimensional echocardiography. Am J Cardiol 1984;54: 115 l1153. 3. Roberts WC. Aneurysm (redundancy) of the atria1 septum (fossa ovale membrane) and prolapse (redundancy) of the mitral valve. Am J Cardiol 1984;54:1153-1154. 4. Gallet B, Malergue MC, Adams C, Saudemont JP, Collot AMC, Druon MC, Hiltgen M. Atria1 septal aneurysm-a potential cause of systemic embolism. An echocardiographic study. Br Heart J 1985;53:292-297. 5. Belkin RN, Waugh RA, Kisslo J. Interatrial shunting in atrial septal aneurysm. Am J Cardial 1986;57:310-312. 6. Cheng TO. Paradoxical embolism. A diagnostic challenge and its detection during life. Circulation 1976;53:565-568. 7. Cheng TO. Mitral valve prolapse. Dis Man 1987;33:481-534. 6. Cheng TO. Mitral valve prolapse. Annu Reu Med 1989:40:201-211. 9. Alexander MD, Bloom KR, Hart P, D’Silva F, Murgo JP. Atria1 septal aneurysm: a cause for midsystolic click. Report of a case and review of the literature. Circulation 1981;63: 1186-1188. 10. Abinader EG, Rokey R, Goldhammer E, Kuo LC, Said E. Prevalence of atria1 septal aneurysm in patients with mitral valve prolapse. Am J Cardiol 1988;62:1139-1140. il. Schreiner G, Erbel R, Mohr-Kahaly S, Kramer G, Henkel B, Meyer J. Nachweis von aneurysmen des vorhofseptums mit hilfe der transijsophagealen echokardiographie. Z Kardiol 1985;74:440-444. 12. Cheng TO. Echocardiography and paradoxical embolism. Ann Intern Med 1981;95: 515. 13. Cheng TO. Atria1 septal aneurysm as a catrse of cerebral embolism in young patients. Stroke 1988;19:408.
328
14. Canny M, Drobinski G, Thomas D, Gautier JC, Awada A, Leclerc JP, Gong L, ChaneWoon-Mine. M. Gandibakhch I. Anturvsme de la cloison i~terauriculaire. Diagnostic &hocardiographique. Arch Ma1 Coeur 1984;77:337342.
Interaction Between Amiodarone and Phenytoin Nolan et al’ reported an interaction between phenytoin and amiodarone. Although they clearly demonstrated an interaction between amiodarone and phenytoin (probably involving enzyme inhibition), we are concerned about some of the conclusions drawn. First, the recommendation that a dosage reduction of phenytoin by 25 to 30% be made after the addition of amiodarone may lead to serious errors. Phenytoin displays Michaelis-Menten (MM) kinetics (at therapeutic concentrations)2 and a 25% dosage reduction would, by the equation below, reduce the plasma concentration by 50 to 75%, from 10 and 20 mg/ liter, respectively: Css = dose/day X Km Vm - dose/day This could lead to poor control of epilepsy or arrhythmias, and possibly to withdrawal symptoms. According to the equation, Nolan et al should have recommended a dose reduction of only 10% to maintain the mean concentrations of phenytoin before the addition of amiodarone (6.7 mg/liter). Second, quoting clearances has little relevance to drugs that display MM kinetics, because the elimination rate is variable, depending on serum concentration. Third, the study title included the term “steady-state,” which may be misleading because amiodarone has a half-life of 25 f 12 days3 and would not be expected to be at steady state at the time of the study. If steady state had been achieved, the degree of enzyme inhibition may well have been greater than that seen. We conclude that the data presented by Nolan et al is sufficient only to prove that an interaction does exist and that a dosage reduction of phenytoin may be required. Clearly this is a case for increased therapeutic drug monitoring and not for specific guidelines that are inappropriate. S.B. Duffull S.K. McKenzie
Christchurch, New Zealand 2 August 1990 1. Nolan PE Jr, Erstad BL, Hoyer GL, Bliss M, Gear K, Marcus FI. Steady-state interaction between amiodarone and phenytoin in normal subjects. Am J Cardiol 1990;65:1252-1257. 2. Winter ME, ed. Basic Clinical Pharmacokinetics. Washington: Applied Therapeutics, 1983:184-187. 3. Mammen GJ, ed. Clinical Pharmacokinetics Drug Data Handbook, 2nd edition. Auckland, New Zealand: Adis Press, 1990:40.
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67
REPLY: We thank Duffull and McKenzie for their comments regarding our investigation and conclusions. We arrived at our recommendation of an initial 25 to 30% reduction in phenytoin doses when concomitant amiodarone is instituted in the following way. Grech-Belanger demonstrated that the depressive effect of amiodarone on aromatic ring hydroxylation occurred via competitive inhibition.’ In that phenytoin principally undergoes aromatic ring hydroxylation to form 5-(phydroxyphenyl)-5-phenylhydantoin,2 we assumed that amibdarone~ competitively inhibited nhenvtoin metabolism. When competitive inhibition of substrate (i.e., phenytoin) metabolism occurs, the Km of the metabolic reaction is increased.2 Km is the concentration at which substrate metabolism is 50% of Vm, the maximum rate of substrate metabolism. Therefore, in the equation presented by Duffull and McKenzie, the observed steadv-state increases in. serum phenytoin concentrations during concomitant phenytoin and amiodarone treatment should have occurred in proportion to the amiodaronemediated increases in the Km of phenytoin. The percent decrease in the dose of phenytoin required to maintain pre-amiodarone serum concentrations is variable, but dependent upon both the baseline Km and the percent increase in Km caused by amiodarone. For example, assuming an average Vm of 7 mg/kg/day,2 and using the mean daily dose of phenytoin of 250 mg/day, a calculated Km of 7.4 pg/ml would be expected from our pre-amiodarone mean concentration of 6.7 Mg/ml. To achieve our observed mean phenytoin concentration of 10.3 pg/ml after the addition of amiodarone, the calculated Km is 11.4 pg/ml, a 54% increase from baseline. A 22% reduction in the daily dose of phenytoin would therefore be required to achieve the pre-amiodarone concentration of 6.7 rg/ml. It appears from their calculations that Duffull and McKenzie used average estimates of Km and Vm, 4 pg/ml and 7 mg/kg/day,2 respectively, but did not take into account any changes in the Km of phenytoin during coadministration with amiodarone. Interestingly, in the first case report by McGovern et al,3 their patient required a 33% reduction in the dose of phenytoin when concurrently receiving amiodarone in order to achieve serum concentrations of phenytoin similar to those with phenytoin alone. Second, we do agree with Duffull and McKenzie that clearance is a term most appropriately reserved for drugs that display first-order rather than MichaelisMenten (MM) pharmacokinetics. However, in our paper we purposefully used the term “approximate oral clearance for phenytoin” in order to convey to readers that we were only estimating the clearance of phenytoin, a drug that demonstrates nonlinear or MM kinetics. For drugs that demonstrate MM kinetics, Cheng and Jusko4 discuss the concept of a “time-averaged clearance,” which varies inversely in relation to dose, and which can be calculated in a manner similar to
This “newly discovered” cause of stroke in patients with MVP also has an important therapeutic implication. The embolic risk here would make what would otherwise have been a simple anatomic curiosity a potentially serious anomaly. This has led some authors to propose surgical repair of ASA associated with systemic embolism, irrespective of its size, in order to prevent the risk of embolic recurrence and to avoid the need for lifelong anticoagulant therapy.i4 Teung 0. Cheng, MD Washington, D.C. 30 July 1990 1. Rahko PS, Xu QB. Increased prevalence of atria1 septal aneurysm in mitral valve prolapse. Am J Cardiol 1990:66:235-231. 2. Iliceto S, Papa A,Sorino M, Rizzon P. Combined atria1 septal aneurysm and mitral valve prolapse: detection by two-dimensional echocardiography. Am J Cardiol 1984;54: 115 l1153. 3. Roberts WC. Aneurysm (redundancy) of the atria1 septum (fossa ovale membrane) and prolapse (redundancy) of the mitral valve. Am J Cardiol 1984;54:1153-1154. 4. Gallet B, Malergue MC, Adams C, Saudemont JP, Collot AMC, Druon MC, Hiltgen M. Atria1 septal aneurysm-a potential cause of systemic embolism. An echocardiographic study. Br Heart J 1985;53:292-297. 5. Belkin RN, Waugh RA, Kisslo J. Interatrial shunting in atrial septal aneurysm. Am J Cardial 1986;57:310-312. 6. Cheng TO. Paradoxical embolism. A diagnostic challenge and its detection during life. Circulation 1976;53:565-568. 7. Cheng TO. Mitral valve prolapse. Dis Man 1987;33:481-534. 6. Cheng TO. Mitral valve prolapse. Annu Reu Med 1989:40:201-211. 9. Alexander MD, Bloom KR, Hart P, D’Silva F, Murgo JP. Atria1 septal aneurysm: a cause for midsystolic click. Report of a case and review of the literature. Circulation 1981;63: 1186-1188. 10. Abinader EG, Rokey R, Goldhammer E, Kuo LC, Said E. Prevalence of atria1 septal aneurysm in patients with mitral valve prolapse. Am J Cardiol 1988;62:1139-1140. il. Schreiner G, Erbel R, Mohr-Kahaly S, Kramer G, Henkel B, Meyer J. Nachweis von aneurysmen des vorhofseptums mit hilfe der transijsophagealen echokardiographie. Z Kardiol 1985;74:440-444. 12. Cheng TO. Echocardiography and paradoxical embolism. Ann Intern Med 1981;95: 515. 13. Cheng TO. Atria1 septal aneurysm as a catrse of cerebral embolism in young patients. Stroke 1988;19:408.
328
14. Canny M, Drobinski G, Thomas D, Gautier JC, Awada A, Leclerc JP, Gong L, ChaneWoon-Mine. M. Gandibakhch I. Anturvsme de la cloison i~terauriculaire. Diagnostic &hocardiographique. Arch Ma1 Coeur 1984;77:337342.
Interaction Between Amiodarone and Phenytoin Nolan et al’ reported an interaction between phenytoin and amiodarone. Although they clearly demonstrated an interaction between amiodarone and phenytoin (probably involving enzyme inhibition), we are concerned about some of the conclusions drawn. First, the recommendation that a dosage reduction of phenytoin by 25 to 30% be made after the addition of amiodarone may lead to serious errors. Phenytoin displays Michaelis-Menten (MM) kinetics (at therapeutic concentrations)2 and a 25% dosage reduction would, by the equation below, reduce the plasma concentration by 50 to 75%, from 10 and 20 mg/ liter, respectively: Css = dose/day X Km Vm - dose/day This could lead to poor control of epilepsy or arrhythmias, and possibly to withdrawal symptoms. According to the equation, Nolan et al should have recommended a dose reduction of only 10% to maintain the mean concentrations of phenytoin before the addition of amiodarone (6.7 mg/liter). Second, quoting clearances has little relevance to drugs that display MM kinetics, because the elimination rate is variable, depending on serum concentration. Third, the study title included the term “steady-state,” which may be misleading because amiodarone has a half-life of 25 f 12 days3 and would not be expected to be at steady state at the time of the study. If steady state had been achieved, the degree of enzyme inhibition may well have been greater than that seen. We conclude that the data presented by Nolan et al is sufficient only to prove that an interaction does exist and that a dosage reduction of phenytoin may be required. Clearly this is a case for increased therapeutic drug monitoring and not for specific guidelines that are inappropriate. S.B. Duffull S.K. McKenzie
Christchurch, New Zealand 2 August 1990 1. Nolan PE Jr, Erstad BL, Hoyer GL, Bliss M, Gear K, Marcus FI. Steady-state interaction between amiodarone and phenytoin in normal subjects. Am J Cardiol 1990;65:1252-1257. 2. Winter ME, ed. Basic Clinical Pharmacokinetics. Washington: Applied Therapeutics, 1983:184-187. 3. Mammen GJ, ed. Clinical Pharmacokinetics Drug Data Handbook, 2nd edition. Auckland, New Zealand: Adis Press, 1990:40.
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67
REPLY: We thank Duffull and McKenzie for their comments regarding our investigation and conclusions. We arrived at our recommendation of an initial 25 to 30% reduction in phenytoin doses when concomitant amiodarone is instituted in the following way. Grech-Belanger demonstrated that the depressive effect of amiodarone on aromatic ring hydroxylation occurred via competitive inhibition.’ In that phenytoin principally undergoes aromatic ring hydroxylation to form 5-(phydroxyphenyl)-5-phenylhydantoin,2 we assumed that amibdarone~ competitively inhibited nhenvtoin metabolism. When competitive inhibition of substrate (i.e., phenytoin) metabolism occurs, the Km of the metabolic reaction is increased.2 Km is the concentration at which substrate metabolism is 50% of Vm, the maximum rate of substrate metabolism. Therefore, in the equation presented by Duffull and McKenzie, the observed steadv-state increases in. serum phenytoin concentrations during concomitant phenytoin and amiodarone treatment should have occurred in proportion to the amiodaronemediated increases in the Km of phenytoin. The percent decrease in the dose of phenytoin required to maintain pre-amiodarone serum concentrations is variable, but dependent upon both the baseline Km and the percent increase in Km caused by amiodarone. For example, assuming an average Vm of 7 mg/kg/day,2 and using the mean daily dose of phenytoin of 250 mg/day, a calculated Km of 7.4 pg/ml would be expected from our pre-amiodarone mean concentration of 6.7 Mg/ml. To achieve our observed mean phenytoin concentration of 10.3 pg/ml after the addition of amiodarone, the calculated Km is 11.4 pg/ml, a 54% increase from baseline. A 22% reduction in the daily dose of phenytoin would therefore be required to achieve the pre-amiodarone concentration of 6.7 rg/ml. It appears from their calculations that Duffull and McKenzie used average estimates of Km and Vm, 4 pg/ml and 7 mg/kg/day,2 respectively, but did not take into account any changes in the Km of phenytoin during coadministration with amiodarone. Interestingly, in the first case report by McGovern et al,3 their patient required a 33% reduction in the dose of phenytoin when concurrently receiving amiodarone in order to achieve serum concentrations of phenytoin similar to those with phenytoin alone. Second, we do agree with Duffull and McKenzie that clearance is a term most appropriately reserved for drugs that display first-order rather than MichaelisMenten (MM) pharmacokinetics. However, in our paper we purposefully used the term “approximate oral clearance for phenytoin” in order to convey to readers that we were only estimating the clearance of phenytoin, a drug that demonstrates nonlinear or MM kinetics. For drugs that demonstrate MM kinetics, Cheng and Jusko4 discuss the concept of a “time-averaged clearance,” which varies inversely in relation to dose, and which can be calculated in a manner similar to