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European Journal of Clinical Pharmacology

, Volume 24, Issue 4, pp 485–494 | Cite as

Serum concentrations of amiodarone during long term therapy. Relation to dose, efficacy and toxicity

  • M. Stäubli
  • J. Bircher
  • R. L. Galeazzi
  • H. Remund
  • H. Studer
Originals

Summary

In 17 patients on long term therapy with amiodarone, serum drug levels measured by HPLC were related to pharmacological effects. At steady state, serum levels were directly proportional to the dose, 5 mg/kg per day leading to an average serum level of approximately 2.5 µmol/l. The non-amiodarone level of iodine averaged 4-times higher than the level of amiodarone iodine. The elimination half-life of amiodarone ranged from 21 to 78 days, and of non-amiodarone iodine from 24 to 160 days. Control of arrhythmias was satisfactory in all 12 evaluable patients, when the serum amiodarone level exceeded 1.5 µmol/l. Deterioration of vision and polyserositis occurred only at amiodarone levels above 4 µmol/l. Tentatively, a therapeutic range of 1.5 to 4 µmol/l is proposed. In contrast, thyroid dysfunction was observed at any amiodarone level. In view of the narrow therapeutic window, therapy with amiodarone may be optimized by monitoring its serum level and in addition, thyroid function should be regularly checked.

Key words

amiodarone pharmacokinetics therapeutic serum level thyroid function antiarrhythmic therapy adverse effects 

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References

  1. 1.
    Van Schepdael J, Solvay H (1970) Etude clinique de l'amiodarone dans les troubles du rhythme cardiac. Presse Med 78: 1849–1850Google Scholar
  2. 2.
    Vastesaeger MM, Gillot PH, Van der Straeten P (1971) L'effet antiarhythmique de l'amiodarone (L 3428). Bruxelles Med 51: 99–104Google Scholar
  3. 3.
    Rosenbaum MB, Chiale PA, Ryba D, Elizari MV (1974) Control of tachyarrhythmias associated with Wolff-Parkinson-White Syndrome by amiodarone hydrochloride. Am J Cardiol 34: 215–223Google Scholar
  4. 4.
    Rosenbaum MB, Chiale PA, Halpern MS, Nau GJ, Przbybylski J, Levi RJ, Lazzari JO, Elizari MV (1976) Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 38: 934–944Google Scholar
  5. 5.
    Wellens HJJ, Lie KI, Bär FW, Wesdorp JC, Dohmen HJ, Düren DR, Durrer D (1976) Effect of amiodarone in the Wolff-Parkinson-White Syndrome. Am J Cardiol 38: 189–194Google Scholar
  6. 6.
    Wheeler PJ, Puritz R, Ingram DV, Chamberlain DA (1979) Amiodarone in the treatment of refractory supraventricular and ventricular arrhythmias. Postgrad Med J 55: 1–9Google Scholar
  7. 7.
    Coumel P, Fidelle J (1980) Amiodarone in the treatment of cardiac arrhythmias in children: One hundred thirty-five cases. Am Heart J 100: 1063–1069Google Scholar
  8. 8.
    Heger JJ, Prystowsky EN, Jackman WM, Naccarelli GV, Warfel KA, Rinkenberger RL, Zipes DP (1981) Amiodarone. Clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 305: 539–545Google Scholar
  9. 9.
    Kaski JC, Girotti LA, Messuti H, Rutitzky B, Rosenbaum MB (1981) Long-term management of sustained, recurrent, symptomatic ventricular tachycardia with amiodarone. Circulation 64: 273–279Google Scholar
  10. 10.
    McKenna WJ, Harris L, Perez G, Krikler DM, Oakley C, Goodwin JF (1981) Arrhythmia in hyertrophic cardiomyopathy II: Comparison of amiodarone and verapamil in treatment. Br Heart J 46: 173–178Google Scholar
  11. 11.
    Nademanee K, Hendrickson JA, Cannom DS, Goldreyer BN, Singh BN (1981) Control of refractory life-threatening ventricular tachyarrhythmias by amiodarone. Am Heart J 101: 759–768Google Scholar
  12. 12.
    Dreifus LW, Ogawa S (1977) Quality of the ideal antiarrhythmic drug. Am J Cardiol 39: 466–468Google Scholar
  13. 13.
    Leak D, Eydt JN (1979) Control of refractory cardiac arrhythmias with amiodarone. Arch Intern Med 139: 425–428Google Scholar
  14. 14.
    Podrid PJ, Lown B (1981) Amiodarone therapy in symptomatic, sustained refractory atrial and ventricular tachyarrhythmias. Am Heart J 101: 374–379Google Scholar
  15. 15.
    Côté P, Bourassa MG, Delaye J, Janin A, Froment R, David P (1979) Effects of amiodarone on cardiac and coronary hemodynamics and on myocardial metabolism in patients with coronary artery disease. Circulation 59: 1165–1172Google Scholar
  16. 16.
    Andreasen F, Agerbaek H, Bjerregaard P, Gøtzsche H (1981) Pharmacokinetics of amiodarone after intravenous and oral administration. Eur J Clin Pharmacol 19: 293–299Google Scholar
  17. 17.
    Kannan R, Nademanee K, Hendrickson JA, Rostami HJ, Singh BN (1982) Amiodarone kinetics after oral doses. Clin Pharmacol Ther 31: 438–444Google Scholar
  18. 18.
    Haffajee C, Lesko L, Canada A, Alpert JS (1981) Clinical pharmacokinetics of amiodarone. Circulation 64 [Suppl 4]: 263 (Abstract)Google Scholar
  19. 19.
    Broekhuysen J, Laruel R, Sion R (1969) Recherches dans la série des benzofurannes XXXVII. Etude comparée du transit et du métabolisme de l'amiodarone chez diverses espèces animales et chez l'homme. Arch Int Pharmacodyn Ther 177: 340–359Google Scholar
  20. 20.
    Canada AT, Lesko LJ, Haffajee CI (1981) Disposition of amiodarone in patients with tachyarrhythmias. Curr Ther Res 30: 968–974Google Scholar
  21. 21.
    Babel J, Stangos N (1970) Lésions oculaires iatrogènes; l'action d'un nouveau médicament contre l'angor pectoris. Arch Ophthalmol (Paris) 30: 197–208Google Scholar
  22. 22.
    D'Aminco DJ, Kenyon KR, Ruskin JN (1981) Amiodarone Keratopathy. Drug-induced lipid storage disease. Arch Ophthalmol (New York) 99: 257–261Google Scholar
  23. 23.
    Delage C, Lagacé R, Huard J (1975) Pseudocyanotic pigmentation of the skin induced by amiodarone: a light and electron microscopic study. Can Med Assoc J 17: 1205–1208Google Scholar
  24. 24.
    Meier C, Kauer B, Müller U, Ludin HP (1979) Neuromyopathy during chronic amiodarone treatment. A case report. J Neurol 220: 231–239Google Scholar
  25. 25.
    Larre P, Coquet M, Maupetit J (1981) Neuropathie à l'amiodarone. Nouv Presse Med 10: 2750Google Scholar
  26. 26.
    Diley SA, Williams SE, Cooke NJ (1982) Alveolitis after treatment with amiodarone. Br Med J 284: 161–162Google Scholar
  27. 27.
    Jonckheer MH, Blockx P, Kaivers R, Wyffels G (1973) Hyperthyroidism as a possible complication of the treatment of ischemic heart disease with amiodarone. Acta Cardiol (Brux) 28: 192–200Google Scholar
  28. 28.
    Savoie JC, Léger FA, Massin JP, Laurent MF, Lewin F (1976) L'hyperthyroidie induite par l'iode sur une glande thyroide apparemment normale. Nouv Presse Med 39: 2593–2597Google Scholar
  29. 29.
    Keidar S, Grenadier E, Palant A (1980) Amiodarone-induced thyrotoxicosis: four cases and a review of the literature. Postgrad Med J 56: 356–358Google Scholar
  30. 30.
    Studer H, Stäubli M, Meinerzhagen A, Voegelin M, Bircher J (1980) Besonderheiten der antiarrhythmischen Therapie mit Amiodaron. In: Gross F (ed) Neue Aspekte der medikamentösen Behandlung des Herzinfarktes. Huber, Bern, pp 89–102Google Scholar
  31. 31.
    Stäubli M, Bischof P, Wimpfheimer C, Studer H (1981) Amiodaron (Cordarone) und Schilddrüse. Schweiz Med Wochenschr 111: 1590–1596Google Scholar
  32. 32.
    Wimpfheimer C, Stäubli M, Schädelin J, Studer H (1982) Prednisone in amiodarone-induced thyrotoxicosis. Br Med J 284: 1835–1836Google Scholar
  33. 33.
    Burger A, Dinicheret D, Nicod P, Jenny M, Lemarchand-Béraud T, Valloton MB (1976) Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin, and thyrotropin. J Clin Invest 58: 255–259Google Scholar
  34. 34.
    Jonckheer MH, Blockx P, Broeckaert I, Cornette C, Beckers C (1978) “Low T3 Syndrome” in patients chronically treated with an iodine-containing drug, amiodarone. Clin Endocrinol 9: 27–35Google Scholar
  35. 35.
    Melmed S, Nademanee K, Reed AW, Hendrickson JA, Singh BN, Hershman JM (1981) Hyperthyroxinemia with bradycardia and normal thyrotropin secretion after chronic amiodarone administration. J Clin Endocrinol Metab 53: 997–1001Google Scholar
  36. 36.
    Nademanee K, Singh BN, Hendrickson JA, Reed AW, Melmed S, Hershman J (1982) Pharmacokinetic significance of serum reverse T3 levels during amiodarone treatment: a potential method for monitoring chronic drug therapy. Circulation 66: 202–211Google Scholar
  37. 37.
    Lauber K (1975) Iodine determination in biological material. Kinetic measurement of the catalytic activity of iodide. Anal Chem 47: 769–771Google Scholar
  38. 38.
    Sachs L (1974) Angewandte Statistik, 4th edition. Springer, Berlin Heidelberg New YorkGoogle Scholar
  39. 39.
    Harris L, McKenna WJ, Rowland E, Storey GCA, Krikler DM, Holt DW (1981) Plasma amiodarone and desethyl amiodarone levels in chronic oral therapy. Circulation 64 [Suppl 4]: 263 (Abstract)Google Scholar
  40. 40.
    Chopra IJ (1981) Triiodothyronines in health and disease. Springer, Berlin Heidelberg New YorkGoogle Scholar
  41. 41.
    Singh BN, Collett JT, Chew CYC (1980) New perspectives in the pharmacologic therapy of cardiac arrhythmias. Prog Cardiovasc Dis 22: 243–301Google Scholar
  42. 42.
    Rakita L, Sobol SM (1981) Amiodarone treatment for refractory arrhythmias: dose-ranging and importance of high initial dosage. Circulation 64 [Suppl 4]: 263 (Abstract)Google Scholar

Copyright information

© Springer-Verlag 1983

Authors and Affiliations

  • M. Stäubli
    • 1
  • J. Bircher
    • 2
  • R. L. Galeazzi
    • 1
  • H. Remund
    • 3
  • H. Studer
    • 1
  1. 1.Department of MedicineUniversity of BernBernSwitzerland
  2. 2.Department of Clinical PharmacologyUniversity of BernBernSwitzerland
  3. 3.Department of OphthalmologyUniversity of BernBernSwitzerland

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