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Cardiovascular Drugs and Therapy

, Volume 9, Issue 5, pp 709–714 | Cite as

Electrophysiological evaluation of the sodium-channel blocker carbamazepine in healthy human subjects

  • Göran Kennebäck
  • Lennart Bergfeldt
  • Torbjörn Tomson
Antiarrhythmics

Summary

Carbamazepine (CBZ) is a sodium-channel blocker used mainly for the treatment of epileptic seizures and neuralgias. It may impair the function of the cardiac conduction system in susceptible patients, but its electrophysiological effects have not been thoroughly assessed in the normal heart, which was the aim of the present study. Ten healthy volunteers, mean age 32 years, underwent two electrophysiological investigations at baseline and three at different dose levels of CBZ. The transesophageal atrial stimulation technique was used to evaluate sinus node function, refractoriness of the atrial myocardium, atrioventricular conduction, and ventricular depolarization and repolarization (as reflected by the QRS, JT, and QT intervals) at spontaneous rhythm and after atrial pacing. Atropine was administered to facilitate 1:1 conduction and assessment of rate-dependent effects. At the highest CBZ dose (800 mg/day), which gave plasma concentrations within the upper therapeutic range, the PQ interval was mildly prolonged (151 vs. 159 msec; p<0.01). In addition, the shortening of the JT interval normally seen at higher pacing rates was counteracted by high-dose CBZ, as demonstrated by a lower mean slope of the regression line after atropine and CBZ than after atropine alone (0.17 vs. 0.20; p<0.05). No other effects were detected. At therapeutic levels CBZ had minimal effects on the healthy conduction system, supporting its safe use in the absence of cardiac disease.

Key Words

AV conduction carbamazepine electropharmacology cardiac electrophysiology rate-related effects repolarization 

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References

  1. 1.
    Willow M, Catterall WA. Inhibition of binding of [3H]batra-chotoxinin A 20-alpha-benzoate to sodium channels by the anticonvulsant drugs diphenylhydantoin and carbamazepine.Mol Pharmacol 1982;22:627–635.Google Scholar
  2. 2.
    Courtney KR, Etter EF. Modulated anticonvulsant block of sodium channels in nerve and muscle.Eur J Pharmacol 1983;88:1–9.Google Scholar
  3. 3.
    Willow M, Gonoi T, Catterall WA. Voltage clamp analysis of the inhibitory actions of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells.Mol Pharmacol 1985;27:549–558.Google Scholar
  4. 4.
    Mattsson R. General principles. Selection of antilepleptic drug therapy. In: Levy R, Mattsson R, Meldrum B, Penry JK, Dreifuss FE, eds.Antiepileptic Drugs, 3rd ed. New York: Raven Press, 1989:103–115.Google Scholar
  5. 5.
    Sternebring B. Convulsive seizures in the withdrawal phase.Nord Psychiatr Tidsskr 1989;41(Suppl 17):41–44.Google Scholar
  6. 6.
    Ballenger JC. The clinical use of carbamazepine in affective disorders.J Clin Psychiatry 1988;49(Suppl 4):13–19.Google Scholar
  7. 7.
    Neppe VM. Carbamazepine nonresponsive psychosis.J Clin Psychiatry 1988;49(Suppl 4):22–28.Google Scholar
  8. 8.
    Davis J, Matsubara T, Scheinman M, Katzung B, Hondeghem H. Use-dependent effects of lidocaine on conduction in canine myocardium: Application of the modulated receptor hypothesis in vivo.Circulation 1986;74:205–214.Google Scholar
  9. 9.
    Katzung BG. New concepts of antiarrhythmic drug action.Prog Cardiol 1987;15:5–18.Google Scholar
  10. 10.
    Hondeghem LM, Katzung BG. Antiarrhythmic agents: The modulated receptor mechanism of action of sodium and calcium channel-blocking drugs.Ann Rev Pharmacol Toxicol 1984;24:387–423.Google Scholar
  11. 11.
    Carmeliet E. Action potential duration and refractoriness. In: Singh BN, Wellens HJJ, Hiraoka M, eds.Electropharmacological Control of Cardiac Arrhythmias. To Delay Conduction or to Prolong Refractoriness? New York: Futura, 1994:33–46.Google Scholar
  12. 12.
    Steiner C, Wit AL, Weiss MB, Damato A. The antiarrythmic actions of carbamazepine (Tegretol).J Pharmacol Exp Ther 1970;173:323–325.Google Scholar
  13. 13.
    Steinberg MI, Greenspan K. Intracellular electrophysiological alterations in canine cardiac conducting tissue induced by aprindine and lignocaine.Cardiovasc Res 1976;10:236–244.Google Scholar
  14. 14.
    Kuppersmith J. Electrophysiological and antiarrhythmic effects of lidocaine in canine acute myocardial ischemia.Am Heart J 1979;97:360–366.Google Scholar
  15. 15.
    Kennebäck G, Bergfeldt L, Vallin H, Tomson T, Edhag O. Electrophysiologic effects and clinical hazards of carbamazepine treatment for neurologic disorders in patients with abnormalities of the cardiac conduction system.Am Heart J 1991;121:1421–1429.Google Scholar
  16. 16.
    Kasarskis EJ, Kuo C-S, Berger R, Nelson KR. Carbamazepine-induced cardiac dysfunction. Characterization of two distinct clinical syndromes.Arch Intern Med 1992;152:186–191.Google Scholar
  17. 17.
    Kennebäck G, Bergfeldt L, Tomson T, Spina E, Edhag O. Carbamazepine induced bradycardia—a problem in general or only in susceptible patients? A 24-h long-term electrocardiogram study.Epilepsy Res 1992;13:141–145.Google Scholar
  18. 18.
    Kennebäck G, Bergfeldt L. Transesophageal atrial stimulation. A study on reproducibility in normal subjects.Eur J Cardiac Pacing Electrophysiol 1994;4:108–115.Google Scholar
  19. 19.
    Tomson T, Svensson J-O, Hilton-Brown P. Relationship of intraindividual dose to plasma concentration of carbamazepine: Indication of dose-dependent induction of metabolism.Ther Drug Monit 1989;11:533–539.Google Scholar
  20. 20.
    Janse MJ, van der Steen ABM, van Dam RT, Durrer D. Refractory period of the dog's ventricular myocardium following sudden changes in frequency.Circ Res 1969;24:251–262.Google Scholar
  21. 21.
    Seed WA, Noble MIM, Oldershaw P, et al. Relation of human cardiac action potential duration to the interval between beats: Implications for the validity of rate corrected QT interval (QTc).Br Heart J 1987;57:32–37.Google Scholar
  22. 22.
    Bergfeldt L, Melander H, Schenck-Gustafsson K. Time-dependent variation in the cardiac conduction system assessed in young healthy individuals at weeks' interval: Implications for clinical trials.J Am Coll Cardiol 1991;18:792–800.Google Scholar
  23. 23.
    Guss SB, Kastor JA, Josephson ME, Scharf DL. Human ventricular refractoriness. Effects of cycle length, pacing site and atropine.Circulation 1976;53:450–455.Google Scholar
  24. 24.
    Hojer J, Malmlund H O, Berg A. Clinical features in 28 consecutive cases of laboratory confirmed massive poisoning with carbamazepine alone.Clin Toxicol 1993;31:449–458.Google Scholar
  25. 25.
    Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. The Sicilian Gambit. A new approach to the classification of antiarrythmic drugs based on their actions on arrhythmogenic mechanisms.Circulation 1991;84:1831–1851.Google Scholar

Copyright information

© Kluwer Academic Publishers 1995

Authors and Affiliations

  • Göran Kennebäck
    • 1
  • Lennart Bergfeldt
    • 2
  • Torbjörn Tomson
    • 3
  1. 1.Division of Cardiology, Department of MedicineKarolinska Institute at Huddinge University HospitalHuddingeSweden
  2. 2.Department of CardiologyKarolinska HospitalStockholmSweden
  3. 3.Department of Neurology, Karolinska Hospital and Department of Clinical PharmacologyHuddinge University Hospital, Karolinska InstituteStockholmSweden

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