Cardiotoxicity of Histamine and the Possible Role of Histamine in the Arrhythmogenesis Produced by Certain Antihistamines
Since 1990 it has repeatedly been reported that some histamine H1 receptor antagonists (e.g. terfenadine and astemizole) are able to produce ventricular arrhythmias (e.g. torsade de pointes) when they are given at dosages above the therapeutic range and/or administered together with cytochrome P-450 3A4 inhibitors, such as ketoconazole or erythromycin. Although the mechanism by which these arrhythmias are produced remains unclear, the recently reported ability of these drugs to block outward K+ currents has been suggested as the cause of their arrhythmogenic effects. Alternatively, we have observed that some H1 antihistamines, including terfenadine and astemizole, are able to release histamine from guinea-pig cardiac mast cells. Thus, we have proposed that the liberated histamine, acting through an H2 receptor-stimulating mechanism, can prolong the action potential duration and hence induce arrhythmogenic effects. This paper describes experimental observations supporting the hypothesis that some H1 antihistamines can induce severe cardiac arrhythmias via the local release of histamine.
Unable to display preview. Download preview PDF.
- 1.Dale H, Laidlaw P. Histamine shock. J Physiol (Lond) 1919; 52: 355–90Google Scholar
- 3.Levi R, Rubin L, Gross S. Histamine in cardiovascular function and dysfunction: recent developments. In: Uvinas B, editor. Handbook of experimental pharmacology. Berlin: Springer-Verlag, 1991; 97: 347–84Google Scholar
- 4.Gristwood R, Owen D, Smith I. Inhibition by cimetidine of cardiac stimulation due to mast cell degranulation. Br J Pharmacol 1980; 70: 105–6Google Scholar
- 5.Heredia A, Beleta J, Llenas J, et al. Terfenadine and the main metabolite of loratadine release histamine from cardiac mast cells: possible cardiotoxic consequences. Ann Allergy Asthma Immunol 1997; 78: 142Google Scholar
- 7.Cardelús I, Llenas J, Gristwood R, et al. Terfenadine increases the force of contraction of guinea pig ventricular strips by a histamine H2-dependent mechanism. Br J Pharmacol 1995; 114: 258PGoogle Scholar
- 11.Caron J, Adamantidis M, Bordet R, et al. Effets proarythmiques des antihistaminiques H1. Lett Pharmacol 1996; 10: 200–7Google Scholar
- 12.Levi R, Hordof A, Edie R, et al. Histamine effect on human atria. Circulation 1978; 58: 105Google Scholar
- 14.Ginsburg R, Erikson M, Bristow M, et al. Histamine receptors in rabbit, pig and human myocardium. Clin Res 1980; 28: 6AGoogle Scholar
- 22.Capurro N, Levi R. Immunologic release of histamine from the heart: inhibition by dibutyryl cyclic AMP. Fedn Proc 1971; 30: 499Google Scholar
- 25.Pellerat J, Murat M. Action des antihistaminiques de synthèse sur l’histaminémie. C R Soc Biol Paris 1946; 140: 297Google Scholar
- 26.Arunlakshana O. Histamine release by antihistamines. J Physiol 1952; 119:47Google Scholar