Cardiac Toxicity of Azole Antifungals
- 1 University of Mississippi Schools of Medicine & Pharmacy, Jackson, USA
- 2 University of Mississippi Schools of Medicine & Pharmacy, Jackson, USA
- 3 Department of Pharmacology and Toxicology, Jackson, USA
- 4 Department of Pathology, Jackson, USA
- 5 Department of Pathology, Jackson, USA
- 6 Department of Biochemistry, Jackson, USA.
Abstract
Cardiac toxicity is an uncommon side effect of anti-fungal therapy. Until the recent reports of itraconazole (ITZ) associated cardiac failure, amphotericin was the antifungal most frequently reported with arrhythmias. We evaluated the cardiac effect of azole antifungals, specifically ITZ, and possible mechanisms of toxicity. Ex vivo live-heart studies were performed utilizing Sprague Dawley rats. Short exposure (<5 minutes), random crossover, dose ranging studies were performed with each pharmacologic agent. ITZ focused trials also included dose ranging utilizing a non-crossover design. The only azole found to have significant toxicity was ITZ. At ITZ ~ ED 25 (2 - 2.5 ug/mL) exposures, contractility decreased by 22.2% ± 15.7% and amplitude of left ventricular pressure decreased by 11% ± 0.17%. Electron micrograph and alterations in mitochondrial respiration suggest mitochondrial toxicity as an underlying mechanism. In conclusion, ITZ was associated with reductions in contractility, possibly secondary to mitochondrial dysfunction and dilated cardiomyopathy.
- S. R. Ahmad, S. J. Singer and B. G. Leissa, “Congestive Heart Failure Associated with Itraconazole,” Lancet, Vol. 357, No. 9270, 2001, pp. 1766-1767.
- Institute of Laboratory Animal Resources (US) and Committee on Care and Use of Laboratory Animals, “Guide for the Care and Use of Laboratory Animals,” Public Health Service, US Department of Health and Human Services, Bethesda, 1996.
- Code of Federal Regulations Title 9, “Animals and Animal Products,” Animal Welfare, Chapter 1, Subchapter A, Parts 1 and 3, 2009.
- H. Liu, Q. Zheng and J. M. Farley, “Antimuscarinic Actions of Anti-histamines on the Heart,” Journal of Biomedical Science, Vol. 13, No. 3, 2006, pp. 395-401.
- J. D. Cleary, J. Hayman, J. Sherwood, G. P. Lasala and T. Piazza-Hepp, “Amphotericin B Overdose in Pediatric Patients with Associated Cardiac Arrest,” The Annals of Pharmacotherapy, Vol. 27, No. 6, 1993, pp.715-719.
- P. J. Danaher, M. K. Cao, G. M. Anstead, M. J. Dolan and C. C. DeWitt, “Reversible Dilated Cardiomyopathy Related to Amphotericin B Therapy,” Journal of Antimicrobial Chemotherapy, Vol. 53, No. 1, 2004, pp.115117. doi:10.1093/jac/dkg472
- M. Tofukuji, C. Metais, S. Y. Wang, S. L. Alper and F. W. Sellke, “Clotrimazole is a Potent Vasodilator of the Rat Coronary Microcirculation,” Journal of Surgical Research, Vol. 77, No. 1, 1998, pp. 6-10. doi:10.1006/jsre.1998.5320
- M. J. Hernandez-Benito, R. Macianskiene,K. R. Sipido, W. Flameng and K. Mubagwa, “Suppression of Transient Outward Potassium Currents in Mouse Ventricular Myocytes by Imidazole Antimycotics and by Glybenclamide,” Journal of Pharmacology and Experimental Therapeutics, Vol. 208, No. 2, 2001, pp. 598-606.
- I. M. Fearon, S. G. Ball and C. Peers, “Clotrimazole Inhibits the Recombinant Human Cardiac L-type Ca2+ Channel α1C Subunit,” British Journal of Pharmacology, Vol. 129, No. 3, 2000, pp. 547-554. doi:10.1038/sj.bjp.0703106
- B. Tunctan, S. Altug, O. Uludag and N. Abacioglu, “Effects of Econazole on Receptor-Operated and Depolarization-Induced Contractions in Rat Isolated Aorta,” Life Sciences, Vol. 67, No. 19, 2000, pp. 2393-2401. doi:10.1016/S0024-3205(00)00822-5
- “Sporonox [Package Insert],” Raritan, Ortho Biotech Products, L.P., New York, 2009.
- “Advisory for Fungal Drugs,” FDA Consumer, Vol. 35, No. 4, 2001, p. 4.
- V. M. Figueredo, “Chemical Cardiomyopathies: The Negative Effects of Medications and Non-Prescribed Drugs on the Heart,”American Journal of Medicine, Vol. 124, No. 6, 2011, pp. 480-488.