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Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes.
J Pharmacol Exp Ther. 2002 Oct; 303(1):218-25.JP

Abstract

Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed to study the different electrophysiological effects of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin in a previously developed experimental model of proarrhythmia. In 37 Langendorff-perfused rabbit hearts, erythromycin (150-300 microM, n = 13) clarithromycin (150-300 microM, n = 13), and azithromycin (150-300 microM, n = 11) led to similar increases in QT interval and monophasic action potential (MAP) duration. In bradycardic (atrioventricular-blocked) hearts, eight simultaneously recorded epi- and endocardial MAPs demonstrated increased dispersion of repolarization in the presence of all three antibiotics. Erythromycin and clarithromycin led to early afterdepolarizations (EADs) and torsade de pointes (TdP) after lowering of potassium concentration. In the presence of azithromycin, no EAD or TdP occurred. Erythromycin and clarithromycin changed the MAP configuration to a triangular pattern, whereas azithromycin caused a rectangular pattern of MAP prolongation. In 13 additional hearts, 150 microM azithromycin was administered after previous treatment with 300 microM erythromycin and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization but show a different proarrhythmic potential (erythromycin > clarithromycin > azithromycin). In the presence of azithromycin, neither EAD nor TdP occur. This effect may be related to a rectangular pattern of action potential prolongation, whereas erythromycin and clarithromycin cause triangular action potential prolongation and induce TdP.

Authors+Show Affiliations

Hospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology and Institute for Arteriosclerosis Research, Münster, Germany. milbergp@uni-muenster.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12235254

Citation

Milberg, Peter, et al. "Divergent Proarrhythmic Potential of Macrolide Antibiotics Despite Similar QT Prolongation: Fast Phase 3 Repolarization Prevents Early Afterdepolarizations and Torsade De Pointes." The Journal of Pharmacology and Experimental Therapeutics, vol. 303, no. 1, 2002, pp. 218-25.
Milberg P, Eckardt L, Bruns HJ, et al. Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes. J Pharmacol Exp Ther. 2002;303(1):218-25.
Milberg, P., Eckardt, L., Bruns, H. J., Biertz, J., Ramtin, S., Reinsch, N., Fleischer, D., Kirchhof, P., Fabritz, L., Breithardt, G., & Haverkamp, W. (2002). Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes. The Journal of Pharmacology and Experimental Therapeutics, 303(1), 218-25.
Milberg P, et al. Divergent Proarrhythmic Potential of Macrolide Antibiotics Despite Similar QT Prolongation: Fast Phase 3 Repolarization Prevents Early Afterdepolarizations and Torsade De Pointes. J Pharmacol Exp Ther. 2002;303(1):218-25. PubMed PMID: 12235254.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes. AU - Milberg,Peter, AU - Eckardt,Lars, AU - Bruns,Hans-Jürgen, AU - Biertz,Julia, AU - Ramtin,Shahram, AU - Reinsch,Nico, AU - Fleischer,Dirk, AU - Kirchhof,Paulus, AU - Fabritz,Larissa, AU - Breithardt,Günter, AU - Haverkamp,Wilhelm, PY - 2002/9/18/pubmed PY - 2002/10/22/medline PY - 2002/9/18/entrez SP - 218 EP - 25 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 303 IS - 1 N2 - Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed to study the different electrophysiological effects of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin in a previously developed experimental model of proarrhythmia. In 37 Langendorff-perfused rabbit hearts, erythromycin (150-300 microM, n = 13) clarithromycin (150-300 microM, n = 13), and azithromycin (150-300 microM, n = 11) led to similar increases in QT interval and monophasic action potential (MAP) duration. In bradycardic (atrioventricular-blocked) hearts, eight simultaneously recorded epi- and endocardial MAPs demonstrated increased dispersion of repolarization in the presence of all three antibiotics. Erythromycin and clarithromycin led to early afterdepolarizations (EADs) and torsade de pointes (TdP) after lowering of potassium concentration. In the presence of azithromycin, no EAD or TdP occurred. Erythromycin and clarithromycin changed the MAP configuration to a triangular pattern, whereas azithromycin caused a rectangular pattern of MAP prolongation. In 13 additional hearts, 150 microM azithromycin was administered after previous treatment with 300 microM erythromycin and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization but show a different proarrhythmic potential (erythromycin > clarithromycin > azithromycin). In the presence of azithromycin, neither EAD nor TdP occur. This effect may be related to a rectangular pattern of action potential prolongation, whereas erythromycin and clarithromycin cause triangular action potential prolongation and induce TdP. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12235254/full_citation DB - PRIME DP - Unbound Medicine ER -