Erythromycin and repolarization

Macrolides increase repolarization heterogeneity. They have different arrhythmogenic potential even when the QTc increase is similar (so repolarization prolonging per se is not the mechanism). J Pharmacol Exp Ther. 2002 Oct;303(1):218-25, Cardiovasc Res. 2001 May;50(2):345-53. Erythromycin also increases transmural repolarization heterogeneity by different effect on M cells, endocardial and epicardial cells, and induces early afterdepolarizations in M cells J Am Coll Cardiol. 1996 Dec;28(7):1836-48

Triangular MAPs are associated with TdP [when heterogenity/instability are also present] while rectangular MAPs, even if QTc is prolonged, are not J Pharmacol Exp Ther. 2002 Oct;303(1):218-25.

Erythromycin, when associated with other drugs that inhibit or compete with CYP3A4, leads to increase risk of sudden death N Engl J Med. 2004 Sep 9;351(11):1089-96; proarrhythmia is a rare occurence in monotherapy, despite QT prolongation Pharmacotherapy. 1995 Nov-Dec;15(6):687-92

Erythromycin prolongs repolarization in both atrial and ventricular myocites, an effect which may be canceled by the administration of magnesium Cardiovasc Drugs Ther. 2002 Jul;16(4):327-33.

There is a delay in the APd prolongation effect of erythromycin compared with disopyramide, which means that the maximum of repolarization changes are not expected to take place at the time of the peak of administration, but later. Also, the effect is more important in vivo than in vitro, so there may be other mechanisms involved beyond extracellular channel blocking J Pharm Pharmacol. 2003 Jul;55(7):995-1002; there may be supplementary information on this in J Cardiovasc Pharmacol Ther. 1998 Jan;3(1):29-36; the delay and the fact that it must be due to blocking on the intracellular side of the membrane is further explored in Naunyn Schmiedebergs Arch Pharmacol. 1997 Jun;355(6):743-50

Other macrolides and fluoroquinolones have similar effect although in general of lower intensity Expert Opin Drug Saf. 2002 Jul;1(2):121-8.

Erythromycin was not proarrhythmic in rabbits: Eur J Pharmacol. 2002 Aug 2;449(1-2):143-53 and Cardiovasc Res. 2001 May;50(2):345-53, except under bradycardia and hypokaliemia J Cardiovasc Pharmacol. 1998 Sep;32(3):425-34

The QTc prolonging effect is cumulative and is installed in a day or two South Med J. 1999 Dec;92(12):1178-82.

Cardiac arrhythmias with erythromycin are more important in women JAMA. 1998 Nov 25;280(20):1774-6 as well as in rabbit females compared to males J Womens Health. 1998 Jun;7(5):547-57

Other studies at cellular level: Anesthesiology. 1997 Nov;87(5):1172-81, Naunyn Schmiedebergs Arch Pharmacol. 1997 Jun;355(6):743-5, Circulation. 1995 Jun 15;91(12):3010-6, Circulation. 1993 Oct;88(4 Pt 1):1832-44