Cardiac Actions of Erythromycin

Abstract

Context.-Erythromycin is a widely used antibiotic that infrequently causes QTprolongation and torsades de pointes cardiac arrhythmias. For antiarrhythmic drugs, women are at a higher risk for these cardiac arrhythmias, but few other classes of drugs have been studied. Objectives.-Todeterminewhetherfemalesexisariskfactorforcardiacarrhythmias associated with erythromycin, and if this can be correlated with in vitro measurements of the QT-response to erythromycin in male and female rabbit hearts. Design.-Food and Drug Administration (FDA) MEDWATCH database analysis and in vitro experiment. Main Outcome Measures.-Cardiac arrhythmia reports associated with erythromycin from 1970 until 1996 classified by patient sex and age, and effect of female sex on erythromycin-induced QT-prolongation in isolated perfused rabbit hearts. Results.-We observed a sex difference in cardiac arrhythmias associated with administration of erythromycin. A total of 346 cases were found in the FDA database: 201 females (58%), 110 males (32%), and 35 unspecified (10%). Forty-nine were life-threatening ventricular arrhythmias and deaths directly related to intravenous erythromycin lactobionate: 33 women (67%) and 16 men (33%) (P = .03). During the same period, no sex imbalance was present in the prescription pattern for intravenous erythromycin lacobionate (men 47%, women 49%, unspecified 4%). Perfusion with erythromycin caused significantly greater QT-prolongation in female rabbit hearts (mean [SD], 11.8% [2.3%]) than in male hearts (6.9% [2.1%]; P = .03). Conclusions.-As has been shown in reports of antiarrhythmic drugs, we found a female predominance in the FDA reports of erythromycin-associated cardiac arrhythmias. Based on in vitro experiments, a sex difference in cardiac repolarization response to erythromycin is a potential contributing factor.

Non-genomic Action of Sex Steroid Hormones and Cardiac Repolarization

“…[17][18][19][20][21][22][23] drug-induced arrhythmia, an acquired long QT syndrome (LQTS), is associated with prolonged QT c intervals, resulting from delay of cardiac repolarization caused mostly by inhibition of the human ether-a-go-go-related gene (hERG) channel, which conducts the rapid component of the delayed rectifier K + current (I Kr ). Thus, regulatory agencies including Food and drug Administration (FdA) and Pharmaceuticals and Medical devices Agency (PMdA) require hERG inhibition data for any drug candidate referred as hERG pre-clinical test.…”

“…[24][25][26][27] However, the predictivity of hERG test is often debated because of too many false positives. Actually, the incidence of drug-induced arrhythmia is also affected by other risk factors such as gender [17][18][19] or/and sympathetic * To whom correspondence should be addressed. e-mail: junkokuro.bip@mri.tmd.ac.jp…”

“…[17][18][19]30) The higher risks in women have been thought to be associated with prolonged baseline QT c intervals in women about 20-ms in comparison with those in men. 1) The gender differences in QT c intervals appear to correlate with age-dependent changes in serum levels of sex hormones.…”

“…44) Although clinical impacts of estrogen on drug-induced LQTS are still debated, chronic application of estrogen has some impact in some cases of drug-induced LQTS. 7,9,19) In rabbit papillary muscle, chronic treatment with 17β-estradiol (E2) enhanced APd prolongation and the incidence and magnitude of EAd induced by E4031, a hERG blocker. 7) Because the E2 treatment did not affect baseline electrocardiographic characteristics, chronic E2 treatment appears to reduce the repolarization reserve.…”

Compartmentalized Regulations of Ion Channels in the Heart

“…46,47) Women are more prone to develop TdP than men in response to QT-prolonging drugs, with 65-75% of the drug-induced TdP occurring in women. [46][47][48][49] Because drug-induced arrhythmias is the most common reason for withdrawal of medication from drug-development, pre-clinical trials and the retail market, pharma- The targeting protein Yotiao binds to the carboxy terminal domain of KCNQ1 via a LIZ motif (sawtooth in figure) and recruits PKA and PP1 directly to the channel microdomain to regulate the channel via phosphorylation of Ser 27) in the amino terminus (upper panel).…”