Drug-induced QT prolongation in women during the menstrual cycle

Rodríguez, I.; Kilborn, Michael J.; Liu, X.K; Pezzullo, John C.; Woosley, Raymond L.

doi:10.1016/s1062-1458(01)00329-4

Cited by 46 publications

(86 citation statements)

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“…For example, women may metabolize antiarrhythmic drugs differently than men at different points in their menstrual cycle, which could lead to different responses to treatment in younger women. 21 Also, young women may be less likely to manifest cardiac arrhythmias at different points in their menstrual cycle. 22,23 Women's smaller size may lead to decreased electrical impedance and increase the success of cardioversion.…”

Section: Discussionmentioning

confidence: 99%

Out-of-hospital cardiac arrest in men and women

Kim¹,

Fahrenbruch²,

Cobb³

et al. 2002

ACC Current Journal Review

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Background-The incidence of sudden cardiac death is roughly 3 times greater in men than in women. However, in patients treated for out-of-hospital cardiac arrest, the relationships between sex and survival after adjustment for age and cardiac rhythm are unclear. Methods and Results-In this retrospective cohort study, we examined 7069 men and 2582 women who were treated for out-of-hospital cardiac arrest in Seattle and suburban King County between 1990 and 1998. We compared successful prehospital resuscitation (hospital admission) and survival from event to discharge in men and women. Women had markedly reduced rates of ventricular fibrillation (VF), slightly older age, fewer witnessed arrests, and fewer arrests in public locations than men. Although their unadjusted resuscitation rate was lower (29% versus 32%, PϽ0.0001), women had a greater likelihood of resuscitation than men after adjustment for VF (odds ratio [OR] 1.13; 95% confidence interval [CI], 1.03 to 1.25) and after adjustment for VF plus additional factors (OR, 1.27; 95% CI, 1.14 to 1.41). The difference in resuscitation rates between men and women decreased as they aged (test for trend, PϽ0.0001). Unadjusted survival rates were also lower in women than in men (11% versus 15%, PϽ0.0001). Women had similar survival after adjustment for VF (OR, 0.97; 95% CI, 0.85 to 1.11) and after adjustment for VF plus additional factors (OR, 1.09; 95% CI, 0.93 to 1.27). Conclusions-The lower unadjusted resuscitation and survival rates observed in women were primarily due to women's lower incidence of VF, a relatively favorable cardiac rhythm. After adjustment for VF and other factors, women had higher resuscitation rates than men, but similar rates of survival from event to discharge.

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Section: Discussionmentioning

confidence: 99%

Out-of-hospital cardiac arrest in men and women

Kim¹,

Fahrenbruch²,

Cobb³

et al. 2002

ACC Current Journal Review

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“…[7][8][9][10] Recent clinical data 7,9 together with experiments in rabbits 8,10 suggest that testosterone may provide protection against TdP induced by I Kr -blocking drugs. The present investigation determined that testosterone given to normal female rabbits can shorten baseline APD, lessen the rate-dependence of APD prolongation, and protect against drug-induced excessive prolongation of repolarization.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10] Bidoggia et al 7 showed that women with virilization exhibit a shorter and faster repolarization time than normal women and castrated men, suggesting that testosterone is an important modulator of ventricular repolarization. In addition, Rodriguez et al 9 demonstrated that women are at greater risk of drug-induced QT prolongation during menstruation and the ovulatory phase of the menstrual cycle, with decreased risk during the luteal phase.…”

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confidence: 99%

Testosterone Diminishes the Proarrhythmic Effects of Dofetilide in Normal Female Rabbits

et al. 2002

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Background-Recent clinical and experimental data suggest that testosterone may protect males against the deleterious effects of repolarization-prolonging drugs. This study tests the hypothesis that 5␣-dihydrotestosterone (DHT) protects normal females against drug-induced excessive prolongation of repolarization. Methods and Results-We used microelectrode techniques to study isolated preparations of rabbit ventricular endocardium from age-matched normal control female rabbits and female rabbits treated with DHT for 4 weeks. Serum 17␤-estradiol levels were identical in the control and DHT-treated animals, whereas DHT levels were high (equaling those in normal males) only in the DHT-treated animals. Basal action potential duration to 90% repolarization (APD 90 ) was significantly shorter in DHT-treated (155Ϯ7.4 ms, nϭ32) than control females (178Ϯ6.7 ms, nϭ29; PϽ0.05) at cycle lengthϭ1000 ms. The increase in APD 90 induced by 10 Ϫ8 mol/L dofetilide at cycle lengthϭ1000 ms was significantly less in DHT-treated females than normal females (⌬APD 90 ϭ8Ϯ7 and 29Ϯ5 ms, respectively, PϽ0.05). At 10 Ϫ6 mol/L dofetilide, the incidence of early afterdepolarizations was 28% in DHT-treated and 55% in normal female rabbits (PϽ0.05). Conclusions-Elevating DHT levels diminishes the effects of dofetilide to increase APD and induce early afterdepolarizations in females. Moreover, treatment of females with DHT results in prolongation of APD and an incidence of early afterdepolarization equal to values previously reported by us for dofetilide-treated normal males. That serum levels of 17␤-estradiol were the same in DHT-treated and untreated females suggests that estradiol is not involved in the response to dofetilide. Thus, these data suggest that DHT and perhaps other androgenic hormones may protect normal females against the risk of dofetilide-induced arrhythmia. Key Words: arrhythmia Ⅲ sex Ⅲ dofetilide Ⅲ hormones D rugs that prolong the QT interval induce a greater incidence of arrhythmias (ie, torsades de pointes [TdP]) in women than in men. [1][2][3] The greater propensity to druginduced TdP in females is generally associated with a sex-related difference in ventricular repolarization in the heart such that the rate-corrected QT interval is longer in females than males. 4 -6 Recent clinical and experimental studies propose that gonadal steroids may modulate the sex-related differences in QT interval and propensity toward drug-induced TdP. [7][8][9][10] Bidoggia et al 7 showed that women with virilization exhibit a shorter and faster repolarization time than normal women and castrated men, suggesting that testosterone is an important modulator of ventricular repolarization. In addition, Rodriguez et al 9 demonstrated that women are at greater risk of drug-induced QT prolongation during menstruation and the ovulatory phase of the menstrual cycle, with decreased risk during the luteal phase.Given that progesterone levels are higher during the luteal than the ovulatory and menstruation phases, Rodriguez et al suggest that androgen ...

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“…This was based on the assumption that the intersubject standard deviation of the absolute QT c (Bazett's correction) was approximately 18 ms. 28 For the purpose of analysis, we categorized only the *4 homozygotes as PMs and all other genotypes as EMs. A twotailed, nonparametric (Mann-Whitney U-test) was used to compare pharmacokinetic parameters with respect to sex, CYP2D6 genotype, and haloperidol-induced side effects.…”

Section: Statistical and Power Analysismentioning

confidence: 99%

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

Desai

Tanus‐Santos

et al. 2003

Pharmacogenomics J

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We studied the pharmacokinetics and QT interval pharmacodynamics of a single 10 mg dose of oral haloperidol in a randomized, double-blind, placebo-controlled, crossover trial of healthy poor (PMs) and extensive (EMs) metabolizers of CYP2D6. There was a statistically significant greater mean QT c on haloperidol (421.6720.1 ms) than on placebo (408.4718.5 ms, P ¼ 0.0053) occurring 10 h post haloperidol/placebo administration. Men and women had similar ranges of QT c changes from placebo. Despite a statistically significant greater mean elimination half-life (19.173.6 vs 12.974.0 h, P ¼ 0.04) and lower mean apparent oral clearance (12.874.1 vs 27.0711.3 ml/min/kg, P ¼ 0.02) of haloperidol in CYP2D6 PMs than in EMs, this exposure change did not translate into marked QT c changes from baseline that could be considered clinically important. Although the magnitude of the mean QT c prolongation on haloperidol relative to placebo is relatively small, it may assume significance in the presence of other risk factors for QT prolongation. The Pharmacogenomics Journal (2003) 3, 105-113. doi:10.1038/sj.tpj.6500160Keywords: haloperidol; CYP2D6 genotype; QT INTRODUCTION Schizophrenia is a common psychiatric disease with a lifetime prevalence of nearly 1% of the general population 1 that is associated with an increased risk of premature death. A recent meta-analysis revealed that schizophrenic patients are 1.5 times more likely of dying from all causes compared to an age-and gendermatched cohort of the general population. 2 While it is not known how much of this excess risk can be attributed to antipsychotic-induced cardiotoxicity, it is clear that many antipsychotics are arrhythmogenic. 3 Among the antipsychotic drugs, haloperidol remains one of the most widely used worldwide. Haloperidol-induced ventricular arrhythmias of the torsades de pointes (TdP) type have been reported with a range of doses starting as low as 4 mg 4 administered over a 24 h period and as high as 825 mg 5 over a 24-h period. Cardiac side effects at high doses likely involve excessive exposure to haloperidol. However, the extent to which low doses of haloperidol contribute to QT interval prolongation in the absence of risk factors 6 such as age, concomitant medications, electrolyte imbalances, ischemic heart disease, or congenitally prolonged QT intervals is less well characterized. Prolongation of the QT interval is a biomarker for the malignant ventricular arrhythmia of TdP.In vitro cardiac electrophysiology studies that we have conducted demonstrate that supratherapeutic concentrations of haloperidol prolong the heart rate corrected QT interval (QT c ) by approximately 26% in an isolated perfused feline heart model. 7 The mechanism of haloperidol-mediated QT prolongation

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Drug-induced QT prolongation in women during the menstrual cycle

Cited by 46 publications

References 0 publications

Out-of-hospital cardiac arrest in men and women

Out-of-hospital cardiac arrest in men and women

Testosterone Diminishes the Proarrhythmic Effects of Dofetilide in Normal Female Rabbits

Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6

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