QT Prolongation and Torsade de Pointes Induced by Fluoroquinolones: Infrequent Side Effects from Commonly Used Medications

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Abstract

Although very useful agents, fluoroquinolones are associated with a number of adverse events, some with considerable clinical significance. Prolongation of the QT interval, for example, is an adverse effect associated with the use of fluoroquinolones. Fluoroquinolones prolong the QT interval by blocking voltage-gated potassium channels, especially the rapid component of the delayed rectifier potassium current I<sub>Kr</sub>, expressed by HERG (the human ether-a-go-go-related gene). According to the available case reports and clinical studies, moxifloxacin carries the greatest risk of QT prolongation from all available quinolones in clinical practice and it should be used with caution in patients with predisposing factors for Torsades de pointes (TdP). Although gemifloxacin, levofloxacin, and ofloxacin are associated with a lower risk of QT prolongation compared with moxifloxacin, they should also be used with caution in patients at risk for QT prolongation. Ciprofloxacin appears to be associated with the lowest risk for QT prolongation and the lowest TdP rate. The overall risk of TdP is small with the use of fluoroquinolones. Clinicians can minimize that risk by avoiding prescriptions of multiple medications associated with QT-interval prolongation, especially in high-risk patients.

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Most cited references 28

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A structural basis for drug-induced long QT syndrome.

Anya Lin, Claudio M Sanguinetti, Janice Chen … (2000)

Mutations in the HERG K(+) channel gene cause inherited long QT syndrome (LQT), a disorder of cardiac repolarization that predisposes affected individuals to lethal arrhythmias [Curran, M. E. , Splawski, I., Timothy, K. W., Vincent, G. M., Green, E. D. & Keating, M. T. (1995) Cell 80, 795-804]. Acquired LQT is far more common and is most often caused by block of cardiac HERG K(+) channels by commonly used medications [Roden, D. M., Lazzara, R., Rosen, M., Schwartz, P. J., Towbin, J. & Vincent, G. M. (1996) Circulation 94, 1996-2012]. It is unclear why so many structurally diverse compounds block HERG channels, but this undesirable side effect now is recognized as a major hurdle in the development of new and safe drugs. Here we use alanine-scanning mutagenesis to determine the structural basis for high-affinity drug block of HERG channels by MK-499, a methanesulfonanilide antiarrhythmic drug. The binding site, corroborated with homology modeling, is comprised of amino acids located on the S6 transmembrane domain (G648, Y652, and F656) and pore helix (T623 and V625) of the HERG channel subunit that face the cavity of the channel. Other compounds that are structurally unrelated to MK-499, but cause LQT, also were studied. The antihistamine terfenadine and a gastrointestinal prokinetic drug, cisapride, interact with Y652 and F656, but not with V625. The aromatic residues of the S6 domain that interact with these drugs (Y652 and F656) are unique to eag/erg K(+) channels. Other voltage-gated K(+) (Kv) channels have Ile and Val (Ile) in the equivalent positions. These findings suggest a possible structural explanation for how so many commonly used medications block HERG but not other Kv channels and should facilitate the rational design of drugs devoid of HERG channel binding activity.

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HERG, a human inward rectifier in the voltage-gated potassium channel family

M. Trudeau, G. Robertson, B Ganetzky … (1995)

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Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition.

G Dresser, Philip Spence, Swneke D Bailey (1999)

Drug interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance. Pharmacokinetic interactions often occur as a result of a change in drug metabolism. Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes. The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition. Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein. Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice. Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfenadine, astemizole, cisapride or pimozide. Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ('statins') and CYP3A4 inhibitors. Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil. Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors. Ataxia can occur with carbamazepine, and ergotism with ergotamine, following the addition of a CYP3A4 inhibitor. Beneficial drug interactions can occur. Administration of a CYP3A4 inhibitor with cyclosporin may allow reduction of the dosage and cost of the immunosuppressant. Certain HIV protease inhibitors, e.g. saquinavir, have low oral bioavailability that can be profoundly increased by the addition of ritonavir. The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related. Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Less pronounced pharmacokinetic interactions may still be clinically important for drugs with a steep concentration-response relationship or narrow therapeutic index. In most cases, the extent of drug interaction varies markedly among individuals; this is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age. Interactions may occur under single dose conditions or only at steady state. The pharmacodynamic consequences may or may not closely follow pharmacokinetic changes. Drug interactions may be most apparent when patients are stabilised on the affected drug and the CYP3A4 inhibitor is then added to the regimen. Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction.

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Author and article information

Journal

Journal ID (publisher-id): CRD

Journal ID (nlm-ta): Cardiology

Journal ID (doi): 10.1159/issn.0008-6312

Title: Cardiology

Publisher: S. Karger AG

ISSN (Print): 0008-6312

ISSN (Electronic): 1421-9751

Publication date Subscription-year: 2011

Publication date (Print): December 2011

Publication date (Electronic): 13 December 2011

Volume: 120

Issue: 2

Pages: 103-110

Affiliations

^aDepartment of Medicine and ^bAl-Sabah Arrhythmia Institute, St. Luke’s Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, N.Y., USA

Author notes

*Alexandros Briasoulis, MD, Department of Medicine, St. Luke’s Roosevelt Hospital Center, 515 West 59th Street, New York, NY 10019 (USA), Tel. +1 212 523 4000, E-Mail alexbriasoulis@gmail.com, ab3347@columbia.edu

Article

Publisher ID: 334441 Other ID: Cardiology 2011;120:103–110

DOI: 10.1159/000334441

PubMed ID: 22156660

SO-VID: 5912f424-13ab-4c40-9838-5acc2d5f72e2

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 26 August 2011

Date accepted : 10 October 2011

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Figures: 3, Tables: 1, Pages: 8

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QT Prolongation and Torsade de Pointes Induced by Fluoroquinolones: Infrequent Side Effects from Commonly Used Medications

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Karger: Cardiovascular System

Most cited references 28

A structural basis for drug-induced long QT syndrome.

HERG, a human inward rectifier in the voltage-gated potassium channel family

Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition.

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Cited by 40

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