Drug-induced proarrhythmia and use of QTc-prolonging agents: Clues for clinicians

https://doi.org/10.1016/j.hrthm.2005.07.017Get rights and content

Use of drugs with the potential for prolongation of the QTc interval and proarrhythmia is a growing challenge facing clinicians. Many pharmaceutical agents have been denied approval for human use, approved with restrictions and warnings regarding proarrhythmia, or withdrawn from the market based upon arrhythmic risk. Despite known risk factors for QTc prolongation and drug-induced arrhythmia, precise prediction of the risk of torsades de pointes (TdP) in an individual patient remains difficult. The mechanism of drug-induced TdP typically involves use of an agent that blocks the IKr cardiac potassium current, often in combination with risk-amplifying factors such as high drug levels, reduced drug metabolism, polypharmacy, and patient-specific factors such as gender, age, and genetic polymorphism. For the clinician, an integrated approach involving appreciation of the risk factors for proarrhythmia combined with computer-based risk assessment is the best method for reducing the risk of drug-induced proarrhythmia in clinical practice.

Introduction

Drug-induced proarrhythmia is a growing challenge shared by the pharmaceutical industry, prescribing clinicians, and regulatory bodies charged with evaluating and monitoring drug safety. The greatest risk of drug-induced proarrhythmia with current agents is the risk of prolongation of the corrected QT interval (QTc) on the electrocardiogram (ECG), which can be associated with a potentially life-threatening form of polymorphic ventricular tachycardia termed torsades de pointes (TdP). Drugs with proven lengthening of the QTc interval or a definite association with TdP are common and are estimated to compose approximately 2% to 3% of all prescriptions written.1 Among the most common noncardiac drugs with QTc interaction seen in clinical practice are antibiotics and psychotropic drugs,2 which in the vast majority of cases are prescribed by noncardiologists. Although uncommon in routine clinical practice, TdP is extremely difficult to predict accurately despite known risk factors and mechanism. A large number of drugs in clinical use are associated with QTc prolongation based upon studies in humans, animals, and various experimental preparations (Figure 1).

Because of the risk of drug-induced arrhythmia associated with QTc prolongation, regulatory agencies now require detailed evaluation of the effects of new agents on cardiac repolarization prior to drug approval, as well as postmarketing surveillance of approved drugs with perceived risk. As a result of this scrutiny, a number of drugs have been denied approval for use in humans, have received approval with warnings related to QTc effects (either at the time of approval or relabeled after initial approval), or have been withdrawn from the market after previously unappreciated proarrhythmic effects were detected (Figure 2). The pharmaceutical industry and regulatory bodies are charged with safety monitoring at all stages of drug evaluation, both before and after approval for human use. Despite the industry and regulatory body monitoring, clinicians ultimately are responsible for the safety of the patients to whom they prescribe drugs. Many approved drugs have the potential—either demonstrated or theoretical—for QTc prolongation and TdP. As a result, prescription of all agents must be based upon informed evaluation of the risks and benefits of each drug compared with available alternatives.

A mechanistic understanding of drug-induced arrhythmia has been appreciated only recently. In the 1920s, quinidine (a new antiarrhythmic agent at that time) was associated with syncope. Advances in ECG monitoring in the ensuing decades identified pause-dependent polymorphic ventricular tachycardia, later termed TdP, as the responsible mechanism.3, 4 Similarly, cases of cardiac toxicity with antipsychotics and antihistamines were reported in the 1960s and 1970s, but the cases were poorly understood, and little regulatory oversight was in practice. In concert with growing appreciation of drug-induced arrhythmia, the first descriptions of heritable syndromes linking a long QTc interval with sudden cardiac death were reported.4, 5, 6 Knowledge of both drug-induced QTc lengthening and the heritable long QTc syndromes has proved complementary in elucidating the mechanisms responsible for the clinical features of TdP.

Section snippets

Terfenadine: a case study

Terfenadine is a nonsedating antihistamine that was widely used (>100 million prescriptions filled while an approved agent) prior to its withdrawal from the market in 1998. Use of terfenadine at therapeutic concentrations produces a measurable increase in the QTc interval, but the increase is relatively modest (6–8 ms average QTc increase across the dosing interval, 18 ms at peak drug levels).7 Furthermore, terfenadine appeared to be safe in large, postapproval monitoring of approximately

Mechanisms of drug-induced arrhythmia

In order to understand the molecular basis of QTc prolongation, an understanding of the molecular basis of the QT interval is critical (for review, see Fenichel et al.13). The QT interval represents a summation of the entire duration of the cardiac action potentials of ventricular cardiomyocytes, from the onset of depolarization until the completion of repolarization. The membrane voltage is governed by inward currents (primarily sodium and calcium), which lead to depolarization, and outward

Risk factors for proarrhythmia

In order to assess the risk of drug-induced TdP in an individual patient, the known effects of the drug and the dose in question on the QT and QTc interval must be considered. In addition, careful attention must be given to the susceptibility of the individual patient, including the presence of known risk factors for drug-induced TdP and the use of concomitant medications, which may exhibit pharmacodynamic or pharmacokinetic interactions with the drug in question. As demonstrated with

Strategies for clinicians

Drug-induced TdP is a rare but potentially lethal event; therefore, it must be considered by all clinicians who prescribe drugs. It would be possible for regulatory bodies to reduce but not eliminate entirely the risk of TdP by declining to approve any drug with the potential to prolong the QTc interval, even to a modest degree. Although intuitively appealing, this approach inevitably would harm the public interest by denying patients access to many therapeutic agents whose proven clinical

Computer-assisted approaches

As our understanding of drug-induced arrhythmia and the number of medications with potential proarrhythmic effects continues to grow, the burden on clinicians to be aware of and consider the proarrhythmic potential of prescribed drugs becomes ever greater. Most drugs with proarrhythmic potential are prescribed by noncardiologists, and it is unrealistic to expect physicians to stay current with advancing knowledge on the proarrhythmic potential of all drugs in clinical use. Lists of drugs with

Conclusion

An increasing number of drugs with the potential to prolong the QTc interval and cause TdP are being used in routine clinical practice. Research on the molecular and cellular bases of the cardiac action potential and of genetic long QT syndromes has shed considerable light on the mechanisms responsible for drug-induced QT prolongation. Despite the increased knowledge, TdP in the clinical setting remains difficult to predict and is related to multiple variables, including patient age, gender,

Acknowledgments

This work was funded in part by a Clinical Investigator Training Program award (Harvard/MIT Health Sciences and Technology-Beth Israel Deaconess Medical Center, in collaboration with Pfizer Inc. and Merck & Co.) to EKH.

References (37)

  • D.M. Roden

    Drug-induced prolongation of the QT interval

    N Engl J Med

    (2004)
  • O.C. Ward

    A new familial cardiac syndrome in children

    J Isr Med Assoc

    (1964)
  • M. Jurima-Romet et al.

    Terfenadine metabolism in human liver

    Drug Metab Dispos

    (1994)
  • P.K. Honig et al.

    Terfenadine-ketoconazole interaction

    JAMA

    (1993)
  • R.E. Benton et al.

    Grapefruit juice alters terfenadine pharmacokinetics, resulting in prolongation of repolarization on the electrocardiogram

    Clin Pharmacol Ther

    (1996)
  • R.R. Fenichel et al.

    Drug-induced torsades de pointes and implications for drug development

    J Cardiovasc Electrophysiol

    (2004)
  • C.H. Luo et al.

    A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes

    Circ Res

    (1994)
  • C.E. Clancy et al.

    Inherited and acquired vulnerability to ventricular arrhythmiascardiac Na+ and K+ channels

    Physiol Rev

    (2005)
  • Cited by (0)

    View full text