(Circulation. 1996;94:607-609.)
© 1996 American Heart Association, Inc.
Articles |
Of Oocytes and Runny Noses
the Departments of Pharmacology and Pediatrics, College of Physicians and Surgeons, New York, NY.
Correspondence to Michael R. Rosen, MD, the Department of Pharmacology, College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032.
Key Words: Editorials • arrhythmia • antiarrhythmia agents
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Introduction |
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The paper by Roy et al1 detailing the effects of the nonsedating antihistamine terfenadine on two K channels in an oocyte system and published in the current issue of Circulation may seem at first blush to deal with esoterica. Yet, a disturbing number of case reports2 3 and papers4 5 6 7 in the medical literature have documented QT-interval prolongation and torsade de pointes in patients taking terfenadine alone or together with antimycotics such as ketoconazole or antibiotics such as erythromycin. On the basis of such information, any physician considering therapy with nonsedating antihistamines must incorporate awareness of the acquired long-QT syndrome in the decision-making process.
The study by Roy et al1 is also a reminder that our knowledge concerning acquired long-QT syndrome is advancing with impressive rapidity in ways that impact directly on our understanding of pathophysiology and patient care. Families of drugs including but not limited to antiarrhythmics that prolong repolarization by blocking K+ channels or increasing inward Na+ currents,8 macrolide antibiotics, and pyrrole antimycotics3 4 5 6 7 all have the potential to prolong the QT interval and induce arrhythmias and/or death. With respect to the mechanism whereby nonsedating antihistamines prolong the QT interval, the focus of investigation has been the delayed rectifier current, IK. A major breakthrough here came in the report by Woosley et al4 demonstrating terfenadine block of IK in feline ventricle. Subsequently, terfenadine has been reported to block the transient outward current (Ito1) as well as the ultrarapid (IKur), rapid (IKr), and slow (IKs) components of IK in human atrial myocytes.9 Although the above-mentioned work4 9 suggested that the effects of terfenadine on a component or components of IK might explain its toxic potential in human ventricle, the study by Roy et al1 of its actions on both Kv 1.5 (the putative IKur gene10 ) and HERG (the human ether-a-gogo–related gene apparently responsible for IKr11 12 ) in xenopus oocytes indicates that the sensitivity of HERG to terfenadine block is 10 times greater than the sensitivity of Kv 1.5. This suggests that an interaction with human ventricular HERG is central to the block of IK and to the clinical manifestations of the terfenadine-induced acquired long-QT syndrome. That the carboxylate metabolite of terfenadine, which retains nonsedating, antihistaminic characteristics, has no effect on the channel may point to new directions in drug development for this class of compound, as mentioned by Roy et al.1 This conclusion is based on the assumption that the metabolite not only has no effect on HERG or other K channels in the oocyte system but will show a comparable lack of effect in myocytes as well, an important caveat because drug-receptor interactions in oocyte systems and myocardial cells represent a very different pharmacology.
One can extend the implications of studies such as that by Roy et al1 beyond antihistamines. For example, IKr is generally accepted as the target of a variety of K channel–blocking antiarrhythmic drugs, including E4031, dofetilide, and D-sotalol,8 the latter of which was recently found in the SWORD trial13 to induce an unacceptably high incidence of sudden death in a group of patients after myocardial infarction. At first glance, this provides another drug interaction of concern, that is, between any antiarrhythmic drug that blocks K channels (or indeed prolongs repolarization for any reason) and nonsedating antihistamines. If one assumes the common target channel for all these pharmacological agents is HERG, another worrisome outcome of our evolving body of information is the conclusion that drugs interacting with HERG may have too much of a proarrhythmic potential in some settings to permit their free exploitation for therapeutic benefit. The case is perhaps clearest for those antiarrhythmics that are IKr blockers and whose effect to prolong repolarization is greatest at low heart rates (so-called "reverse use dependence"). Ideally, such drugs should prolong repolarization at rapid heart rates, for which their ability to increase refractoriness would be most effective in combating tachyarrhythmias. As for drugs whose therapeutic potential lies in other areas, such as the nonsedating antihistamines, the macrolide antibiotics, and the pyrrole antimycotics, heightened awareness concerning their use, and especially their use together, must be ensured, and consideration of a risk/benefit ratio must allow for the possibility of the acquired long-QT syndrome and sudden death.
Much as we know about acquired long-QT syndrome, there still is much to be learned. It had been thought that the drug-induced acquired long-QT syndrome might be a forme fruste of the congenital variant. This would interpret the acquired long-QT syndrome as the result of one or several of the point mutations or deletions in HERG described for the congenital long-QT syndrome (see Reference 14 for review). However, a preliminary report15 of 25 patients with acquired long-QT syndrome suggests no linkage between the acquired and congenital long-QT syndromes on the basis of screening for single-strand conformational polymorphisms in the regions of HERG that are the sites of genetic mutation in the congenital syndrome. Nonetheless, other linkages between the two conditions still may be identified.
Another worrisome question arises from the gender-related differences in the long-QT syndromes. Certainly, for the congenital long-QT syndrome, there is a predilection for expression of the disease and the risk of sudden death in female subjects.16 With respect to antiarrhythmics that prolong repolarization, the SWORD trial included 437 women randomized between placebo and D-sotalol groups. There were 3 deaths in the former and 14 in the latter group, which suggests an increased risk for women taking this drug (A.L. Waldo, personal communication). Whether the same risk for women will hold true in the setting of terfenadine administration is uncertain; however, in a recent compilation,4 the admittedly small number of deaths described (25 in all) showed a distribution such that 60% were female. These data are of interest but cannot in any way be interpreted definitively, as we have inadequate knowledge of the overall characteristics of the population to whom the drug was administered. In any event, understanding of the pathophysiology underlying the expression of long-QT syndrome in female patients must await further delineation of the role of sex hormones in the determination of K channel structure and function17 18 as well as the interactions of drugs and gonadal steroids with hepatic metabolic systems whose function is influenced importantly by these steroids. Also of major concern are the cytochrome P-450 enzymes involved in the metabolism of a variety of molecules and whose inhibition is associated with elevated levels of terfenadine.
Yet another worry is the following: although the potential perils inherent in the administration of the nonsedating antihistamines, macrolide antibiotics, pyrrole antimycotics, and related drugs may be increasingly apparent to the astute physician, there is no certainty of the extent to which such awareness has spilled over to the general public. Certainly, warnings with respect to terfenadine are clearly marked in the package insert. But in the parts of the world where this and related drugs are sold over the counter, such warnings may not be enough. There may be further concerns, as follows: the 
-adrenergic agonist phenylephrine is frequently included in cold or allergy formulations. Given the large body of evidence that -agonists prolong repolarization (see Reference 19 for review), is it possible that such agents may interact with the nonsedating antihistamines to further prolong repolarization, thereby posing an additional threat? And lest one assume that concerns about antihistamines and acquired long-QT syndrome should be limited only to the nonsedating compounds, a recent preliminary report20 found that diphenhydramine, a sedating antihistamine, prolonged the QT interval of Langendorff-perfused cat hearts, albeit with an order of magnitude less potency than the nonsedating antihistamine astemizole. It has been suggested20 that whereas with general use, there need be little concern about an association between diphenhydramine and long-QT syndrome, in settings of drug overdose or liver disease, this may become a significant issue.
In closing, recent advances in molecular genetics and membrane biophysics have clearly reached a stage at which they impact importantly on our awareness of clinical pathophysiology. In the field of arrhythmias, they have begun to unravel the mysteries of the congenital and the acquired long-QT syndromes. As a result, it should be clearer than ever that much of what the clinician may have viewed as the esoterica of some aspects of basic research nonetheless are providing some of our most exciting advances. That a single genetic link will ultimately be found between congenital and acquired long-QT syndrome is unlikely; however, I do not doubt that research in this direction will continue to educate and enlighten us in ways that are both intellectually satisfying and clinically useful.
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Selected Abbreviations and Acronyms |
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. Roy M-L, Dumaine R, Brown AM. HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. Circulation. 1996;94:817-823.
2.
Monahan BP, Ferguson CL, Killeavy ES, Lloyd BK, Troy J, Cantilena LR. Torsades de pointes occurring in association with terfenadine use. JAMA.. 1990;264:2788-2790.
3.
Zimmermann M, Duruz H, Guinand O, Broccard O, Levy P, Lacatis D, Bloch A. Torsades de pointes after treatment with terfenadine and ketoconazole. Eur Heart J.. 1992;13:1002-1003.
4.
Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of the cardiotoxic actions of terfenadine. JAMA.. 1993;269:1532-1536.
5.
Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. JAMA.. 1993;269:1513-1518.
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7. Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther.. 1992;3:231-238.
8. Members of the Sicilian Gambit. Antiarrhythmic Therapy: A Pathophysiologic Approach. Armonk, NY: Futura Publishing Co Inc; 1994.
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12.
Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science.. 1995;269:92-95.
13. Waldo AL, Camm AJ, deRuyter H, Freidman PL, MacNeil DJ, Pitt JB, Pratt CM, Rodda BE. Survival with oral D-sotalol in patients with left ventricular dysfunction after myocardial infarction: rationale, design, and methods (the SWORD trial). Am J Cardiol.. 1995;75:1023-1027.[Medline] [Order article via Infotrieve]
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15. Wei J, Warhen M, Murray K, Daw R, Roden D, George A. Absence of HERG and SCN5A mutations in acquired long QT syndrome. Circulation. 1995;92(suppl I):I-275. Abstract.
16.
Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, Hall WJ, Weitkamp L, Vincent GM, Garson A Jr, Robinson JL, Benhorin J, Choi S. The long QT syndrome: prospective longitudinal study of 328 families. Circulation.. 1991;84:1136-1144.
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18. Drici MD, Burklow TR, Haridasse H, Glazer RI, Woosley RL. Regulation of K channel expression and cardiac repolarization in the rabbit heart by sex steroid hormones. Clin Pharmacol Ther.. 1996;59:189. Abstract.
19.
Terzic A, Puceat M, Vassort G, Vogel SM. Cardiac 1-adrenoceptors: an overview. Pharmacol Rev.. 1993;45:147-175.[Medline]
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20. Woosley RL, Wang WX, Chen Y. Effects of diphenhydramine (DPH) on cardiac repolarization. Clin Pharmacol Ther.. 1996;59:189. Abstract.
This article has been cited by other articles:
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  W Haverkamp, G Breithardt, A.J Camm, M.J Janse, M.R Rosen, C Antzelevitch, D Escande, M Franz, M Malik, A Moss, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology Eur. Heart J., August 1, 2000; 21(15): 1216 - 1231. [PDF]
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 W. Haverkamp, G. Breithardt, A.J. Camm, M. J Janse, M. R Rosen, C. Antzelevitch, D. Escande, M. Franz, M. Malik, A. Moss, et al. The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: Clinical and regulatory implications: Report on a Policy Conference of the European Society of Cardiology Cardiovasc Res, August 1, 2000; 47(2): 219 - 233. [Full Text] [PDF]
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