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(Circulation. 1995;91:2220-2225.)
© 1995 American Heart Association, Inc.

Articles

Regulation of Potassium Channels by Nonsedating Antihistamines

Presented in part at the 43rd Annual Scientific Session of the American College of Cardiology, Atlanta, Ga, March 13-17, 1994.

Charles I. Berul, MD; Martin Morad, PhD

From the Division of Cardiology, The Children's Hospital of Philadelphia (Pa) (C.I.B.), and the Department of Pharmacology, Georgetown University Medical Center, Washington, DC (M.M.).

Correspondence to Dr Martin Morad, Department of Pharmacology, Georgetown University School of Medicine, 3900 Reservoir Rd, NW, Washington, DC 20007.

	Abstract

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Background Terfenadine and astemizole are widely prescribed nonsedating antihistamines that have been associated with QT-interval prolongation and ventricular arrhythmias. Since potassium channels are intrinsically involved in repolarization, this study was designed to evaluate the effect of the nonsedating antihistamines on potassium channel modulation.

Methods and Results The whole-cell patch-clamp technique was used to study K⁺ currents in enzymatically isolated rat and guinea pig ventricular myocytes. Three distinct K⁺ channels were examined: the inward rectifier (I_K1), the delayed rectifier (I_K), and the transient outward (I_to) currents. The dialyzing pipette solution was buffered with EGTA, and ionic channels other than potassium were pharmacologically inhibited or electrically inactivated. Both astemizole and terfenadine suppressed the I_K1 channel by 17% to 50% in a voltage-dependent manner in rat and guinea pig myocytes. I_to was evaluated in rat ventricular myocytes. Both drugs also inhibited the maintained component of I_to to a lesser extent, by 23%, in a dose-dependent, reversible manner. I_K was examined mainly in guinea pig myocytes. Terfenadine but not astemizole slightly inhibited I_K, by 9%, and only at higher drug concentrations. The medications had dose-dependent inhibitory actions, with specific K⁺ channel suppression evident only beginning at concentrations >0.1 µmol/L.

Conclusions These findings suggest that the mechanism of action of the rare proarrhythmic effects of the nonsedating antihistamines appears to be secondary to potassium channel blockade. A significant voltage-dependent blockade of the I_K1 channel was demonstrated, as well as additional inhibitory effects on I_to and I_K channels. These actions lead to delayed repolarization, QT interval prolongation, and enhanced susceptibility to the development of premature ventricular depolarizations. Caution is advised in the prescription of nonsedating antihistamines, particularly in patients at risk of elevated serum levels of the antihistamine or patients with existing repolarization abnormalities.

Key Words: antihistamines • potassium • repolarization

	Introduction

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Antihistamines are a group of structurally diverse compounds frequently prescribed for treatment of allergies, urticarial diseases, and symptoms associated with upper respiratory infections. The medications act via specific blockade of the H₁ histamine receptors, present in skin, pulmonary, gastrointestinal, neural, and cardiac tissues. Terfenadine (Seldane) and astemizole (Hismanal), a second generation of H₁ receptor antagonists, are two widely used nonsedating antihistamines that differ pharmacologically from first-generation antihistamines by having preferential affinity for the peripheral H₁ receptors versus the brain H₁ and cholinergic receptors.¹ They also poorly penetrate the blood-brain barrier when given in therapeutic dosage.^{2 3} Recently, there have been several reports of adverse cardiac effects in patients taking this group of drugs. Cardiac arrhythmias were initially reported in patients who intentionally or accidentally ingested overdoses of either astemizole^{4 5 6 7 8 9 10 11} or terfenadine.^{12 13} Young children have presented with syncope, associated with QT-interval prolongation, and malignant ventricular arrhythmias, including torsade de pointes.^{6 7} These proarrhythmic effects have typically been seen only with overdose, liver disease, or concomitant administration of a medication that interferes with hepatic cytochrome P-450 enzymatic metabolism (ie, ketoconazole, macrolide antibiotics, cimetidine, etc).^{13 14 15 16 17 18}

The modulation of histamine receptors in cardiac tissue can have profound effects on atrioventricular conduction and arrhythmogenesis.¹⁹ Histamine receptors are inhomogeneously distributed in the heart, with more activity in the atria than ventricles and distinctly different cardiac responses to H₁ versus H₂ histamine receptor stimulation or inhibition.^{19 20} The prolongation of the QT interval seen with antihistamine cardiotoxicity suggests that delayed repolarization may play a part in the arrhythmogenic potential of these medications. To determine the cellular electrophysiological basis for the proarrhythmic effects of these drugs, this study was designed to investigate the actions of two H₁ receptor antagonists, terfenadine and astemizole, on various potassium (K⁺) channels of cardiac myocytes.

	Methods

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Cell Isolation
Ventricular myocytes were obtained from male guinea pigs (200 to 300 g) and Wistar rats (100 to 200 g) by a previously described rapid enzymatic isolation procedure.²¹ Myocytes were dispersed and allowed to settle for at least 1 hour at room temperature (22°C to 24°C) before being used. Animal experimentation was performed in accordance with the guidelines of the University of Pennsylvania Committee on Laboratory Animal Studies and the American Heart Association's position statement on research animal usage.

Solutions and Technique
The whole-cell patch-clamp technique²² was used to evaluate individual ionic currents with a Dagan model 8900 patch-clamp amplifier connected to an IBM computer with P-CLAMP 5.5 software package (Axon Instruments). Heat-polished borosilicate glass pipettes (World Precision Instruments) with tip resistances of 1.0 to 2.5 m were used to establish a gigaohm seal and continuity with the intracellular medium. The dialyzing internal pipette solution was highly EGTA-buffered and contained 135 mmol/L KCl, 10 mmol/L NaCl, 5 mmol/L HEPES, 5 mmol/L Mg-ATP, and 10 µmol/L cAMP, titrated with KOH to a pH of 7.20. The control external perfusate was a modified Tyrode's solution and contained (in mmol/L): NaCl 137, KCl 5.4, MgCl₂ 1, HEPES 5, and glucose 10, titrated with NaOH to pH 7.4.

Drugs
Astemizole (Janssen Research Foundation) was obtained as the base powder and dissolved in distilled water with 0.01% ethyl alcohol and 0.01% acetic acid. Aliquots (1 mL) were frozen at a 1 mmol/L stock concentration. Terfenadine base (Sigma Chemical Co) was dissolved in distilled water with 0.01% ethyl alcohol and frozen at 1 mmol/L concentration. In the experimental solutions, varying concentrations from 1 nmol/L to 1 µmol/L of each drug were added to fresh control Tyrode's solution. In some of the experiments, the control solution also contained comparable quantities of the stock vehicle, 0.01% ethyl alcohol and 0.01% acetic acid. A multibarrel concentration clamp system (Vibraspec, Inc) was used to rapidly (<100 ms) exchange the extracellular solution and drug concentrations immediately surrounding an individual myocyte.

Ionic Channels
Since cardiac K⁺ channels are voltage-gated, three different voltage-clamp protocols were used to specifically evaluate the kinetics of the individual K⁺ channels. The inward rectifier potassium channel (I_K1) was activated by 200-ms test pulses to -100 mV from a holding potential of -40 mV to inactivate the Na⁺ channel. The voltage dependence of I_K1 was determined by stepwise 10-mV increases in the test voltage, ranging between 0 and -150 mV. In this group of myocytes, calcium current (I_Ca) was also blocked by the addition of either 2 mmol/L nickel or 1 µmol/L nisoldipine.

The delayed rectifier K⁺ channel (I_K) was measured primarily in guinea pig ventricular myocytes with 300-ms conditioning pulses from -90 to -10 mV, followed by test pulses to +50 mV for 1200 ms. Conditioning pulses to -10 mV were used to inactivate I_Na, I_Ca, and I_to. The current/voltage (I/V) relation for I_K was constructed by incremental 10-mV increases in the test potential from 0 to +100 mV.

The transient outward K⁺ current (I_to) was measured only in the rat ventricular myocytes by a protocol using -90-mV holding potentials and test potentials of +80 mV for 200-ms duration. The I_to was defined as the initial transient deflection lasting 20 to 30 ms, while the maintained portion of the current was measured at the end of the pulse. The voltage dependence of I_to was measured by 10-mV stepwise increases in the test pulses from -90 to +100 mV. In some experiments, I_Ca and I_Na were blocked by 1 µmol/L nisoldipine and 10 µmol/L tetrodotoxin, respectively, to measure the time course of activation of I_to more accurately.

Statistics
Data are summarized as current, adjusted for cell capacitance, expressed as peak current density in picoamperes per picofarad (pA/pF) and reported as mean±SEM. The mean percent inhibition (% block) and amount of recovery of the current on drug washout (% recovery) was tabulated. Each cell served as its own control, with data acquisition before, during, and after drug application. Statistical analysis also included the two-tailed Student's t test for paired samples. A two-factor ANOVA using % block as the outcome variable was performed to determine whether the drug effects were channel specific and whether the antihistamines differed in their K⁺ channel inhibitory actions.

	Results

Top Abstract Introduction Methods Results Discussion References

 
The effects of the nonsedating antihistamines astemizole and terfenadine were studied in three families of cardiac potassium channels: I_K, I_K1, and I_to. The I_to was studied in rat, the I_K was studied in guinea pig ventricular myocytes, and the I_K1 was studied in both species. The drug actions are analyzed according to species, drug concentration, and the specific K⁺ channel.

Modulation of I_K1
Large inward K⁺ currents were recorded in response to hyperpolarizing pulses negative to -80 mV in both rat and guinea pig ventricular myocytes. The major qualitative difference in the inward rectifier currents of the two species was the presence of a relatively larger outward component of I_K1 in the guinea pig myocytes, reaching a maximal value around -50 mV.

Fig 1 shows the effects of astemizole and terfenadine on the kinetics and voltage dependence of I_K1 in the guinea pig and rat myocytes. The suppressive effects of both drugs occurred slowly (t_1/2=45 seconds), and the effects were mostly reversible, recovery occurring within 2 to 5 minutes after drug washout (Fig 1A). There was no significant effect of either drug on I_K1 at concentrations <0.1 µmol/L. The suppressive effects of both drugs occurred in a dose-dependent manner from 0.1 to 10 µmol/L (Fig 1B). Astemizole reversibly inhibited I_K1 by 25%, from 30.5±4.6 to 22.2±4.7 pA/pF (P<.001, n=10: 6 guinea pig and 4 rat cells), with 93% recovery on drug washout. Terfenadine (1 to 10 µmol/L) also reversibly inhibited the I_K1. I_K1 was suppressed by 39% in the presence of 10 µmol/L terfenadine, from a mean value of 45.7±6.7 pA/pF before terfenadine application to 27.3±5.0 pA/pF (P<.005, n=5: 4 guinea pig and 1 rat myocyte). Fig 1C shows an example of astemizole-induced suppression of the inward rectifier current in a guinea pig ventricular myocyte at different potentials. Examination of the astemizole block revealed that the block was occurring in a voltage-dependent manner, with a 17% mean block at -100 mV and 31% inhibition at -150 mV (n=18: 9 guinea pig and 9 rat myocytes). Similar to astemizole, the block of I_K1 with terfenadine was also voltage-dependent, such that the drug inhibited I_K1 by 10% to 17% at -100 mV, increasing to 25% to 50% block at -150 mV (Fig 1D). After drug washout, the current recovered to 36.8±5.4 pA/pF, ie, to 82% of control values.

View larger version (21K): [in this window] [in a new window]   Figure 1. A, Graph showing time course of inhibitory effect of 1 µmol/L astemizole (AST) on the inwardly rectifying potassium channel (Ik1) in a guinea pig ventricular myocyte. The current density (pA/pF) is measured with successive depolarizing pulses (from -40 to -120 mV) delivered at 5-second intervals. Application of AST leads to inhibition of Ik1 in a progressive fashion. After a 5-minute equilibration period, the drug is washed out of the extracellular perfusate, and the current recovers. All experiments were performed at room temperature (25°C). The cell capacitance was 136 pF. B, Graph showing dose-dependence of AST and terfenadine (TERF) effect on Ik1, measured after depolarizing pulses from -40 to -120 mV. External drug concentrations ranged from 10 nmol/L to 10 µmol/L. The maximum Ik1 inhibition is shown as percent block, with baseline current normalized to 100% for each experiment. C, Graph showing voltage dependence of AST on Ik1 in a rat ventricular myocyte. Stepwise (10-mV) hyperpolarizing pulses from a -40-mV holding potential to -150 mV were used to activate Ik1 at successive potentials. Current/voltage (I/V) relation was obtained in each cell at baseline, 2 minutes after application of 1 µmol/L AST, and after 5 minutes of drug washout. Graph illustrates the voltage-dependent inhibition of Ik1 by AST with recovery on washout. Inset shows original current tracings of Ik1 in the presence and absence of AST when Ik1 is activated by a pulse from -50 to -100 mV. Cell capacitance was 154 pF. D, Graph showing effect of 1 µmol/L TERF on Ik1 in a guinea pig ventricular myocyte. Similar to AST in panel C, 1 µmol/L TERF leads to suppression of Ik1 in a voltage-dependent manner. Inset shows tracings of Ik1 activated in the presence and absence of 1 µmol/L TERF by hyperpolarizing pulses from -50 to -120 mV. CTL indicates control.

Modulation of I_to
The I_to was studied primarily in rat ventricular myocytes, because this species strongly expresses the channel. Holding potentials of -90 mV were used to study this channel, because holding potentials positive to -80 mV reduce the availability of I_to significantly.²³ Significant K⁺ current through the I_to channel could be measured at voltages positive to +10 mV. The kinetics of the inactivation of I_to varied from cell to cell, suggesting differential expression of the channel in different parts of the ventricle. The activation of I_to is always accompanied by a maintained current component (pedestal type), which has an activation potential similar to that of I_K but which cannot be inactivated by conditioning potentials (-10 mV) that almost fully inactivate the transient component of I_to.

Fig 2 illustrates the effects of astemizole and terfenadine on the kinetics and voltage dependence of I_to in rat ventricular myocytes. Astemizole appeared to suppress both the peak transient and the maintained components of I_to equally, such that the effect on the transient current was small, even at high drug concentrations (1 or 10 µmol/L). The inset in Fig 2A shows that I_to is suppressed by 1 µmol/L astemizole, without significant changes in its kinetics. Fig 2B illustrates the inhibitory effects of both astemizole and terfenadine on the I_to channel in rat ventricular myocytes at differing concentrations. No significant inhibitory effect of either drug was found at concentrations below 0.1 µmol/L. Astemizole reversibly inhibited I_to in rat ventricular myocytes by 23%, from 14.6±4.3 to 11.0±2.7 pA/pF (P<.05, n=3). Terfenadine, like astemizole, decreased I_to, from 16.1±2.9 to 14.3±2.7 pA/pF (P=.05, n=2).

View larger version (18K): [in this window] [in a new window]   Figure 2. A, Graph showing actions of astemizole (AST) on the transient outward K+ current (Ito) in a rat ventricular myocyte. The graph illustrates the current/voltage (I/V) relation in control (Ctl) solution and after the addition of 1 µmol/L AST to the external perfusate. Ito is activated by 150-ms depolarizing pulses from -80 mV in 10-mV sequential steps to +120 mV. Inset shows original tracings of Ito activated by depolarization from -80 to +60 mV in the presence and absence of AST. The maintained component of Ito appears to be moderately suppressed by AST. B, Graph showing dose dependence of AST and terfenadine (TERF) inhibitory action on Ito in rat ventricular myocytes. Ito was measured after depolarizing pulses from -80 to +60 mV. External drug concentrations ranged from 10 nmol/L to 10 µmol/L for AST and from 10 nmol/L to 1 µmol/L for TERF. No significant inhibitory effect was seen at <1µmol/L concentrations. The maximal Ito inhibition is shown as percent block of the current activated in the control solutions and normalized to 100% for each experiment.

Modulation of I_K
The I_K activates slowly in ventricular myocytes of most mammalian species, but the current appears to be absent in the rat ventricle. In the present study, I_K was examined in guinea pig myocytes by use of a conditioning potential to -10 mV to inactivate both Na⁺ and Ca²⁺ currents before the activation of I_K. The I_K has been reported to have both Ca²⁺- and voltage-dependent components²⁴ and appears to be modulated by cAMP-dependent phosphorylation.^{25 26} Therefore, in this study we examined I_K only in highly Ca²⁺-buffered guinea pig ventricular myocytes so as to minimize the Ca²⁺-dependent component of this current.

The inset in Fig 3A shows superimposed tracings of activation of I_K at +60 mV in control solution and after addition of 1 µmol/L astemizole, demonstrating only slight current suppression. The effect of astemizole at different potentials (Fig 3A, graph) also confirms only a minor effect at all voltages examined. At 10 µmol/L concentrations, both terfenadine and astemizole appeared to suppress I_K more effectively, but at these concentrations, both drugs also strongly suppressed both Na⁺ and Ca²⁺ channel currents, suggesting nonspecific actions. At concentrations <10 µmol/L, astemizole had no significant inhibitory effects on the I_K, with current density ranging from 4.1±1.0 pA/pF before to 4.1±1.1 pA/pF after astemizole application (P=.6, n=18: 12 guinea pig and 6 rat myocytes). Terfenadine (1 to 10 µmol/L), on the other hand, decreased I_K slightly but statistically significantly, from 4.2±0.8 to 4.0±0.7 pA/pF (P<.05, n=8: 5 guinea pig and 3 rat myocytes), with 99% recovery on washout (Fig 3B).

View larger version (16K): [in this window] [in a new window]   Figure 3. A, Graph showing effect of 1 µmol/L astemizole (AST) or terfenadine (TERF) on the voltage dependence of the delayed rectifier K+ channel (Ik) in a guinea pig ventricular myocyte. Stepwise 10-mV depolarizing pulses activated Ik at potentials positive to +20 mV. INa and ICa were inactivated by conditioning pulses to -20 mV. The current/voltage (I/V) relation in control (Ctl) solutions is compared with that obtained in 1 µmol/L of either AST or TERF. Little or no significant effect is evident at the voltage ranges examined. Inset shows original tracings of Ik, acquired during addition of 1 µmol/L TERF to the perfusate, with little or no apparent suppressive effect. B, Graph showing dose-response relation for AST and TERF on Ik in guinea pig ventricular myocytes. Ik was activated by membrane depolarization from -80 to -20 mV conditioning pulses to inactivate INa and ICa, followed by depolarizing pulses from -20 to +60 mV. Drug concentrations ranged from 10 nmol/L to 10 µmol/L. No significant suppressive effect was found at concentrations <10 µmol/L. The maximal Ik inhibition is shown as percent block, with baseline current normalized to 100% for each experiment.

Fig 4 summarizes the mean suppressive effects of astemizole and terfenadine on the potassium channels I_K, I_K1, and I_to in both species evaluated. A two-way ANOVA was performed, comparing the effects of the antihistamines on each of three K⁺ channels. This demonstrated a significant difference between modulation of each channel, indicating channel-specific current inhibition. An interaction effect was also evident in the ANOVA (P=.04), suggesting an additional difference between the two nonsedating antihistamines as well as on each individual channel.

View larger version (17K): [in this window] [in a new window]   Figure 4. Bar graph showing summary of the effects of astemizole (AST) and terfenadine (TERF) on three potassium channels: the delayed rectifier, inward rectifier, and transient outward (Ik, Ik1, and Ito) currents. The control currents were normalized to 100%. The mean current densities after application of 1 µmol/L of either TERF or AST are shown for the Ik, Ik1, and Ito K+ channels. Both drugs effectively inhibit Ik1, but AST appears somewhat more effective on Ito. At 1 µmol/L, neither drug appears to have a significant effect on IK.

	Discussion

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The major finding of these experiments is that terfenadine and astemizole significantly inhibited the I_K1 in both guinea pig and rat ventricular myocytes. In the rat myocytes, both drugs also blocked a component of the I_to. Terfenadine, but not astemizole, additionally blocked I_K to a small extent.

The results of our experiments with terfenadine are consistent with previous studies showing the suppressive effect of terfenadine on the I_K in cat and human myocytes.^{27 28} In cat ventricular myocytes, the I_K-associated tail currents on deactivation of the channel were prominent and were markedly suppressed by terfenadine.²⁷ In guinea pig ventricular myocytes, we did not find a similarly large suppression of I_K tail current. However, the amplitude of the tail current appears to be somewhat species dependent, ie, quite large in cat, shark, and frog ventricular myocytes and relatively small in human and rodent myocytes.^{27 28 29 30 31 32} In addition, since deactivation of I_K at -40 mV may activate a significant amount of I_K1, we did not measure tail currents so as to avoid complications from simultaneous activation of I_K and I_K1 in the same cell. Therefore, in guinea pig ventricular myocytes, we measured K⁺ currents through I_K channels only at positive potentials, when I_K1 is inactivated. Using this procedure, we measured only small suppressive effects of these drugs on I_K channel. The absence of significant suppressive effects of these drugs on I_K was somewhat surprising, since most drugs that prolong the QT interval are thought to do so primarily by inhibition of I_K. Since I_K has both voltage- and Ca²⁺-dependent components and has been shown to be strongly temperature-dependent,²⁵ it is possible that the nonsedating antihistamines may have more selective Ca²⁺- or temperature-dependent effects on this current. Since the experiments described here were carried out in EGTA-buffered myocytes at room temperature, such effects of the drugs remain to be explored.

Somewhat surprisingly, we found a significant voltage-dependent suppression of I_K1 channel in both guinea pig and rat ventricular myocytes. The I_K1 channel not only is responsible for maintaining a stable cardiac resting potential near the K⁺ equilibrium potential^{33 34} but also determines the time course of rapid repolarization of cardiac action potential. The inhibition of I_K1 would necessarily cause a prolongation of the rapid repolarization phase of the action potential,^{35 36 37} which may result in an increase in the vulnerable period, enhancing the chances of aberrant excitation and arrhythmia in the presence of the drugs.

The rat ventricular myocytes also express a large transient K⁺ current, which is present in human cells but poorly developed in guinea pig heart.^{38 39} Not only is there species-dependent variability in the degree of I_to expression, but also there appears to be regional tissue disparity as well, with a greater expression of I_to in epicardium versus endocardium in the ventricle of mammals, including humans.⁴⁰ The inhibition of I_to by the antihistamines would contribute to the prolongation of action potential, especially at potentials positive to -20 mV, at which this channel is strongly activated.

Modulation of Potassium Channels and Arrhythmogenesis
Modulation of K⁺ channels can have marked effects on the repolarization phase of the cardiac action potential. In contrast to the nonsedating antihistamines, the class III antiarrhythmic agents, such as amiodarone and sotalol, act predominantly via inhibition of I_K.⁴¹ Many of the other non–class III antiarrhythmic agents also possess some class III properties (ie, APD prolongation) via inhibitory effects on potassium channels. Flecainide, for example, classified as an IC agent because of its potent Na⁺ channel blocking action, also blocks I_K without effect on I_K1 in single cardiac myocytes.³² Tedisamil blocks both I_K and I_to in rat ventricular myocytes without significant effect on I_K1, independent of the phosphorylation state of the channels.⁴² N-Acetylprocainamide, the active metabolite of procainamide, inhibits I_K and blocks I_K1 to a lesser extent.⁴¹ Thus, antiarrhythmic drugs appear to suppress predominantly I_K, with little effect on I_K1. Nonsedating antihistamines, on the other hand, in guinea pig and rat ventricular myocytes appear to have little modulatory effect on I_K channel but have a significant inhibitory action on I_K1, rendering them potentially arrhythmogenic under overdose conditions or when the I_K1 channel is already compromised.

The rare proarrhythmic actions of these structurally unrelated but functionally similar nonsedating antihistamines appear to be secondary to potassium channel blockade. These effects were evident only at high drug concentrations, consistent with the scarcity of clinical reports of arrhythmias and sudden death, despite the widespread use of these agents. Blockade of I_K1 and I_to would lead to a delay in action potential repolarization, QT interval prolongation on the ECG, and enhanced susceptibility to premature depolarizations in the vulnerable period, particularly in the Purkinje fibers, in which significant inward Na⁺ current is activated through the I_f channel at voltages negative to -55 mV. It is important to note that I_K1 inhibition would prolong the rapid repolarization phase, rendering the action potential triangular in shape. Many animal models of long QT syndrome and torsade de pointes use cesium to mimic the syndrome.⁴³ It is well established that cesium is a potent blocker of the I_K1 channel, with little or no effect on I_to or I_K channels. The nonsedating antihistamines at high concentrations may work by a similar mechanism to prolong the QT interval.

Terfenadine and astemizole have significant actions on the cardiac K⁺ channels. These medications should be taken only in the recommended doses and avoided in those patients who have impairment of hepatic metabolism, either due to intrinsic liver disease or secondary to concomitant administration of medications metabolized via the cytochrome P-450 enzymatic system. The nonsedating antihistamines should also be used with caution in patients who have inherent abnormalities of ventricular repolarization, such as the long-QT syndrome, and in patients taking class III–type antiarrhythmic medications and other QT interval–prolonging drugs.

	Acknowledgments

 
This research was supported by funds from NIH grant RO1-HL-16152-22. The authors wish to gratefully acknowledge the work of Tammy Sweeten, MS, for expert technical support and Amy Snyder for help with manuscript preparation.

Received August 15, 1994; revision received November 14, 1994; accepted November 25, 1994.

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