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(Circulation Research. 1995;76:110-119.)
© 1995 American Heart Association, Inc.

Articles

Cardiac Electrophysiological Actions of the Histamine H₁-Receptor Antagonists Astemizole and Terfenadine Compared With Chlorpheniramine and Pyrilamine

Joseph J. Salata, Nancy K. Jurkiewicz, Audrey A. Wallace, Raymond F. Stupienski, III, Peter J. Guinosso, Jr, Joseph J. Lynch, Jr

From the Department of Pharmacology, Merck Research Laboratories, West Point, Pa.

Correspondence to Joseph J. Salata, Department of Pharmacology, Merck Research Laboratories, Sumneytown Pike, PO Box 4, WP26-265, West Point, PA 19486.

	Abstract

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Abstract We compared the cardiac electrophysiological actions of two types of H₁-receptor antagonists—the piperidines, astemizole and terfenadine, and the nonpiperidines, chlorpheniramine and pyrilamine—in vitro in guinea pig ventricular myocytes and in vivo in chloralose-anesthetized dogs. Astemizole and terfenadine significantly increased action potential duration of guinea pig myocytes. This concentration-dependent prolongation of action potential duration was reverse frequency dependent and led to development of early afterdepolarizations, which occurred more frequently at higher concentrations and slower pacing frequencies. Astemizole and terfenadine potently blocked the rapidly activating component of the delayed rectifier, I_Kr, with IC₅₀ values of 1.5 and 50 nmol/L, respectively. At 10 µmol/L, terfenadine but not astemizole blocked the slowly activating component of the delayed rectifier, I_Ks (58.4±3.1%), and the inward rectifier, I_K1 (20.5±3.4%). Chlorpheniramine and pyrilamine blocked I_Kr relatively weakly (IC₅₀=1.6 and 1.1 µmol/L, respectively) and I_Ks and I_K1 less than 20% at 10 µmol/L. Astemizole and terfenadine (1.0 to 3.0 mg/kg IV) significantly prolonged the QTc interval and ventricular effective refractory period in vivo. Chlorpheniramine and pyrilamine (3.0 mg/kg) did not significantly affect these parameters. Block of repolarizing K⁺ currents, particularly I_Kr, by astemizole and terfenadine produces reverse rate–dependent prolongation of action potential duration and development of early afterdepolarizations, delays ventricular repolarization, and may underlie the development of torsade de pointes ventricular arrhythmias observed with the use and abuse of these agents.

Key Words: early afterdepolarization • delayed rectifier potassium current • torsade de pointes

	Introduction

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Excessive prolongation of the electrocardiographic QT interval, reflecting delayed myocardial repolarization and prolonged action potential duration (APD), is associated with the development of ventricular arrhythmia, particularly torsade de pointes polymorphic ventricular tachycardia. Prolongation of the QT interval may be congenital or may result from electrolyte abnormalities, dietary deficiencies, or exposure to drugs.¹ Torsade de pointes is most commonly caused by class IA and class III antiarrhythmic drugs but may also occur with a wide spectrum of structurally and therapeutically unrelated drugs.^{1 2 3 4 5}

Several cases of torsade de pointes recently have been reported in patients administered the nonsedating histamine H₁-receptor antagonists astemizole^{6 7 8 9 10} and terfenadine,¹¹ prompting warnings for potentially serious adverse cardiovascular events with these agents.¹² The fact that overdose of either of these drugs leads to QT prolongation and torsade de pointes suggests a common mechanism affecting cardiac repolarization. Previous studies have demonstrated block of several components of the cardiac delayed rectifier and other potassium currents by terfenadine.^{13 14 15 16} Therefore, we designed this study to assess the effects of the piperidine-containing H₁-receptor antagonists astemizole and terfenadine on APD and various ionic currents in guinea pig isolated ventricular myocytes. The effects were compared with those of two standard, non–piperidine-containing H₁-receptor antagonists, chlorpheniramine and pyrilamine. In addition, the macroscopic cardiac electrophysiological effects of these agents were assessed on in vivo correlates of myocardial APD, namely, electrocardiographic QT interval and ventricular refractory period, in chloralose-anesthetized dogs. This study is the first extensive cellular electrophysiological characterization of astemizole and the first electrophysiological comparison of the piperidine-containing and non–piperidine-containing H₁-receptor antagonists, the latter of which apparently do not induce torsade de pointes.

	Materials and Methods

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In Vitro Studies in Guinea Pig Isolated Ventricular Myocytes
Cell Preparation
Guinea pig ventricular myocytes were isolated as described previously.¹⁷ Guinea pig hearts were perfused retrogradely through the aorta at a rate of 10 mL/min with an oxygenated (100% O₂), Ca²⁺-free HEPES-buffered saline (HBS) containing (mmol/L) NaCl 132, KCl 4, MgCl₂ 1.2, HEPES 10, and glucose 10, pH 7.2, at 37°C. Hearts were perfused in three stages: first with standard Ca²⁺-free HBS for 5 minutes, second with the same solution containing 300 U/mL type II collagenase (Worthington Biochemical Corp) plus 0.5 to 1.0 U/mL type XIV protease (Sigma Chemical Co) for 8 minutes, and finally with HBS containing 0.2 mmol/L CaCl₂ for an additional 5 minutes. The enzyme-digested heart was cut into small pieces, placed in 20 mL HBS containing 0.2 mmol/L CaCl₂, and shaken until single cells were dissociated from the small pieces. The cells then were filtered through 200-µm nylon mesh and resuspended in HBS containing 1.8 mmol/L CaCl₂ and stored at 24°C to 26°C until used for experiments, usually within 8 hours after isolation.

Action Potential Studies
Transmembrane potentials were recorded using conventional glass microelectrodes as described previously.¹⁸ Microelectrodes were filled with 3 mol/L KCl (tip resistances, 35 to 60 M) and were connected to the headstage of an Axoclamp 2A amplifier (Axon Instruments). Cells were superfused with 1.8 mmol/L Ca²⁺ HBS at a rate of 2 mL/min at 37°C. Action potentials were evoked by passing brief current pulses (1 millisecond, 1.2 times threshold) through the recording electrode using an active bridge circuit. Cells were stimulated at a frequency of 1 Hz during a 10- to 15-minute stabilization period before control measurements were obtained. Only cells showing normal resting potentials and action potential configuration were used in this study (Fig 1). Action potentials were studied at frequencies of 1 and 3 Hz during control and at 10 minutes after superfusion with test agents at cumulatively increasing drug concentrations. Individual action potentials were sampled after 10-second trains of stimuli at each frequency, and four samples were digitally averaged and then measured for each condition.

View larger version (10K): [in this window] [in a new window]   Figure 1. Plots show effects of terfenadine on action potentials of guinea pig isolated ventricular myocytes. Measurements were made at frequencies of 3 and 1 Hz. Action potential recordings are superimposed for control (C) and after 10 minutes of superfusion with 10 and 30 nmol/L terfenadine in panels A and B. Early afterdepolarizations occurred at 1 Hz after the terfenadine concentration was increased to 100 nmol/L in this cell (panel C).

Voltage-Clamp Studies
Voltage-clamp techniques were generally the same as those in previous studies.^{19 20} Microelectrodes were made from square-bore (1.0 mm outer diameter) borosilicate capillary tubing (Glass Company of America). Electrodes were filled with 0.5 mol/L K⁺ gluconate, 25 mmol/L KCl, and 5 mmol/L K₂ATP and had resistances of 3 to 7 (average, 5.5±0.3) M. A List EPC-7 clamp amplifier was used to voltage clamp the isolated cells. Series resistance was compensated 40% to 70%, and current was low-pass filtered at a cutoff frequency of 1 kHz.

Voltage clamp was performed using the whole-cell recording mode, and cell perfusion was minimized by maintaining constant negative pressure on the electrode using a 1-mL gas-tight syringe attached to the suction port of the microelectrode holder via air-tight tubing. These electrodes minimized "rundown" of the time-dependent delayed rectifier K⁺ current amplitude (I_K) commonly observed during whole-cell recording²¹ but limited the size of currents that could be accurately measured because of significant series resistance. Cells in which the maximal voltage error was greater than 5 mV were excluded from this study. Maximal voltage error was calculated based on the measured uncompensated series resistance, percent compensation, and the largest current measured in a given cell.

Outward potassium currents were measured during superfusion of the cells at a rate of 2 mL/min with Ca²⁺-free HBS (35°C) containing 0.4 µmol/L nisoldipine to block L-type Ca²⁺ current (I_Ca). Cells were voltage-clamped at a holding potential (V_h) of either -50 or -40 mV to inactivate inward Na⁺ current (I_Na). In some experiments, 20 µmol/L tetrodotoxin was used to block residual I_Na. The "steady-state" current-voltage (I-V) relation for K⁺ currents was examined initially by using a slowly depolarizing voltage ramp beginning at -110 mV and ending at +50 mV at a rate of 32 mV/s (5 seconds total). I_K was measured as the difference from the initial instantaneous current, following the settling of the capacity transient, to the final (steady-state) current level during depolarizing voltage steps to various test potentials (V_t). Tail current amplitude (I_Ktail) was measured as the difference from the holding current level to the peak I_Ktail on return to V_h. Inward rectifier K⁺ current (I_K1) was measured as the absolute current, uncorrected for leak, either during depolarizing voltage ramps or at the end of 225-millisecond hyperpolarizing voltage steps from a V_h of -40 mV. Data acquisition and analysis were performed using PCLAMP software (Axon Instruments) and an IBM-compatible 486 computer.

Concentration-response relations were determined by measuring action potentials or currents in each cell during control conditions and during superfusion with (at most two) successively increasing concentrations of a given drug. Concentration-response curves (Fig 6) were fit to a logistic equation, Y=(a-d)/[1+(X/c)^b]+d, using a Marquardt-Levenburg algorithm for least-squares nonlinear regression analysis. Using this equation, a and d are maximal and minimal responses estimated for infinite and zero concentrations, respectively; c is the inflection point that estimates the 50% effective concentration (IC₅₀); and b is the slope factor (Hill coefficient). During the time required (4 to 8 minutes) to achieve steady-state drug effects, I_Ktail measured after a voltage step from -50 to -10 mV, which was used to quantify I_Kr, decreased by an average of 5% even in the absence of drug or vehicle. Because of this "rundown" of the current, the concentration-response curves were fit with a minimal inhibition of 5% (Fig 6). Compounds were dissolved in dimethyl sulfoxide at stock concentrations of either 1 or 10 mmol/L and diluted directly into HBS using serial dilutions to achieve final concentrations. The vehicle dimethyl sulfoxide at the concentrations used had no significant effect on any of the parameters measured in this study.

View larger version (21K): [in this window] [in a new window]   Figure 6. Line graph shows concentration dependence of block of the rapidly activating component of the delayed rectifier (IKr) by astemizole, terfenadine, chlorpheniramine, and pyrilamine. Data expressed as a percent of control were obtained by measuring the inhibition of the repolarizing tail current using the protocol defined in Fig 5. Data are mean±SEM; n5.

In Vivo Studies in Anesthetized Dogs: Electrocardiographic and Electrophysiological Effects
Surgical Preparation
The surgical preparation, instrumentation, and methods for the measurement of electrocardiographic, ventricular electrophysiological, and hemodynamic parameters have been described previously.^{19 22} Briefly, purpose-bred male or female mongrel dogs (7.4 to 12.4 kg) were anesthetized with 80 to 100 mg/kg IV -chloralose, and the animals were ventilated with a volume-cycled respirator. The right femoral artery and vein were isolated and cannulated for the measurement of systemic arterial pressure and for test agent administration, respectively. A left thoracotomy was performed in the fourth intercostal space, the pericardium incised, and the heart suspended in a pericardial cradle. A platinum epicardial bipolar electrode was sutured to the left atrial appendage for atrial pacing, and a stainless steel bipolar plunge electrode was sutured to the anterior surface of the left ventricle for determination of ventricular excitation threshold and refractory periods. Limb electrodes were attached for continuous recording of the lead II electrocardiogram.

Experimental Protocol
The following parameters were determined before and after cumulative intravenous administration of test agents: sinus heart rate, systemic arterial pressure, electrocardiographic intervals including a rate-corrected QTc interval [QTc=(QT ms)(R-R s)^-1/2] and a "paced QT" interval determined during 2.5-Hz atrial pacing, ventricular excitation threshold (VET), and ventricular effective refractory period (VERP, determined at 2xVET). Five groups of five to seven dogs each were randomized to the intravenous administration of either vehicle (n=6, 9.3±0.5 kg) or cumulative doses of 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg of astemizole (n=7, 8.3±0.2 kg), terfenadine (n=6, 8.9±0.2 kg), chlorpheniramine (n=7, 8.6±0.3 kg), or pyrilamine (n=5, 9.5±0.8 kg). Indicated dosages reflect amounts of free base compound. Each dose of test agent was administered over 5 minutes, with electrophysiological testing begun 15 minutes after the termination of intravenous infusion. Polyethylene glycol 200 (20% vol/vol) in 5% dextrose in distilled water served as the vehicle for all test agents.

Materials
(+)-Chlorpheniramine maleate, pyrilamine maleate, and terfenadine were obtained from Sigma Chemical Co. Astemizole was obtained from Research Diagnostics.

Statistics
Data are expressed as mean±SEM. Action potential data were assessed using a three-way ANOVA to determine significant within-treatment variations. Dunnett's t test was used to determine significance of individual treatment means compared with control mean values (Tables 1 and 2). A multivariate repeated-measures ANOVA with comparison to the vehicle control group was used to identify significant within-group changes in electrocardiographic and electrophysiological parameters in vivo (Tables 4 and 5).

View this table: [in this window] [in a new window]   Table 1. Concentration- and Frequency-Dependent Effects of Astemizole on Action Potential Parameters of Guinea Pig Isolated Ventricular Myocytes

View this table: [in this window] [in a new window]   Table 2. Concentration- and Frequency-Dependent Effects of Terfenadine on Action Potential Parameters of Guinea Pig Isolated Ventricular Myocytes

View this table: [in this window] [in a new window]   Table 4. Effects of Cumulative Intravenous Administration of Astemizole to Chloralose-Anesthetized Dogs

View this table: [in this window] [in a new window]   Table 5. Effects of Cumulative Intravenous Administration of Terfenadine to Chloralose-Anesthetized Dogs

	Results

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In Vitro Studies in Guinea Pig Isolated Ventricular Myocytes
Action Potential Studies
Fig 1 shows an example of the effects of 10 and 30 nmol/L terfenadine at frequencies of 3 Hz (A) and 1 Hz (B). Tables 1 and 2 summarize the effects of astemizole and terfenadine on action potential parameters, and Fig 2 graphs the effects on APD. Astemizole and terfenadine significantly increased APD in a concentration- and frequency-dependent manner without affecting other measured parameters. APD was prolonged more at slow (1-Hz) than at fast (3-Hz) stimulus frequencies (Fig 2), an effect termed reverse-frequency dependence.²³ Notably, both astemizole and terfenadine produced early afterdepolarizations (EAD) at higher concentrations and at slower stimulus frequencies (eg, Fig 1C). Terfenadine elicited EAD at a stimulus frequency of 1 Hz in one of five cells at 30 nmol/L and in two of four cells at 100 nmol/L. Likewise, astemizole evoked EAD in two of four cells at 3 nmol/L. EAD occurred more frequently and at lower concentrations of either compound during stimulation at slower frequencies (eg, 0.5 Hz; data not shown).

View larger version (18K): [in this window] [in a new window]   Figure 2. Bar graph shows concentration and frequency dependence of the effects of astemizole and terfenadine on action potential duration (APD) of guinea pig isolated ventricular myocytes. Data are mean±SEM expressed as percent change from control (n4).

Voltage-Clamp Studies
I-V Relation of Outward K⁺ Currents. The "steady-state" I-V relation for K⁺ currents was studied during a slowly depolarizing voltage ramp. A typical N-shaped I-V relation caused by rectification of I_K1 with a reversal potential of approximately -85 mV was obtained during control conditions (Fig 3). Terfenadine (1 µmol/L) or astemizole (10 nmol/L) caused a net negative shift of the I-V relation at voltages from -40 to +30 mV. This effect is essentially identical to the effect observed previously with methanesulfonanilide class III antiarrhythmic agents (E-4031, dofetilide, sotalol) in guinea pig ventricular myocytes, which was attributed to the block of a rapidly activating and inwardly rectifying component of the delayed rectifier K⁺ current, designated I_Kr in these cells.^{19 24} The similarities to I_Kr include a drug-sensitive current that peaks between -10 and -20 mV in nominally Ca²⁺-free solution and decreases in a voltage-dependent manner at more positive potentials, consistent with the inwardly rectifying property of I_Kr. Neither agent produced any consistent effect on currents outside the range of -40 to +30 mV, indicating that at these concentrations terfenadine and astemizole do not affect either the slowly activating component of the delayed rectifier K⁺ current (I_Ks) or I_K1.

View larger version (13K): [in this window] [in a new window]   Figure 3. Tracings show voltage ramp clamps of guinea pig isolated ventricular myocytes. In each panel, control (C) currents are superimposed with those after exposure to each test agent. A, 10 nmol/L astemizole; cell capacitance, 105 pF. B, 1 µmol/L terfenadine; cell capacitance, 103 pF. From an initial holding potential of -50 mV, voltage ramps begin at -110 mV and slowly depolarize (32 mV/s) to +50 mV over 5 seconds.

Effect on Inward Rectifier K⁺ Current (I_K1). I_K1 was measured using slowly depolarizing voltage ramps (as in Fig 3) or during 225-millisecond hyperpolarizing voltage steps between -120 and -40 mV from a V_h of -40 mV. In either case, outward I_K1 peaked at approximately -60 mV. With the use of hyperpolarizing voltage steps, I_K1 was 3.18±0.30 pA/pF at -60 mV and -7.16±0.70 pA/pF at -100 mV during control and was 3.08±0.30 and -7.23±0.80 pA/pF, respectively, after superfusion with 10 µmol/L astemizole (n=4). Likewise, I_K1 was 4.53±0.60 pA/pF at -60 mV and -12.89±2.01 at -100 mV during control and was 3.22±0.40 and -11.59±1.75 pA/pF after superfusion with 10 µmol/L terfenadine (n=5). Thus, at 10 µmol/L, terfenadine decreased I_K1 by an average of 27.2±6.2% during a voltage step to -60 mV and by a similar amount (20.5±3.4%) during a voltage ramp at -60 mV (Table 3), whereas astemizole, chlorpheniramine, and pyrilamine had no effect on I_K1.

View this table: [in this window] [in a new window]   Table 3. Block of Potassium Current Subtypes in Isolated Guinea Pig Myocytes by Astemizole, Terfenadine, Chlorpheniramine, and Pyrilamine

Effect on Time-Dependent Outward Current (I_K). I_K (I_Kr+I_Ks) was recorded during 225-millisecond (a duration similar to the APD during control conditions) test pulses from a V_h of -50 mV to V_t between -40 and +50 mV. Tetrodotoxin (20 µmol/L) was present throughout this group of experiments. Fig 4 shows the effects of astemizole (0.1 µmol/L) on the I-V relations for the time-dependent I_K (C) and repolarizing tail current, I_Ktail (D). Representative currents measured at V_t to -10 and +50 mV are shown during control (A) and after superfusion with 0.1 µmol/L astemizole (B). These V_t values were chosen to highlight effects on I_Kr and I_Ks selectively. Astemizole eliminated or decreased total I_K when measured at V_t0 mV (C). At V_t0 mV, astemizole had no consistent effect on time-dependent I_K, as exemplified by comparing the top traces of Fig 4A and 4B. Astemizole also blocked I_Ktail almost completely at V_t0 mV, but there was no further appreciable block of I_Ktail at V_t>0 mV (D). Terfenadine (1 µmol/L) produced nearly identical effects on the I-V relations for I_K and I_Ktail of guinea pig myocytes in this study (data not shown) and confirm similar findings in cat ventricular myocytes.¹³

View larger version (19K): [in this window] [in a new window]   Figure 4. Voltage dependence of block of the delayed rectifier K+ current, IK, by astemizole. A and B, Tracings show example currents recorded during control and after exposure to 0.1 µmol/L astemizole using 225-millisecond test pulses to -10 and +50 mV from a Vh of -50 mV. Horizontal scale corresponds to the zero current level. C and D, Line graphs show current-voltage relations for time-dependent IK current during the pulse and repolarizing tail current (IKtail) respectively. Current amplitudes during control and after exposure to 0.1 µmol/L astemizole are superimposed in each graph. Cell capacitance, 97±4 pF. Data are mean±SEM (n=6). Tetrodotoxin (20 µmol/L) was present throughout.

The voltage dependence of the block of I_K by astemizole and terfenadine indicated that both drugs selectively inhibited I_Kr (Fig 3 and 4). We examined these effects further using conditions that selectively activate I_Kr (500-millisecond voltage steps from a V_h of -50 mV to a V_t of -10 mV, Ca²⁺-free external solution). During control (Fig 5A and 5C), I_Kr activated relatively rapidly and achieved an apparent steady-state level during the pulse and appeared as a rapidly deactivating tail current on repolarization to V_h. Astemizole (10 nmol/L) or terfenadine (1 µmol/L) inhibited the time-dependent current and eliminated the tail current completely at these maximal inhibitory concentrations (Fig 6). Activation of the control (with blanking of the first 10 milliseconds) and the drug-sensitive currents was closely fit by a single exponential function (see Fig 5 legend), whereas two exponential components were often apparent in the deactivating I_Ktail. The average time constants of activation (_a, mean±SEM, n=5) were 77±4 and 49±7 milliseconds for the control currents and 56±4 and 42±7 milliseconds for the astemizole and terfenadine drug-sensitive currents, respectively. These results indicate that both astemizole and terfenadine potently block I_Kr.

View larger version (15K): [in this window] [in a new window]   Figure 5. Tracings show effects of astemizole (A) and terfenadine (C) on time-dependent outward current (IK) and repolarizing tail current (IKtail) elicited during a 500-millisecond depolarizing voltage step from a Vh of -50 mV to a Vt of -10 mV. IKtail was measured on repolarization to Vh. Drug-sensitive currents were obtained by digital subtraction of the current traces in the presence of 10 nmol/L astemizole (B) and 1 µmol/L terfenadine (D) from the respective control current traces. The activation phase of control and drug-sensitive currents was fit to a single exponential function: I(t)=A0+A1[1-exp(1-t/a). Time constants (milliseconds) of activation (a) were 73 (A) and 61 (C) during control and 63 (B) and 57 (D) for respective drug-sensitive currents in these examples. Note difference between vertical scales of A and C vs B and D.

We examined the effects of these agents at higher concentrations on I_Ks, which was maximized by using a 1-second depolarizing voltage step from a V_h of -50 mV to a V_t of +50 mV (compare Fig 4). At 10 µmol/L, terfenadine inhibited I_Ks an average of 58.4%, astemizole had no effect, and both chlorpheniramine and pyrilamine inhibited I_Ks slightly (Table 3).

Concentration Dependence of Block of I_Kr. We examined the concentration dependence of inhibition of I_Kr using the protocol of Fig 5, and the resulting concentration-response curves are superimposed in Fig 6. Both astemizole and terfenadine inhibited I_Kr potently (IC₅₀, 1.5 and 50 nmol/L; Hill coefficient, 0.99 and 0.93, respectively). Chlorpheniramine and pyrilamine also inhibited I_Kr but much less potently (IC₅₀, 1.6 and 1.1 µmol/L; Hill coefficient, 1.2 and 1.9, respectively).

In Vivo Studies in Anesthetized Dogs: Electrocardiographic and Electrophysiological Effects
The effects of cumulative administrations of 0.01 to 3.0 mg/kg IV astemizole, terfenadine, chlorpheniramine, and pyrilamine on heart rate, electrocardiographic intervals, and VERP were assessed in chloralose-anesthetized dogs. The effects of the four test agents on two in vivo correlates of myocardial APD, VERP and the rate-corrected electrocardiographic QTc interval, are compared graphically in Fig 7A and 7B, respectively. Astemizole and terfenadine significantly increased the QTc interval, paced QT interval, and VERP at doses of 1.0 and 3.0 mg/kg (Tables 4 and 5, respectively). Terfenadine also slowed sinus heart rate and prolonged the electrocardiographic PR interval at the highest dose tested (Table 5). In contrast, neither chlorpheniramine nor pyrilamine significantly altered QTc or paced QT intervals, VERP, heart rate, or PR interval. None of the test agents altered the electrocardiographic QRS interval in the dose range tested.

View larger version (23K): [in this window] [in a new window]   Figure 7. Line graphs show effects of cumulative intravenous administrations of astemizole, terfenadine, chlorpheniramine, pyrilamine, or vehicle (control) on ventricular effective refractory period (VERP, A) and electrocardiographic QTc interval (B) in chloralose-anesthetized dogs. Data are mean±SEM; n=5-7.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In this study we found that the piperidine-containing histamine H₁-receptor antagonists astemizole and terfenadine significantly increased APD of guinea pig isolated myocytes in a concentration- and reverse frequency–dependent manner. These agents also produced EAD at high concentrations or slow stimulus frequencies. Astemizole and terfenadine potently blocked the rapidly activating component of the delayed rectifier, I_Kr, with IC₅₀ values of 1.5 and 50 nmol/L, respectively. Terfenadine at high concentrations (10 µmol/L) also blocked the slowly activating component of the delayed rectifier, I_Ks, by 58.4±3.1% and the inward rectifier, I_K1, by 20.5±3.4%. Surprisingly, the non–piperidine-containing H₁-receptor antagonists chlorpheniramine and pyrilamine also blocked I_Kr, although rather weakly, with IC₅₀ values of 1.6 and 1.1 µmol/L, respectively, and blocked I_Ks slightly (<20%) at high concentrations (10 µmol/L). In chloralose-anesthetized dogs, astemizole and terfenadine (1.0 to 3.0 mg/kg IV) significantly prolonged the QTc interval and VERP. In contrast, chlorpheniramine and pyrilamine did not significantly alter these in vivo indexes of ventricular repolarization at doses up to 3.0 mg/kg IV. Because these latter agents were devoid of significant effects in vivo, even at multiples of the therapeutic doses comparable to those of astemizole or terfenadine, they were not characterized more extensively in vitro.

The time-dependent cardiac delayed rectifier K⁺ current, I_K, in guinea pig^{20 24 25} (and probably dog²⁶ ) consists of at least two components, designated I_Kr and I_Ks. These components are differentiated by their pharmacological block and Ca²⁺ sensitivity, by their voltage dependence and kinetics of activation and deactivation, and by their rectification properties. I_Kr is distinguished based on its sensitivity to La³⁺, E-4031, and other class III antiarrhythmic agents and is so named to indicate its rapid rate of activation and strong inwardly rectifying properties at positive potentials.^{20 24} In the absence of extracellular Ca²⁺, the voltage dependence of I_Kr activation is shifted in the negative direction (half-point of activation, V=-40 mV), whereas the activation range of I_Ks is shifted in the positive direction (V=+22 mV).²⁴ Under these conditions, I_Kr contributes almost exclusively to outward time-dependent current during step depolarizations to potentials of -10 mV, especially at short pulse durations. Moreover, on repolarization to a V_h of -50 mV, I_Kr deactivates slowly and composes most if not all of the tail current. At +50 mV, I_Kr conducts very little time-dependent current because of its intense inward rectification, and this allows for relatively selective measurement of I_Ks as time-dependent current, especially during long test pulse durations (1 second). We used these distinguishing characteristics to study selectively the effects on I_Kr and I_Ks as demonstrated previously.¹⁹

Several recent studies have explored the cardiac electrophysiological effects of terfenadine. In a voltage-clamp study in feline isolated ventricular myocytes, terfenadine but not its active metabolite terfenadine carboxylate blocked I_Ktail with an IC₅₀ of 150 nmol/L, and this potency was comparable to that of quinidine (180 nmol/L).¹³ In the cat, I_K has been reported to consist of only one component and based on pharmacological block of I_Ktail appears to be similar to I_Kr of guinea pig.²⁷ The very rapidly activating delayed rectifier K⁺ current, designated fHK, which was cloned from human heart and stably expressed in human embryonic kidney (HEK-293) cells, was blocked potently by terfenadine (IC₅₀=367 nmol/L) but weakly by its metabolites (high micromolar concentration).¹⁴ The current expressed by this clone is similar kinetically to the rapidly activating delayed rectifier K⁺ current observed in human atrial myocytes²⁸ and to the current expressed by the highly homologous protein HK2 cloned from human ventricle.^{29 30} In preliminary studies of human atria, terfenadine (1 µmol/L) blocked the fHK (Kv1.5) type current by 42%, whereas the transient outward current (I_to) was reduced by 15%.¹⁵ Terfenadine decreased dV/dt_max (IC₅₀=1.3 µmol/L) of the action potential recorded in canine Purkinje fiber, suggesting a reduction in I_Na.³¹ There were minimal effects, however, on canine Purkinje fiber APD, suggesting little effect on repolarizing K⁺ currents. This lack of effect on APD might have been due to tissue or species differences in currents or their relative sensitivity to the drug. Ignoring different experimental conditions, the current that is most sensitive to block by terfenadine appears to be I_Kr as measured in guinea pig myocytes in the present study.

Terfenadine is rapidly and extensively (99.5%) metabolized during the first pass by hepatic P-450 oxidative enzymes in humans.³² During short-term oral administration of therapeutic doses of terfenadine (60 or 180 mg), average peak serum terfenadine concentrations occur between 1 and 2 hours after dosing and are 3.2 and 9.5 nmol/L, respectively. After an overdose associated with QTc prolongation, the serum level of terfenadine may be as high as 100 nmol/L.³³ Coadministration of agents that inhibit cytochrome P-450, such as ketoconazole, also can result in high serum levels of terfenadine (172 nmol/L), severe QTc prolongation, and episodes of torsades de pointes.^{11 34} In the present study, terfenadine at concentrations of 10 and 30 nmol/L significantly increased APD with occasional EAD at 30 nmol/L, whereas at 100 nmol/L, EAD, which are thought to underlie torsades de pointes,³⁵ were observed frequently.

Astemizole, like terfenadine, undergoes extensive first-pass metabolism, but excretion is extremely slow. The apparent terminal half-life is approximately 20 hours for astemizole, whereas that of its major metabolite desmethylastemizole is 12 days.³⁶ During normal maintenance dosing, serum levels of astemizole and its hydroxylated metabolites range between 4 and 11 nmol/L.⁸ In patients with manifest cardiac abnormalities, serum concentrations of astemizole plus its hydroxylated metabolites range from 65 to 200 nmol/L.^{6 7 8 9 10} The concentration and percentage of unchanged astemizole in these cases are uncertain, as are the potential electrophysiological actions of its metabolites. These issues require further study. Nevertheless, it is reasonable to conclude that astemizole concentrations that extremely prolonged APD and produced EAD in the present study (1 to 3 nmol/L) could easily have been achieved in these clinical situations.

We further studied the cardiac electrophysiological actions of these agents in vivo during intravenous dosing in chloralose-anesthetized dogs. The dog was deemed an appropriate species because it responds through either prolongation of the QT interval or increase in the ventricular refractory period to a variety of mechanistically diverse interventions that modulate ventricular repolarization.^{22 37 38 39} Accordingly, terfenadine prolongs QTc interval and increases ventricular refractoriness after oral administration in conscious dogs.⁴⁰ Dogs, like humans, rapidly metabolize terfenadine.^{41 42} In parallel with our cellular electrophysiological findings, both astemizole and terfenadine significantly increased the QT interval and VERP in anesthetized dogs. However, chlorpheniramine and pyrilamine had no effect on these in vivo indexes of ventricular repolarization at matched doses up to 3.0 mg/kg IV. The action potential and voltage-clamp studies in vitro indicated that astemizole blocked the repolarizing K⁺ current, I_Kr, more potently than terfenadine, whereas in vivo astemizole and terfenadine (1.0 to 3.0 mg/kg IV) produced nearly equivalent prolongation of the QT interval and VERP. However, at 0.3 mg/kg, astemizole but not terfenadine significantly increased VERP, which might be the most sensitive measure in vivo. Nevertheless, this apparent discordance between the in vitro and in vivo potency of these two agents may stem from fundamental variables introduced in the conduct of the studies. These include compound absorption, distribution and access to the target, and species differences in the relative contribution of K⁺ current subtype to ventricular repolarization. This latter point may be particularly relevant in comparing the activities of the different agents across species, because astemizole appears to be a selective blocker of I_Kr, whereas terfenadine may block multiple K⁺ channel subtypes including I_Kr, I_Ks, and I_K1. Recent evidence also indicates a possible action on I_to at micromolar concentrations,¹⁶ which may be relevant to our in vivo findings in the dog, but this current has not been identified in guinea pig.

Recently, interest and concern have heightened regarding the effects of the histamine H₁-receptor antagonists astemizole and terfenadine on cardiac electrophysiological activity. This concern has been prompted by reports of adverse cardiovascular effects during apparently normal therapeutic doses or overdoses of these two agents, whereas no such reports exist for chlorpheniramine or pyrilamine. Other precipitating factors include hepatic dysfunction, hypokalemia, or concomitant use of other drugs that inhibit oxidative P-450 enzymes, such as ketoconazole, ciprofloxacin, or macrolide antibiotics.⁴³ Presenting symptoms include recurrent syncope, sinus arrhythmia, atrioventricular block of varying degree, severe QT interval prolongation, and torsade de pointes ventricular tachycardia in patients administered either astemizole^{6 7 8 9 10} or terfenadine.¹¹ Given the manifestation of proarrhythmia with astemizole and terfenadine as torsade de pointes associated with QT interval prolongation, it is likely that the proarrhythmic activity of these agents results primarily from an interference with ventricular repolarizing currents as we (this study) and others^{13 14 15 16} have demonstrated. The sinus and atrioventricular nodal arrhythmias observed with these agents may stem from an additional inhibitory action on I_Ca.⁴⁴

Direct effects of histamine on cardiac function are well documented.⁴⁴ In a variety of species, histamine has positive inotropic and chronotropic actions, has negative dromotropic effects, modulates cardiac electrophysiological activity, and promotes arrhythmia, particularly in the setting of ischemic myocardial injury.^{45 46 47} Histamine enhances the delayed rectifier outward K⁺ current (I_K) in isolated guinea pig ventricular myocytes.⁴⁸ This enhancement of I_K was blocked by the histamine H₂-receptor antagonist cimetidine but was unaffected by the histamine H₁-receptor antagonist chlorpheniramine. Overall, interactions with histamine receptors that could account for the cardiac actions of astemizole and terfenadine are either mediated by H₂-receptors or are opposite those expected for H₁-receptor antagonism.

Possible Limitations of the Voltage-Clamp Studies
The conditions that we used in this study allowed for selective albeit not specific measurement of individual K⁺ currents. We could not exclude completely "rundown" or "runup" and crossover between I_Kr and I_Ks (compare Fig 5) or contributions from other minor current components. One contributing factor might have been rapidly and/or slowly inactivating I_Na.¹⁸ From a V_h of -50 mV, there was evidence of a very rapidly inactivating residual inward current superimposed on the instantaneous outward current (compare Fig 5A and 5C) apparent in the kinetics of activation that was eliminated by tetrodotoxin (compare Fig 4A). Nevertheless, when we excluded the first 10 milliseconds of activation, outward time-dependent current amplitude in the absence of tetrodotoxin was essentially identical to the overall time-dependent current amplitude in the presence of tetrodotoxin. Another possible contributor was I_Kp, an outward K⁺ current that activates very rapidly during depolarizations to plateau potentials and does not inactivate during pulses as long as 600 milliseconds.⁴⁹ During complete block of I_Ktail, even in the presence of tetrodotoxin, a very small time-dependent current remained during the pulse (compare Fig 4B) that resembled I_Kp. Because measurement of I_Ktail after a V_t to -10 mV was used to quantitate the effects on I_Kr, contamination by I_Ks, I_Na, or I_Kp was unlikely. I_Na or I_Kp might have had a minor contribution to the measurement of the relatively large I_Ks.

Conclusions
The actions of astemizole and terfenadine on APD in vitro and correspondingly QT interval and VERP in vivo are qualitatively identical to those of specific class III antiarrhythmic agents such as dofetilide,¹⁷ MK-499,¹⁹ and E-4031.²⁰ The voltage dependence of block of the time-dependent current, I_K, and the tail current, I_Ktail, by astemizole (Fig 4) and terfenadine¹³ indicates that they predominantly block I_Kr, mimicking the effects of the class III agents. Terfenadine also blocked I_Ks by 58% and I_K1 by 20% but at concentrations 200 times (10 µmol/L) the IC₅₀ for block of I_Kr; thus, it is unlikely that these actions contribute to the effects on repolarization except perhaps at extremely high plasma concentrations. We conclude that block of I_Kr is the major mechanism by which these agents increase APD, prolong refractoriness, and slow repolarization. At high doses, excessive prolongation of APD and the development of EAD may underlie the appearance of torsade de pointes ventricular arrhythmia.

Clinical Implications
Because astemizole and terfenadine act to block repolarizing K⁺ currents, their use with class III or class IA antiarrhythmic agents or other drugs that are known to affect cardiac K⁺ (and possibly Ca²⁺) channels should be contraindicated. Extreme caution should be observed also in patients with hepatic dysfunction or during concomitant use of other drugs that inhibit oxidative P-450 enzymes, such as ketoconazole, ciprofloxacin, or macrolide antibiotics. In these situations, compromised metabolism leading to elevated levels of parent drug may precipitate cardiac arrhythmias. Isoproterenol increases heart rate, hastens atrioventricular conduction time, and antagonizes the prolongation of refractoriness induced by class III antiarrhythmic agents that block I_Kr.⁵⁰ Therefore, isoproterenol or other catecholamines theoretically may provide the best means to prevent or reverse arrhythmias associated with astemizole and terfenadine.

	Acknowledgments

 
We thank Tim Schofield for his expert assistance in performing the statistical analyses.

Received March 28, 1994; accepted September 29, 1994.

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