Suppression of ventricular arrhythmias in man by d-propranolol independent of beta-adrenergic receptor blockade.

To investigate the mechanisms of ventricular arrhythmia suppression by propranolol, we determined the antiarrhythmic efficacy of d-propranolol in 10 patients with frequent ventricular ectopic depolarizations (VEDs) and nonsustained ventricular tachycardia. After an initial placebo phase, 40 mg d-propranolol was administered orally every 6 h with dosage increased every 2 d until arrhythmia suppression (greater than or equal to 80% VED reduction), intolerable side effects, or a maximal dosage (1,280 mg/d) was reached. Response was verified by documenting return of arrhythmia during a final placebo phase. Arrhythmia suppression occurred in six patients while two more had partial responses. Effective dosages were 320-1,280 mg/d (mean 920 +/- 360, SD) of d-propranolol with corresponding plasma concentrations of 60-2,280 ng/ml (mean 858 +/- 681). For the entire group, the QTc interval shortened by 4 +/- 4% (P = 0.03). Arrhythmia suppression was accompanied by a reduction in peak heart rate during exercise of 0-29%. To determine whether arrhythmia suppression could be attributed to beta-blockade, racemic propranolol was then administered in dosages producing the same or greater depression of exercise heart rate. In 3/8 patients, arrhythmias were not suppressed by racemic propranolol indicating that d-propranolol was effective via a non-beta-mediated action. By contrast, in 5/8 patients racemic propranolol also suppressed VEDs. We conclude that propranolol suppresses ventricular arrhythmias by both beta- and non-beta-adrenergic receptor-mediated effects.

Adenosine A1-receptor occupancy predicts A1-receptor antagonist effects of N-0861.

OBJECTIVE: To evaluate the relationship between dose of N-0861 ([+/-]N6-endo-norbornan-2-yl-9-methyladenine), N-0861 plasma concentrations, and antagonism of adenosine-induced slowing of atrioventricular nodal conduction and to evaluate A1-receptor occupancy by antagonist present in plasma of subjects after administration of N-0861 to determine A1-selectivity of these effects. METHODS: The study was conducted in patients undergoing a clinically indicated electrophysiology study to evaluate atrioventricular nodal conduction. Nineteen subjects were enrolled in the study and received adenosine (60 to 140 microg/kg) before or during a bolus dose and maintenance infusion of specific doses of N-0861. Adenosine-induced slowing of atrioventricular nodal conduction was determined by measuring A-H intervals on the intracardiac electrocardiograms. Plasma concentrations of N-0861 were determined with an HPLC method. A1-Receptor occupancy by antagonist present in plasma from identical time points was determined with use of a radioreceptor assay. RESULTS: A linear relationship was shown between plasma concentration and dose of N-0861. A-H interval lengthening by 60 microg/kg adenosine was reduced by administration of N-0861. A linear relationship was observed between A1 occupancy and N-0861 concentration and between occupancy and antagonism of adenosine-induced A-H prolongation. CONCLUSION: The results suggest that the effect of N-0861 on antagonism of adenosine-induced prolongation of A-H interval, at the doses used in this study, were the result of effects at the A1 receptor.

d-sotalol reduces heart rate in vivo through a beta-adrenergic receptor-independent mechanism.

d-Sotalol was developed as an antiarrhythmic agent with a relative lack of antagonist activity at beta-adrenergic receptors. Exercise heart rate reduction has been observed after administration to humans. The purpose of this study was to determine directly whether this effect of d-sotalol was attributable to beta-blockade. Plasma samples from normal volunteers who randomly received either atenolol, d-sotalol, or placebo were used in an in vitro radioreceptor assay to determine occupancy of beta 1-adrenergic receptors by antagonist present in the plasma. Occupancy was compared with the observed pharmacologic effects. A reduction in exercise heart rate of 7.7% +/- 3.8% for d-sotalol and 15.9% +/- 3.0% for atenolol occurred with beta 1-adrenergic receptor occupancy of 0% and 33.9% +/- 21.4%, respectively. Absence of antagonist effect in the radioreceptor assay eliminates the potential role of beta 1-blockade in d-sotalol-induced heart rate reduction. This effect is most likely a result of prolongation of the sinus node action potential duration.

Chlorpheniramine plasma concentration and histamine H1-receptor occupancy.

The plasma concentration-response relationship of the antihistamine chlorpheniramine is poorly characterized. This study examined concurrently the concentrations of chlorpheniramine and presence of H1-receptor antagonist in plasma after administration of 8 mg chlorpheniramine in normal volunteers. Six extensive metabolizers and five poor metabolizers, as judged by CYP2D6 phenotype (dextromethorphan metabolic ratio), were enrolled in the study. More than 80% occupancy of H1-receptors by antagonist in plasma was observed for 12 hours after the dose in extensive metabolizers and greater than 60% from 12 to 30 hours in poor metabolizers, when plasma concentrations had fallen below those that should result in 50% occupancy of receptors. The results suggest that (+/-)-chlorpheniramine plasma concentrations do not predict H1-receptor antagonist in plasma. In addition, a role is suggested for CYP2D6 in formation of a potent active metabolite of chlorpheniramine.

Loratadine and terfenadine interaction with nefazodone: Both antihistamines are associated with QTc prolongation.

BACKGROUND AND OBJECTIVE: Nefazodone inhibits CYP3A; therefore coadministration with CYP3A substrates such as terfenadine or loratadine may result in increased exposure to these drugs. A potential pharmacodynamic consequence is electrocardiographic QTc prolongation, which has been associated with torsade de pointes cardiac arrhythmia. Therefore a clinical pharmacokinetic-pharmacodynamic evaluation of this potential interaction was conducted. METHODS: A randomized, double-blind, double-dummy, parallel group, multiple-dose design was used. Healthy men and women who were given doses of 60 mg of terfenadine every 12 hours, 20 mg of loratadine once daily, and 300 mg of nefazodone every 12 hours were studied. Descriptive pharmacokinetics (time to maximum concentration, maximum concentration, and area under the plasma concentration-time curve) were used for the examination of interactions among the respective parent drugs and metabolites. QTc prolongation (mean value over the dosing interval) was the pharmacodynamic parameter measured. Kinetic and dynamic analysis was used for the examination of pooled concentration and QTc data with the use of a linear model. RESULTS: Concomitant nefazodone treatment markedly increased the dose interval area under the plasma concentration-time curve of both terfenadine (mean value, 17.3 +/- 8.5 ng. mL/h versus 97.4 +/- 48.9 ng. mL/h; P <.001) and carboxyterfenadine (mean value, 1.69 +/- 0.48 microg. h/mL versus 2.88 +/- 0.53 microg. h/mL; P <.001) and moderately increased the dose interval area under the plasma concentration-time curve of both loratadine (mean value, 31.5 +/- 27.9 ng. h/mL versus 43.7 +/- 25.9 ng. h/mL; P <.014) and descarboethoxyloratadine (mean value, 73.4 +/- 54.9 ng. h/mL versus 81.9 +/- 26.2 ng. h/mL; P <.002). The mean QTc was unchanged with terfenadine alone; however, it was markedly prolonged with concomitant nefazodone and terfenadine (mean [90% confidence interval] prolongation 42.4 ms [34.2, 50.6 ms]; P <.05). Similarly, the mean QTc was unchanged with loratadine alone; however, it was prolonged with concomitant nefazodone and loratadine (21.6 ms [13.7, 29.4 ms]; P <.05). Nefazodone alone did not change mean QTc. QTc was positively correlated with terfenadine plasma concentration (r (2) = 0.21; P =.0001). Similarly, QTc was positively correlated with loratadine plasma concentration (r (2) = 0.056; P =.0008) but with a flatter slope. There was no relationship between QTc and nefazodone plasma concentration during treatment with nefazodone alone (r (2) = 0.002, not significant). CONCLUSIONS: In healthy men and women, concomitant nefazodone treatment at a therapeutic dose increases exposure to both terfenadine and carboxyterfenadine. This increased exposure is associated with marked QTc prolongation, which is correlated with terfenadine plasma concentration. A similar interaction occurs with loratadine, although it is of lesser magnitude. Concomitant administration of nefazodone with terfenadine may have predisposed individuals to the arrhythmia associated with QTc prolongation, torsade de pointes, when terfenadine was available for clinical use. However, a new finding is that in the context of higher than clinically recommended daily doses (20 mg) of loratadine concomitant administration with a metabolic inhibitor such as nefazodone can also result in QTc prolongation.

Pharmacokinetics and pharmacodynamics of sotalol in a pediatric population with supraventricular and ventricular tachyarrhythmia.

OBJECTIVE: This pharmacokinetic-pharmacodynamic study was designed to define the steady-state relationship between pharmacologic response and dose or concentration of sotalol in children with cardiac arrhythmias, with an emphasis on neonates and infants. METHODS: The treatment consisted of an upward titration with unit doses of 10, 30, and 70 mg of sotalol per square meter of body surface area. The patients received 3 doses at each dose level. The dosing interval was 8 hours. The Class III and beta-blocking activities of sotalol were derived from the QT and R-R intervals, respectively, of the surface electrocardiogram, which was recorded at 6 scheduled times before and after the third, sixth, and ninth doses. During these three dose intervals, 4 scheduled blood samples were also collected. Drug concentrations were measured with a validated nonstereoselective liquid chromatographic tandem mass spectrometric detection assay. Pharmacokinetic and pharmacodynamic parameters were obtained with standard methods. RESULTS: Twenty-one centers enrolled 25 patients in the study: 7 were neonates, 9 were infants, and 11 were children between the ages of 2 years and 12 years. The area under the drug concentration-time curve increased proportionately with dose. The apparent oral clearance of sotalol was linearly correlated with body surface area and creatinine clearance. The smallest children (body surface area <0.33 m2) displayed greater drug exposure than the larger children. The increase of QTc and R-R intervals was dose dependent. At the 70-mg/m(2) dose level, the mean (+/- standard deviation) maximum increase for the QTc interval was 14% +/- 7% and the average Class III effect during a dose interval was 7% +/- 5%. At the same dose level, the mean maximum increase of the R-R interval was 25% +/- 15% and the average beta-blocking effect during a dose interval was 12% +/- 13%. The effects tended to be larger in the smallest children. The Class III response and the plasma concentrations of sotalol were linearly related. The treatment was well tolerated. CONCLUSIONS: The steady-state pharmacokinetics of sotalol were dose proportionate. Pharmacologically important beta-blocking effects were observed at the 30-mg/m2 and 70-mg/m2 dose levels. Important Class III effects were seen at the 70-mg/m2 dose level. The Class III effect was linearly related to the drug concentration.

The electrocardiographic effects of cetirizine in normal subjects.

OBJECTIVE: To establish whether the antihistamine cetirizine has the potential to prolong the QTc interval in normal volunteers at up to six times the usual recommended dose. METHODS: Twenty-five healthy volunteers were studied in a prospective, double-blind crossover design conducted on inpatients in a Clinical Research Center. The primary end point of the study was QTc prolongation on the surface electrocardiogram (ECG). Plasma concentrations of cetirizine were also measured for pharmacokinetic analysis. The end point for the pharmacokinetic analysis was the dose/area under the concentration-time curve (apparent clearance of an oral dose). The subjects received the following three treatments in random sequence: placebo, 20 mg/day cetirizine, and 60 mg/day cetirizine for 7 consecutive days. A series of baseline ECGs was recorded over 2 days before each treatment, while the subject receiving placebo. ECG effects of the treatments were then compared with the baseline ECGs. RESULTS: Analysis of variance showed no difference between the treatment groups (placebo, 20 mg cetirizine, and 60 mg cetirizine every day) in effect on QTc compared with baseline. A paired Student t test showed no difference in dose/area under the concentration-time curve between the 20 mg/day and 60 mg/day dosing groups at steady state. CONCLUSION: In healthy volunteers, cetirizine does not prolong the QTc interval at doses of up to six times the usual recommended dose.

Mexiletine and tocainide: a comparison of antiarrhythmic efficacy, adverse effects, and predictive value of lidocaine testing.

Thirty patients received one of the lidocaine analogues--mexiletine or tocainide--orally for treatment of symptomatic ventricular arrhythmias. Crossover to the other analogue was allowed if initial drug treatment was unsuccessful, and the controlled use of other marketed oral antiarrhythmic agents was permitted. After follow-up of 7 +/- 3 months (SD), mexiletine was successful in 5 of 13 patients initially and in 5 of 14 patients who failed to respond to tocainide. Tocainide was successful in 1 of 17 patients initially and in 2 of 7 who did not respond to mexiletine. Combination therapy was used in nearly half of all ultimately successful drug trials. A common cause of drug trial failure for both drugs was the occurrence of adverse effects that frequently appeared well after hospital discharge. Response to lidocaine was a sensitive but nonspecific predictor of clinical outcome with mexiletine or tocainide that helped to identify drug-resistant patients. Finally, although mexiletine provided effective antiarrhythmic therapy more often than tocainide, response to one lidocaine analogue did not predict response to the other.

Immediate- versus controlled-release disopyramide: importance of saturable binding.

OBJECTIVE: To examine the effects of saturable plasma binding on the pharmacokinetics of immediate-release (IR) and controlled-release (CR) disopyramide. BACKGROUND: Saturable binding causes a lack of correspondence between the pharmacokinetics of total and unbound plasma disopyramide. Levels of total drug may therefore be insensitive to important differences between formulations. METHODS: Patients receiving long-term disopyramide underwent serial blood sampling during withdrawal of equivalent doses of IR and CR disopyramide, and during accumulation of IR disopyramide. Plasma disopyramide was measured by enzyme-multiplied immunoassay technique, protein binding by ultrafiltration, and alpha 1-acid glycoprotein by radial immunodiffusion. Pharmacologic effect was assessed by use of high-speed ECGs. Values for plasma area under the concentration-time curve and elimination half-life were determined from the log-plasma concentration data; rate of plasma drug accumulation was determined by nonlinear modeling. RESULTS: Saturable plasma binding was evident in all patients. Comparison of total to unbound drug showed that peak-to-trough ratios during steady state were smaller (1.45 versus 2.39; p < 0.001), elimination half-life was longer (12.1 versus 4.5 hours; p < 0.001), and the time to achieve 50% of steady-state levels during drug accumulation was shorter (8.1 versus 4.3 hours; p < 0.05). Comparison of IR and CR disopyramide showed that unbound drug levels for CR disopyramide revealed lower peak plasma concentrations (0.75 versus 0.96 micrograms/ml) and peak-to-trough ratios (1.83 versus 2.31; p < 0.001). Trough plasma concentrations were similar. Fluctuations in ECG intervals during usual dosing were observed only with IR disopyramide. CONCLUSIONS: Because of saturable plasma binding, total plasma concentrations underestimate fluctuations in unbound disopyramide during usual dosing and are insensitive to significant differences between IR and CR formulations. CR disopyramide provides less interdose variation in free drug levels and more constant pharmacologic effects.

Pharmacokinetic, pharmacodynamic, and safety evaluation of an accelerated dose titration regimen of sotalol in healthy middle-aged subjects.

BACKGROUND: Current labeling recommends that therapy with sotalol be initiated in a monitored setting at 80 mg every 12 hours for 2 to 3 days, followed by 120 to 160 mg every 12 hours for at least 2 days before safety and efficacy can be ascertained and patients discharged. An accelerated titration regimen that shortens hospital stay without compromising patient safety would improve the usefulness of the drug. Although such regimens have been used by clinicians, they have not been formally evaluated. METHODS: Healthy, middle-aged sedentary men and women received sotalol in a double-blind, two-way crossover study with a 2-week washout phase to evaluate an accelerated titration regimen--placebo every 6 hours for four doses, followed by 80 mg sotalol every 6 hours for four doses, then 160 mg sotalol every 12 hours for nine doses--and compare it with the standard titration--placebo alternating with 80 mg sotalol every 6 hours for eight doses, followed by 160 mg sotalol every 12 hours for nine doses. QT intervals, RR intervals, and sotalol concentrations in plasma were measured at specific times throughout the study and during washout in a similar fashion for both regimens. RESULTS: Thirty-four subjects completed both regimens. The target prolongation of QTc (90% of the value achieved at steady state) was achieved 22 1/2 hours sooner with the accelerated titration regimen (P = .0003). There were no cardiovascular adverse events during either loading phase. At no time during the accelerated titration regimen did the sotalol concentrations in plasma or the QTc or RR interval prolongation exceed the values eventually achieved at steady state. The relationship between sotalol concentration and QTc was linear and independent of the regimen. CONCLUSION: The accelerated titration regimen for sotalol can shorten the time to attain the dosage usually required to effectively control arrhythmias, without excessive QT prolongation and the associated increased risk of torsades de pointes. The hospital stay of patients in whom antiarrhythmic therapy with sotalol is initiated can be shortened by 1 day if this accelerated titration regimen is used.

Concentration/response relations for the multiple antiarrhythmic actions of sotalol.

Sotalol, one of the first beta-receptor antagonists synthesized, is a promising investigational agent with remarkable efficacy for treatment of patients with ventricular and supraventricular arrhythmias. Unlike other beta blockers, sotalol also possesses class III antiarrhythmic action, evidenced by prolongation of the myocardial action potential duration. This additional action probably accounts for the greater antiarrhythmic efficacy of sotalol compared with other beta blockers. Sotalol's class III antiarrhythmic action becomes apparent at concentrations higher than those necessary for significant beta-receptor antagonism, both in vitro and in human subjects. In a study correlating dosage and antiarrhythmic response with prolongation of rate-corrected QT (QTc) (a measure of class III action) and the degree of beta-receptor blockade (assessed by the reduction of the maximal exercise-induced heart rate), 11 of 17 patients had an antiarrhythmic response. Eight of these 11 responders had been unresponsive to conventional beta-receptor antagonists. The plasma concentration associated with significant QTc prolongation (2.55 micrograms/ml) was found to be much greater than that associated with 50% reduction in maximal slowing of heart rate (0.8 micrograms/ml). As with other beta-receptor antagonists, the activities of sotalol's 2 stereoisomers differ, with the I-isomer having far more beta-blocking activity. However, both isomers have equal class III antiarrhythmic activity. When increasing doses of the d-isomer of sotalol (50 to 400 mg every 12 hours) were evaluated in patients with chronic ventricular arrhythmias, arrhythmia frequency was suppressed greater than 80% in 3 patients and 50% in 1 patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical pharmacokinetics of moricizine.

Moricizine is well absorbed after oral administration and undergoes extensive first-pass metabolism. The drug has a large apparent volume of distribution (approximately 4 liters/kg), exhibits extensive plasma protein binding (approximately 95%) and produces at least 30 metabolites. Indirect evidence indicates that some of those metabolites may be pharmacologically active. The elimination half-life of moricizine is 2 to 6 hours, but its duration of antiarrhythmic action is much longer suggesting active metabolites. Moricizine induces its own metabolism with no change in pharmacologic effect. It also induces the metabolism of theophylline and specific pathways of antipyrine. Cimetidine reduces metabolism of moricizine but does not alter its pharmacologic effects. This observation provides further support for the hypothesis that the metabolites of moricizine contribute to the pharmacologic actions during therapy and indicate that plasma level monitoring is not likely to be of value. There are no known clinically significant pharmacokinetic interactions between moricizine and digoxin, warfarin or propranolol. Excessive prolongation of the PR interval has been seen in some patients receiving both digoxin and moricizine, probably due to additive electrophysiologic effects of the 2 drugs.

Tocainide plus quinidine for treatment of ventricular arrhythmias.

Tocainide and quinidine were administered both as single agents and in combination to 14 patients with chronic ventricular arrhythmias. Therapy with tocainide was limited by the occurrence of dose-related adverse reactions in 8 patients, but could be titrated to a dose that was well-tolerated in 13 of 14 and effective in 2 of 13. The addition of quinidine gluconate to the tolerated dose of tocainide increased the number of patients with arrhythmia suppression from 2 to 6. After tocainide washout, quinidine alone suppressed arrhythmias in only 3 patients. Analysis of electrocardiogram intervals showed that the drugs had additive effects on the coupling interval of the sinus beat to the predominant ectopic beat, but exerted antagonistic effects on the corrected QT interval. These findings suggest that the combination may be clinically useful, exerting pharmacologic effects unlike either agent alone.

SSRI safety in overdose.

BACKGROUND: The morbidity and mortality caused by tricyclic antidepressant (TCA) overdose are well recognized. Among newer antidepressants, the selective serotonin reuptake inhibitors (SSRIs) are thought to be safer in overdose. This study was designed to describe the signs, symptoms, and mortality associated with SSRI overdose. METHOD: English-language articles identified through MEDLINE (1985 through 1997), and case reports from the American Association of Poison Control Centers (AAPCC) (1987 through 1996) and United States Food and Drug Administration (FDA) adverse event database (through 1997) that describe findings of fatal and nonfatal overdoses involving SSRIs alone or in combination with other ingestants were reviewed. RESULTS: SSRI antidepressants are rarely fatal in overdose when taken alone. During the 10 years that SSRI antidepressants have been marketed, there have been remarkably few fatal overdoses reported in the literature or to the AAPCC or FDA involving ingestion only of an SSRI. Moderate overdoses (up to 30 times the common daily dose) are associated with minor or no symptoms, while ingestions of greater amounts typically result in drowsiness, tremor, nausea, and vomiting. At very high doses (> 75 times the common daily dose), more serious adverse events, including seizures, electrocardiogram (ECG) changes, and decreased consciousness may occur. SSRI overdoses in combination with alcohol or other drugs are associated with increased toxicity, and almost all fatalities involving SSRIs have involved coingestion of other substances. CONCLUSION: The SSRI antidepressants are far safer than the TCAs in overdose. There is no apparent difference among SSRIs with respect to overdose safety.

Vasodepressor syncope. Diagnosis and management.

Vasodepressor syncope is a common medical problem that can be diagnosed through an accurate history and upright tilt testing. In most cases, patients experience a striking decrease in syncopal episodes following a tilt test, and long-term therapy is not necessary. In the rare patient who experiences no prodrome and continues to experience injury-causing syncope, empiric therapy with drugs or dual-chamber pacing has to be considered despite the lack of controlled trials establishing the efficacy of such therapies.

Alterations in heart rate following radiofrequency ablation in the treatment of reentrant supraventricular arrhythmias: relation to alterations in autonomic tone.

To determine the relation between the creation of endocardial lesions and alterations in autonomic tone, we analyzed heart rate variability in patients undergoing radiofrequency catheter ablation for symptomatic supraventricular tachycardia. Elevated heart rates are frequently noted after radiofrequency catheter ablation for supraventricular arrhythmias. It has been postulated that this elevation may be secondary to alterations in cardiac autonomic tone. Since heart rate variability is a measure of autonomic nervous system activity, we used this technique to examine the heart rate elevation and to characterize postablation autonomic changes. Thirty-eight patients undergoing 44 radiofrequency catheter ablation procedures were included in the study. Total arrhythmic substrates treated included 34 accessory pathways and 13 AV nodes with dual physiology. Twenty-four hour ambulatory electrocardiographic recordings were obtained in a drug-free state prior to, ablation early postablation, and late postablation. Spectral and nonspectral analyses of heart rate variability were performed. Subgroup analyses were also done on specific cohorts. Subgroups included patients undergoing accessory pathway ablations, AV node modifications, and ablation of septal and nonseptal targets. To determine whether the amount of tissue damage was related to changes in heart rate variability, we analyzed the relation between the total energy delivered to the endocardium and the peak change in creatine kinase and heart rate variability. In this population, a significant transient increase in heart rate was noted following radiofrequency ablation. All time and frequency domain parameters of heart rate variability showed significant reversible decreases. These changes were independent of target site and arrhythmia substrate. There was no correlation noted between the changes in heart rate variability and either the total amount of energy applied to the endocardium or the change in creatine kinase. Increased heart rates and decreased heart rate variability occur following radiofrequency catheter ablation for supraventricular tachycardia. Clinically, the predominant effect is that of decreased parasympathetic tone. Since these transient changes are independent of arrhythmic substrate or ablation site in the atria, a rich parasympathetic innervation of the heart is proposed.

Pharmacologic evaluation of standard and controlled-release disopyramide.

Controlled-release disopyramide offers many potential advantages over the standard formulation for improved patient compliance, possible reduction of concentration-related adverse effects, and predictability of pharmacologic effect. The pharmacology of disopyramide, potential advantages and disadvantages of the use of sustained- (or controlled-)release formulations of drugs, and the preliminary finding of our use of controlled-release disopyramide are described. Controlled-release disopyramide is a promising addition to the antiarrhythmic formulary that may increase the clinical utility of disopyramide.

Clinical pharmacology and beta-blocking efficacy of propafenone.

Propafenone, like encainide and flecainide, is an antiarrhythmic drug characterized by slow kinetics of interaction with cardiac sodium channels. In addition, it shares structural similarities with propranolol and has been shown to exert consistent beta-blocking action in vitro. On the other hand, the extent of beta-blockade noted after oral administration of propafenone in vivo has been reported to range from undetectable to clinically significant. Although the explanation for this discrepancy was initially unclear, recent work has convincingly demonstrated that the degree of beta-blockade during propafenone therapy reflects genetically determined variations in the metabolism of the parent drug, which has greater beta-blocking potency than do its metabolites. At lower dosages, beta-blockade is significantly greater and more likely to be clinically noticeable in the small percentage of patients who have poor metabolism and in whom deficient 5-hydroxylation is associated with higher plasma propafenone concentrations. Because this metabolic pathway is saturable, at the usual highest clinical dosage (900 mg/24 h) plasma propafenone concentration rises disproportionately in patients with normal 5-hydroxylation, and more comparable degrees of beta-blockade are noted in both metabolizer types. Beta-blockade during propafenone therapy, which can contribute both to the genesis of side effects and to the suppression of arrhythmias, is a potentially important drug effect that can largely be predicted by genetic variations in the metabolism of the drug.

Influence of ventricular fibrillation duration on defibrillation energy in dogs using bidirectional pulse discharges.

The automatic implantable defibrillator device typically discharges 5-30 seconds after detection of ventricular fibrillation. To investigate the importance of the duration of ventricular fibrillation on defibrillation, the effects of ventricular fibrillation durations of 5, 15, and 30 seconds on the energy requirements for successful internal defibrillation were compared in 15 closed chest dogs with internal electrodes. The electrode configuration utilized a transvenous right heart catheter with two electrodes and a precordial subcutaneous patch electrode, with a single bidirectional pulse discharged between the distal catheter electrode and the proximal catheter and patch electrodes. Curves of energy vs. percentage of successful defibrillation were constructed and logistic regression was used to derive 90% and 50% successful energy doses (ED90 and ED50). The mean ventricular fibrillation activation interval just prior to defibrillation was determined from discrete RV endocardial electrograms. Four dogs died during testing, all because of inability to defibrillate after 30 s of ventricular fibrillation. In the remaining 11 dogs, the ED90 increased from (mean +/- SD) 27 +/- 13J at 5 s to 41 +/- 14J at 30 s (p less than .01). The mean ventricular fibrillation activation interval decreased from 107 +/- 21 ms at 5 s to 95 +/- 18 ms at 30 s (p less than .01). In conclusion, the energy required for internal defibrillation in dogs using this electrode configuration increases with longer durations of ventricular fibrillation, and is associated with more rapid ventricular fibrillation activation intervals.