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.

Selecting appropriate first-line antiarrhythmic agents: comparative pharmacological profiles.

An understanding of the pharmacological issues presented here will help the physician treat arrhythmias in a manner that will meet the therapeutic goals of relieving clinical symptoms, reducing the risk of sudden death, and prevention of treatment-related adverse effects. Most of the issues presented here are qualitative. It usually is not necessary to memorize quantitative data, e.g., to know the exact clearance or exact volume of distribution of a drug in a given setting, but we do need to know qualitatively what kind of changes to expect and alter dosing or drug selection accordingly. Armed with this knowledge, we can more appropriately and safely treat patients with cardiac arrhythmias.

Pharmacokinetics of recombinant human superoxide dismutase.

Superoxide dismutase (SOD) disposition was studied in order to design a rational approach for drug administration in the setting of acute myocardial infarction. Four chronically instrumented conscious dogs received the following dosage regimens of recombinant human SOD (rhSOD) on successive days: (a) 5 mg/kg left atrial (LA) bolus, (b) 5 mg/kg central vein (CV) bolus, (c) 15 mg/kg CV bolus, and (d) 5 mg/kg CV infusion over 60 min; additionally, all dogs received (e) a 5 mg/kg CV bolus under pentobarbital anesthesia. Serial serum samples were obtained after each dose and serial myocardial samples were obtained after dose (e). The serum rhSOD concentration was measured by radioimmunoassay and the data were fit to a two-compartment model. The distribution half-life was 7.8 +/- 1.7 min (mean +/- SEM), and the elimination half-life was 51.1 +/- 5.9 min; the central compartment volume of distribution (Vc) was 81 +/- 26 ml/kg and the steady-state volume of distribution was 156 +/- 20 ml/kg. The dosage regimen had no influence on clearance rates. Peak plasma concentrations (micrograms/ml) for the dosage regimens were (a) 65 +/- 28, (b) 89 +/- 19, (c) 214 +/- 61, (d) 20 +/- 5, and (e) 86 +/- 9. The peak level following continuous infusion did not occur until 50 min of infusion and was only one-fourth of the level achieved with a bolus of the same dose. Myocardial levels were less than 1% of serum levels, suggesting negligible rhSOD penetration into the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

Alternating sequence of retrograde atrial activation in patients with dual AV nodal physiology.

Patients with dual AV nodal physiology have been demonstrated to have earliest retrograde activation sequence of the fast pathway in the lower septal right atrium and slow pathway in the proximal coronary sinus, and the posterior atrial septum. This case report describes a patient with dual AV nodal physiology demonstrating a dual sequence of retrograde activation with 2:1 block occurring in the fast pathway causing the conduction to proceed alternately via fast then slow pathway. This sequence was abolished by atropine allowing conduction to proceed via fast pathway. Surgical cure of patients with reentrant AV nodal tachycardia suggests the presence of two anatomically distinct AV nodal-like pathways. This case report confirms this observation and further suggests preferential autonomic modulation of the fast pathway.

The automatic implantable cardioverter defibrillator: T wave sensing in the newest generation.

The AICD uses an automatic gain control amplifier for detecting the small electrograms during ventricular fibrillation. The latest generation of the AICD appears to have a more sensitive lock on gain amplifier, as 6 of 76 patients implanted with the new AICD had double counting of the QRS-T wave complex resulting in asymptomatic discharges. Solutions to the problem of limiting these asymptomatic discharges are difficult and include slowing of the heart rate with beta blockers, changing the lead system, or replacement of the device. One of the six patients was treated with beta blockers. Three patients had their device changed, two patients requested the inactivation of their device until a rate programmable unit was available. The potential for T wave sensing in a lock on gain amplifier represents the unique dilemma between detecting small electrograms of ventricular fibrillation, and detecting diastolic events which occur shortly after the QRS complex.

Initial dosage selection of antiarrhythmic therapy.

The success or failure of antiarrhythmic drug treatment depends, in part, on the selection of the initial dosage. Too low a dosage can lead to unnecessary (and frequently life-endangering) delays in achievement of arrhythmia suppression. Conversely, an excessively high dosage can lead to intolerable toxicity and cessation of treatment. The recommended approach to therapy is to begin with a relatively low dosage, i.e., the lowest dosage with a reasonable chance of producing a favorable response, and titrating the dose upward as needed. Dose titration should be guided by clinical response and, when appropriate, concentrations of the drug and any active metabolites in the plasma. In situations frequently encountered in practice, however, the initial dosage must be modified because of interindividual differences in drug disposition. These changes in drug pharmacokinetics can arise from a variety of factors, including disease processes (e.g., congestive heart failure, cirrhosis and renal failure), concomitant medications (e.g., hepatic enzyme inducers such as phenytoin and inhibitors such as amiodarone), drug formulation, protein binding and inherited drug metabolism capacity. Knowledge of these factors can help the clinician to avoid potential pitfalls in initial dosage selection and can enhance the changes of successful drug treatment of arrhythmias.

The development and testing of intravenous dosing regimens: application to flecainide for the suppression of ventricular arrhythmias.

A two-part pharmacokinetic approach was used to prospectively develop and test intravenous flecainide infusion regimens for the acute therapy for ventricular arrhythmias. Initially, each of nine known responders to oral flecainide was given a rapid flecainide infusion to characterize pharmacokinetic parameters and determine the minimum effective concentration for each patient. These data were used to calculate individually appropriate three-stage flecainide infusions of predetermined durations in eight patients. The three-stage infusions (0.15 +/- 0.02 mg flecainide acetate/kg/min for 5 minutes, 0.046 +/- 0.004 mg/kg/min for 60 minutes, and 0.31 +/- 0.05 mg/kg/hr for 5 to 47 hours; mean +/- SE) resulted in 95% +/- 0.1% suppression of ventricular ectopic depolarizations. Based on these results, six additional patients received a uniform infusion regimen (0.1 mg/kg/min for 5 minutes, 0.025 mg/kg/min for 2 hours, and 0.25 mg/kg/hr for 46 hours). Supplemental doses of 0.25 mg/kg were given (four doses per patient). With this protocol, ventricular ectopic depolarizations were 82.6% +/- 8.5% suppressed. Measured plasma flecainide concentrations were not significantly different from those predicted by pharmacokinetic models. A prompt and sustained antiarrhythmic effect was obtained with an intravenous regimen of flecainide determined by a prospective pharmacokinetic approach. However, the dosages developed in this study may have to be modified for patients with impaired cardiac or renal function.

Potent electrophysiologic effects of the major metabolites of propafenone in canine Purkinje fibers.

Marked interindividual variability has been reported in the plasma concentrations of the antiarrhythmic agent propafenone required for arrhythmia suppression. One possible explanation is the variable generation of active metabolites: it is known that the major metabolite 5-hydroxypropafenone and the more recently described metabolite N-depropylpropafenone can accumulate in plasma to concentrations similar to those of propafenone, and 5-hydroxypropafenone has proven active in animal models. We therefore compared the effects of these metabolites to those of propafenone on action potential characteristics of canine Purkinje fibers at a wide range of cycle lengths. After base-line measurements, propafenone or 5-hydroxypropafenone was superfused at successive concentrations of 0.1, 0.3 and 1.0 microM for 30 min each and measurements were repeated. Both drugs depressed maximum phase zero upstroke slope of the action potential (Vmax); 5-hydroxypropafenone was similar to propafenone in potency with both causing significant effects at very low concentrations (0.1 microM). Vmax depression was cycle length-dependent and the time constants for onset of and recovery from use-dependent Vmax depression were similar. The compounds also shortened action potential duration at 50% but not 90% repolarization. N-depropylpropafenone produced electrophysiologic effects that were similar to those of propafenone and 5-hydroxypropafenone but was less active. We conclude that these metabolites are sufficiently potent that they may explain at least in part the unpredictable concentration-response relationship seen with propafenone.

Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences.

The relationship between debrisoquine metabolic phenotype and the pharmacokinetics and pharmacodynamics of propafenone was studied in 28 patients with chronic ventricular arrhythmias (22 extensive metabolizers [EMs] and six poor metabolizers [PMs] of debrisoquine). EMs were characterized by a shorter propafenone elimination half-life (5.5 +/- 2.1 vs 17.2 +/- 8.0, p less than .001), lower average plasma concentration (Cp) (1.1 +/- 0.6 vs 2.5 +/- 0.5 ng/ml/mg daily dosage, p less than .001), and higher oral clearance (1115 +/- 1238 vs 264 +/- 48 ml/min, p less than .001). The active metabolite 5-hydroxypropafenone, assayed in 12 patients, was identified in nine of 10 EMs but in neither of the PMs. A lower incidence of central nervous system side effects was noted in EMs (14% vs 67%, p less than .01). The magnitude of QRS widening at any given propafenone Cp was greater in EMs than PMs. There was no significant difference between EMs and PMs in effective propafenone dose or frequency of antiarrhythmic response. Inhibition of debrisoquine 4-hydroxylation by propafenone was demonstrated both in vivo and in a human liver microsomal system in vitro. We conclude that propafenone is metabolized via the same cytochrome P-450 responsible for debrisoquine's 4-hydroxylation, and that its pharmacokinetics and concentration-response relationships and the incidence of central nervous system side effects are different in patients of different debrisoquine metabolic phenotype.

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.

Encainide disposition in patients with chronic cirrhosis.

The antiarrhythmic agent encainide undergoes extensive first-pass hepatic metabolism after oral dosing. The active metabolites O-desmethylencainide and 3-methoxy-O-desmethylencainide are formed in subjects who are extensive metabolizers (EMs), a phenotypic trait that cosegregates with that of debrisoquin. Because of the possibility that drug metabolism is altered by liver dysfunction, the disposition of encainide and its metabolites was studied in six such EMs with cirrhosis and compared with that in eight normal subjects of the same phenotype. Patients with cirrhosis had lower systemic and oral clearances of encainide, resulting in a threefold increase in oral bioavailability. The plasma concentration of encainide was significantly higher among the patients with cirrhosis, whereas the plasma levels of the respective metabolites were comparable with those in normal subjects, resulting in no change in the patient's ECG intervals. Encainide is, therefore, an example of a drug in which cirrhosis causes a three- to fourfold increase in parent drug concentrations. However, because no change occurs in the levels of the pharmacologically active metabolites, dosage adjustment is probably not required in patients with cirrhosis.

Concentration-dependent pharmacologic properties of sotalol.

Sotalol is a nonselective beta-receptor antagonist that prolongs action potential duration and refractoriness in vitro at higher concentrations than those associated with heart rate slowing. To determine if this additional action can be expressed in humans, 17 patients with chronic stable ventricular premature complexes were studied. Each patient was hospitalized and arrhythmia frequency was quantified during a 48-hour drug-free baseline and during every third day of therapy with increasing incremental sotalol dosages. The dosages were 160, 320, 640 and 960 mg/day, administered in 1 or 2 doses. An index of action potential duration, the rate-corrected QT (QTc), was measured using serial 12-lead electrocardiograms on the third day of each dosage at presumed steady state and the degree of beta-receptor blockade was assessed by the reduction of the maximal exercise-induced heart rate. Of the 17 patients, 11 had an antiarrhythmic response (70 to 100% reduction in VPCs), at a wide range of plasma concentrations (340 to 3,440 ng/ml). The responders to sotalol included 8 patients in whom therapy with conventional beta-receptor antagonists had failed. In the group as a whole, the concentration associated with significant QTc prolongation (2,550 ng/ml) was greater than that associated with 50% reduction of the maximal slowing in heart rate (804 ng/ml). Sotalol was generally well tolerated, but in 1 nonresponder torsades de pointes developed 3 hours after the first 640-mg dose at a plasma sotalol concentration well within the concentration range measured in other patients. Sotalol's repolarization-prolonging actions are seen at higher concentrations than those associated with heart rate slowing and may contribute to its clinical effects.

Clinical pharmacokinetics of disopyramide.

Disopyramide is an antiarrhythmic agent with proven efficacy in the management of atrial and ventricular arrhythmias. The drug is well absorbed and undergoes virtually no first-pass metabolism. Peak concentrations are achieved approximately 0.5 to 3.0 hours after a dose. Absorption is reduced and slightly slowed in patients with acute myocardial infarction. Disopyramide is excreted as unchanged drug (two-thirds) or as the metabolite mono-N-desisopropyldisopyramide, with elimination via both renal and biliary routes. Elimination half-life is approximately 7 hours in normal subjects and patients, but is prolonged in patients with renal insufficiency (creatinine clearance less than 60 ml/min). Disopyramide exhibits complex protein binding. It is bound to alpha 1-acid glycoprotein (AAG), an acute phase reactant, and binds in a concentration-dependent (saturable) manner. The unbound fraction is reduced in the presence of elevated concentrations of AAG, as are found in acute myocardial infarction and in some chronic haemodialysis patients and renal transplant recipients. Free disopyramide concentrations are low relative to total concentration in these patients. Because the pharmacological effects of disopyramide are determined by unbound drug, changes in the unbound fraction could make total disopyramide concentrations misleading as a guide to therapy. Changes in protein binding do not, however, alter free disopyramide or metabolite concentrations, both of which are dependent only on dosage and intrinsic clearance. Free drug concentration measurement could potentially improve therapeutic monitoring, but is as yet of unproven clinical value. Disopyramide is cleared more rapidly in children than in adults, and therefore children require higher dosages to attain therapeutic concentrations.

Clinical pharmacology of old and new antiarrhythmic drugs.

The number of antiarrhythmic drugs available in the United States is increasing, with the discovery of antiarrhythmic properties of drugs previously marketed for other indications (phenytoin, imipramine) and the development of several new drugs, many of which are likely to become commercially available in the next 5 years. The currently available drugs and several promising investigational drugs are reviewed in this report. Their optimal use is dependent on an understanding of their electropharmacologic effects, pharmacokinetics, drug interactions, and clinical pharmacology. Such use may allow better attempts to reduce arrhythmia-related death and morbidity.

Clinical pharmacology of propafenone: pharmacokinetics, metabolism and concentration-response relations.

Propafenone is a promising new antiarrhythmic agent marketed in Europe for the past 7 years. The drug is remarkable for great interindividual variability in its pharmacokinetic and pharmacodynamic properties. Propafenone undergoes extensive presystemic clearance that appears to be saturable, with bioavailability increasing as dosage increases. The drug is highly protein bound. Elimination half-life is 5 to 8 hours in most patients, although a range of 2 to 32 hours has been reported. Propafenone slows intracardiac conduction in a concentration-dependent manner. It is a weak beta-adrenergic blocker, but this property is of uncertain clinical significance. The major metabolic pathway for propafenone begins with aromatic ring hydroxylation, a pathway that may be determined by genetic factors.

Flecainide dose-response relations in stable ventricular arrhythmias.

Flecainide acetate was evaluated in a placebo-controlled, dose-ranging study performed in patients with stable, high-frequency ventricular arrhythmias. Three centers studied 35 patients in a 3-stage protocol. After a placebo baseline, increasing oral dosages from 100 to 300 mg twice daily were evaluated. Placebo was then reinstituted and after arrhythmia had recurred, the patients were discharged on the effective dosage to return to the clinic for evaluation 7 and 14 days later. Thirty of 35 patients had more than 80% suppression (mean 96%) of ventricular premature complexes (VPCs) and more than 95% reduction in complex VPCs. Arrhythmia suppression was seen at dosages of 100 to 200 mg twice daily in 73% of the patients. Twenty-three percent of patients required 500 to 600 mg/day. Mild side effects were seen in 46% of patients. These resolved or became tolerable at lower dosages in most patients. Effective therapy continued for 2 years in 24 of 29 patients, without any evidence of chronic toxicity. Pharmacokinetic studies indicate that many patients require 5 to 7 days of constant dosing before reaching steady state. Flecainide acetate is an effective antiarrhythmic with a narrow range of effective dosages.

Potential applications of free drug level monitoring in cardiovascular therapy.

Cardiovascular drugs, as a class, have low therapeutic indices, but also have great therapeutic potential. Plasma concentration information is therefore often of value when using these drugs. Unfortunately, the total plasma concentration may not reflect the concentration of pharmacologically active free drug, since a number of factors including disease states, heparin anticoagulation, non-linear binding characteristics, and in vitro artefacts can affect the protein binding of these agents. This may also explain their poor dose-response relationships and great interindividual variability in plasma concentration data. Careful studies relating bound and free drug concentration to pharmacological response may provide the clinician with a better guide to therapy, and enhance the usefulness of these drugs.