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Biomedical subjects

R L Woosley

Publications and source records attributed to R L Woosley.

At least 109 records · Page 6Linked to original sources
PubMed1988

Electrophysiologic effects of intravenous and oral sotalol for sustained ventricular tachycardia secondary to coronary artery disease.

The electrophysiologic effects of intravenous sotalol (1.5 mg/kg load followed by 0.008 mg/kg maintenance, mean dose 150 +/- 23 mg) and oral sotalol (mean dose 583 +/- 204 mg daily) were prospectively evaluated in 16 patients undergoing electrophysiologic evaluation for sustained ventricular tachycardia (VT) secondary to coronary artery disease. Electrocardiographic intervals, indexes of sinus and atrioventricular node function and indexes of atrial and ventricular function were assessed. Inducibility or noninducibility of sustained VT and characteristics of the induced arrhythmia were also evaluated. Intravenous and oral sotalol exerted similar beta-blocking effects, which included significant prolongation of sinus cycle length (baseline 820 +/- 165 ms, intravenous sotalol 1,077 +/- 206 ms, oral sotalol 1,141 +/- 306 ms), AH interval (baseline 126 +/- 43, intravenous sotalol 169 +/- 42, oral sotalol 197 +/- 55 ms) and Wenckebach cycle length (baseline 375 +/- 70, intravenous sotalol 460 +/- 84, oral sotalol 449 +/- 68 ms). Both intravenous and oral sotalol also prolonged repolarization and refractoriness including significant increases in QT interval (baseline 338 +/- 47, intravenous sotalol 417 +/- 35, oral sotalol 450 +/- 70 ms), atrial effective refractory period (baseline 240 +/- 38, intravenous sotalol 330 +/- 71, oral sotalol 299 +/- 26 ms) and right ventricular effective refractory period (baseline 241 +/- 16, intravenous sotalol 289 +/- 35, oral sotalol 291 +/- 22 ms).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1988

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.

Aged↗
PubMed1988

Overview of the clinical pharmacology of antiarrhythmic drugs.

Antiarrhythmic drugs have been recognized to possess 1 or more classes of antiarrhythmic action. This classification scheme is useful, but has major limitations because the available drugs and their metabolites have multiple actions. This report presents an overview of the distinguishing features of the most frequently used agents having class I or III actions. Agents with class I actions are local anesthetic agents that depress the fast inward depolarizing sodium current and thereby slow the rate of the rise of the action potential (phase 0). This category is further divided into classes IA, IB, and IC according to the degree of potency as sodium channel inhibitors, and the individual effects of the drug on action potential, conduction velocity and repolarization. Included in the spectrum of agents with class I action are quinidine, procainamide, disopyramide, lidocaine, tocainide, mexiletine, flecainide, amiodarone, encainide and lorcainide. The antiarrhythmic drugs that exert class III action lengthen repolarization and refractoriness; included in this category are amiodarone, quinidine, bretylium and sotalol. Because of the broad range of effects that antiarrhythmic agents may exert, safe and effective therapy requires a thorough familiarity with the pharmacologic profile of each drug administered and a careful evaluation of the presenting condition and the patient history. In some cases, a multiple drug regimen may be most appropriate. Various combinations such as class IA and IB agents, have been shown to slow conduction synergistically and increase refractoriness while keeping adverse effects to a minimum.

Action Potentials↗
PubMed1988

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.

Adult↗
PubMed1988

Plasma concentrations of quinidine, its major metabolites, and dihydroquinidine in patients with torsades de pointes.

We examined the hypothesis that excess accumulation of major quinidine metabolites or the commercial impurity dihydroquinidine contributes to the development of polymorphic ventricular tachycardia (torsades de pointes, [TdP]) in patients taking quinidine. Total and free plasma concentrations of these compounds were measured by reverse-phase HPLC with fluorescence detection and equilibrium dialysis in 19 patients with TdP and 38 control patients tolerating quinidine therapy without toxicity. No significant differences were found between the two groups of patients. Ratios of metabolite or dihydroquinidine to quinidine varied up to tenfold among patients but were similarly distributed in the TdP and control groups. Only the metabolite 3-hydroxyquinidine was present at free plasma concentrations that exceeded free concentrations of quinidine. We conclude that although quinidine metabolism is highly variable, there does not appear to be any correlation between the plasma concentrations of quinidine, its metabolites or dihydroquinidine, and the subsequent development of TdP.

Humans↗
PubMed1988

Antiarrhythmic activity, electrocardiographic effects and pharmacokinetics of the encainide metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide in man.

Although encainide is an effective antiarrhythmic agent, plasma concentrations and pharmacologic effects are not well correlated. One explanation is the generation of active metabolites: while in most patients (extensive metabolizers; EMs) concentrations of the metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (3MODE) are higher than those of encainide, a small subset (poor metabolizers; PMs) lack the ability to extensively biotransform encainide. Considerable data from studies in vitro and animal studies, as well as indirect evidence in patients, indicate that ODE and 3MODE produce the effects seen during long-term encainide therapy in EMs. We now report the initial direct evaluation of the pharmacologic actions of these metabolites of encainide in man. Nine patients with ventricular arrhythmias, seven of the EM phenotype and two of the PM phenotype, were studied. Chronic high-frequency ventricular arrhythmias were suppressed by encainide therapy in seven of nine; monitoring arrhythmia frequency during withdrawal of encainide allowed definition of plasma concentrations of encainide and metabolites associated with arrhythmia suppression. Intravenous infusions of both ODE and 3MODE suppressed chronic ventricular arrhythmias, while infusions of placebo had no effect. ODE clearance was a function of metabolizer phenotype, with higher clearance (mean 914 ml/min; range 554 to 1,314) in EMs than in PMs (434, 298 ml/min); moreover, 3MODE was detected during ODE infusions in all seven EMs but in neither PM. 3MODE clearance was more uniform (mean 289 ml/min in EMs [range 180-410] vs 300 and 78 ml/min in the two PMs) and ODE was not detected in any subject during 3MODE infusion. Encainide itself was not detected after any infusion of ODE or 3MODE. During withdrawal of encainide therapy, ODE plasma concentration at the time of arrhythmia recurrence was 55 +/- 40 ng/ml (mean +/- SD), while ODE by infusion was effective at a concentration of 37 +/- 15 ng/ml. Similarly, plasma concentration of 3MODE at the time of arrhythmia recurrence after withdrawal of chronic encainide was 116 +/- 35 ng/ml and that during 3MODE infusion was 105 +/- 50 ng/ml. While both compounds prolonged QRS duration, ODE was the more potent, increasing QRS by 9.2 +/- 1.6% per 100 ng/ml vs 1.2 +/- 0.5% per 100 ng/ml for 3MODE. On the other hand, 3MODE prolonged the corrected JT interval by 1.9 +/- 0.6% per 100 ng/ml, while ODE shortened it by 2.7 +/- 1.9% per 100 ng/ml.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1988

Competition between lidocaine and one of its metabolites, glycylxylidide, for cardiac sodium channels.

The modulated receptor hypothesis states that sodium channels have a specific receptor for antiarrhythmic drugs. Therefore, two agents that block sodium channels by binding to this receptor are expected to compete for occupancy. Glycylxylidide (GX) is a deethylated metabolite of lidocaine that accumulates in patients on lidocaine therapy. In single, voltage-clamped cardiocytes, GX, like lidocaine, blocked cardiac sodium channels in a use-dependent manner. However, its kinetics of recovery from block were markedly different from lidocaine: at potentials between -80 and -100 mV, GX-blocked channels recovered faster and more completely than lidocaine-blocked channels but recovered more slowly at more negative potentials (-120 to -140 mV). If lidocaine and GX compete for a common receptor, then there are conditions in which addition of a "faster" drug to a "slower" drug will produce less block than the slower drug alone. At potentials between -120 and -140 mV, addition of GX (slower drug) to lidocaine always increased the level of block, but addition of lidocaine to GX decreased the block in four of nine experiments and did not increase it in three of nine experiments. Conversely, at potentials between -80 and -100 mV, addition of lidocaine (slower drug) to GX always increased block, whereas addition of GX to lidocaine reduced the level of block in five of 16 experiments and did not increase it in seven of 16 experiments. Thus, upon addition of more blocker, the sodium current increased in 36% of cases or did not decline in 76% of cases. These results can be explained by the modulated receptor hypothesis with two drugs competing for the same receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Clinical pharmacokinetics of encainide.

The disposition kinetics of the new antiarrhythmic agent encainide are a function of the genetic polymorphism which also controls debrisoquin 4-hydroxylation. In the majority of subjects (extensive metabolisers) encainide undergoes extensive first-pass hepatic biotransformation to the active metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE). The plasma concentrations of these metabolites are higher than those of encainide, and pharmacological effects correlate better with plasma metabolite concentrations than they do with those of encainide itself. In poor metabolisers, who make up to 7% of the population, a first-pass effect is absent, encainide clearance is lower, and plasma encainide concentrations are higher than those in extensive metabolisers. In poor metabolisers, plasma concentrations of active metabolites are low or undetectable, and the effects of encainide therapy can be closely correlated with plasma concentrations of the parent drug. Despite the marked differences in encainide disposition between extensive and poor metabolisers, the dosages which produce pharmacological effects (QRS prolongation and arrhythmia suppression) are similar in both groups. Encainide biotransformation is impaired in hepatic disease, but no major dosage changes are required. On the other hand, excretion of encainide and its metabolites is impaired in individuals with renal disease, and starting dosages should be decreased. The time required to achieve steady-state concentrations of metabolites (in extensive metabolisers) and of encainide itself (in poor metabolisers) is similar (3 to 5 days); therefore, the dosage should be increased no more often than every 3 to 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1988

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.

Action Potentials↗
PubMed1987

Pharmacokinetics of moricizine HCl.

Moricizine HCl is a phenothiazine derivative with antiarrhythmic properties. It was developed in the USSR and is now undergoing clinical evaluation. Although preliminary work has shown moricizine HCl to be effective in treating both atrial and ventricular arrhythmias, little is known of its pharmacokinetics. There is a 4-fold variability in range for its elimination half-life and in volumes of distribution and clearance. There is a linear relation for peak plasma levels and area under the plasma concentration/time curve with regard to single-dose administration of moricizine HCl. The bioavailability of moricizine HCl connotes extensive first-pass effect, or presystemic metabolism. Very little of moricizine is excreted unchanged; it is extensively metabolized to certain compounds that are present in plasma for extended periods. Moricizine is extensively (92% to 95%) bound to plasma protein. Its coadministration with cimetidine leads to additive systemic effects; however, there is no evidence of alterations in steady-state levels when moricizine HCl is coadministered with digoxin. Because moricizine is a drug with active metabolites, its concentration/effect profile is complex; this poses a challenge for accurate dose titration. This may, however, be a helpful challenge in that the metabolites may one day prove useful in therapy. This surmise warrants further study.

Anti-Arrhythmia Agents↗
PubMed1987

Pharmacologic causes of arrhythmogenic actions of antiarrhythmic drugs.

All currently known antiarrhythmic agents can induce or worsen arrhythmias. Inappropriate dosage selection, mistakenly based on pharmacokinetic data from "normal" subjects, may result in adverse reactions when an antiarrhythmic drug is given to patients. Unexpected variations in drug clearance can increase plasma concentration of antiarrhythmic agents and aggravate arrhythmias. Changes in the rate of drug metabolism by the liver, e.g., due to cessation of alcohol or drugs that induce hepatic metabolism, can reduce drug clearance, making a previously well-tolerated dose toxic. Another possible explanation for adverse drug reactions is nonlinear protein binding. Recently, genetic determinants of drug metabolism have been identified as explanations of interindividual variations in drug responsiveness. Finally, the interactions of antiarrhythmic agents may also lead to aggravation of arrhythmias. A better understanding of the pharmacology of antiarrhythmic agents can reduce, if not prevent, the occurrence of potentially lethal proarrhythmic events.

Anti-Arrhythmia Agents↗
PubMed1987

Pharmacokinetics and pharmacodynamics of antiarrhythmic agents in patients with congestive heart failure.

Changes in the pharmacokinetics of antiarrhythmic agents may be anticipated in patients with congestive heart failure (CHF), although the magnitude or direction of change is not always predictable. Factors complicating antiarrhythmic therapy in patients with CHF include both physiologic changes resulting from the disease state and unwanted effects of drug therapy for CHF. The volume of distribution is often significantly decreased (by as much as 50%) and loading doses should be reduced proportionately. Decreased blood flow to the liver and kidneys and decreased hepatic drug-metabolizing activity serve to diminish drug clearance. In some cases, simultaneous decreases in volume of distribution and clearance may result in little, if any, change in elimination half-life, despite higher plasma concentrations. Conversely, the elimination half-life of antiarrhythmic agents may be doubled in patients with CHF, necessitating a reduction in dosage. In the latter case, the time needed to reach steady state is lengthened, so that premature escalation of dosage may lead to excessive drug accumulation. In terms of their pharmacodynamics, most antiarrhythmic agents have a degree of negative inotropic effect at some concentration, and patients with reduced myocardial reserve are especially vulnerable to these effects. Some of the newer agents (such as tocainide, mexiletine, and encainide) appear to cause only minimal myocardial depression. Potential complications during therapy with all antiarrhythmic agents that are of special concern in patients with CHF include diuretic-induced hypokalemia, proarrhythmia, and possible interactions with cardiac glycosides and other drugs. Therapy for patients with CHF should be initiated with low doses of the agent selected, and the dosage carefully titrated while the patient is monitored, to confirm both efficacy and the absence of adverse effects. During subsequent outpatient therapy the patient should be carefully observed for sign of unexpected reactions, toxicity, or electrolyte imbalance.

Anti-Arrhythmia Agents↗
PubMed1987

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.

Adult↗