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Biomedical subjects

R L Woosley

Publications and source records attributed to R L Woosley.

At least 163 records · Page 9Linked to original sources
PubMed1984

Influence of genetic polymorphism on the metabolism and disposition of encainide in man.

The metabolism of the new, highly effective antiarrhythmic agent, encainide, appears to be polymorphically distributed in a similar fashion to the genetically determined oxidative biotransformation of debrisoquine. Accordingly, the disposition of encainide and known metabolites was investigated after simultaneous acute i.v. (radiolabeled) and single and multiple oral (nonradiolabeled) dosing to two groups of normal subjects characterized as "poor" (PM) and "extensive" (EM) metabolizers of debrisoquine. Pronounced differences in both the plasma concentration/time curves and the 24-hr urinary excretion of encainide and metabolites were observed between the two phenotypes. In the EM group, the oral bioavailability of encainide was only about 25 to 30% because of extensive presystemic (first-pass) metabolism, and no accumulation occurred after multiple oral dosing with 50 mg every 8 hr for 3 days, as the elimination half-life of the drug was about 2.5 hr. The major metabolite formed was O-desmethylencainide which accounted for almost half of the identified urinary metabolites and represented about 10% of the administered dose. This metabolite was present in 5- to 10-fold higher concentrations in the plasma than unchanged drug and accumulated almost 2-fold after multiple oral dosing. 3-Methoxy-O-desmethylencainide also was present at higher concentrations than encainide and accumulated on multiple dosing similarly to O-desmethylencainide. N,O-didesmethylencainide was a minor metabolite only detectable in the urine and N-desmethylencainide was not measurable in either plasma or urine. In contrast, in the PM group, encainide plasma concentrations were 10- to 20-fold higher than in the EMs after both oral and i.v. administration and the elimination half-life was 3- to 4-fold longer.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Importance of metabolites in antiarrhythmic therapy.

The presence of metabolites with pharmacologic activity can produce unanticipated drug efficacy or toxicity. This is particularly true during treatment with drugs that have narrow therapeutic-toxic ratios, such as the antiarrhythmic agents. The presence of active metabolites can often be inferred from variability in the relation between pharmacologic effect and steady-state plasma concentrations of the parent drug. Moreover, metabolites may ordinarily be unimportant but can accumulate to therapeutic (or toxic) levels in disease states such as congestive heart failure, renal failure and hepatic failure. Further characterization of the contribution of such metabolites during treatment requires direct evaluation of their pharmacology in vitro, in animal models and, if indicated, in man. Procainamide and its active metabolite N-acetylprocainamide provide the best and most complete example of this sequence of observations. Other drugs, including quinidine, disopyramide, verapamil and the investigational agents encainide and lorcainide, have active metabolites for which pharmacologic activity is less well-defined. Further studies in this area will help reduce the frequency of antiarrhythmic drug adverse effects, make successful therapy more frequent, and perhaps allow insights into structure-activity relations.

Acecainide↗
PubMed1983

Amiodarone dosing: a proposal based on its pharmacokinetics.

The available data concerning amiodarone dosing may be summarized as follows: (1) there is an empirically demonstrated improvement in lag before onset of antiarrhythmic effect if amiodarone is given initially in large "loading" doses. (2) A regimen such as that described in this article may allow more predictable and safe therapy and should be evaluated in patients, in order to develop uniform dosing guidelines. (3) Amiodarone clearance appears to decrease with time, and for this reason guidance of long-term therapy by plasma concentration determinations could potentially improve safety and efficacy. However, a close correlation between drug levels and drug toxicity and efficacy is lacking. (4) Finally, plasma concentrations, although potentially useful for monitoring long-term therapy, are likely to be unhelpful or misleading during the 4- to 6-week loading period at the beginning of treatment.

Amiodarone↗
PubMed1983

Electrophysiologic actions of high plasma concentrations of propranolol in human subjects.

The authors have previously shown that 40% of patients whose ventricular arrhythmias respond to propranolol require plasma concentrations in excess of those producing substantial beta-receptor blockade (greater than 150 ng/ml). However, the electrophysiologic actions of propranolol have only been examined in human beings after small intravenous doses achieving concentrations of less than 100 ng/ml. In this study, the electrophysiologic effects of a wider concentration range of propranolol was examined in nine patients. Using a series of loading and maintenance infusions, measurements were made at baseline, at low mean plasma propranolol concentrations (104 +/- 17 ng/ml) and at high concentrations (472 +/- 68 ng/ml). Significant (p less than 0.05) increases in AH interval and sinus cycle length were seen at low concentrations of propranolol, with no further prolongation at the high concentrations; these effects are typical of those produced by beta-blockade. However, progressive shortening of the endocardial monophasic action potential duration and QTc interval were seen over the entire concentration range tested (p less than 0.05). At high concentrations, there was significant (p less than 0.05) further shortening of both the QTc and monophasic action potential duration beyond that seen at low propranolol concentrations, along with a progressive increase in the ratio of the ventricular effective refractory period to monophasic action potential duration. No significant changes were seen in HV interval, QRS duration or ventricular effective refractory period. In summary, the concentration-response relations for atrioventricular conductivity and sinus node automaticity were flat above concentrations of 150 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1983

Electrophysiologic actions of O-demethyl encainide: an active metabolite.

Differences between the electrophysiologic actions of the antiarrhythmic agent encainide have been reported after short-term intravenous and oral administration. Only prolongation of the HV interval and QRS duration have been described immediately after short-term intravenous administration of encainide in dogs and man. However, during oral therapy or more prolonged infusions, prolongation of the AH interval and atrial and ventricular effective refractory periods have also occurred. In most patients receiving encainide therapy, metabolites (O-demethyl encainide and 3-methoxy-O-demethyl encainide) accumulate during prolonged therapy to concentrations greater than those of the parent drug. We compared the electrophysiologic action of O-demethyl encainide with that of saline in anesthetized dogs to determine if this metabolite has pharmacologic activity and whether its electrophysiologic effects could account for the disparities noted between effects of intravenous and oral encainide therapy. An initial pharmacokinetic evaluation allowed design of a series of loading and maintenance infusions that produced plasma concentrations similar to those seen during encainide therapy in man (concentration after first maintenance dose, 149 +/- 27 ng/ml [+/- SE] and after second maintenance dose, 230 +/- 45 ng/ml). Significant increases in atrial effective refractory period and ventricular refractoriness, and prolongation of AH interval and HV conduction time were observed. These effects are similar to those reported after prolonged oral encainide therapy but are substantially different from those seen after short-term infusions of encainide. These findings indicate that the difference between the electrophysiologic actions of intravenous and oral encainide may be due to pharmacologic effects of at least one encainide metabolite, O-demethyl encainide.

Action Potentials↗
PubMed1982

Selection of an antiarrhythmic drug for a sudden-death-prevention trial.

Several therapeutic approaches have sought to prevent the occurrence of sudden cardiac death. Many sudden deaths are presumed to be due to an arrhythmia, but the drugs best known for antiarrhythmic activity, the local anesthetic agents, have not been suitable prophylactic agents because of their toxicities and other undesirable pharmacologic characteristics. Several new drugs in this class have been synthesized and are currently being tested for antiarrhythmic activity in clinical trials. One of them may prove to be worthy of a large-scale clinical trial to determine whether chronic arrhythmia suppression reduces the risk of sudden death. The characteristics of the "ideal" antiarrhythmic agent are discussed, and a brief summary of the drugs currently being tested in the United States is presented. The discussion of each drug emphasizes the characteristics that might make it suitable--or unsuitable--for use in a sudden-death trial. Many agents being tested are clearly not satisfactory for such a trial. However, they may be prototypes for an ideal drug or combination of drugs that might yet be developed.

Acecainide↗
PubMed1982

Antiarrhythmic effects of the quaternary propranolol analog that does not induce beta-adrenergic blockade.

Pranolium chloride (dimethylpropranolol chloride) is a nonbeta blocking quaternary ammonium that has structural similarities to propranolol and bretylium that exert antiarrhythmic effects in animals. In initial studies, eight patients with chronic ventricular arrhythmias were given gradually increasing intravenous doses of pranolium (up to 3 mg/kg) obtaining plasma concentrations up to 7 micrograms/ml without change in pulse, blood pressure, or arrhythmia frequency. We therefore evaluated the response to pranolium in seven similar patients at doses up to 10 mg/kg as an infusion of 100 microgram/kg/min over 40 to 100 min. At plasma concentrations of 4.7 to 12.2 micrograms/ml, there was suppressing of ventricular ectopic depolarization (greater than 90%) in three subjects and in two others there was partial suppression (49% and 82%). Arrhythmia frequency was unchanged in two. At plasma concentrations of 4.1 to 17.2 micrograms/ml four subjects developed nausea (two of these also vomited) and to experienced perioral numbness. There was no change in sinus heart rate, supine or standing blood pressure, venous reflex response (adrenergic reflex venoconstriction), or ECG intervals in any subject. Pranolium appeared to have antiarrhythmic efficacy in five of seven subjects, without evidence of beta-adrenergic blockade or interference with sympathetic neuron function known to occur with its congeners, propranolol and bretylium. There is a narrow margin between pranolium efficacy and toxicity. It may, however, be a prototype for antiarrhythmic drugs that do not exert undesirable effects on the adrenergic nervous system.

Adult↗
PubMed1982

Propranolol and depression.

The authors report the cases of 3 patients who had depressive episodes after administration of propranolol for medical illnesses. The depressive episodes were severe, occurred in a dose-dependent manner, and promptly remitted when propranolol was discontinued. Physicians' awareness of this complication, especially in cases of patients with a history of depression, may reduce the occurrence of this drug reaction.

Adult↗
PubMed1982

Antiarrhythmic activity of the O-demethyl metabolite of encainide.

Clinical trials of the new antiarrhythmic agent encainide have demonstrated a high degree of efficacy in association with marked slowing of intracardiac conduction (prolongation of QRS). Indirect evidence has strongly suggested that at least some of these effects are mediated by the O-demethyl metabolite. The activity of a series of dosages of O-demethyl encainide, encainide and procainamide were compared against aconitine-induced ventricular arrhythmias in rats. Effective dosages were lowest for O-demethyl encainide and highest for procainamide: a 25% increase in the time to aconitine-induced ventricular tachycardia was produced by 0.02, 0.46 and 13 microM/kg of O-demethyl encainide, encainide and procainamide, respectively. QRS prolongation correlated well (r greater than 0.7, p less than .001) with enhanced survivorship for each agent tested and the cycle length of the ventricular tachycardia induced was lengthened in a dose-related fashion. Post-mortem plasma analysis showed that concentrations of the metabolite usually associated with pharmacological activity were present after encainide administration. However, encainide itself produced antiarrhythmic and electrocardiographic effects even when its metabolism was blocked. We conclude that both O-demethyl encainide and encainide exert antiarrhythmic actions in this model, but the metabolite is active at much lower dosages.

Aconitine↗
PubMed1981

The implications of procainamide metabolism to its induction of lupus.

The principal metabolic pathway of procainamide leads to formation of the less toxic N-acetyl-procainamide and the rapid acetylator phenotype is associated with a lower incidence of procainamide-induced lupus. Another metabolic pathway forms a reactive metabolite which causes revertants in the Ames test and covalently binds to microsomal protein. A study of the metabolism of procainamide revealed three metabolites that have not been previously described. A comparison of the metabolites of N-acetylprocainamide with those of procainamide suggests possibilities for the identity of the reactive metabolite. The hypotheses to be discussed explore the relationships between the formation of a reactive metabolite and the induction of lupus.

Acecainide↗
PubMed1981

Recurrent ventricular tachycardia in the absence of overt heart disease: clinical characteristics and response to drug therapy.

Eight patients, seven of them women, have been followed up for a mean of 8.1 years (range, three to 18) with the uncommon syndrome of recurrent frequent episodes of ventricular tachycardia in the absence of overt cardiac abnormality. The mean age at diagnosis was 25 years (range, 12 to 44). Serious symptoms were common: five patients had syncope, cardiac arrest, and/or cerebrovascular accidents. Multiple measures to characterize this population, including study of symptoms, response to exercise, degree of prematurity of ventricular ectopic depolarizations, and response to antiarrhythmic drugs, showed little uniformity. An individualized approach to therapy, taking into account age and symptoms as well as frequency of arrhythmia, was used. Excellent control of arrhythmia was eventually achieved in four patients, but only after multiple drug trials (mean 5.3, range two to eight trials per patient) had been ineffective. Prognosis in this syndrome is generally good, but serious complications occur frequently enough that vigorous therapy is justified in selected patients.

Adolescent↗
PubMed1981

Tolerance to the humoral and hemodynamic effects of caffeine in man.

Acute caffeine in subjects who do not normally ingest methylxanthines leads to increases in blood pressure, heart rate, plasma epinephrine, plasma norepinephrine, plasma renin activity, and urinary catecholamines. Using a double-blind design, the effects of chronic caffeine administration on these same variables were assessed. Near complete tolerance, in terms of both humoral and hemodynamic variables, developed over the first 1-4 d of caffeine. No long-term effects of caffeine on blood pressure, heart rate, plasma renin activity, plasma catecholamines, or urinary catecholamines could be demonstrated. Discontinuation of caffeine ingestion after 7 d of administration did not result in a detectable withdrawal phenomenon relating to any of the variables assessed.

Adult↗