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Biomedical subjects

R L Woosley

Publications and source records attributed to R L Woosley.

At least 127 records · Page 7Linked to original sources
PubMed1987

Frequency- and orientation-dependent effects of mexiletine and quinidine on conduction in the intact dog heart.

Myocardial conduction depends on the magnitude of the fast inward sodium current as well as on cardiac fiber orientation, with more rapid propagation along myocardial fibers than across them. Although antiarrhythmic drugs depress the sodium current in a frequency-dependent fashion in vitro, their effects on conduction in the intact ventricle have been less well studied. We therefore evaluated the frequency- and orientation-dependent actions of mexiletine, quinidine, and their combination on epicardial conduction in 24 pentobarbital-anesthetized dogs. These interventions were chosen because the time constant of recovery from sodium-channel blockade by mexiletine in vitro is shorter than that from blockade by quinidine, and because we have previously shown that the combination of these drugs is often clinically effective when single-agent therapy fails. An electrode array that permitted measurement of conduction times in multiple orientations over short segments of epicardium without contamination by rapid Purkinje fiber propagation or by latency or virtual cathode effects at the stimulus site was developed for these studies. In all animals, the atrioventricular node was destroyed by injection of formalin to permit measurements over a wide range of cycle lengths (250 to 1500 msec). In the absence of drugs, conduction in any direction was frequency independent. In the presence of mexiletine, however, frequency-dependent increases in conduction times were found at cycle lengths of 600 msec or less; these changes were significantly greater in orientations for which baseline conduction was rapid. Quinidine, on the other hand, increased conduction times at all tested cycle lengths without significant orientation-dependent effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Frequency-dependent interactions of mexiletine and quinidine on depolarization and repolarization in canine Purkinje fibers.

The use of the antiarrhythmic agents mexiletine and quinidine in combination can be clinically beneficial when single agent therapy is ineffective in ventricular tachyarrhythmias. We therefore compared the effects of mexiletine (10 microM), quinidine (10 microM) and a series of their combinations (total concentration 10 microM) in canine cardiac Purkinje fibers driven at a wide range of stimulation frequencies. All treatments depressed Vmax in tissues driven rapidly (cycle length 300 msec), but only with greater than or equal to 5 microM quinidine was Vmax depressed at longer cycle lengths. Moreover, the time constants for development of and recovery from frequency-dependent block were different: short (200-500 msec) for mexiletine, long (3-5 sec) for quinidine and intermediate or biexponential for the combination. Although both drugs depressed Vmax (albeit with different time dependencies), action potential duration at all cycle lengths from 300 to 8000 msec was shortened by mexiletine, lengthened by quinidine and largely unaltered by combinations. Fibers treated with quinidine in low Ko and driven at slow rates developed marked action potential prolongation and abnormal automaticity in the form of early afterdepolarizations; the addition of mexiletine was sufficient to reverse this effect. In summary, mexiletine and quinidine produced different and frequency-dependent effects on depolarization and repolarization. The effects of their combinations reflected these actions, with opposing actions on repolarization at any stimulation rate but additive frequency-dependent depression of Vmax. We conclude that the clinically beneficial effects of this combination may reflect additive frequency-dependent effects on cardiac sodium channels in the face of unaltered repolarization time.

Action Potentials↗
PubMed1987

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.

Anti-Arrhythmia Agents↗
PubMed1987

Comparative in vitro electrophysiology of quinidine, its major metabolites and dihydroquinidine.

Although metabolites of quinidine are active in animal models and can accumulate to plasma levels similar to those of quinidine during chronic therapy, their effects on cardiac transmembrane action potentials have not been reported. We therefore examined the effects of quinidine, its major metabolites, 3-hydroxyquinidine, quinidine-N-oxide, O-desmethylquinidine, and 2'-oxoquinidinone, and a common commercial impurity, dihydroquinidine, on action potentials from canine Purkinje fibers. Using standard microelectrode techniques, measurements at stimulation basic cycle lengths (BCLs) of 300 to 8000 msec were made at base line and repeated after a 1 hr of superfusion with a 10 microM concentration of drug or vehicle controls. Vehicle controls (n = 5) produced no change in maximum phase 0 upstoke slope of the action potential (Vmax) or action potential duration at 90% repolarization (APD90). Vmax depression when present was greatest at short BCL with statistically significant changes seen at BCL = 300 msec with all compounds tested except quinidine-N-oxide. The time constants for the onset of and recovery from frequency-dependent Vmax depression were similar to those of quinidine. In contrast, changes in APD90 were greatest at long BCL, with significant prolongation seen with all drugs at BCL = 4000 msec. In addition, the agents prolonging repolarization to the greatest extent, quinidine, dihydroquinidine, 3-hydroxyquinidine and O-desmethylquinidine, caused early afterdepolarizations at long BCL. We conclude that these metabolites and dihydroquinidine may contribute to the antiarrhythmic and/or arrhythmogenic effects of quinidine therapy.

Action Potentials↗
PubMed1986

Disposition kinetics of encainide and metabolites.

Interpretation of plasma concentration data during encainide therapy is predicated on an understanding of the role of active metabolites during treatment. In over 90% of patients, encainide is rapidly biotransformed to O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (3-MODE), which persist in plasma hours after encainide itself is undetectable. This metabolism occurs in the liver, and encainide clearance is sufficiently high that a significant first-pass effect is seen during oral therapy (bioavailability 30 +/- 7%). In these extensive metabolizers, ODE and 3-MODE appear to mediate the arrhythmia suppression and electrocardiographic changes seen during encainide therapy. In less than 10% of patients, a genetic defect prevents expression of the enzyme responsible for the rapid biotransformation of encainide. In this poor metabolizer subset, the systemic clearance of encainide is 10-fold lower than in extensive metabolizers (0.18 +/- .002 vs 1.9 +/- 0.2 liters/min), the first-pass effect is virtually absent (bioavailability 83% to 88%), plasma concentrations are higher and an antiarrhythmic effect may be seen at usual encainide doses. Minimally effective plasma concentrations appear to be 35 ng/ml (ODE), 100 ng/ml (3-MODE) and 300 ng/ml (encainide), making ODE one of the most potent sodium channel blockers yet used in man. The elimination half-life of encainide is 2.3 +/- 0.3 hours in extensive metabolizer patients. Despite this rapid elimination, encainide can be administered every 8 to 12 hours in both extensive and poor metabolizer subsets; this is because of slowly eliminated metabolites in extensive metabolizers and slower elimination of encainide itself (11.3 +/- 0.3 hours) in poor metabolizers.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1986

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.

Arrhythmias, Cardiac↗
PubMed1986

Effects of congestive heart failure on the pharmacokinetics and pharmacodynamics of antiarrhythmic agents.

Changes in the pharmacokinetics of antiarrhythmic agents should be expected in patients with congestive heart failure (CHF). The direction of the changes, however, is not always predictable. The volume of distribution is often decreased by as much as 40%, and loading doses should, therefore, be appropriately reduced. Drug clearance may also be diminished due to decreased blood flow to the liver and kidneys, as well as decreased hepatic drug-metabolizing activity. Infusion rates should similarly be lowered to avoid toxicity. However, decreases in both volume of distribution and clearance may result in little, if any, change in elimination half-life, despite higher plasma concentrations. On the other hand, the elimination half-life of antiarrhythmic agents that have a large volume of distribution and are highly cleared by the liver may be twice as long in patients with CHF compared with normal subjects. Thus, the total daily dose of drug should also be lower in these patients. In addition, the time necessary to reach steady state is longer, so that premature dose escalation may lead to excessive drug accumulation. In terms of their pharmacodynamic effects, all antiarrhythmic agents have the potential to manifest a degree of negative inotropy, which must be anticipated as a possible side effect in patients with CHF. Some of the newer agents, such as tocainide and encainide, appear to cause only minimal myocardial depression. Other potential complications of all antiarrhythmic therapy include proarrhythmia and possible drug interactions with digitalis and diuretics.

Amiodarone↗
PubMed1986

Further evidence for the lack of association between acetylator phenotype and systemic lupus erythematosus.

An association between host acetylator phenotype and idiopathic systemic lupus erythematosus (SLE) has been sought for over a decade, without a definitive result. We have observed that the frequency of the slow acetylator phenotype was similar in 64 patients with idiopathic SLE (38%), 60 healthy volunteers (50%), and 52 non-SLE medical service patients (44%). The slow acetylator phenotype was not more frequent among subgroups of the SLE patients defined by demographic features or specific manifestations of disease. Our results, as well as a majority of previously published results, do not provide evidence for an association between acetylator phenotype and idiopathic SLE.

Acetylation↗
PubMed1986

Altered distribution of debrisoquine oxidation phenotypes in patients with systemic lupus erythematosus.

Oxidative metabolism in patients with systemic lupus erythematosus (SLE) was studied using the antihypertensive drug, debrisoquine. The metabolism of this drug to its principal metabolite, 4-hydroxydebrisoquine, is catalyzed by a discrete isozyme of cytochrome P-450. The extent of this reaction exhibits genetic polymorphism, with 2 phenotypes, "poor metabolizers" and "extensive metabolizers," discernible in the normal population. We observed the poor metabolizer debrisoquine phenotype in 9 of 42 patients with idiopathic SLE (21%), in contrast with 12 of 147 healthy volunteers (8%), which is a significant difference in frequency (P less than 0.04). These data provide further evidence for altered oxidative metabolism in SLE and support the concept that genetic differences in oxidative metabolism of endogenous compounds, such as sex steroid hormones, or of xenobiotics might influence susceptibility to SLE.

Adult↗
PubMed1986

Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care.

Quinidine therapy is one of the most common causes of the acquired long QT syndrome and torsade de pointes. In reviewing clinical data in 24 patients with the quinidine-associated long QT syndrome, 20 of whom had torsade de pointes, we have delineated several heretofore unreported or underemphasized features. (1) This adverse drug reaction occurred either in patients who were being treated for frequent nonsustained ventricular arrhythmias or for atrial fibrillation or flutter. (2) In patients being treated for atrial fibrillation, torsade de pointes occurred only after conversion to sinus rhythm. (3) Although most patients developed the syndrome within days of starting quinidine, four had torsade de pointes during long-term quinidine therapy, usually in association with hypokalemia. (4) Because of the large experience with this entity at our institution, we have been able to estimate the risk as at least 1.5% per year. (5) Twenty of the 24 patients had at least one major, easily identifiable, associated risk factor including serum potassium below 3.5 mEq/L (four); serum potassium between 3.5 and 3.9 mEq/L (nine); high-grade atrioventricular block (four); and marked underlying, (unrecognized) QT prolongation (two). Plasma quinidine concentrations were low, being at or below the lower limit of the therapeutic range in half of patients. The ECG features typically included absence of marked QRS widening, marked QT prolongation (by definition), and a stereotypic series of cycle length changes just prior to the onset of torsade de pointes. Torsade de pointes started after the T wave of a markedly prolonged QT interval that followed a cycle that had been markedly prolonged (usually by a post ectopic pause).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Clinical features and basic mechanisms of quinidine-induced arrhythmias.

Quinidine therapy is one of the most common causes of the acquired long QT syndrome and the morphologically distinctive tachyarrhythmia torsade de pointes. Clinical data from our institution and others have revealed a number of characteristic features: quinidine plasma concentrations are generally low, marked QRS prolongation is absent, hypokalemia is frequent and abrupt heart rate slowing just before the initiation of a paroxysm is almost invariable. The lack of correlation between plasma quinidine concentrations and this adverse drug effect raises the possibility either that external factors (for example, hypokalemia) modulate the response to quinidine in vivo or that one or more unmeasured active metabolites play a role. Therefore, the effect of alterations in extracellular potassium and stimulation rate on the electrophysiologic effects of quinidine were examined in canine Purkinje fibers. It was found that a form of triggered automaticity, early afterdepolarizations, is reliably produced in the presence of quinidine when extracellular potassium is lowered and the stimulation rate is slowed. More recently, the effects of a number of quinidine metabolites, as well as the commonly found impurity dihydroquinidine, were characterized in canine Purkinje fibers in a similar fashion. Although quinidine was the most potent of the substances tested, both dihydroquinidine and 3-hydroxyquinidine prolonged action potential and produced early afterdepolarizations as did quinidine at long cycle lengths. Quinidine-induced torsade de pointes is a potentially lethal adverse drug effect, occurring in 1 to 3% of patients. Hypokalemia and slow heart rates are commonly observed in a clinical setting and, in the tissue bath, quinidine and several of its metabolites induce abnormal automatic behavior when extracellular potassium is lowered and stimulation rate is slowed.(ABSTRACT TRUNCATED AT 250 WORDS)

Acecainide↗
PubMed1986

Encainide disposition in patients with renal failure.

The antiarrhythmic agent encainide undergoes extensive presystemic biotransformation to form O-desmethylencainide (ODE) and 3-methoxy-ODE (MODE) in subjects who exhibit the extensive metabolizer (EM) phenotype for debrisoquin 4-hydroxylation. These metabolites contribute significantly to the overall antiarrhythmic activity and are extensively excreted in the urine. Therefore, the effects of renal impairment on the disposition of encainide and its metabolites were studied in seven EM patients with renal failure and compared with those in eight healthy normal subjects of the same phenotype. After a single dose of encainide, its systemic and oral clearances were significantly lower and its elimination t1/2 was shorter in patients with renal failure than in healthy volunteers. This shortening was explained by a significant reduction in steady-state volume of distribution in renal failure. After chronic dosing to steady state, quantitatively similar changes were seen. Chronic oral dosing produced 80% higher levels of ODE (the most pharmacodynamically active metabolite) and 167% higher levels of MODE as compared with healthy volunteers. The prolongations in ECG intervals were similar in the two groups despite the higher encainide dose in the normal subjects. In conclusion, patients with renal failure will require lower doses of encainide because of both reduced encainide clearance and increased accumulation of active metabolites.

Acute Kidney Injury↗
PubMed1986

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.

Administration, Oral↗
PubMed1986

Co-inheritance of the polymorphic metabolism of encainide and debrisoquin.

O-demethylation of the investigational antiarrhythmic encainide was found to be correlated with the genetically determined hydroxylation of debrisoquin in 20 randomly selected and unrelated subjects and in five members of one family. Extensive metabolizers of debrisoquin had a mean (+/- SD) encainide elimination t1/2 of 1.19 +/- 0.98 hours (range 0.25 to 3.4 hours). Poor metabolizers of debrisoquin (two normal subjects and three family members) had a mean t1/2 of 13.2 +/- 0.73 hours (range 7.8 to 22.4 hours). The elimination rate constant of encainide and the fractional excretion of O-desmethyl encainide in urine were linearly related to the fractional urinary excretion of 4-hydroxy-debrisoquin. Poor metabolizers could be identified after a 50 mg dose of encainide by the fractional excretion of O-desmethyl encainide in urine or the absence of (1) measurable ECG changes or (2) O-desmethyl encainide in plasma. The correlation between excretion of O-desmethyl encainide and 4-hydroxy-debrisoquin suggests that significant numbers of the caucasian population (7% to 9%) are likely to be poor metabolizers of encainide and to have markedly different pharmacokinetics and plasma concentration-response relationships than extensive metabolizers.

Administration, Oral↗