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Biomedical subjects

D M Roden

Publications and source records attributed to D M Roden.

At least 163 records · Page 9Linked to original sources
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

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

Effect of Fluosol-DA on infarct morphology and vulnerability to ventricular arrhythmia.

Although the blood substitute perfluorochemical Fluosol-DA has been shown to reduce experimental myocardial infarct size, the electrophysiologic properties of the surviving myocardium have not been assessed. Twenty-six dogs underwent closed-chest occlusion of the proximal left anterior descending coronary artery. Prior to infarction animals were randomly assigned to one of three treatment groups: groups receiving blood exchange with either Fluosol-DA (F = 9) or autologous heparinized blood (H = 8), given 30 minutes following occlusion over the next 30 minutes (these animals were ventilated with 100% oxygen for 6 hours), or a control group (C = 9) receiving no exchange transfusion and ventilated with room air. On the third postmyocardial infarction day the animals underwent programmed stimulation. The area at risk was defined by injecting different colored microvascular dyes into the three coronary beds, and the area of necrosis was defined by sectioning ventricular slices and staining with Mallory's trichrome stain. Infarct size was significantly reduced in the Fluosol-DA-treated group as compared to the heparin-treated and control groups when expressed as a percentage of the area at risk (F = 53.3 +/- 10, H = 67.2 +/- 12.8, C = 73.6 +/- 11.4: F vs H p less than 0.05; F vs C p less than 0.01). Ventricular tachycardia was inducible and sustained in 16 animals (3F, 6H, and 7C), and there was morphologic correlation with greater endocardial necrosis and smaller viable epicardial regions. In the 10 animals (6F, 2H, and 2C) without sustained ventricular tachycardia, there was greater epicardial viability and sparing of the endocardial regions with irregularity of the borders between viable and necrotic myocardium. We conclude that Fluosol-DA not only decreases infarct size but also modifies infarct morphology to reduce electrical instability.

Animals↗
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↗
PubMed1986

Indications for different modes of surgical therapy in medically refractory ventricular arrhythmias.

Fifty-one adult patients were referred for surgical treatment during the time period from July 1980 to November 1985. The average age was 59 +/- 6 years (19-70 years). All patients had symptomatic ventricular tachycardia that was refractory to standard or experimental drug therapy. On the basis of patient condition, site of arrhythmia, ventricular function, and extent of coronary disease, 21 patients were classed as good risk (GR) while 30 patients were thought to represent a poor surgical risk (PR). Thirty-two patients (15 GR, 17 PR) underwent electrophysiologic guided endocardial resection of arrhythmic foci. The hospital mortality was 12% (4/32), and two additional patients died late. All deaths were in poor risk patients. Recurrent arrhythmia was the primary cause of death in only one patient. Nineteen patients have required automatic internal cardioverter defibrillation (AICD) or chronic burst pacing (BP) with an implantable radiofrequency stimulator, with no operative mortality. AICD implantation was chosen for 13 drug refractory patients who were either poor surgical risk and/or had a tachycardia rate above 130 beats/minute with multiple scars or a multifocal tachycardia. Six additional patients who had tachycardia less than 130 beats/minute and whose arrhythmia could be safely terminated with BP had radiofrequency stimulator implantation. The one late death in this group was in a medically noncompliant patient. On the basis of this experience, we feel that map-guided endocardial resection should be offered to all good risk patients with a single scar and unifocal tachycardia who are refractory to medical treatment. This operation should be considered in all patients who have frequent, life-threatening attacks of tachycardia of any sort on maximum drug therapy. The remainder can be well managed with an AICD if their tachycardia rate is greater than 130 beats/minute or with BP using a radiofrequency stimulator.

Adult↗
PubMed1985

Spectrum of antiarrhythmic response to encainide.

Encainide is effective in suppressing non-life-threatening ventricular arrhythmias; however, inconsistent results have been noted in patients with more serious ventricular arrhythmias. Thirty-seven patients with drug-resistant ventricular arrhythmias were studied. Patients in group I (n = 11) has sustained ventricular tachycardia and those in group II (n = 26) had nonsustained ventricular arrhythmias. In group I, 8 patients had remote myocardial infarction, congestive heart failure and sustained ventricular tachycardia requiring repeated cardioversion (group Ia). None of these patients responded to encainide treatment, but 6 did have an antiarrhythmic response (complete in 3 and only partial in 3) to other investigational antiarrhythmic agents. Three patients in group I, all without ischemic heart disease (group Ib), had an excellent antiarrhythmic response to encainide, as did 21 of 26 patients in group II. In 4 of 5 patients in group II who did not respond, the dosage was limited due to the development of sinus pauses, atrioventricular block or bundle branch block, and in 3 of these 4 patients preexisting conduction disease was evident (PR longer than 0.2 second or QRS longer than 0.12 second). Diplopia occurred while taking the maximal oral dosage in the fifth patient. At 21.5 months of follow-up, 14 of the original 24 patients who responded to encainide continue to receive it; 3 have died (all due to natural progression of left ventricular dysfunction) and encainide was discontinued in 7: in 2 because of syncope, in 2 because of new-onset atrial fibrillation, in 1 patient because of exercise-induced polymorphic ventricular tachycardia, in 1 because of diplopia and in 1 because of skin exanthem.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1985

Bretylium: relations between plasma concentrations and pharmacologic actions in high-frequency ventricular arrhythmias.

Although it is widely assumed that the early arrhythmogenic and pressor responses to bretylium are caused by catecholamine release from the adrenergic neuron, this assumption has not been systematically studied in humans. Pharmacologic responses to a placebo infusion and 3 separate bretylium infusions (2.5, 5.0, 10 mg/kg over 60 minutes) were assessed in 6 patients with recurrent, nonsustained ventricular tachycardia. Plasma bretylium concentration, blood pressure (BP), plasma norepinephrine (NE) concentration, arrhythmia frequency and adrenergic neuronal blockade (assessed by the presence or absence of reflex venoconstriction) were measured. Adrenergic blockade was seen with every bretylium infusion and at a time when relatively small amounts of bretylium had been administered (range 160 to 750 mg, median 252). Temporal relations (p less than 0.03) were noted among the time of onset of adrenergic neuronal blockade, onset of the pressor response, increase in NE plasma concentration and increase in ventricular arrhythmia frequency. BP responses during the infusions were linearly related to change in plasma NE at the time of development of adrenergic neuronal blockade. Bretylium plasma concentrations higher than 3 micrograms/ml were frequently associated with a short-lived pressor response. There was a significant relation (p less than 0.06) between the increase in plasma NE during the infusion and an increase in ventricular arrhythmia frequency. Reduction in arrhythmia frequency was seen in only 1 patient, beginning 6 hours after the development of adrenergic neuronal blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

QT prolongation and arrhythmia suppression.

It seems possible to draw some overall conclusions from the data on antiarrhythmic drug-induced QT prolongation and its role in drug effects. At one end of the spectrum are patients with highly exaggerated QT responses during therapy, most often in the setting of hypokalemia and long cycle lengths (post-ectopic pauses, bradycardia). These patients may be at high risk for development of arrhythmias during therapy. It should also be remembered that the presence of hypokalemia may render antiarrhythmic agents less effective in general. On the other hand, modest QT prolongation in the course of therapy with an antiarrhythmic drug may well be a marker of reduction of dispersion of action potential durations or refractory periods and hence represent an antiarrhythmic effect. The clinical actions of these drugs in patients with arrhythmias strongly suggest that this is the case. New agents with the ability to reduce dispersion of repolarization or of refractoriness without inducing arrhythmias may well become the agents of choice for the treatment of serious cardiac rhythm disturbances.

Acecainide↗
PubMed1985

Action potential prolongation and induction of abnormal automaticity by low quinidine concentrations in canine Purkinje fibers. Relationship to potassium and cycle length.

Marked QT prolongation with induction of polymorphous ventricular tachycardia ("Torsades de Pointes") is a well-described phenomenon during quinidine therapy, frequently occurring at low plasma quinidine concentrations, low serum potassium, and slow heart rates. We have therefore assessed the dose-electrophysiological effects of quinidine as a function of extracellular potassium and cycle length in canine Purkinje fibers, using standard microelectrode techniques. Quinidine (1 microM) prolonged action potential at 90% repolarization, while leaving phase zero upstroke slope (Vmax) unchanged at a cycle length 300-8000 msec; at 10 microM, Vmax depression became evident. Increases in the action potential at 90% repolarization were most marked at long cycle lengths and low extracellular potassium (in contrast to Vmax depression) and were partially reversed by tetrodotoxin (1 microM). The relationship between log of cycle length and action potential at 90% repolarization was linear (for cycle length 300-8000 msec) in the absence of quinidine. Quinidine increased the slope of this relationship in a concentration-related fashion, whereas increasing extracellular potassium shifted the curve rightward (without changing slope), regardless of the presence or absence of quinidine. Action potentials were also measured following pauses of 5-60 seconds. In the absence of quinidine, the action potential depolarization returned to its baseline value in a monoexponential fashion (time constant 36.0 +/- 4.9 sec, mean +/- SE, n = 10). In the presence of 1 microM quinidine, this return was better fit as a biexponential process (time constants 4.2 +/- 1.2 and 40.7 +/- 6.2 seconds, n = 14). At slow stimulation rates (cycle length greater than 4000 msec) in low extracellular potassium (2.7 mM), quinidine produced early afterdepolarizations in 7/14 (50%) of fibers at 1 microM and 14/18 (78%) at 10 microM. Early afterdepolarizations were eliminated by increasing stimulation rates, raising the extracellular the extracellular potassium concentration to 5 mM, or adding tetrodotoxin. These data suggest that prolongation by quinidine of action potentials at 90% repolarization is multifactorial, with both a "tonic" prolonging effect and a prominent frequency-dependent action potential shortening effect. At long cycle lengths and low extracellular potassium, low quinidine concentrations consistently produced early after-depolarizations. The parallels between this form of triggered activity and clinical arrhythmias induced by quinidine suggest that early afterdepolarizations may play a role in quinidine-induced Torsades de Pointes.

Action Potentials↗
PubMed1985

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.

Adrenergic beta-Antagonists↗