Correlation between serum concentration and pharmacological effect on atrioventricular conduction time of the antiarrhythmic drug propafenone

Keller, Konrad; G, Meyer-Estorf; Beck, O. A.; Hochrein, H

doi:10.1007/bf00606676

Cited by 64 publications

(22 citation statements)

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“…The mean elimination half-life of propafenone in our group of patients is 6 hr, which is considerably longer than the mean half-life of 3.6 hr previously reported. 6 We also found that there was large interindividual variability in elimination half-life (range 2.4 to 11.8 hr). This vanrability was not explained by clinical factors such as age, liver disease, heart failure, or the presence of concomitant medications that could interfere with the elimination of a drug that is highly metabolized.…”

mentioning

confidence: 52%

Clinical pharmacology of propafenone.

Connolly¹,

Kates²,

Lebsack³

et al. 1983

Circulation

178

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We determined the efficacy, pharmacokinetics, and plasma concentration-response relationships of propafenone, a promising new antiarrhythmic drug. Thirteen patients with frequent and complex ventricular premature beats were studied after receiving four increasing doses, during drug washout and during a randomized double-blind placebo-controlled trial, to evaluate the optimal dose in each patient. A nonlinear relationship was found between propafenone dose and steady-state mean concentration with a 10-fold increase in drug concentration as dose increased threefold from 300 to 900 mg/day. There was great intersubject variability in elimination half-life (mean 6 hr, range 2.4 to 11.8), steady-state mean concentration on 900 mg/day of propafenone (mean 1008 ng/ml, range 482 to 1812), and "therapeutic" plasma concentration (mean 588 ng/ml, range 64 to 1044). The interaction of these three parameters in individual patients determined the duration of the antiarrhythmic action of propafenone during washout (mean 11.5 hr, range 4 to 22). There was a greater than 90% reduction of ventricular premature beats in 10 subjects during dose ranging and in seven during double-blind crossover. Side effects requiring discontinuation of the drug occurred in three patients and included apparent worsening of arrhythmias in two. We conclude that propafenone effectively suppresses ventricular arrhythmias and that nonlinear drug accumulation and intersubject variability in elimination of half-life, steady-state mean plasma concentration, and therapeutic concentration indicate a need for individual therapy. Circulation 68, No. 3, 589-596, 1983. PROPAFENONE is a promising new antiarrhythmic drug. In microelectrode experiments with guinea pig atria and sheep Purkinje cells, the drug slows the rate of rise of the action potential and decreases the action potential duration.",2 Propafenone also has weak ,Bblocking and Ca+ + antagonist properties in isolated tissues.1 Initial placebo-controlled trials in humans show that propafenone is effective for suppressing ventricular ectopic activity.4' Previous studies suggest that propafenone has a short half-life of 3 to 4 hr but that the duration of its antiarrhythmic effects may last longer.6'7 Studies with limited data have yielded con flicting information on the ability to predict antiarrhythmic effect from propafenone concentration. between plasma concentration and antiarrhythmic effect. MethodsProtocol design. Patients with high-frequency ventricular premature beats (VPBs) were candidates for this study if they did not have disabling angina, heart failure, or unstable intercurrent illness. A complete history was obtained, physical and laboratory examinations were performed, and a baseline 48 hr ambulatory electrocardiogram (ECG) was taken to establish a minimum baseline VPB frequency of B 1440 VPBs/24 hr after antiarrhythmic drugs had been discontinued for at least five half-lives. Digoxin was continued in one patient with atrial fibrillation, and propranolol was continued in one pat...

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mentioning

confidence: 52%

Clinical pharmacology of propafenone.

Connolly¹,

Kates²,

Lebsack³

et al. 1983

Circulation

178

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“…"he samples were shaken for 30 min and centrifuged, and the upper organic phase was transferred to conical tubes and evaporated in a water bath at 40 "C. Propafenone concentrations were measured by the HPLC procedure described by Keller et a1. 12 The Knauer HPLC used was equipped with a Knauer UV detector and a stainlese steel (6 mm i.d. x 25 cm) column, packed with Lichrosorb Si 60.…”

Section: Methodsmentioning

confidence: 99%

Prediction of the Disposition of Propafenone in Humans and Dogs from Pharmacokinetic Parameters in Other Animal Species

Puigdemont

Guitart

Mora

et al. 1991

Journal of Pharmaceutical Sciences

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“…The wide range of concentrations of propafenone tested (0.037-37.8 jig ml[') includes not only the therapeutic plasma levels (0.5-2 tg ml-': 1.3 x 10-6-5.3 x 10-6M; Keller et al, 1978;Karagueuzian et al, 1983;Conolly et al, 1983), but also the toxic plasma levels of the drug. The doses selected for pretreatment ofanimals were chosen from the results of Dieckmann et al (1981).…”

Section: Discussionmentioning

confidence: 99%

“…In these two series of pretreated animals plasma concentrations of propafenone were measured with a high-pressure liquid chromatographic method as described by Keller et al (1978). This method allowed sufficiently precise determinations of levels down to 1-2 ng ml-'.…”

Section: Experiments In Propafenone-pretreated Animalsmentioning

confidence: 99%

Electrophysiological effects of propafenone in untreated and propafenone‐pretreated guinea‐pig atrial and ventricular muscle fibres

Delgado

Tamargo

Tejerina

1985

British J Pharmacology

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1 The electrophysiological effects of propafenone (10-7 to 10-4M) were studied on guinea-pig isolated atrial and ventricular muscle fibres obtained from untreated animals and animals pretreated with propafenone, 3 and 1Omg kg-', for 28 days. 2 In untreated atria propafenone produced a dose-dependent decrease in the rate and maximum following frequency, prolonged the sinus node recovery time and reduced the maximum chronotropic responses to isoprenaline. 3 In untreated atrial and ventricular muscle fibres propafenone depressed action potential amplitude and V,"ax, reduced the resting membrane potential and prolonged the action potential duration (APD) and the effective refractory period, lengthening the effective refractory period relative to APD.4 Propafenone depressed the amplitude and V,,.x. and shortened the duration of the slow action potentials induced by isoprenaline and caffeine in K-depolarized papillary muscles. 5 Pretreatment with propafenone reduced atrial rate, but did not modify the action potential characteristics compared to the values obtained in untreated atria. Further addition of propafenone produced similar but more marked changes in untreated atria. 6 In ventricular muscle fibres pretreated with 3 mg kg-, action potential characteristics before and after further addition of propafenone were similar to those obtained in untreated fibres. However, muscles pretreated with 10 mg kg-' exhibited a significant prolongation of the APD compared to that in untreated muscles or those pretreated with 3 mg kg-'; further addition ofpropafenone shortened the APD even when this parameter was of similar value to those observed in the other two series of experiments. 7 It is concluded that even though the effects of propafenone are similar to those of quinidine (class I antiarrhythmic), it also exhibited class II and class IV actions. In pretreated animals a prolongation of the APD (class III action) could also be involved in the antiarrhythmic effects of the drug.

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Correlation between serum concentration and pharmacological effect on atrioventricular conduction time of the antiarrhythmic drug propafenone

Cited by 64 publications

References 4 publications

Clinical pharmacology of propafenone.

Clinical pharmacology of propafenone.

Prediction of the Disposition of Propafenone in Humans and Dogs from Pharmacokinetic Parameters in Other Animal Species

Electrophysiological effects of propafenone in untreated and propafenone‐pretreated guinea‐pig atrial and ventricular muscle fibres

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