An Unusual Case Of Right Ventricular Outflow Tract Tachycardia

In this report, we describe an unusual case of right ventricular outflow tract (RVOT) tachycardia with episodes of repetitive monomorphic ventricular tachycardia (VT), paroxysmal sustained VT and incessant monomorphic VT of the same morphology. Diltiazem, adenosine, or metoprolol failed to interrupt these arrhythmias. However, administration of intravenous propafenone completely eliminated all ventricular ectopic activity. Electrophysiologic study performed off propafenone showed that the ventricular ectopic activity originated from a single locus at the anterior wall of the RVOT. Two radiofrequency applications at this site resulted in complete elimination of ventricular ectopic activity.     

General pharmacology of diprafenone,a new class lc antiarrhythmic agent,and 5-hydroxydiprafenone,an active metabolite

This study compareo the effects of diprafenone, a new class lc antiarrhythmic agent, and 5-hydroxydiprafenone (5-OHDP), an active metabolite of diprafenone, to standard class l antiarrhythmic agents (propafenone, flecainide, or lidocaine), in several pharmacologic models, to ascertain the potential for side effects relative to the currently available class l antiarrhythmic agents. Diprafenone and propafenone decreased blood pressure and heart rate in anesthetized rabbits at 3 and 7 mg/kg, i.v., respectively. Neuromuscular transmission in rabbit gastrocnemius muscle was partially (38%) inhibited after 3 mg/kg of diprafenone and 7 mg/kg of propafenone. Diprafenone and 5-OHDP (10^?4M), but not lidocaine, inhibited aggregation of human platelets evoked by sodium arachidonate and adenosine diphosphate. Diprafenone, fleoainide, and 5-OHDP (10^?4M) inhibited the contractile responses of guinea pig vas deferens to norepinephrine and spontaneous and bradykinin-evoked contractions of the guinea pig uteri. Diprafenone and 5-OHDP, but not flecainide, relaxed rabbit bronchial smooth muscle contracted by acetylcholine. Diprafenone, 5-OHDP and propafenone (10^?5M and 10^?4M) also depressed the contractile responses of canine mesenteric arteries to transmural nerve stimulation. Thus, high concentrations of diprafenone (10^?5M and 10^?4M) depress smooth muscle and neural function. The depressant effects occur with 4ndash;40 times the antiarrhythmic concentration of diprafenone and are shared by propafenone and, in part, by 5-OHDP and flecainide. It is unlikely that major peripheral side effects will occur with therapeutic doses of diprafenone in man.     

Effects of Oral Propafenone Therapy on Chronic Myocardial Pacing Threshold

The effects of oral propafenone therapy on pacing threshold were studied in 36 patients chronically paced for sick sinus syndrome or AV block. The pacemakers, all unipolar models and with noninvasive threshold measurement facilities, were: 9 VVI, 15 AAI, and 12 DDD. Each patient received an initial propafenone dose of 450 mg/day, that in 18 cases was increased to 900 mg/day. Threshold was tested at baseline and at each dosage after 7 days of therapy. With the lower propafenone dosage the threshold, measured at 2.5 V, rose from 0.14 +/- 0.10 to 0.21 +/- 0.16 msec (+55%) in the atrium (P less than 0.0001) and from 0.10 +/- 0.08 to 0.15 +/- 0.09 msec (+63%) in the ventricle (P less than 0.0001). In the 18 patients who received both dosages, the mean atrial and ventricular threshold increased from 0.12 +/- 0.10 to 0.17 +/- 0.14 msec with the lower dose and to 0.27 +/- 0.22 msec (+125%) with the higher dose (P less than 0.0001 for both increments). With the 900 mg/day dose, a threshold increment greater than or equal to 300% was observed in 15% of the stimulated chambers. A good linear correlation (r = 0.76) was found between the ventricular threshold increment and the drug induced QRS widening. In conclusion, treatment with oral propafenone increases atrial and ventricular stimulation threshold in pacemaker patients. Threshold increment is dose dependent and proportional to the drug induced QRS widening. In the majority of the cases the threshold increment is not clinically significant, but caution must be used in prescribing high doses of the drug to patients with high baseline threshold.     

Mexiletine and Propafenone: A Comparative Study of Monotherapy, Low, and Full Dose Combination Therapy

The electrophysiological effects of combination therapy of mexiletine and propafenone were assessed using standard 12-Iead electrocardiogram (standard ECG), signal-averaged EGG (SAECG), and ambulatory ECG in 31 patients with ventricular arrhythmias. All patients underwent mexiletine monotherapy (M-mono), propafenone monotherapy (P-mono), low dose combination therapy (low M 4- P), and full dose combination therapy (full M + P). Full M + P increased the PQ interval and QRS duration to the same extent as P-mono did. Low M + P increased PQ interval and QRS duration to a lesser extent than P-mono and full M + P did. P-mono and full M + P significantly decreased root mean square (RMS) and increased f-QRS in SAECG, while M-mono and low M + P showed only a weak trend. SAECGs with late potentials increased in number with treatments; 9 in predrug control, 11 on M-mono, 15 on P-mono, 10 on low M + P, and 14 on full M + P. The percent suppression of frequent premature ventricular contractions (PVCs) (> 1,000/day) with M-mono, P-mono, low M + P, and full M + P were 46.4 ± 9.0,56.6 ± 10.4,64.4 ± 9.2, and 71.4 ± 7.1, respectively, and those of frequent couplets (> 10/day) were 58.3 ± 17.7, 62.6 ± 23.6, 87.5 ± 6.2, and 92.1 ± 4.0, respectively. Thus, full dose combination of mexiletine and propafenone exhibited the maximum antiarrhythmic efficacy without enhancement of effects on standard ECG and SAECG. Low dose combination therapy showed better antiarrhythmic efficacy in association with lesser effects on standard ECG and SAECG compared with propafenone monotherapy.     

地尔硫与普罗帕酮在家兔体内的药动学相互作用

6只家兔随机交叉试验,单用或合用地尔硫和普罗帕酮,结果合用后普罗帕酮的Ke和CL/F较单用时明显减少,T_(1╱2)(ke)平均延长0.701h,C_(max1)、C_(max2),AUC_(0～∞)分别增大85.74％、75.55％和56.75％,而地尔硫的CL/P和Vd/F在合用后显著减少。     

Propafenone in a usual dose produces severe side-effects: the impact of genetically determined metabolic status on drug therapy

Abstract. We report the case of an elderly lady presenting with dizziness, a head injury resulting from a fall and bradycardia. Propafenone 150 mg t.i.d. had been prescribed for atrial fibrillation with tachyarrhythmia, induced by hyperthyroidism, 18 months earlier. A toxic concentration of parent propafenone, and no 5-hydroxy metabolite, was detected in a plasma sample. Symptoms disappeared after the discontinuation of propafenone. The poor metaboliser (PM) phenotype of sparteine/debrisoquine was assumed and subsequently confirmed by phenotyping (sparteine test) and genotyping (allele-specific polymerase chain reaction). The PM phenotype is common in European populations, with a prevalence of about 7%. If drugs with narrow therapeutic ranges undergo genetically polymorphic metabolism, toxicity may arise even with recommended doses. Individualization of doses is required to avoid adverse effects.     

牛磺酸、普罗帕酮合用抗实验性心律失常作用及对心肌收缩力的影响

目的　研究牛磺酸、普罗帕酮及二者合用对实验性心律失常的对抗作用及对麻醉大鼠心肌收缩力的影响。方法　采用氯化钡或乌头碱诱发大鼠心律失常 ,以室性双向性心律失常持续时间和发生率及引起室早、室速、室颤的乌头碱剂量为指标 ,观察牛磺酸、普罗帕酮单用及合用对二种模型的影响 ;观察单用及合用对麻醉大鼠心率 (HR)、左室收缩压(LVSP)、左室内压最大上升速率 (+LVdp/dtmax)等血流动力学指标的影响。结果　BaCl2 模型中 ,联合用药组较同剂量单用药组的心律失常发生率降低 ,持续时间缩短。乌头碱模型中 ,联合用药组较同剂量单用药组的乌头碱剂量增大。血流动力学结果显示 ,iv 2mg·kg-1的普罗帕酮对麻醉大鼠心脏有明显的负性肌力作用 ,而与iv 5 0mg·kg-1牛磺酸合用时则无明显的负性肌力作用。结论　牛磺酸和普罗帕酮对BaCl2 及乌头碱诱发的室性心律失常有抗心律失常作用 ,二者合用作用增强 ;小剂量牛磺酸与普罗帕酮合用可克服普罗帕酮的心功能抑制作用     

Inhibition of L-type calcium current by propafenone in single myocytes isolated from the rabbit atrioventricular node

1. The atrioventricular node (AVN) is an important part of the conduction system in the heart and is a significant site of antiarrhythmic drug action. The class 1 antiarrhythmic propafenone is effective in treating a variety of arrhythmias, including those involving the AVN. In this study, we have investigated the effects of propafenone on ionic currents in single rabbit AVN cells, focusing in particular on those on L-type calcium current (I_Ca,L).
2. With a standard K-based internal dialysis solution, exposure to 5 μM propafenone reduced significantly the amplitude of I_Ca,L. In spontaneously active AVN myocytes, action potential upstroke velocity was decreased by propafenone exposure, consistent with the observed change in I_Ca,L.
3. By use of a Cs-based internal dialysis solution to record I_Ca,L selectively, voltage clamp test pulses were applied from a holding potential of −40 mV to +10 mV (stimulation frequency 0.33 Hz). Propafenone 5 μM reduced mean I_Ca,L density at +10 mV from −9.58±1.05 pA/pF to −4.19±0.60 pA/pF (P<0.002). A range of propafenone concentrations were applied which reduced I_Ca,L in a dose-dependent manner (IC₅₀ 1.7 μM). When test pulses were applied to a range of potentials, propafenone reduced I_Ca,L at each potential without significantly affecting the activation curve for this current. Thus, propafenone reduced I_Ca,L conductance, without affecting the voltage-dependent activation properties of the current.
4. I_Ca,L block by propafenone exhibited tonic-, use- and frequency-dependent characteristics.
5. In the presence of propafenone, the voltage-dependence of inactivation of I_Ca,L was shifted 8 mV in the hyperpolarizing direction. Also, the recovery of I_Ca,L from inactivation was slowed by propafenone.
6. The I_Ca,L blocking properties of propafenone may mediate some of the antiarrhythmic properties of this agent, particularly in regions of the heart such as the AVN in which I_Ca,L contributes significantly to the action potential upstroke.

     

Pharmacokinetics and pharmacodynamics of propafenone during acute and chronic administration

Summary The pharmacokinetics of propafenone and 5-OH-propafenone and their relationship with the antiarrhythmic action and side effects have been studied in 10 patients with stable, frequent, premature ventricular beats (224–928 premature ventricular complexes/h). Observations were made after a single dose of propafenone 300 mg p.o., and after 1 and 3 months (only 5 out of 10 patients) of therapy with 300 mg t.d.s.After 1 month of treatment the plasma elimination half-life of propafenone (6.7 h) was almost twice as long as after a single dose (3.5 h), and the area under the plasma propafenone concentration-time curve (7620 ng·ml^–1·h) was significantly larger than after single dose (3522 ng·ml^–1·h); this was also true for the metabolite. The ratio of the AUCs of 5-OH-propafenone and propafenone decreased from the single dose (0.63) to 1 month (0.32). These variables remained stable up to 3 months.Eight patients had 75% reduction of premature ventricular complexes after 3 days of therapy, and in 7 they were completely suppressed; the response was maintained over 1 to 3 months. Side effects were minor and in no case had the drug to be withdrawn or the dose reduced.Thus, the kinetics of propafenone were time-dependent. Its active metabolite did not accumulate greatly during chronic treatment. The lasting antiarrhythmic effect observed in some patients suggests a b.d.s. regimen instead of t.d.s. dosing in selected patients.