Drug interaction studies and encainide use in renal and hepatic impairment

Quart, Barry; Gallo, Duane G.; Sami, Magdi; Wood, Alastair J.J.

doi:10.1016/0002-9149(86)90112-8

Cited by 25 publications

(13 citation statements)

References 31 publications

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“…These studies of the impact of disease states on the disposition of encainide used only subjects with the apparent extensive metaboliser trait. In one subject with the poor metaboliser phenotype and advanced cirrhosis, encainide disposition was similar to that in healthy subjects with the poor metaboliser phenotype (Quart et al 1986a). The metabolic fate of encainide in the rare patient with the poor metaboliser trait and advanced renal disease is unknown.…”

Section: Impact Of Dilease Statu or Concomitant Drug Therapy On Encaimentioning

confidence: 61%

“…Average steady-state concentrations of digoxin were not altered significantly, e.g. 1.05 ± 0.14 ~g/L with placebo vs 1.03 ± 0.11 ~g/L with encainide 25mg four times a day in 17 cases (Quart 1986a). The pharmacokinetic consequences of combining encainide with amiodarone, another potent inhibitor of drug metabolism, are unknown.…”

Section: Impact Of Dilease Statu or Concomitant Drug Therapy On Encaimentioning

confidence: 95%

“…Mean plasma concentrations of encainide, ODE and MODE all rose 32 to 43%. The mechanism(s) and clinical consequences of this interaction are unknown, but exaggerated encainide effect might be anticipated (Quart et al 1986a). Digoxin can slow conduction in the atrioventricular node, but no additive toxicity has been observed when digoxin and encainide are combined.…”

Section: Impact Of Dilease Statu or Concomitant Drug Therapy On Encaimentioning

confidence: 99%

“…Although encainide, ODE, and MODE are 80 to 90% bound to plasma proteins, no displacement interactions are 145 known or anticipated based on in vitro studies with the cardioactive drugs (digoxin, verapamil, lignocaine, propranolol, desmethylimipramine, chlorpromazine, diazepam, and warfarin) [Quart et al 1986a]. The specific protein fraction to which these agents are bound (albumin vs ai-acid glycoprotein) is unknown.…”

Section: Impact Of Dilease Statu or Concomitant Drug Therapy On Encaimentioning

confidence: 99%

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Clinical Pharmacokinetics of Encainide

Roden

Woosley

1988

Clinical Pharmacokinetics

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The disposition kinetics of the new antiarrhythmic agent encainide are a function of the genetic polymorphism which also controls debrisoquin 4-hydroxylation. In the majority of subjects (extensive metabolisers) encainide undergoes extensive first-pass hepatic biotransformation to the active metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE). The plasma concentrations of these metabolites are higher than those of encainide, and pharmacological effects correlate better with plasma metabolite concentrations than they do with those of encainide itself. In poor metabolisers, who make up to 7% of the population, a first-pass effect is absent, encainide clearance is lower, and plasma encainide concentrations are higher than those in extensive metabolisers. In poor metabolisers, plasma concentrations of active metabolites are low or undetectable, and the effects of encainide therapy can be closely correlated with plasma concentrations of the parent drug. Despite the marked differences in encainide disposition between extensive and poor metabolisers, the dosages which produce pharmacological effects (QRS prolongation and arrhythmia suppression) are similar in both groups. Encainide biotransformation is impaired in hepatic disease, but no major dosage changes are required. On the other hand, excretion of encainide and its metabolites is impaired in individuals with renal disease, and starting dosages should be decreased. The time required to achieve steady-state concentrations of metabolites (in extensive metabolisers) and of encainide itself (in poor metabolisers) is similar (3 to 5 days); therefore, the dosage should be increased no more often than every 3 to 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Impact Of Dilease Statu or Concomitant Drug Therapy On Encaimentioning

confidence: 61%

Section: Impact Of Dilease Statu or Concomitant Drug Therapy On Encaimentioning

confidence: 95%

Section: Impact Of Dilease Statu or Concomitant Drug Therapy On Encaimentioning

confidence: 99%

Section: Impact Of Dilease Statu or Concomitant Drug Therapy On Encaimentioning

confidence: 99%

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Clinical Pharmacokinetics of Encainide

Roden

Woosley

1988

Clinical Pharmacokinetics

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“…Cimetidine increased the plasma concentrations of encainide and its 2 major metabolites, O-demethyl-encainide and 3-methoxy-O-demethyl-encainide, in 13 healthy volunteers (Quart et al 1986). The results of studies investigating the cimetidineflecainide interaction are inconsistent; one study reported that cimetidine increased the AVC of flecainide but had no effect on its Cmax, tmax or halflife in healthy volunteers (Tjandra-Maga et aI.…”

Section: Antiarrhythmicsmentioning

confidence: 99%

Clinical Relevance of Cimetidine Drug Interactions

Shinn

1992

Drug Safety

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The excellent efficacy and tolerability profiles of H2-antagonists have established these agents as the leading class of antiulcer drugs. Attention has been focused on drug interactions with H2-antagonists as a means of product differentiation and because many patients are receiving multiple drug therapy. The main mechanism of most drug interactions involving cimetidine appears to be inhibition of the hepatic microsomal enzyme cytochrome P450, an effect which may be related to the different structures of H2-antagonists. Ranitidine appears to have less affinity than cimetidine for this system. There have been many published case reports and studies of drug interactions with cimetidine, but many of these have provided pharmacokinetic data only, with little information concerning the clinical significance of these findings. Nevertheless, the coadministration of cimetidine with drugs that have a narrow therapeutic margin (such as theophylline) may potentially result in clinically significant adverse effects. The monitoring of serum concentrations of drugs coadministered with cimetidine may reduce the risk of adverse events but does not abolish the problem. However, for most patients, concomitant administration of cimetidine with drugs possessing a wide therapeutic margin is unlikely to pose a significant problem.

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Reevaluation of digoxin‐encainide interactions using an animal model

Weinhouse

Tribble

Jarenwattananon

et al. 1988

Clinical Cardiology

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Summary: The effects of intravenous encainide on digoxin-induced atrial ectopic tachycardia (AET) were investigated in the rat using 3-channel simultaneous limblead electrocardiography. Pentobarbital-anesthetized (35 mg/kg, intraperitoneal) adult male rats were given digoxin subcutaneously, 30 mg/kg. After onset of AET, rats received either saline (0.5 ml/kg) or encainide; 0.25,0.5, 1 .O, or 2.0 mg/kg intravenously in repeated doses at 15-min intervals. At all doses, encainide converted digoxininduced AET to ventricular arrhythmias, prolonged recovery time, and increased mortality in comparison to salinetreated animals. An additional gmup of anesthetized rats was not given digoxin. These animals received encainide (2.0 mg/kg, intravenously) in repeated doses at 15-min intervals and developed dose-related increases in the P-R interval only. Blood samples were obtained by cardiac puncture from 12 additional anesthetized, digoxin-treated rats 5 min after the fourth intravenous dose of saline (0.5 ml/kg, n=6) orencainide (l.Omg/kg, n=6). Serum was prepared and analyzed by affinity column-mediated immunoassay. Digoxin levels were the same in both groups. These results suggest that encainide may exacerbate digoxin-induced arrhythmias (pmarrhythmic effect) in this species. In view of our findings of digoxin-encainide interactions in the rat, we recommend caution if these drugs are coadministered in humans.

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Drug interaction studies and encainide use in renal and hepatic impairment

Cited by 25 publications

References 31 publications

Clinical Pharmacokinetics of Encainide

Clinical Pharmacokinetics of Encainide

Clinical Relevance of Cimetidine Drug Interactions

Reevaluation of digoxin‐encainide interactions using an animal model

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