Digoxin-diltiazem interaction

Oyama, Yohtaro; Fujii, Satoshi; Kanda, Kohichi; Akino, Emiko; Kawasaki, Hisao; Nagata, Masami; Goto, Katsumi

doi:10.1016/s0002-9149(84)91653-9

Cited by 54 publications

(13 citation statements)

References 5 publications

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“…It is, however, still controversial whether diltiazem affects the disposition of cardiac glycosides. Recent studies have shown that steady-state plasma concentrations of digoxin and ,3-methyldigoxin also increase as much as 50% after coadministration of diltiazem in a dose of 180 mg/day (Kuhlmann 1985;Oyama et al 1984). In contrast, two recent studies have shown no significant interaction between dig-444 oxin and diltiazem (Beltrami et al 1985;Elkayam et al 1985).…”

Section: Digoxinmentioning

confidence: 99%

Clinical Pharmacokinetics of Verapamil, Nifedipine and Diltiazem

Echizen

Eichelbaum

1986

Clinical Pharmacokinetics

180

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The calcium antagonists diltiazem, nifedipine and verapamil are widely used in the treatment of coronary heart disease, arterial hypertension, certain supraventricular tachyarrhythmias and obstructive hypertrophic cardiomyopathy. During recent years their pharmacokinetic properties and metabolism have been studied in more detail. Although these 3 calcium antagonists exhibit great diversity in chemical structure, they exhibit common pharmacokinetic properties. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. Their systemic plasma clearances are high and dependent on liver blood flow. Therefore, their bioavailabilities (diltiazem 40 to 50%; nifedipine 40 to 50%; verapamil 10 to 30%) are low despite almost complete absorption following oral administration. During long term treatment, oral clearance decreases and bioavailability increases due to saturation of hepatic first-pass metabolism. Pronounced intra- and inter-individual variations in clearance and bioavailability are observed. In patients with liver cirrhosis the various pharmacokinetic parameters are grossly altered. Clearance decreases, elimination half-life is substantially prolonged, and bioavailability more than doubles. In addition, the volume of distribution increases. Whereas renal disease has no impact on the pharmacokinetics of diltiazem and verapamil, elimination half-life of nifedipine increases in relation to the degree of renal impairment due to an increase in volume of distribution. Systemic clearance, however, remains unchanged. The data so far available indicate that the plasma concentrations of these drugs correlate with both their electrophysiological and haemodynamic effects. However, no effective therapeutic plasma concentration range has been firmly established. As reliable clinical end-points are available for dose titration of calcium antagonists, it is doubtful whether therapeutic drug monitoring will be of great value. Calcium antagonists are often administered in combination with a variety of other drugs. Thus, the potential for both pharmacodynamic and pharmacokinetic drug interaction exists. The interaction between digoxin and these drugs is of clinical importance. Verapamil and diltiazem cause a significant increase in plasma digoxin concentrations. In contrast, nifedipine does not lead to a significant increase in the plasma digoxin concentration. The mechanism responsible for this interaction is inhibition of both renal and non-renal digoxin clearance.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Digoxinmentioning

confidence: 99%

Clinical Pharmacokinetics of Verapamil, Nifedipine and Diltiazem

Echizen

Eichelbaum

1986

Clinical Pharmacokinetics

180

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“…Kinetic interaction be tween calcium channel blockers and cardiac glycosides has recently been demonstrated [Klein et ah, 1982;Pedersen, 1982;Belz et ah, 1983;Schwartz, 1985;Oyama et ah, 1984], The kinetic interaction results in the elevation of plasma digoxin concentration and the phenomenon has at least partially been explained by a reduced renal clearance of digoxin in the presence of calcium chan nel blockers [Pedersen et al, 1981], Thus, verapamil has been shown to elevate the plasma digoxin concentration by 60-100% [KJein et al, 1982;Pedersen, 1982;Belz et al, 1983;Schwartz et al, 1982], Similar increases in the plasma digoxin concentra tions have been demonstrated in presence of nifedipine and diltiazem [Belz et al, 1983;Schwartz, 1985;Oyama et al, 1984], Even though there are large increases in the plasma digoxin concentrations in pres ence of calcium channel blockers, digoxin rarely produced cardiotoxicity, as one would expect in most cases [Schwartz et al, 1982]. In addition, some investigators observed an enhancement in the inotropic response, without any cardiotoxicity, in patients re ceiving both digitalis and verapamil [Babich et al, 1984], These observations may suggest the possibility of interaction between cal cium channel blockers and cardiac glyco sides at the myocardial level.…”

Section: Introductionmentioning

confidence: 97%

Protective Effect of Verapamil upon Ouabain-Induced Cardiac Arrhythmias

Khatter¹,

Navaratnam²,

Hoeschen³

1988

Pharmacology

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Protective influence of verapamil upon ouabain-induced cardiac arrhythmias was investigated in anesthetized (α-chloralose 60 mg/kg and urethane 500 mg/kg) open-chest guinea pigs. Verapamil in doses between 100 and 150 μg/kg significantly increased (80–90%) the dose of ouabain, necessary to cause ventricular arrhythmias. This was also associated with a larger survival rate. A larger dose of verapamil (225 μg/kg) caused a further increase in the dose of ouabain, necessary for the initiation of arrhythmias, but in all the cases second or third degree heart block occurred. Verapamil (150 μg/kg) also prevented the development of fatal arrhythmias and death, when it was administered at the onset of ventricular ectopy. However, once the arrhythmias were firmly established, verapamil was ineffective in reversing the toxic response. The data suggests that verapamil exerts a protective effect against the development of digitalis-induced cardiac arrhythmias in doses which are comparable to therapeutic levels in humans. The larger doses of verapamil, however, will be contradicted because of the slowing of AV node and the likelihood of complete heart block.

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“…Contradictory results have been reported form studies of the pharmacokinetic interaction between digoxin and diltiazem (Oyama et al 1984;Rameis et al 1984). In 12 healthy volunteers, twice daily doses of diltiazem 90mg were reported to produce a significant 20% increase in mean steady-state serum digoxin concentrations (Rameis et al 1984), associated with a 27% decrease in calculated total body clearance of digoxin and a similar increase in elimination half-life.…”

Section: Diltiazemmentioning

confidence: 94%

“…However, the conclusions of this study are somewhat complicated by the fact that the subjects received /3-acetyldigoxin with the assumption that diltiazem had no effect on the formation of digoxin from this precursor drug. Oyama et al (1984) investigated the diltiazem interaction in 17 patients with atrial fibrillation who received either digoxin or /3-medigoxin (/3-metildigoxin). Mean ste~dy-state serum digoxin concentrations increased from 25 to 59%.…”

Section: Diltiazemmentioning

confidence: 99%

Pharmacokinetic Interactions with Digoxin

Rodin

Johnson

1988

Clinical Pharmacokinetics

100

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Numerous pharmacological agents have been shown to produce clinically significant pharmacokinetic interactions with digoxin. Drugs which reduce digoxin absorption include the antacids aluminium hydroxide, magnesium hydroxide and magnesium trisilicate, the antidiarrhoeals kaolin and pectin, the hypocholesterolaemic agent cholestyramine and the chemotoxins cyclophosphamide, vincristine and bleomycin. Certain antibiotics including sulphasalazine, neomycin and aminosalicylic acid reduce digoxin absorption while others, including erythromycin and tetracycline, increase the bioavailability of digoxin in some patients. Capsule preparations of digoxin in solution are less subject to several of the interactions which affect the absorption and bioavailability of digoxin tablets. Various drugs induce alterations in the volume of distribution and clearance of digoxin. Cardiac patients receiving digoxin therapy are particularly prone to interactions with commonly co-administered medications such as the antiarrhythmics quinidine and amiodarone, the calcium channel blockers verapamil and nifedipine, and possibly some vasodilating agents. Studies of digoxin interactions have yielded discrepant results, indicating the need for careful analysis of investigational design before arriving at clinical conclusions.

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Digoxin-diltiazem interaction

Cited by 54 publications

References 5 publications

Clinical Pharmacokinetics of Verapamil, Nifedipine and Diltiazem

Clinical Pharmacokinetics of Verapamil, Nifedipine and Diltiazem

Protective Effect of Verapamil upon Ouabain-Induced Cardiac Arrhythmias

Pharmacokinetic Interactions with Digoxin

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