Clinical Digoxin Toxicity in the Aged in Association With Co‐Administered Verapamil

Gordon, Michael S.; Goldenberg, Leslie M. C.

doi:10.1111/j.1532-5415.1986.tb04908.x

Cited by 10 publications

(5 citation statements)

References 16 publications

(59 reference statements)

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“…Inhibition of human Pgp transport by verapamil in vivo is known to decrease the extent of renal tubular elimination of digoxin. This finding correlated with increased digoxin blood plasma concentrations from 60 to 90 % [32,36] and lead to adverse drug reactions from digoxin toxicity [31,38].…”

Section: Introductionmentioning

confidence: 86%

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

2016

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SynopsisDrug-drug interactions (DDIs) and associated toxicity from cardiovascular drugs represents a major problem for effective co-administration of cardiovascular therapeutics. A significant amount of drug toxicity from DDIs occurs because of drug interactions and multiple cardiovascular drug binding to the efflux transporter P-glycoprotein (Pgp), which is particularly problematic for cardiovascular drugs because of their relatively low therapeutic indexes. The calcium channel antagonist, verapamil and the cardiac glycoside, digoxin, exhibit DDIs with Pgp through non-competitive inhibition of digoxin transport, which leads to elevated digoxin plasma concentrations and digoxin toxicity. In the present study, verapamil-induced ATPase activation kinetics were biphasic implying at least two verapamil-binding sites on Pgp, whereas monophasic digoxin activation of Pgp-coupled ATPase kinetics suggested a single digoxin-binding site. Using intrinsic protein fluorescence and the saturation transfer double difference (STDD) NMR techniques to probe drug-Pgp interactions, verapamil was found to have little effect on digoxin-Pgp interactions at low concentrations of verapamil, which is consistent with simultaneous binding of the drugs and non-competitive inhibition. Higher concentrations of verapamil caused significant disruption of digoxin-Pgp interactions that suggested overlapping and competing drug-binding sites. These interactions correlated to drug-induced conformational changes deduced from acrylamide quenching of Pgp tryptophan fluorescence. Also, Pgp-coupled ATPase activity kinetics measured with a range of verapamil and digoxin concentrations fit well to a DDI model encompassing non-competitive and competitive inhibition of digoxin by verapamil. The results and previous transport studies were combined into a comprehensive model of verapamil-digoxin DDIs encompassing drug binding, ATP hydrolysis, transport and conformational changes.

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Section: Introductionmentioning

confidence: 86%

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

2016

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“…21 Several early clinically relevant interactions have been well documented between some cardiovascular drugs and digoxin, such as spironolactone-digoxin, 22,23 quinidine-digoxin, 24 and verapamil-digoxin. 25,26 These interactions were implicated by interfering the renal tubular secretion of digoxin. 27 Digoxin is partially metabolized by Eubacterium lentum, which occurs predominantly in the colon.…”

Section: Discussionmentioning

confidence: 99%

“…Digoxin has been used clinically for more than 2 centuries, but therapeutic drug monitoring of digoxin still poses a serious challenge to clinicians. Despite the large number of publications available for digoxin drug interactions, no general consensus could be reached either about what is considered a relevant interaction or what is judged as “no interaction.” 21 Several early clinically relevant interactions have been well documented between some cardiovascular drugs and digoxin, such as spironolactone‐digoxin, 22,23 quinidine‐digoxin, 24 and verapamil‐digoxin 25,26 . These interactions were implicated by interfering the renal tubular secretion of digoxin 27 .…”

Section: Discussionmentioning

confidence: 99%

Absence of a Clinically Relevant Interaction Between Etanercept and Digoxin

Zhou¹,

Parks²,

Patat³

et al. 2004

The Journal of Clinical Pharma

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Etanercept, a soluble recombinant human tumor necrosis factor receptor (TNFr), is effective and well tolerated in the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis. The primary objective of this study was to investigate the potential pharmacokinetic and pharmacodynamic interaction between digoxin and etanercept at steady state. In a crossover, open-label, nonrandomized, 3-period study, 12 healthy male subjects received loading oral doses of digoxin 0.5 mg every 12 hours on day 1 and 0.25 mg every 12 hours on day 2, followed by a daily maintenance dose of 0.25 mg for a total of 27 days. Etanercept was administered as a twice-weekly 25-mg subcutaneous dose beginning on day 9 and continuing up to day 37 for a total of 9 doses. All ratios of maximum plasma concentration (C(max)) and area under the plasma concentration versus time curve (AUC) for pharmacokinetics of digoxin fell within the confidence interval of 0.8 to 1.25. Although not considered clinically relevant, the mean C(max) and AUC of etanercept were 4.2% and 12.5% lower, respectively, when etanercept was given with digoxin than when administered alone. There were no clinically relevant changes in the electrocardiogram (ECG) parameters, and adverse events did not increase when both drugs were combined. In conclusion, there is no clinically relevant interaction between etanercept and digoxin, and both drugs can be safely coadministered without the need for a dosage adjustment.

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“…Although most cardiac drugs can be used in the elderly, amiodarone and digoxin must be used with caution and at low doses, and the planned duration of therapy reassessed periodically. 7 Dosages of antiarrhythmic drugs are monitored predominantly on clinical grounds, but from time to time drug levels are required for optimising care and avoiding toxicity, e.g. serum digoxin levels are useful in determining toxicity.…”

Section: Antiarrhythmic Drugsmentioning

confidence: 99%

Management of Cardiac Rhythm Disturbances in the Ageing Heart

Chase

O’Donnell

Farouque

2008

Pharmacy Practice and Res

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The elderly experience a high proportion of chronic diseases, of which cardiac rhythm disturbances comprise a significant portion. Due to ageing-related metabolic and physiological changes, the management of cardiac rhythm disturbances will need to be modified and it is essential to be aware of the pharmacodynamics and pharmacokinetics of the drugs used. Non-drug treatment modalities, such as implantable cardioverterdefibrillators or radiofrequency ablation, which are increasingly available for use in the elderly, need to be considered periodically. The critical applications of drug and non-drug therapy of cardiac arrhythmias in the elderly are discussed in this article.

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Clinical Digoxin Toxicity in the Aged in Association With Co‐Administered Verapamil

Cited by 10 publications

References 16 publications

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

Absence of a Clinically Relevant Interaction Between Etanercept and Digoxin

Management of Cardiac Rhythm Disturbances in the Ageing Heart

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