| Digoxin drug drug interactions: Interactions affecting excretion • Examples of Drugs that decrease digoxin excretion: • ACE inhibitors • Anti-thyroid agents • Amiodarone • Cyclosporin • Diltiazem • Itraconazole • Propafenone • Quinidine • Quinine • Spironolactone • Trimethoprim • Verapamil • NSAIDs • Examples of Drugs that increase digoxin excretion: Thyroxine Digoxin is primarily excreted unchanged in the urine and, therefore, its blood concentrations can be significantly affected by drugs which affect the ability of the kidney to excrete it. A small amount is also excreted into the bile and, although this is a less significant route of excretion, it may also be affected by the concurrent administration of other drugs. Drugs affecting both renal and non-renal (biliary) excretion Various mechanisms have been suggested for the significant increase in digoxin levels caused by amiodarone, propafenone, quinidine and verapamil, including increases in digoxin bioavailability by amiodarone, quinidine and propafenone; displacement of digoxin from its tissue binding sites by amiodarone and quinidine, and decreases in the volume of distribution of digoxin by verapamil and propafenone. However, all four of these drugs appear primarily to increase digoxin concentrations by inhibiting both its renal and extra-renal (biliary) excretion. Although the interactions with all four drugs are clinically significant, in practice digoxin is most commonly used with amiodarone or verapamil in patients with resistant atrial fibrillation. Digoxin levels begin to increase after a few days in most patients treated with either combination. With amiodarone the interaction may then develop over one to four weeks but with verapamil the increase in levels usually reaches a maximum within 14 days. The interaction observed with verapamil is dose dependent and significant increases in digoxin concentrations of about 40 per cent are observed with 160mg verapamil daily. A dose of 240mg verapamil daily will produce an increase of about 60 to 80 per cent but there is no further increase in digoxin levels with higher doses. It is important that concurrent use of amiodarone or verapamil with digoxin is monitored. Serum digoxin levels should be measured and downward dose adjustments made to avoid toxicity. Recommendations to reduce the digoxin dose by a third to a half have been made. Drugs affecting renal excretion Other drugs solely reduce the renal excretion of digoxin. For example, trimethoprim has been reported to cause increases in serum digoxin levels of about 25 per cent and cyclosporin has caused significant rises which have resulted in toxicity. Both of these drugs are believed to reduce the renal tubular secretion of digoxin, although a reduction in creatinine clearance noted with the administration of cyclosporin could also contribute to the changes observed. The rise in digoxin levels noted with trimethoprim is usually modest and the digoxin dose is not normally adjusted unless symptoms of toxicity are observed. If cyclosporin and digoxin are used concurrently, the limited data available suggest that the digoxin dose will need to be reduced. Some non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, diclofenac and ibuprofen, have also been associated with increased digoxin levels. Data are limited but it is believed that they probably reduce the renal excretion of digoxin. Patients on NSAIDs and digoxin should, therefore, be monitored for symptoms of toxicity. Concurrent use of digoxin with angiotensin-converting enzyme (ACE) inhibitors should not present a problem, unless the patient develops renal failure as a result of their use. The clinical effectiveness of digoxin treatment is influenced by the thyroid status of the patient. Untreated hyperthyroid patients require higher doses of digoxin than euthyroid (normal) patients, while untreated hypothyroid patients require lower doses. There is evidence that the glomerular filtration rate is changed by thyroid status and this could account for these observations. As thyroid status is returned to normal by the use of either thyroxine or anti-thyroid drugs, the digoxin dose may need to be adjusted accordingly. Increases in digoxin levels have also been reported when it is given with spironolactone. Although there is some evidence that this is due to a reduction in the renal excretion of digoxin, there is more substantial evidence to indicate that spironolactone may interfere with certain serum digoxin assays. It is recommended that patients receiving this combination should be monitored clinically for symptoms of toxicity, unless the digoxin assay has been proved not to be affected by spironolactone. Drugs affecting non-renal excretion Quinine has been reported to cause a substantial increase in digoxin levels in some patient whereas, in others, the rise observed has been clinically insignificant. It is believed that the interaction occurs as a result of reduced biliary excretion. The effects of concurrent use should be monitored. Significant rises in digoxin levels seem most likely with quinine doses greater than 600mg per day. Increases in digoxin levels have also been reported in some patients taking diltiazem and itraconazole. The increases may be due to reduced digoxin excretion but no specific mechanism is stated. Toxicity can result from these interactions but because not all patients seem to be affected, clinical monitoring for symptoms of toxicity is recommended. Hydroxychloroquine may also increase digoxin levels via an unknown mechanism. While there are only a few reports of the interaction occurring, patients on concurrent therapy should be observed for toxicity. |
Drug Interactions
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