Digoxin

Mechanism

Quinidine inhibits renal and intestinal P-glycoprotein – digoxin clearance drops 50%. Concentration doubles with digoxin toxicity risk (bradycardia, AV block, ventricular arrhythmias).

Symptoms

Nausea, vomiting, visual disturbances, bradycardia, AV block within 5–7 days.

Management

Reduce digoxin by 50% when starting quinidine. Check level on day 5.

Mechanism

Like other NSAIDs, aspirin reduces renal excretion of digoxin, so digoxin blood levels rise, sometimes to toxic values (aspirin 100 mg and 500 mg SmPCs). The US digoxin label (FDA) links this to the fall in glomerular filtration and tubular secretion caused by NSAIDs. Salicylates can also strengthen the effect of digoxin through potassium and magnesium loss, because a heart short of these ions is more sensitive to digoxin (Spanish digoxin SmPC).

Symptoms

Signs of digoxin overdose: nausea, vomiting, loss of appetite, fatigue, visual changes with yellow-green colour vision, and rhythm and conduction disorders, from slow pulse and heart block to ventricular arrhythmias. The risk is higher in older patients, with low body weight, reduced kidney function, or low potassium or magnesium.

Management

Aspirin SmPCs, including those for 100 mg products, do not recommend combining aspirin with digoxin. If the combination cannot be avoided, measure digoxin blood levels when aspirin is started, when its dose changes and when it is stopped (aspirin 100 mg and 500 mg SmPCs). The US digoxin label (FDA) asks for closer monitoring of digoxin levels and signs of toxicity whenever an interacting drug is started, adjusted or stopped, and for individual digoxin dosing with drugs that impair kidney function. Check electrolytes and kidney function periodically, since low potassium and magnesium raise the risk of digoxin toxicity (US digoxin label).

Mechanism

Amiodarone blocks P-glycoprotein in the intestine and renal tubules – the main clearance route of digoxin. Digoxin plasma levels rise 1.7- to 2.5-fold. The narrow therapeutic window of digoxin turns any rise into a risk of acute toxicity.

Symptoms

Nausea, anorexia, visual disturbances (yellow-green halos around lights), arrhythmias ranging from premature beats to ventricular tachycardia. In older adults: confusion, dizziness. Symptoms appear 1–2 weeks after starting amiodarone.

Management

When amiodarone is started, halve the digoxin dose immediately. Measure digoxin level after 1 week (target 0.5–0.9 ng/mL in heart failure). Check potassium and magnesium monthly: hypokalaemia worsens digoxin toxicity.

Mechanism

Amphotericin B causes hypokalaemia, which enhances digoxin binding to cardiomyocyte Na-K-ATPase and potentiates digoxin toxicity.

Symptoms

Bradycardia, arrhythmia, yellow vision.

Management

Check potassium and digoxin levels. Replacement therapy.

Mechanism

Atorvastatin slightly raises digoxin levels: by about 22%, with a 15% rise in AUC, according to the FDA digoxin label. Digoxin has a narrow therapeutic range, so even this increase can lead to toxicity.

Symptoms

Nausea, anorexia, visual disturbances (yellow-green halos around lights), arrhythmias. Older patients: confusion.

Management

Before starting atorvastatin, measure the serum digoxin concentration, then reduce the digoxin dose by about 15–30% or give it less often and keep monitoring the concentration (FDA digoxin label). Draw the sample just before the next digoxin dose or at least 6 hours after the last one (FDA digoxin label). The atorvastatin labels ask for appropriate monitoring of patients taking digoxin (atorvastatin labels).

Mechanism

Ciclosporin inhibits P-glycoprotein and reduces digoxin clearance (ciclosporin SmPC). Digoxin is cleared by the kidneys, so ciclosporin nephrotoxicity can also keep it in the blood longer (both labels). The US Food and Drug Administration (FDA) ciclosporin label describes severe digitalis toxicity within days of starting ciclosporin. The size of the rise cannot be predicted: the FDA digoxin label calls it unclear.

Symptoms

Nausea, vomiting, loss of appetite, weakness, confusion. Visual changes: blurred vision, green-yellow colour changes, halos around lights. Rhythm disorders: ventricular premature beats, often as bigeminy, atrioventricular block, atrial tachycardia with block. Older age, low body weight, reduced kidney function and electrolyte disorders raise the risk of toxicity (digoxin label).

Management

The combination is acceptable only with close monitoring. The ciclosporin SmPC requires close clinical observation to detect digoxin toxicity early, followed by a lower digoxin dose or stopping digoxin. The US Food and Drug Administration (FDA) ciclosporin label says serum digoxin concentrations should be monitored. Measure the digoxin concentration before ciclosporin is started, keep monitoring and reduce the digoxin dose as needed (FDA digoxin label). Draw the sample just before the next digoxin dose or at least 6 hours after the last one (FDA digoxin label). Ciclosporin requires frequent checks of kidney function and raises the risk of hyperkalaemia, so check creatinine and potassium regularly (ciclosporin SmPC). The digoxin SmPC already asks for periodic electrolyte and creatinine checks.

Mechanism

Digoxin is cleared with the help of the P-glycoprotein (P-gp) transporter, and clarithromycin inhibits it, so digoxin blood levels rise (clarithromycin SmPC). The US Food and Drug Administration (FDA) reports a 70% increase in the area under the digoxin concentration curve (digoxin FDA label). Digoxin has a narrow therapeutic index, and older age, low body weight, impaired kidney function, low potassium or magnesium and high calcium predispose to toxicity (digoxin FDA label).

Symptoms

Loss of appetite, nausea, vomiting, visual changes and heart rhythm disorders: bradycardia, heart block, ventricular extrasystoles, ventricular tachycardia and ventricular fibrillation. Life-threatening arrhythmias have been reported with this combination after marketing.

Management

The US Food and Drug Administration (FDA) lists clarithromycin among drugs that raise digoxin levels by more than 50% and for them recommends measuring serum digoxin before starting, reducing the digoxin dose by about 30–50% or giving it less often, and continuing to monitor (digoxin FDA label). Monitor digoxin levels carefully throughout the clarithromycin course (clarithromycin SmPC): after marketing, some patients on this combination showed signs of digoxin toxicity, including life-threatening arrhythmias (clarithromycin SmPC). Monitor more closely when clarithromycin is started and stopped (digoxin FDA label). If signs of toxicity appear, measure the digoxin level and interrupt or adjust the dose (digoxin FDA label).

Mechanism

The transporter P-glycoprotein limits digoxin absorption in the gut and removes it through the kidneys and bile (FDA digoxin label). Diltiazem weakly inhibits this transporter (diltiazem label). In studies, blood digoxin levels rose by about 20%; two studies found a 46–50% rise in digoxin AUC and a third found no significant interaction (diltiazem labels in Spain and the US). The second mechanism does not depend on drug levels: both drugs slow conduction through the atrioventricular (AV) node, and together they can cause bradycardia and AV block up to complete heart block (FDA digoxin label).

Symptoms

Signs of digoxin toxicity: loss of appetite, nausea, vomiting, weakness, dizziness and color vision changes with a yellow-green tint. Cardiac effects are rhythm and conduction disorders: atrioventricular (AV) block of any degree, atrial tachycardia with block, ventricular premature beats, often as bigeminy, and ventricular tachycardia (FDA digoxin label). The combined effect of both drugs on the AV node can slow the pulse even without a rise in digoxin levels; the risk is higher in older patients and at high doses (diltiazem label).

Management

Measure serum digoxin before starting diltiazem. Then reduce the digoxin dose by about 15–30% or give it less often, and keep monitoring levels (FDA digoxin label). Check digoxin levels when diltiazem is started, when its dose changes and when it is stopped, to avoid both over- and under-digitalization (diltiazem labels in Spain and the US). Take blood just before the next digoxin dose or at least 6 hours after the last one. Do not change the dose on a single level without the clinical picture (FDA digoxin label). Both drugs slow the pulse, so watch it closely in older patients and at high doses (diltiazem label).

Mechanism

Dronedarone blocks intestinal P-glycoprotein – the main route of digoxin absorption and elimination. Digoxin plasma levels rise 1.7- to 2.5-fold. Dronedarone also enhances contractile and bradycardic effects.

Symptoms

Nausea, anorexia, visual disturbances (yellow-green halos around lights), arrhythmias ranging from premature beats to ventricular tachycardia. Older adults: confusion, dizziness. Symptoms appear within 1–2 weeks of co-administration.

Management

When dronedarone starts, halve the digoxin dose; check level at 1 week. If sinus node or AV conduction symptoms appear, hold digoxin temporarily.

Mechanism

Furosemide increases urinary loss of potassium and magnesium. Digoxin and potassium compete for the same binding site on the Na+/K+-ATPase: as potassium falls, the blocked fraction of the pump grows and the same blood concentration of digoxin produces a larger effect. The digoxin label states it plainly: agents that cause hypokalaemia or intracellular potassium depletion, among them some diuretics, lithium salts and corticosteroids, increase sensitivity to digoxin. Furosemide itself does not change the glycoside concentration; what changes is the electrolyte background.

Symptoms

Nausea, vomiting, loss of appetite and visual disturbance with a yellow or green halo before any cardiac symptom. Then bradycardia, AV block, ventricular ectopy and confusion in older people. Symptoms appear with potassium below 3.5 mmol/L, even when the digoxin level sits inside the therapeutic range.

Management

Potassium and magnesium before the pair starts, at 1-2 weeks and periodically thereafter; sooner with vomiting, diarrhoea or hot weather. If potassium drops below 4 mmol/L in someone on digoxin, it is corrected with potassium or a potassium-sparing agent. Magnesium is replaced below 0.7 mmol/L, because without it hypokalaemia will not correct. The digoxin level is read together with potassium: a normal value against low potassium does not rule out toxicity.

Mechanism

The hydrochlorothiazide label gives digitalis glycosides their own entry: thiazide-induced hypokalaemia or hypomagnesaemia can favour digitalis-induced arrhythmia. The mechanism matches the one with loop diuretics – competition between digoxin and potassium at the Na+/K+-ATPase – and the digoxin label lists diuretics among agents that raise sensitivity to the glycoside. The thiazide label also asks for hypokalaemia and hypomagnesaemia to be corrected before treatment starts.

Symptoms

Nausea, vomiting, poor appetite, yellow-haloed vision, confusion. On ECG, ventricular ectopy, bradycardia and AV block. Muscle weakness and cramps point to low potassium in their own right, before any digitalis picture appears.

Management

Potassium and magnesium before the thiazide starts and during follow-up. The label asks for hypokalaemia and hypomagnesaemia to be corrected first and for hydrochlorothiazide to be stopped if hypokalaemia comes with muscle weakness, paresis or ECG changes. In a patient on digoxin the potassium target stays above 4 mmol/L; potassium supplementation, a potassium-sparing agent or a change of diuretic all serve.

Mechanism

Additive slowing of atrioventricular (AV) conduction and lowered heart rate. In atrial fibrillation this synergistic ventricular rate control is standard; without atrial fibrillation, bradycardia and AV block risks rise.

Symptoms

Bradycardia (heart rate below 50/min), dizziness, syncope. ECG: first- to second-degree AV block, prolonged PR. Older patients: fatigue, weakness.

Management

The combination is appropriate in atrial fibrillation with preserved or reduced ejection fraction. Check pulse and ECG at 1 and 4 weeks. If pulse drops below 50 or second-degree AV block appears, reduce metoprolol; if symptoms persist, hold digoxin temporarily.

Mechanism

Propafenone inhibits renal P-glycoprotein. Digoxin rises 50-75%.

Symptoms

Nausea, yellow vision, bradycardia.

Management

Reduce digoxin by 50%, check level on day 5.

Mechanism

Spironolactone reduces digoxin clearance and prolongs its half-life, so digoxin levels rise (spironolactone SmPC), by about 25% according to the digoxin label. Spironolactone and its metabolites can also distort digoxin assays that cross-react with them (spironolactone labels).

Symptoms

Nausea, vomiting, loss of appetite, confusion, altered colour vision with yellow-green halos around lights, and heart rhythm disturbances such as bigeminy and atrioventricular block.

Management

Before starting spironolactone, measure the serum digoxin concentration with an assay that does not interact with spironolactone. Then reduce the digoxin dose by about 15–30% or give it less often and keep monitoring the concentration, as the FDA digoxin and spironolactone labels require. The Spanish spironolactone SmPC asks for caution with this combination (spironolactone SmPC). Spironolactone raises potassium, so check potassium and kidney function before starting and regularly during treatment (spironolactone SmPC).

Mechanism

Ticagrelor inhibits P-glycoprotein, which clears digoxin. Digoxin peak concentration rises by 75%, AUC by 28% and trough levels by about 30%, doubling in some individuals.

Symptoms

Nausea, yellow vision, bradycardia.

Management

Measure serum digoxin before starting ticagrelor. Then reduce the digoxin dose by about 15–30% or give it less often, and keep monitoring levels (FDA digoxin label). Check digoxin levels when ticagrelor is started and after any change in its dose (FDA ticagrelor label). The EMA ticagrelor label also requires appropriate clinical and laboratory monitoring with this combination. Ticagrelor itself can cause ventricular pauses and bradycardia, so use it with caution with drugs that slow the heart rate (EMA ticagrelor label). Take blood for digoxin just before the next dose or at least 6 hours after the last one (FDA digoxin label).

Mechanism

Verapamil inhibits P-glycoprotein, which clears digoxin via kidney and intestine. Digoxin plasma concentration rises 50–75%. Digoxin has a narrow therapeutic index (target 0.5–0.9 ng/mL, toxic above 2). Verapamil also amplifies digoxin's bradycardia and AV block.

Symptoms

Nausea, vomiting, visual disturbances (yellow halos), bradycardia below 50, AV blocks, ventricular arrhythmias.

Management

When starting verapamil, reduce digoxin by 30–50% and check level on days 5–7. Alternative calcium channel blocker: amlodipine, which does not inhibit P-glycoprotein. Avoid the combination in the elderly.

Mechanism

Alprazolam raises blood digoxin levels, more often in patients over 65 (alprazolam labels in Spain and the US). The digoxin SmPC also lists alprazolam among drugs that increase serum digoxin. The documents do not say how large the rise is or what causes it: the FDA digoxin label places alprazolam in the group where the size of the effect is unclear. Digoxin has a narrow therapeutic index (FDA digoxin label), so even this rise can lead to toxicity.

Symptoms

Signs of digoxin toxicity: loss of appetite, nausea, vomiting, weakness, dizziness and visual changes, including yellow-green colour vision. Cardiac effects are rhythm and conduction disorders: ventricular premature beats, often as bigeminy, atrial tachycardia with block, atrioventricular block up to complete heart block, ventricular tachycardia (digoxin labels). Alprazolam itself causes drowsiness and muscle weakness, with a risk of falls in older people (alprazolam SmPC).

Management

The combination is not prohibited, but it is managed by digoxin levels. The FDA alprazolam label requires measuring serum digoxin before alprazolam is started, then checking digoxin levels and signs of toxicity frequently and lowering the digoxin dose if needed. The FDA digoxin label requires the same approach whenever an interacting drug is started, changed or stopped. The Spanish alprazolam SmPC requires watching for signs of digoxin toxicity, especially in patients over 65. Patients on digoxin have serum electrolytes and creatinine checked periodically (digoxin SmPC). In older people alprazolam is started at a lower dose (alprazolam SmPC).

Mechanism

Azithromycin inhibits P-glycoprotein (azithromycin SmPC). Digoxin is a P-glycoprotein substrate in the gut and kidneys, so its blood level may rise (both labels). There is a second route: in about 1 in 10 patients, gut bacteria break down 40% or more of an oral digoxin dose, and some antibiotics suppress these bacteria, so more digoxin is absorbed (US Food and Drug Administration (FDA) digoxin label). The level rises gradually as digoxin accumulates, not at once.

Symptoms

Nausea, anorexia, visual disturbances (yellow-green halos around lights), arrhythmias. Older patients: confusion.

Management

The combination calls for digoxin level monitoring. Measure the serum digoxin concentration before azithromycin is started, keep monitoring and reduce the digoxin dose as needed (US Food and Drug Administration (FDA) digoxin label). During and after the azithromycin course, monitor the patient clinically and possibly the digoxin level (azithromycin SmPC). Draw the sample just before the next digoxin dose or at least 6 hours after the last one (FDA digoxin label). Older age, low body weight, reduced kidney function and electrolyte disorders raise the risk of toxicity, so these patients need monitoring most (FDA digoxin label).

Mechanism

Additive bradycardia and atrioventricular (AV) conduction slowing. Used in atrial fibrillation and heart failure for ventricular rate control.

Symptoms

Lower blood pressure, postural dizziness, fatigue. Older patients: fall risk. With additional antihypertensives: bradycardia (pulse below 60/min).

Management

Standard regimen for atrial fibrillation with rapid ventricular response and heart failure. Check pulse and ECG at 1 and 4 weeks. If pulse drops below 50/min or second-degree AV block appears, adjust dose.

Mechanism

In 10–15% of patients, gut flora (mainly Eubacterium lentum) metabolises part of digoxin to inactive products. Ciprofloxacin suppresses this flora — digoxin levels rise by 30–80% in those patients, increasing toxicity risk.

Symptoms

Nausea, vomiting, loss of appetite, confusion, yellow-green halos around lights, arrhythmia (bigeminy, AV block). Symptoms appear earlier in older patients and chronic kidney disease.

Management

For short ciprofloxacin courses (5–7 days), most patients need no adjustment. In older patients and chronic kidney disease, check digoxin level at 5–7 days after antibiotic start. With toxicity signs, reduce dose by 25%. Alternative antibiotics: a cephalosporin (minimal gut flora impact).

Mechanism

St. John's wort is a potent inducer of the CYP3A4 enzyme (and of CYP2C9 and P-glycoprotein). After 1–2 weeks it speeds up the breakdown of Digoxin and lowers its blood level, weakening its effect.

Symptoms

Lower digoxin levels through P-glycoprotein induction, weaker rhythm control and control of heart failure symptoms.

Management

Avoid the combination. If needed, monitor digoxin levels and clinical response.

Mechanism

Rifampicin induces enterocyte P-glycoprotein. Digoxin bioavailability falls by 30%, levels drop — risking loss of rate control in atrial fibrillation or worsening of chronic heart failure.

Symptoms

Return of underlying disease: tachycardia in atrial fibrillation, dyspnoea and oedema in chronic heart failure. After rifampicin stops, digoxin levels may rise sharply.

Management

On the combination, check digoxin levels at 2 and 4 weeks after rifampicin start and 2 weeks after rifampicin stops. Digoxin dose is usually raised by 25–50% during rifampicin and returned to baseline afterward. In atrial fibrillation, consider adding a beta-blocker (bisoprolol, metoprolol) for rate control.

Mechanism

Telmisartan moderately inhibits intestinal P-glycoprotein. Digoxin AUC rises by 20–50%, which may trigger toxicity, especially in older patients and in chronic kidney disease.

Symptoms

Nausea, vomiting, loss of appetite, confusion, yellow-green halos around lights, arrhythmia (bigeminy, AV block). Symptoms appear earlier in older patients and chronic kidney disease.

Management

On telmisartan start, check digoxin levels at 1–2 weeks. In significant chronic kidney disease (clearance below 50 mL/min), reduce digoxin by 25%. In older patients, target 0.5–0.8 ng/mL. Alternatives: losartan or valsartan, with less effect on P-glycoprotein.