chapter
Cardiac glycosides
Pages 9

Unlikely to be clinically significant

CALCIUM CHANNEL BLOCKERS

X-RAY CONTRAST SOLUTIONS

≠ hypotensive effect when intravenous ionic contrast solutions are given to patients on calcium channel blockers

Additive hypotensive effect Consider using a non-ionic X-ray contrast solution for patients on calcium channel blockers

CARDIAC GLYCOSIDES

DIGITOXIN

DIGITOXIN ANTIARRHYTHMICS

DIGITOXIN AMIODARONE Reports of digitoxin toxicity in two patients on digitoxin after starting amiodarone

Uncertain; thought to be due to inhibition of P-gp-mediated renal clearance of digoxin

Watch for digitoxin toxicity

DIGITOXIN PROCAINAMIDE Single case report of toxicity in a patient taking both digitoxin and procainamide

Uncertain at present Watch for digitoxin toxicity

DIGITOXIN ANTIBIOTICS – RIFAMPICIN Plasma concentrations of digitoxin may be halved by rifampicin

Due to ≠ hepatic metabolism Watch for poor response to digitoxin

DIGITOXIN ANTIEPILEPTICS – BARBITURATES, CARBAMAZEPINE, PHENYTOIN

Plasma concentrations of digitoxin may be ↓ by up to half by barbiturates

Possibly ≠ hepatic metabolism Watch for poor response to digitoxin

DIGITOXIN CALCIUM CHANNEL BLOCKERS

Plasma concentrations of digitoxin may be ≠ by diltiazem and verapamil

Uncertain at present Watch for digitoxin toxicity

DIGITOXIN DIURETICS – SPIRONOLACTONE

Conflicting results from volunteer studies; some showed ≠ (up to onethird) in the half-life of digitoxin, others a ↓ (up to one-fifth)

Uncertain at present Watch for either digitoxin toxicity or a poor response, particularly for the first month after starting spironolactone

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CARDIOVASCULAR DRUGS CARDIAC GLYCOSIDES Digoxin

Both colestipol and colestyramine are ion exchange resins that bind bile sodiums and prevent reabsorption in the intestine; this breaks the enterohepatic cycle of digitoxin

Colestipol and colestyramine should be given at least 1.5 hours after digitoxin

DIGOXIN

DIGOXIN AMINOSALICYLATES Sulfasalazine may ↓ digoxin levels. The manufacturers of balsalazide also warn against the possibility of this interaction in spite of a lack of case reports

Uncertain at present Watch for poor response to digoxin; check levels if signs of ↓ effect

DIGOXIN ANALGESICS

DIGOXIN NSAIDs Diclofenac, indometacin and possibly fenbufen, ibuprofen and tiaprofenic acid ≠ plasma concentrations of digoxin and ≠ risk of precipitating cardiac failure and renal dysfunction

Uncertain; postulated that NSAIDinduced renal impairment plays a role; however, since all NSAIDs have this effect, it is not understood why only certain NSAIDs actually influence digoxin levels

Monitor renal function closely. Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN OPIOIDS ≠ concentrations of digoxin may occur with tramadol

Uncertain at present Watch for digoxin toxicity; check levels and ↓ the dose of digoxin as necessary

DIGOXIN ANTACIDS Plasma concentrations of digoxin may be ↓ by antacids

Uncertain; probably ↓ absorption of digoxin

Watch for poor response to digoxin

DIGOXIN ANTIARRHYTHMICS

DIGOXIN AMIODARONE Amiodarone may ≠ plasma levels of digoxin (in some cases up to fourfold)

Uncertain; thought to be due to inhibition of P-gp-mediated renal clearance of digoxin. Amiodarone is also known to inhibit intestinal P-gp, which may ≠ the bioavailability of digoxin

↓ digoxin dose by one-third to onehalf when starting amiodarone. Monitor digoxin levels; watch for digoxin toxicity, especially for 4 weeks after initiating or adjusting amiodarone therapy

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Mechanism Precautions

digoxin

Uncertain at present Monitor PR and ECG closely

DIGOXIN PROPAFENONE Digoxin concentrations may be ≠ by propafenone

Uncertain at present Watch for digoxin toxicity; check digoxin levels if indicated and ↓ digoxin dose as necessary (15-70% is suggested by studies)

DIGOXIN ANTIBIOTICS

DIGOXIN AMINOGLYCOSIDES 1. Gentamicin may ≠ plasma concentrations of digoxin 2. Neomycin may ↓ plasma concentrations of digoxin

1. Uncertain; postulated to be due to impaired renal clearance of digoxin 2. Neomycin ↓ absorption of digoxin; this may be offset in some patients by ↓ intestinal bacterial breakdown of digoxin

1. Monitor digoxin levels; watch for ≠ levels, particularly with diabetes and in the presence of renal insufficiency 2. Monitor digoxin levels; watch for poor response to digoxin

DIGOXIN MACROLIDES Digoxin concentrations may be ≠ by macrolides

Uncertain; postulated that macrolides inhibit P-gp in both the intestine (≠ bioavailability) and kidney (↓ clearance). It is possible that alterations in intestinal flora may also have a role

Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN RIFAMPICIN Plasma concentrations of digoxin may be ↓ by rifampicin

Rifampicin seems to induce P-gpmediated excretion of digoxin in the kidneys

Watch for a ↓ response to digoxin, check plasma levels and ≠ the dose as necessary

DIGOXIN TRIMETHOPRIM, CO-TRIMOXAZOLE

Trimethoprim may ≠ plasma concentrations of digoxin, particularly in elderly people

Uncertain; postulated that trimethoprim ↓ renal clearance of digoxin

Monitor digoxin levels; watch for digoxin toxicity

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CARDIOVASCULAR DRUGS CARDIAC GLYCOSIDES Digoxin

given in tablet form

Cytotoxic-induced damage to the mucosa of the intestine may ↓ absorption; this does not seem to be a problem with liquid or liquid-containing capsule formulations

Watch for poor response to digoxin; check levels if signs of ↓ effect, and consider swapping to liquid digoxin or liquid-containing capsules

DIGOXIN AMINOSALICYLATES Sulfasalazine may ↓ digoxin levels. The manufacturers of balsalazide also warn against the possibility of this interaction in spite of a lack of case reports

Uncertain at present Watch for poor response to digoxin; check levels if signs of ↓ effect

DIGOXIN CICLOSPORIN ≠ plasma digoxin levels, with risk of toxicity. Digoxin may ≠ ciclosporin bioavailability (by 15-20%)

Attributed to inhibition of intestinal P-gp and renal P-gp, which ≠ bioavailability and ≠ renal elimination. Digoxin ≠ bioavailability of ciclosporin due to substrate competition for P-gp

Watch for digoxin toxicity. Monitor plasma digoxin and ciclosporin levels

DIGOXIN CORTICOSTEROIDS Risk of digoxin toxicity due to hypokalaemia

Corticosteroids may cause hypokalaemia

Monitor potassium levels closely. Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN INTERFERON GAMMA Plasma concentrations of digoxin may occur with interferon gamma

Interferon gamma ↓ P-gpmediated renal and biliary excretion of digoxin

Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN PENICILLAMINE Plasma concentrations of digoxin may be ↓ by penicillamine

Uncertain at present Watch for poor response to digoxin

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Possibly due to tacrolimus-induced hyperkalaemia and hypomagnesaemia

Watch for digoxin toxicity. Monitor potassium and magnesium levels

DIGOXIN ANTIDEPRESSANTS

DIGOXIN ST JOHN’S WORT Plasma concentrations of digoxin seem to be ↓ by St John’s wort

St John’s wort seems to ↓ P-gpmediated intestinal absorption of digoxin

Watch for a ↓ response to digoxin

DIGOXIN TRAZODONE Reports of two cases of ≠ plasma concentrations of digoxin after starting trazodone

Uncertain at present Watch for digoxin toxicity; check levels and ↓ the dose of digoxin as necessary

DIGOXIN ANTIDIABETIC DRUGS – ACARBOSE

Acarbose may ↓ plasma levels of digoxin

Uncertain; possibly ↓ absorption of digoxin

Monitor digoxin levels; watch for ↓ levels

DIGOXIN ANTIDIARRHOEALS – KAOLIN

Possibly ↓ levels of digoxin ↓ absorption Separate doses by at least 2 hours

DIGOXIN ANTIEPILEPTICS Phenytoin may ↓ plasma levels of digoxin

Uncertain at present Watch for poor response to digoxin; check levels if signs of ↓ effect

DIGOXIN ANTIFUNGALS

DIGOXIN AMPHOTERICIN Risk of digoxin ≠ by toxicity due to hypokalaemia

Amphotericin may cause hypokalaemia

Monitor potassium levels closely. Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN ITRACONAZOLE Itraconazole may cause ≠ plasma levels of digoxin; cases reported of digoxin toxicity

Itraconazole inhibits P-gpmediated renal clearance and ≠ intestinal absorption of digoxin

Monitor digoxin levels; watch for digoxin toxicity

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CARDIOVASCULAR DRUGS CARDIAC GLYCOSIDES Digoxin

in the presence of heart failure (class II or more severe) or renal insufficiency. No other ACE inhibitors seem to interact in the same way

Uncertain; postulated to be due to ↓ renal excretion of digoxin

Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN ALPHA-BLOCKERS Possibility of ≠ plasma concentrations of digoxin; no cases of toxicity have been reported with doxazosin or prazosin

Doxazosin inhibits P-gp-mediated elimination of digoxin; mechanism with prazosin uncertain at present

Monitor digoxin levels

DIGOXIN ANGIOTENSIN II RECEPTOR ANTAGONISTS

Telmisartan may ≠ plasma levels of digoxin

Uncertain; telmisartan thought to ≠ rate of absorption of digoxin

Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN ANTIMALARIALS

DIGOXIN CHLOROQUINE, HYDROXYCHLOROQUINE

Chloroquine may ≠ plasma concentrations of digoxin

Uncertain at present Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN MEFLOQUINE Risk of bradycardia Uncertain; probably additive effect; mefloquine can cause AV block

Monitor PR and ECG closely

DIGOXIN QUININE Plasma concentrations of digoxin may ≠ when co-administered with quinine

Uncertain, but seems to be due to ↓ non-renal (possibly biliary) excretion of digoxin

Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN ANTIMUSCARINICS PROPANTHELINE

≠ digoxin levels (30-40%) but only with slow-release formulations

Slowed gut transit time allows more digoxin to be absorbed

Use alternative formulation of digoxin

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Mechanism Precautions

LOPINAVIR)

Uncertain; probably due to inhibition of P-gp-mediated renal excretion of digoxin and ≠ intestinal absorption

Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN ANXIOLYTICS AND HYPNOTICS

Alprazolam and possibly diazepam may ≠ digoxin levels, particularly in the over-65s

Uncertain at present Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN BETA-BLOCKERS

DIGOXIN BETA-BLOCKERS Risk of bradycardia and AV block Additive bradycardia Monitor PR, BP and ECG at least weekly until stable

DIGOXIN CARVEDILOL Carvedilol may ≠ digoxin plasma concentrations, particularly in children

↓ P-gp-mediated renal clearance of digoxin

↓ the dose of digoxin by 25%; watch for signs of digoxin toxicity and monitor digoxin levels

DIGOXIN BRONCHODILATORS – BETA-2 AGONISTS

1. Hypokalaemia may exacerbate digoxin toxicity 2. Salbutamol may ↓ digoxin levels (by 16-22%) after 10 days of concurrent therapy

1. Beta-2 agonists may cause hypokalaemia 2. Uncertain

1. Monitor potassium levels closely 2. Clinical significance is uncertain. Useful to monitor digoxin levels if there is a clinical indication of ↓ response to digoxin

DIGOXIN CALCIUM Risk of cardiac arrhythmias with large intravenous doses of calcium

Uncertain; it is known that calcium levels directly correlate with the action of digoxin; therefore, high levels, even if transient, may ≠ the chance of toxicity

It is recommended that parenteral administration of calcium should be avoided in patients taking digoxin. If this is not possible, administer calcium slowly and in small aliquots

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CARDIOVASCULAR DRUGS CARDIAC GLYCOSIDES Digoxin

case reports of significant toxicity 2. ≠ AV block when digoxin is co-administered with verapamil

1. Verapamil seems to inhibit P-gp-mediated renal and biliary clearance of digoxin. Inhibition of intestinal P-gp would also ≠ the bioavailability of digoxin 2. Additive effect

1. It is recommended to ↓ digoxin doses by 33-50% when starting verapamil; monitor digoxin levels and watch for symptoms/signs of toxicity 2. Monitor ECG closely when co-administering digoxin and verapamil, especially when verapamil is being given parenterally

DIGOXIN DILTIAZEM, NIFEDIPINE, FELODIPINE, LACIDIPINE, LERCANIDIPINE, NICARDIPINE, NISOLDIPINE

Possible ≠ plasma concentrations of digoxin

These calcium channel blockers are thought to ↓ the renal excretion of digoxin

Monitor digoxin levels carefully

DIGOXIN DIURETICS

DIGOXIN CARBONIC ANHYDRASE INHIBITORS, LOOP DIURETICS, THIAZIDES

Risk of digoxin toxicity ≠ due to hypokalaemia

Uncertain Monitor potassium levels closely. Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN POTASSIUM-SPARING DIURETICS AND ALDOSTERONE ANTAGONISTS

Eplerenone and spironolactone may ≠ plasma concentrations of digoxin

Uncertain; spironolactone possibly ↓ the volume of distribution of digoxin

Monitor digoxin levels; watch for digoxin toxicity

DIGOXIN GRAPEFRUIT JUICE Possible ≠ efficacy and ≠ adverse effects

Possibly via altered absorption Most patients have been unaffected; consider if unexpected bradycardia or heart block with digoxin

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Mechanism Precautions

for digoxin 2. Liquorice may ≠ the risk of digoxin toxicity 3. Many herbal medicines contain digoxinlike compounds, e.g. black cohosh root, cayenne pepper

1. Bufalin cross-reacts with the antibody used in some digoxin assays. The mechanism of interaction of danshen and ginseng is uncertain at present 2. Liquorice causes electrolyte imbalances, which may precipitate digoxin toxicity

Ask about Chinese herbal remedies in patients taking digoxin; inform the laboratory when monitoring digoxin levels. Watch for symptoms/signs of toxicity in patients taking liquorice-containing remedies

DIGOXIN LIPID-LOWERING DRUGS

DIGOXIN ANION EXCHANGE RESINS Colestipol and colestyramine both may ↓ digoxin levels

Both colestipol and colestyramine are ion exchange resins that bind bile sodiums and prevent reabsorption in the intestine; this breaks the enterohepatic cycle of digoxin

Colestipol and colestyramine should be given at least 1.5 hours after digoxin

DIGOXIN STATINS High-dose (80 mg) atorvastatin may ≠ digoxin levels

Atorvastatin inhibits intestinal P-gp, which ≠ absorption of digoxin

Watch for digoxin toxicity

DIGOXIN MUSCLE RELAXANTS DIGOXIN DEPOLARIZING Risk of ventricular arrhythmias

when suxamethonium is given to patients taking digoxin

Uncertain; postulated that the mechanism involves rapid efflux of potassium from the cells

Use caution and monitor ECG closely if suxamethonium needs to be used in patients taking digoxin

DIGOXIN NON-DEPOLARIZING Case reports of S-T segment/ T wave changes and sinus/atrial tachycardia when pancuronium given to patients on digoxin

Uncertain Avoid pancuronium in patients taking digoxin

DIGOXIN SKELETAL Risk of bradycardia when tizanidine given with digoxin

Tizanidine has a negative inotropic effect

Monitor PR closely