A wide range of drugs is available for the treatment of arrhythmias, although many are either rarely used or are confined to use in acute situations. This article will focus on two of the most commonly prescribed antiarrhythmics — digoxin and amiodarone. These two drugs have an interesting range of drug interactions and, in practice, tend to be the antiarrhythmics that cause the greatest number of problems. Drug interactions involving beta-blockers and verapamil, which are also commonly used as antiarrhythmics, were dealt with in an earlier article in this series.1
Other articles in this series include:
Anticonvulsants (PJ, March 6, 1999, pp325-7)
Antihypertensives (PJ, April 17, pp547-51)
Antiarrhythmic drugs are sometimes used concurrently, with the aim of achieving an improved therapeutic effect. However, some combinations should be used with caution, usually because they have an additive effect that is undesirable. This may occur when drugs with similar effects are used together. The modified Vaughan Williams classification of oral antiarrhythmic drugs, which classifies drugs according to their effects on the electrical behaviour of myocardial cells, can help to predict whether an additive effect may occur when two antiarrhythmics are combined (see Panel 1).
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Panel 1: Modified Vaughan Williams classification of oral antiarrhythmics3
Class i: membrane stabilising drugs
Class ii: beta-blockers Class iii: inhibitors of depolarisation
Class iv: calcium channel blockers
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Most drugs that are used to treat arrhythmias can also provoke them in some circumstances. Hypokalaemia enhances this arrhythmogenic effect.4 Therefore, if a drug which causes loss of potassium (see Panel 2) is used concurrently, potassium levels should be monitored carefully. As mentioned in the previous section, certain antiarrhythmic drugs are associated with prolongation of the QT interval on the ECG. In addition to avoiding the concurrent use of two antiarrhythmic drugs with this potential, concurrent use of other drugs which can cause this effect should also be avoided (see Panel 3).5,6 Digoxin
Digoxin is used for two indications: the treatment of atrial fibrillation and, less commonly, for congestive heart failure. Drug interactions with digoxin are important because there is a relatively narrow gap between blood concentrations of digoxin that are effective and those that are toxic (ie, it has a narrow therapeutic range). Therefore, a small change in serum levels may lead to inadequate digitalisation or to toxicity.
Pharmacodynamic interactions These interactions include those attributed to additive effects and those that involve effects on potassium levels. For example, the concurrent use of digoxin with beta-blockers or calcium channel blockers that have both negative inotropic and chronotropic activity (ie, verapamil or diltiazem), may lead to additive slowing of the heart rate.2,3 Concurrent use is considered necessary in some patients when atrial fibrillation cannot be controlled on digoxin alone; however, patients should be monitored for bradycardia, especially on initiation of combination therapy.
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Panel 2: drugs that cause potassium loss5
Panel 3: non-antiarrhythmics associated with prolongation of the qt interval5,6
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Pharmacokinetic interactions Pharmacokinetic interactions reported with digoxin involve drugs that affect its bioavailability, volume of distribution, tissue binding and excretion. Of these mechanisms, alterations in bioavailability and excretion seem to have the greatest clinical significance. Drugs that decrease digoxin bioavailability Drugs reported to affect the bioavailability of digoxin are listed in Panel 4. Cholestyramine and colestipol are both anion exchange resins that bind to digoxin in the gastrointestinal tract and reduce its bioavailability. Thus, digoxin should be given 1.5 to 2 hours before either of these resins, to minimise the possibility of an interaction.2,3 The significance of the interaction of digoxin with sulphasalazine and sucralfate is not certain. Concurrent use is not contraindicated but the possibility of reduced bioavailability should be considered in the event of inadequate therapeutic response to digoxin.2 Cytotoxic agents and/or radiotherapy can damage the lining of the intestine, which has been reported to reduce the absorption of digoxin tablets by almost 46 per cent.7 Patients on digoxin who are receiving such treatment should be monitored for signs of inadequate digitalisation. The absorption of liquid formulations of digoxin is not significantly reduced and these may be used as an alternative to tablets in such cases. The effects on absorption usually remain for about a week after treatment is withdrawn,so readjustment of digoxin therapy will then be required.3 Drugs that increase digoxin bioavailability Approximately 10 per cent of patients treated with digoxin excrete it in substantial amounts in the faeces and urine as inactive metabolites. The gut flora, in particular Eubacterium lentum, seems to be responsible for this metabolism. When erythromycin, clarithromycin and tetracycline are given, they decimate these organisms and much more digoxin is available for absorption. This results in a marked rise in digoxin blood levels.2,3 Only those 10 per cent of patients who possess the ability to excrete digoxin in this manner are at risk from this interaction but it is not possible to predetermine who these patients will be. Therefore, all patients given these antibiotics while taking digoxin should be monitored for clinical symptoms of toxicity and a reduction in digoxin dose made, if necessary.
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Panel 4: Drugs that affect digoxin bioavailability2,3Drugs that decrease digoxin bioavailability
Drugs that increase digoxin bioavailability
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Interactions affecting excretion Digoxin is primarily excreted unchanged in the urine8 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 bile9 and, although this is a less significant route of excretion, it may also be affected by the concurrent administration of other drugs. (Drugs reported to affect the excretion of digoxin are listed in panel 5.) 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.
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Panel 5: Drugs that affect digoxin excretion2,3Drugs that decrease digoxin excretion
Drugs that increase digoxin excretion
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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.2,3 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.2,3 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.2
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.3 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.2
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.3 It is believed that the interaction occurs as a result of reduced biliary excretion.16 The effects of concurrent use should be monitored. Significant rises in digoxin levels seem most likely with quinine doses greater than 600mg per day.2
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.2,3
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.2,3
Amiodarone is a commonly used antiarrhythmic drug. It is indicated for the treatment of paroxysmal supraventricular, nodal and ventricular tachycardias, atrial fibrillation and flutter, and ventricular fibrillation. Amiodarone has a long half-life of, on average, 50 days.10 Therefore, it is important to remember that interactions can persist for several weeks after amiodarone has been stopped.
Pharmacodynamic interactions As discussed at the beginning of this article, when amiodarone is used in combination with other antiarrhythmics, an additive effect on myocardial depression may be observed. In addition to this, concurrent use of beta-blockers, verapamil or diltiazem may increase the risk of bradycardia and AV block.2,3 Concurrent use may sometimes be therapeutically beneficial but patients should be monitored for adverse effects. Pharmacodynamic interactions involving QT interval prolongation and hypokalaemia were discussed earlier.
Amiodarone is also reported to reduce the effects of thyroid hormones used to treat hypothyroidism, probably because it contains 37 per cent iodine and, consequently, has a number of effects on the thyroid gland. It slows the conversion of T4 to T3, inhibits their cellular uptake and inhibits the binding of T3 to receptors. Therefore, patients taking thyroid hormones who are then given amiodarone should be monitored for any evidence of a changed response to their thyroid treatment.3
Pharmacokinetic interactions This group of interactions can be divided into those where amiodarone activity is affected and those where amiodarone affects the action of other drugs.
Effects on amiodarone Amiodarone activity is affected by two mechanisms — reduction in bioavailability and inhibition of its metabolism.The anion exchange resin cholestyramine can reduce the serum levels and half life of amiodarone by 50 per cent. It is likely that this is because it binds amiodarone in the gut. Patients on concurrent therapy should be monitored and the amiodarone dosage increased if necessary. Administration of amiodarone at least one hour before cholestyramine may reduce the interaction but, because amiodarone is extensively excreted in the bile, it will not be prevented entirely.3
The metabolism of amiodarone has been reported to be inhibited by cimetidine, a P450 enzyme inhibitor,17 and induced by phenytoin, a P450 enzyme inducer.18 Not all patients on amiodarone are affected by cimetidine but patients should be monitored for signs of raised amiodarone concentrations, such as nausea and bradycardia. Amiodarone levels in patients given phenytoin concurrently have decreased to approximately 35 to 50 per cent below predicted values.18Therefore, patients should be checked for signs of therapeutic failure if phenytoin is added to their drug regimen.
Two protease inhibitors, ritonavir and nelfinavir, are potent P450 enzyme inhibitors. Theoretically, they would both be expected to produce a large increase in amiodarone concentrations, due to the inhibition of its metabolism. However, there are no published reports of this interaction to date but it is suggested that there may be an increased risk of ventricular arrhythmias,5 so concurrent use should still be avoided.
Effects of amiodarone Amiodarone inhibits the activity of two cytochrome P450 enzymes — CYP2D6 and CYP2C9. As a consequence, it has been reported to reduce the metabolism of certain drugs (see Panel 6).
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Panel 6: Drugs whose metabolism is inhibited by amiodarone2,3
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It has not been possible within the scope of this article to discuss all the drug interactions that involve antiarrhythmics. The aim has been to provide an understanding of the general interactions which apply to antiarrhythmic drugs, and those which involve the antiarrhythmics on which patients are commonly maintained. This should enable pharmacists to intervene to prevent therapeutic failure or potential toxicity.
CASE STUDY: DIGOXIN — AMIODARONE INTERACTIONA 70 year old woman is admitted to hospital with uncontrolled atrial fibrillation. She is complaining of palpitations and shortness of breath.
What advice should the pharmacist give ?
This interaction occurs in most patients. It becomes clearly evident within a few days and develops over the course of one to four weeks.3 In view of this patient's digoxin level, a recommendation should be made to the doctor to reduce the dose of digoxin to 62.5µg daily, otherwise digoxin toxicity is likely to occur. (ii) Amiodarone increases the anticoagulant effects of warfarin by inhibiting its metabolism. The interaction occurs in the majority of patients and usually develops within two weeks.3
(iii) The patient has a low potassium level, which will potentiate the arrhythmogenic potential of amiodarone and will sensitise the myocardium to the action of digoxin.2,3
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Mrs Lucas is the prescribing adviser for Channel Primary Care Group in East Kent