The potential for drug interactions is high in palliative care due to polypharmacy.[1] The following are some selected drug interactions which are pertinent to palliative care prescribing.

Warfarin

The anticoagulation effect of warfarin can be affected by many drugs.[2] Anticoagulation may increase with:

• dextropropoxyphene (co-proxamol)
• NSAIDs
• amiodarone
• erythromycin, clarithromycin
• quinolone antibiotics (e.g. ciprofloxacin)
• metronidazole
• fluconazole, itraconazole, miconazole, ketoconazole
• stanozolol

Amiodarone

A number of drugs used concomitantly with amiodarone increase the risk of ventricular arrhythmias and the advice is to avoid them:

• tricyclic antidepressants (amitriptyline etc.)
• phenothiazines, haloperidol
• flecainide
• quinine
• erythromycin (parenteral)

The low doses of haloperidol (antiemetic) and TCAs (neuropathic pain) used in palliative care probably carry a low risk, but one that cannot be dismissed.[3]

MAOIs (antidepressants) and selegiline

There is a serious and potentially fatal interaction (serotonin syndrome[4]) between pethidine and MAOIs.[5,6] A similar reaction is seen with selegiline, an MAO-B inhibitor.

No adverse interaction normally occurs in patients on MAOIs given morphine, but there are two isolated and unexplained reports of patients on MAOIs who showed hypotension, marked in one case and accompanied by unconsciousness (and rapidly and effectively reversed by naloxone). Some very limited evidence also suggests that no interaction occurs with methadone.[5]

The concurrent use of MAOIs and phenothiazines is usually safe and effective. The exception appears to be levomepromazine (methotrimeprazine) which has been implicated in two fatal reactions with pargyline and tranylcypromine.[5]

Anticonvulsants

Carbamazepine[7,8] levels are increased (risk of toxicity) with:

• dextropropoxyphene[9,10] (co-proxamol)
• clarithromycin, erythromycin
• fluoxetine, fluvoxamine

Phenytoin levels are increased (toxicity) by:

• clarithromycin, metronidazole, trimethoprim
• fluconazole, miconazole
• omeprazole
• fluoxetine, fluvoxamine
• aspirin
• diltiazem, nifedipine
• amiodarone

Carbamazepine and phenytoin levels are decreased (risk of fits) by corticosteroids.

Carbamazepine, phenytoin and phenobarbital can reduce the efficacy of corticosteroids. This two-way interaction[11,12] is common when managing patients with cerebral tumours.

Antifungal drugs (imidazoles)

(Fluconazole, miconazole, itraconazole, and ketoconazole).

• all enhance warfarin anticoagulation
• fluconazole, miconazole increase phenytoin levels
• fluconazole, miconazole increase sulphonylureas e.g. gliclazide, glibenclamide (risk of hypoglycaemia)
• fluconazole increases celecoxib levels[13] → halve celecoxib dose
• itraconazole, ketoconazole and possibly fluconazole increase sedation with midazolam

PPIs (proton pump inhibitors)

• omeprazole increases blood diazepam levels (increase sedation)
• omeprazole enhances anticoagulation effect of warfarin

Metronidazole

• disulfiram-like reaction with alcohol
• enhances anticoagulation with warfarin
• increases phenytoin blood levels (toxicity)
• increases blood levels of fluouracil (5-FU) increasing toxicity

SSRI antidepressants

• fluoxetine, fluvoxamine increase carbamazepine or phenytoin blood levels (toxicity)
• fluoxetine increases plasma levels of flecainide
• serious reaction with MAOIs, selegiline (serotonin syndrome)[4]
• increased serotonergic effects with St John's wort (avoid)

St John's wort

• increased serotonergic effects with SSRIs (avoid)
• reduced anticoagulant effect of warfarin
• reduced plasma levels of carbamazepine, phenytoin, phenobarbital (risk of fits)
• reduced plasma levels of digoxin

Dextropropoxyphene (in co-proxamol)

• increases blood levels of carbamazepine up to 6-fold[9,10] (toxicity)
• enhanced anticoagulation effect of warfarin

Regular paracetamol may also affect warfarin anticoagulation.[14-20]

Torsades de pointes

An increasing number of drugs have been recognised to prolong the QT interval and potentially cause torsades de pointes, a serious cardiac arrhythmia.[21] A register of drugs that cause QT prolongation is available on the internet at http://www.torsades.org