Drug-drug interactions are an increasing problem in clinical practice, and may result in treatment failures. We describe an 83-year-old man with giant cell arteritis who suffered steroid treatment failure as a result of steroid metabolism induction from concurrent antiepileptic therapy.

Case report

An 83-year-old man with previous cerebral abscess (surgically resected 55 years prior) and postoperative seizure disorder presented with headache, scalp tenderness and reduced left eye visual acuity. His medications were: phenytoin 400mg daily, cilazapril 1.5mg daily, omeprazole 40mg daily, melatonin 3mg nightly, bendrofluazide 2.5mg daily and primidone 500mg daily.

Examination revealed visual acuity of 4/5 in the right eye, and hand movements only in the left eye. Fundoscopy showed left sided ischaemic optic neuropathy. Physical examination was otherwise normal. Bloods are shown in Table 1. Left temporal artery biopsy was diagnostic of giant cell arteritis.

Table 1: Full blood count, serum chemistries, liver function and inflammatory markers on presentation.

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Sight-compromising disease prompted treatment with intravenous methylprednisolone 1g daily for three days. This decreased c-reactive protein (CRP) from 86mg/L to 15mg/L. Oral prednisone 60mg daily was then started, but CRP rose continuously for four days. Re-treatment with three days of intravenous methylprednisolone 500mg daily once again caused a CRP fall for three consecutive days. Upon transition to oral prednisone, this time 80mg daily, CRP rose again. A single intramuscular injection of triamcinolone acetonide 80mg, prednisone 60mg twice daily and 500mg of intravenous cyclophosphamide were prescribed, and CRP declined to normal over four days. He received one further dose of 500mg intravenous cyclophosphamide, and has successfully weaned prednisone to 15mg daily over seven months without symptomatic or biochemical disease recurrence. Though headaches and scalp tenderness resolved within four days, vision did not improve. Primidone was stopped, but phenytoin therapy continues.

His response to potent intravenous and intramuscular steroids and high dose oral steroids, but lack of response to standard treatment doses of oral prednisone, can be explained by CYP 3A4 induction by pheytoin and primidone increasing steroid metabolism.

Discussion

The ageing global population brings with it an increased prevalence of polypharmacy.1 This increases the potential for drug-drug interactions (DDIs). Our case of giant cell arteritis was unresponsive to conventional doses of oral glucocorticoids because of steroid metabolism induction from concomitant antiepileptic therapy. Clinicians must be vigilant to this interaction, especially in the elderly population.

As far back as the 1960s, the importance of DDIs on steroid metabolism were recognised.2 To understand these DDIs, a review of steroid metabolism is necessary. Prednisone is a synthetic corticosteroid, which is metabolically inactive until converted to prednisolone by hepatic 11-beta hydroxysteroid dehydrogenase.3 Prednisolone, the active compound, is metabolised by CYP 3A4, which is prone to interaction with CYP inducers and inhibitors, the main culprits on the inducer list being antiepileptics (especially phenytoin, carbamazepine and phenobarbitone) and rifampicin.3,4

DDIs involving steroids are likely under-recognised. Following a flurry of publications on the subject in the late 1970s and 1980s, the topic of steroid metabolism induction appears to have fallen out of favour in the medical literature. In 1971, the plasma half-life of endogenous cortisol was noted to be reduced by co-administration of phenytoin.2 In 1972, a decrease in respiratory function was noted in a group of asthmatics exposed to phenytoin, presumably due to increased steroid metabolism.5 In 1976, nine steroid-dependent patients with rheumatoid arthritis were administered the enzyme inducer phenobarbitone, and showed a significant deterioration in disease control due to increased steroid metabolism.6 Similar interactions were later observed in neurosurgical patients on dexamethasone and those with steroid-dependent pemphigus.7–9

The increasing prevalence of polypharmacy mandates careful consideration of DDIs when prescribing steroids. Close attention should be paid to current use of CYP-inducing medications such as those mentioned above. Elevated gamma-glutamyltransferase levels (as in our patient) may be a clue to enzyme induction, and steroid doses should be adjusted accordingly.10 Doubling of usual steroid doses may be a good starting point in cases where titration over weeks is not appropriate, eg sight-compromising GCA.11 Failing to do so may result in treatment failure.

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