methylprednisolone

Mechanism

Methylprednisolone (a systemic glucocorticoid) modestly lowers the seizure threshold and induces CYP3A4. Bupropion also lowers the seizure threshold. Combined action raises the risk of episodes, particularly in patients with prior epilepsy or eating disorders.

Symptoms

Seizures (generalised tonic-clonic or focal). In patients without prior epilepsy: isolated episodes; with epilepsy: more frequent seizures. Agitation, anxiety possible.

Management

Avoid the combination in patients with prior epilepsy or eating disorders. If unavoidable, do not increase bupropion dose and discontinue methylprednisolone as soon as possible. Alternative antidepressants without seizure threshold reduction: sertraline, escitalopram.

Mechanism

Additive tendon injury risk. Fluoroquinolones disrupt collagen synthesis in tendon fibres; glucocorticoids suppress repair. FDA carries a boxed warning for tendinitis and Achilles tendon rupture.

Symptoms

Pain and swelling in the Achilles tendon (less often other large tendons). Sudden 'snap' and inability to bear weight indicates rupture. Symptoms typically appear within 1–4 weeks and may persist for months after withdrawal.

Management

Avoid the combination, especially in patients over 60, post-kidney-transplant, and with athletic activity. Alternative antibiotics: a cephalosporin or nitrofurantoin (no tendon effect). If ciprofloxacin is needed, limit physical activity for the entire course and 1 month after.

Mechanism

Clarithromycin blocks CYP3A4 – the main methylprednisolone metabolic route. Methylprednisolone plasma levels rise 2- to 3-fold, with risk of iatrogenic Cushing's syndrome and hyperglycaemia.

Symptoms

Moon face, central obesity, abdominal striae, hypertension, hyperglycaemia (Cushing's syndrome). With prolonged combination and abrupt withdrawal: adrenal insufficiency risk with hypotension and weakness.

Management

For short clarithromycin courses (5–7 days), halve methylprednisolone temporarily. For prolonged therapy, switch antibiotics (azithromycin, doxycycline) or replace methylprednisolone with hydrocortisone (less CYP3A4-dependent).

Mechanism

Ketoconazole strongly blocks CYP3A4 – the main methylprednisolone metabolic route. Methylprednisolone plasma levels rise 2- to 3-fold. Risk of iatrogenic Cushing's syndrome and adrenal insufficiency on withdrawal.

Symptoms

Moon face, central obesity, abdominal striae, hypertension, hyperglycaemia (Cushing's syndrome). With prolonged combination and abrupt withdrawal: adrenal insufficiency risk with hypotension and weakness.

Management

Avoid the combination. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses. If ketoconazole is needed, halve the methylprednisolone dose.

Mechanism

Ritonavir is the most potent CYP3A4 inhibitor available – the main methylprednisolone metabolic route. Methylprednisolone plasma levels rise 5- to 10-fold. High risk of iatrogenic Cushing's syndrome and severe adrenal insufficiency on withdrawal.

Symptoms

Moon face, central obesity, abdominal striae, hypertension, hyperglycaemia (Cushing's syndrome). With prolonged combination and abrupt withdrawal: adrenal insufficiency risk with hypotension and weakness.

Management

Avoid the combination. Alternative glucocorticoid: hydrocortisone (less CYP3A4-dependent) or inhaled/topical routes (no systemic effect). If methylprednisolone is needed, reduce 5-fold and keep the course as short as possible. Taper over several weeks on withdrawal because of suppressed adrenal cortex.