Cimetidine

Cimetidine is the first histamine H2 receptor antagonist and reduces basal, nocturnal and stimulated gastric acid secretion. Its use is now limited by broad cytochrome P450 inhibition, inhibition of renal tubular secretion and antiandrogenic effects, so famotidine or a PPI is usually preferred.

Classification. H2 receptor antagonist; imidazole derivative.

Mechanism. Competitive, reversible blockade of parietal cell H2 receptors. The imidazole ring binds haem iron of cytochrome P450 enzymes, causing inhibition of CYP1A2, CYP2C19, CYP2D6 and CYP3A4.

Additional actions. Inhibits renal organic cation transport (OCT2 and MATE), raising serum creatinine by about 10 to 15% without changing GFR and raising levels of renally secreted cations. Weak androgen receptor antagonism and raised prolactin at high doses.

Pharmacokinetics. Oral bioavailability 60 to 70%; protein binding about 20%; half-life about 2 hours, prolonged in kidney impairment.

Elimination. About 50 to 75% of an oral dose is excreted unchanged in urine; the remainder is metabolised in the liver.

Adult oral doses unless stated. Doses assume normal kidney function. Maximum 2.4 g daily.

Duodenal ulcer. 400 mg twice daily or 800 mg at night for at least 4 weeks. Maintenance 400 mg at night.

Benign gastric ulcer. 400 mg twice daily or 800 mg at night for at least 6 weeks.

NSAID-associated ulcer healing. 400 mg twice daily or 800 mg at night for 8 weeks. A PPI is more effective and is preferred.

Reflux oesophagitis. 400 mg four times daily (with meals and at bedtime) for 4 to 8 weeks.

Zollinger-Ellison syndrome. 400 mg four times daily, adjusted to acid output, up to 2.4 g daily. A PPI is preferred.

Prevention of acid aspiration. 400 mg 90 to 120 minutes before induction of anaesthesia; in labour, 400 mg at the start, then up to 400 mg every 4 hours, maximum 2.4 g daily.

Reduction of pancreatic enzyme degradation in pancreatic insufficiency or short bowel syndrome. 0.8 to 1.6 g daily in four divided doses, 1 to 1.5 hours before meals.

Paediatric dosing.

• Neonate: 5 mg/kg four times daily.

• Age 1 month to 11 years: 5 to 10 mg/kg four times daily, maximum 400 mg each dose.

• Age 12 years and over: adult dosing.

Kidney impairment.

• CrCl 30 to 50 mL/min: 200 mg four times daily.

• CrCl 15 to 30 mL/min: 200 mg three times daily.

• CrCl under 15 mL/min: 200 mg twice daily.

• Haemodialysis: give the dose after dialysis.

Contraindications. Hypersensitivity to H2 receptor antagonists; coadministration with dofetilide.

Before starting. Endoscopy first for alarm features: new dyspepsia over age 55, weight loss, dysphagia, bleeding, iron deficiency anaemia, persistent vomiting or a mass.

Common adverse effects. Headache, dizziness, diarrhoea, rash and tiredness.

Serious adverse effects.

• Confusion, delirium and hallucinations, particularly in older adults and in kidney or liver impairment.

• Gynaecomastia, erectile dysfunction and galactorrhoea with high doses or prolonged use.

• Rare blood dyscrasias, hepatitis, interstitial nephritis and acute pancreatitis.

• Bradycardia and heart block, reported mainly with IV use.

Major interactions. CYP inhibition is dose related and clinically important.

• Warfarin: INR rise; avoid or monitor INR closely.

• Phenytoin, theophylline and lidocaine: raised levels and toxicity; avoid or monitor levels.

• Carbamazepine, tricyclic antidepressants, nifedipine, propranolol and benzodiazepines metabolised by oxidation: raised levels.

• Clopidogrel: reduced activation through CYP2C19 inhibition; avoid.

• Metformin, dofetilide, procainamide and other renally secreted cations: raised levels; dofetilide is contraindicated.

• Reduced absorption of ketoconazole, itraconazole capsules, atazanavir, dasatinib and oral iron.

Special groups.

• Pregnancy: human data are reassuring, but famotidine is preferred because it lacks antiandrogenic and enzyme effects.

• Breastfeeding: concentrated in milk; prefer famotidine.

• Children: limited use; famotidine or a PPI is preferred.

• Older adults: high risk of delirium and interactions; avoid where an alternative exists.

• Liver impairment: reduce dose and monitor mental state, particularly when kidney impairment coexists.

• Regional: inexpensive and sold without prescription in many markets, so screen for self-medication when reviewing warfarin, phenytoin or theophylline control.

Formulations. Tablets 200 mg, 400 mg and 800 mg; oral solution 200 mg in 5 mL. IV formulations are no longer available in many markets.

Oral administration. Take with meals and at bedtime for divided regimens, or as a single dose at bedtime for ulcer healing.

Baseline. Creatinine and calculated CrCl; full medication review for interacting drugs.

Monitoring.

• INR within 3 to 5 days of starting or stopping with warfarin.

• Phenytoin and theophylline levels when coprescribed.

• Mental state in older adults and in organ impairment.

• A small creatinine rise without change in true GFR is expected and does not indicate nephrotoxicity.

• Review response at 4 to 8 weeks; switch to a PPI if healing fails.

Therapeutic drug monitoring. Not applicable.

Stopping. No taper needed. On stopping, levels of interacting drugs fall over several days, so recheck INR and drug levels.

Referral and escalation. Endoscopy for alarm features or failure to respond. Switch to famotidine or a PPI when interactions, gynaecomastia or confusion occur.