Cimetidine
First generation H2 receptor antagonist
Cimetidine was the first approved H2 receptor antagonist and revolutionised the treatment of peptic ulcer disease in the 1970s. The British pharmacologist Sir James Black, who had previously developed the beta blockers, led the programme at SmithKline; he received the 1988 Nobel Prize in Medicine for the discovery of the H2 blockers. In Germany the compound was marketed as Tagamet, but it has since been largely superseded by ranitidine, famotidine and above all proton pump inhibitors, and has been off the German market for years.
Despite the low current prescription volume, cimetidine remains relevant in several contexts. It is still more widely used internationally and is available over the counter in some countries. It is also a textbook example of CYP inhibition: unlike newer H2 blockers, cimetidine inhibits CYP1A2, CYP2C9, CYP2D6 and CYP3A4 and therefore causes numerous drug interactions. When patients bring cimetidine back from abroad, physicians and pharmacists must keep these interactions in mind.
Mechanism of Action
Cimetidine competitively blocks the H2 receptors of the parietal cells in the stomach. Histamine is the main stimulator of hydrochloric acid production at this site; binding to the H2 receptor activates adenylate cyclase, cAMP rises, and the proton pump (H plus/K plus ATPase) is switched on. By blocking this histamine mediated stimulation, basal and meal stimulated acid secretion falls by about 60 to 70 percent. The effect starts within 1 hour of oral intake and lasts 6 to 8 hours.
Unlike the newer H2 blockers ranitidine, famotidine and nizatidine, cimetidine also inhibits several CYP isoenzymes and binds to androgen receptors. CYP inhibition explains the many drug interactions, while the antiandrogenic component accounts for the characteristic endocrine side effects such as gynaecomastia and erectile dysfunction. Modern H2 blockers and proton pump inhibitors do not share this interaction and side effect profile.
Cimetidine is mostly eliminated unchanged by the kidneys with a half life of about 2 hours. Renal impairment prolongs the half life considerably and dose adjustment is required. Oral bioavailability is approximately 60 to 70 percent; food slightly delays absorption without affecting overall exposure.
Indications
- Gastroduodenal ulcers (gastric ulcer, duodenal ulcer) to promote healing
- Relapse prophylaxis after a healed ulcer at a low maintenance dose
- Gastro oesophageal reflux disease (GERD) of mild severity
- Zollinger Ellison syndrome (gastrinoma) with marked hypersecretion, at higher doses
- Stress ulcer prophylaxis in intensive care, now mostly replaced by pantoprazole or other PPIs
- Prophylaxis of aspiration pneumonia before anaesthesia in at risk patients
In modern guidelines for GERD and ulcer disease, proton pump inhibitors such as esomeprazole, pantoprazole and omeprazole are first choice. Cimetidine is hardly prescribed in Germany any more, but remains part of the history of pharmacology and of clinical teaching on drug interactions.
Dosage and Administration
Ulcer therapy: 800 mg once daily at bedtime or 400 mg twice daily for 4 to 8 weeks. Maintenance therapy: 400 mg at bedtime. Zollinger Ellison syndrome: 300 to 600 mg every 6 hours, in individual cases higher. Parenteral stress ulcer prophylaxis: 200 mg intravenously every 4 to 6 hours or a continuous infusion of 50 mg per hour.
The tablet can be taken with or without food and is swallowed with a glass of water. For nocturnal symptoms a single bedtime dose is convenient, because basal acid secretion is strongest at night.
Renal impairment: with a creatinine clearance below 30 ml/min extend the dosing interval or halve the dose; dialysis patients require an additional dose after dialysis. Hepatic impairment: cautious dosing in severe impairment because hepatic metabolism is reduced. Elderly patients: use lower doses and monitor more closely; cimetidine appears on lists of potentially inappropriate medications owing to its CNS side effects and interactions.
Side Effects
Common: diarrhoea, headache, fatigue, dizziness, skin rash, muscle pain.
Uncommon to rare: gynaecomastia in men (due to the antiandrogenic effect), erectile dysfunction, reduced libido, galactorrhoea, menstrual disturbances, elevated liver transaminases, pancreatitis, bradycardia, AV conduction disturbances, confusion and hallucinations in older patients, blood count changes (leukopenia, thrombocytopenia, agranulocytosis).
Rare and important: interstitial nephritis, severe skin reactions such as Stevens Johnson syndrome, autoimmune haemolytic anaemia, acute hepatitis, neurological symptoms such as delirium with high dose therapy or severe renal impairment.
Clinical note: gynaecomastia was reported in up to 4 percent of men on cimetidine and is reversible after stopping therapy. The antiandrogenic effect even led to off label use in androgenetic alopecia and hirsutism, but cimetidine is not approved for these indications and is now obsolete because better alternatives exist.
Interactions
Cimetidine is among the drugs with particularly many clinically relevant interactions, because it inhibits CYP1A2, CYP2C9, CYP2D6, CYP3A4 and renal tubular secretion. A full list is hardly possible; the most important interactions are:
- Vitamin K antagonists (warfarin, phenprocoumon): plasma levels and INR rise markedly, increased bleeding risk
- Theophylline: plasma level rises sharply, toxicity with tachycardia and seizures possible
- Phenytoin, carbamazepine, lamotrigine: anticonvulsant levels rise, risk of neurotoxic effects
- Lidocaine, quinidine, propranolol, metoprolol: elevated plasma levels, cardiovascular risks
- Tricyclic antidepressants, SSRIs: plasma levels rise, additive central effects
- Benzodiazepines (diazepam, midazolam): prolonged action, increased sedation
- Metronidazole, ketoconazole, itraconazole: increased levels and toxicity risk
- Opioids (morphine, methadone): increased sedation and respiratory depression
- Metformin, procainamide, ranitidine: competition for renal tubular secretion, plasma levels of both agents may fluctuate
- Clopidogrel: reduced formation of the active metabolite via CYP2C19 inhibition, attenuated effect (similar to omeprazole)
Special Notes
Why superseded? Cimetidine was pushed into the background by the modern H2 blockers ranitidine and famotidine (fewer interactions, no endocrine side effects) and above all by proton pump inhibitors (stronger and more sustained acid suppression, less tachyphylaxis). Cimetidine has been off the German market for several years, though older patients often still recognise the compound from their own earlier therapy.
Ranitidine context: ranitidine, a successor to cimetidine, was withdrawn in 2020 because of contamination with the carcinogenic nitrosamine NDMA. This shifted further prescriptions towards PPIs and famotidine. Cimetidine is less susceptible to NDMA formation from its molecular structure, but the decline of its market share had already occurred independently.
Pregnancy: possible where clearly indicated; the database rests on decades of clinical experience. Current practice for pathological acid problems in pregnancy prefers antacids, H2 blockers such as famotidine or PPIs. Breastfeeding: passage into breast milk occurs; some sources consider use compatible, others advise caution.
Monitoring: during long term therapy check blood count and liver and kidney values. In older patients monitor cognitive function and analyse interactions with all concomitant medication. With warfarin check INR closely; with theophylline perform serum level checks.
You may also be interested in
- Esomeprazole, modern proton pump inhibitor
- Warfarin, vitamin K antagonist with CYP interactions
- Clopidogrel, P2Y12 antagonist with CYP2C19 dependence
- Phytomenadione, vitamin K antidote
- Mesalazine, for chronic inflammatory bowel disease
Frequently Asked Questions
Why is cimetidine no longer prescribed today?
Proton pump inhibitors such as pantoprazole are superior in efficacy and tolerability, and cimetidine causes many drug interactions through CYP inhibition. Modern H2 blockers such as famotidine do not have these problems. Cimetidine has been off the German market for several years, though it is still partly available in other countries.
Why does cimetidine cause gynaecomastia?
Cimetidine binds as a weak antagonist to androgen receptors and blocks the androgen dependent feedback loop. In some men this raises prolactin and the breast gland enlarges. After discontinuation the gynaecomastia usually regresses. Modern H2 blockers and PPIs do not cause this problem.
I brought cimetidine back from abroad, what do I need to watch?
With any other medicines you take at the same time, cimetidine can intensify effects and side effects, particularly with anticoagulants, antiepileptics and theophylline. Ask your doctor or pharmacist before taking it so that an interaction check can be performed. Switching to an alternative available in Germany, such as famotidine or a PPI, is usually sensible.
Which acid blocker makes most sense today?
For acute symptoms and most chronic indications, proton pump inhibitors such as esomeprazole, pantoprazole and omeprazole are first choice. They suppress acid production more strongly and durably than H2 blockers. For mild reflux symptoms antacids and low dose PPIs are alternatives. H2 blockers still have a role in on demand or second line therapy.
Sources
- EMA, European Medicines Agency
- AWMF, S2k Guideline Gastro oesophageal Reflux Disease
- Gelbe Liste, Cimetidine active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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