Cimetidine

Cimetidine is a gastric acid reducer used in the short-term treatment of duodenal and gastric ulcers.[1] The drug is effective in managing gastric hypersecretion, and therefore, used for the management of reflux esophagitis disease and in the prevention of stress ulcers. With the development of proton pump inhibitors, such as omeprazole, approved for the same indications, cimetidine is available as an over the counter formulation for the prevention of heartburn or acid indigestion, along with the other H2-receptor antagonists. 

In the past, before the approval of proton pump inhibitors, intravenous cimetidine offered a treatment option to seriously ill patients in the intensive care unit who required prophylaxis against stress-induced ulcers through its H2-receptor antagonist.[2]

Recently, several studies have assessed the use of cimetidine in dermatology, including warts, ulceration, and mastocytosis. For example, treatment of multiple warts in pediatric heart transplant recipients.[3] In adults, cimetidine therapy appears to be beneficial with low toxicity in the treatment of recalcitrant warts.[4] This effect may be due to reports of the immunomodulatory properties of this drug, attributed to cimetidine's ability to reduce regulatory/suppressor T cell-mediated immunosuppression.[5]

There are also reports that cimetidine can inhibit heme biosynthesis and results in symptomatic improvement in children with acute intermittent porphyria, and porphyria cutanea tarda. Both conditions are related to erythropoietic protoporphyria, a rare hereditary disease of heme biosynthesis that manifests with severe photosensitivity and hepatotoxicity. The rapid reduction in photosensitivity was observable within weeks of initiating cimetidine systemic therapy, and skin photosensitivity was also improved. Also, there was a reduction in serum erythrocyte protoporphyrin levels, and liver function tests improved with no adverse effects resulted from cimetidine for over two years of treatment.[6]Similar results were reported with the use of cimetidine and lactulose.[7] However, other researchers reported that there is not enough evidence for the benefit of cimetidine in protoporphyria.[8][9]

Other dermatological indications include (i) condylomata acuminate and papillomatosis in young children,[10] (ii) chronic idiopathic urticaria and other types of urticaria,[11] (iii) pruritus after a burn injury,[12], and (iv) in treating “periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome”.[13]

Cimetidine has shown beneficial effects on cell-mediated immunity following burn injury,[14] and alleviated damages induced by long-term low-dose neutron and gamma combined irradiation in animals via antioxidation and immunomodulation.[15]

Other studies support cimetidine as a treatment for bladder pain resulting from interstitial cystitis. There is not yet a conclusion whether the mechanism involves a peptidergic pathway in the human bladder as cimetidine has on the parietal cells of the gastrointestinal tract.[16]

Understanding the physiology of gastric acid secretion is essential for understanding the mechanism of action of cimetidine. The primary stimuli for gastric acid secretion include (i) gastrin, released from antral G cells, (ii) histamine released from oxyntic enterochromaffin-like cells,[17] and (iii) acetylcholine released from antral and oxyntic neurons secondary to parasympathetic (vagal) stimulation. Other stimuli for gastric secretion include ghrelin and motilin. Acid release results from the stimulatory effect of histamine on parietal cells, which is mediated by adenylate cyclase activation and the generation of cyclic AMP (cAMP).[1] This cAMP activates a specific protein kinase, which phosphorylates a yet unknown substrate for the propagation of the stimulatory signal.[18]

 The chief inhibitors of acid secretion are somatostatin released from oxyntic and antral D-cells, cholecystokinin, atrial natriuretic peptides, nitric oxide, and glucagon-like peptide-1.[19]

 The H2-receptor antagonist cimetidine competitively blocks histamine from stimulating the H2-receptors located on the gastric parietal cells (these cells are responsible for hydrochloric acid secretion and secretion of the intrinsic factor). The effect results in reducing the volume of gastric acid secretion from stimuli, including histamine, food, caffeine, and insulin.

Cimetidine is available as an oral tablet and solution. The drug can also be administered parenterally as an intravenous (IV) injection. The recommended dosage of cimetidine for the pediatric patient is 20 to 40 mg/kg/day administered in divided doses every 6 hours (5 to 10 mg for neonates, and 10 to 20 mg for infants; both divided every 6 to 8 hours also). The recommended dosage for the treatment of peptic ulcers in adults is 300 to 400 mg twice daily or 800 mg at bedtime for up to eight weeks. The maintenance dosage of cimetidine is 400 mg per day. Dosages of 200 to 400 mg (OTC formulations) per day are effective at managing or preventing heartburn caused by the intake of caffeine and certain foods. Thus, cimetidine is administered thirty minutes before a meal.

High doses of cimetidine (over 5 g/day) can cause reversible impotence or gynecomastia.[20] This effect appears to be the result of the antiandrogenic potential of cimetidine, which depends on an increase in prolactin levels secondary to histamine H2 receptor blockade. Also, cimetidine has non-specific actions that stimulate prolactin secretion, causing galactorrhea in men in a dose-related pattern.[21][22] The effects could also be related to a blockade of the 2-hydroxylation of estradiol. However, gynecomastia in men is not an adverse effect with the other H2 receptor blockers (ranitidine, famotidine, and nizatidine). 

Patients receiving treatment with drugs metabolized through the cytochrome P450 enzymatic pathway may experience enhanced drug effects resulting from pharmacokinetic interaction when treated concomitantly with cimetidine, as it is a well-known enzyme inhibitor of several CYP isoforms including 1A2, 2C9, 2D6, 3A4 P450 isoforms. Clinically relevant is inhibition of cytochrome 3A4 and 1A2.[20][23]. Inhibition of these enzymes can lead to increased plasma levels of certain drugs including warfarin, tricyclic antidepressants, lidocaine, calcium channel blockers, quinidine, oral sulfonylureas, phenytoin, theophylline, benzodiazepines, and beta-blockers (metoprolol and propranolol). For example, patients treated with warfarin sodium and cimetidine were found to have augmented hypoprothrombinemia and higher blood concentrations of warfarin. Such effects did not occur in patients treated with ranitidine and warfarin sodium. The effect is related to inhibition of hepatic microsomal activity caused by cimetidine, which resulted in reduced metabolic clearance of warfarin and augmented its anticoagulant effect.[24]

The interaction involving beta-blockers (metoprolol or propranolol) results in significant sinus bradycardia and hypotension.[25] Such interaction does not occur with other beta-blockers such as atenolol, or nadolol.

Drug interactions are not observed clinically with other H2-blockers, including ranitidine, famotidine, and nizatidine. Cimetidine raises the pH of the gastric contents. This increased pH may lead to decreased absorption of drugs that require a lower pH to dissolve or increased absorption of drugs with absorption reduced by acid inactivation in the stomach.[26][27]

Impairment of vitamin B12 absorption raises the possibility that long-term, full-dose therapy with cimetidine may produce B12 deficiency similar to that observed in other hypochlorhydric states.[28] This effect is because parietal cells produce intrinsic factor required for vitamin B12 absorption. This effect is more common in younger, female patients and will resolve with the discontinuation of cimetidine therapy.[28]

There is a low incidence of cimetidine-induced hepatitis, suggesting a hypersensitivity-type reaction.[29] There are some reported central nervous system effects, such as headache, dizziness, delirium, drowsiness, and somnolence, which can limit cimetidine's use in the geriatric population and patients with renal and hepatic disorders.[30] Therefore, monitoring of renal function is critical in the elderly to avoid these neuropsychiatric effects. The adverse effects mentioned here, along with the availability of proton pump inhibitors approved for the treatment of similar gastrointestinal conditions, have limited the use of cimetidine.

Cimetidine can induce clinically insignificant elevations of serum creatinine in a high percentage of patients. However, this resolves when the discontinuance of the drug.[31] Recommendations are that patients with a GFR of 10 to 50 ml/minute receive 50% of the normal dose, while patients with a GFR of less than 10 ml/minute receive a dose of 300 mg every 8 to 12 hours. Elderly patients (greater than or equal to 65 years or with a CrCl under 50 mL/minute) should be treated with lower doses to prevent the risk of mental status changes. The use of acid-suppressing drugs during the first trimester of pregnancy is not associated with significant teratogenic risks.[32][33] Therefore, cimetidine is assigned a category B in pregnant females by the FDA, which means that animal studies have failed to show a fetal risk, and there are no adequate and well-controlled studies conducted in pregnant females. Patients who have experienced any hypersensitivity reaction to this drug or any H2-receptor antagonist should avoid cimetidine.