Cimetidine

Cimetidine is a histamine H₂-receptor antagonist which rapidly inhibits both basal and stimulated gastric secretion of acid and reduces pepsin output. It is a reversible, competitive antagonist, and is used as an anti-ulcer drug. It is highly selective in its action, is virtually without effect on H₁-receptors, or indeed on receptors for other autocoids or drugs. Despite the widespread distribution of H₂-receptors in the body, cimetidine interferes remarkably little with physiological functions other than gastric secretion, implying that the extragastric H₂-receptors are of minor physiological importance.

However, H₂ blockers like cimetidine do inhibit those effects on the cardiovascular and other systems that are elicited through the corresponding receptors by exogenous or endogenous histamine.

Cimetidine inhibits gastric acid secretion elicited by histamine or other H₂ agonists in a dose-dependent, competitive manner; the degree of inhibition parallels the plasma concentration of the drug over a wide range. In addition, the H₂ blockers inhibit gastric secretion elicited by muscarinic agonists or by gastrin, although this effect is not always complete.

This breadth of inhibitory effect is not due to non-specific actions at the receptors for these other secretagogues. Rather, this effect, which is non-competitive and indirect, appears to indicate either that these two classes of secretagogues utilise histamine as the final common mediator or, more probably, that ongoing histaminergic stimulation of the parietal cell is important for amplification of the stimuli provided by ACh or gastrin when they act on their own discrete receptors. Receptors for all three secretagogues are present on the parietal cell. The ability of H₂ blockers to suppress responses to all three physiological secretagogues makes them potent inhibitors of all phases of gastric acid secretion. Thus these drugs will inhibit basal (fasting) secretion and nocturnal secretion and also that stimulated by food, sham feeding, fundic distension, insulin, or caffeine. The H₂ blockers reduce both the volume of gastric juice secreted and its hydrogen ion concentration. Output of pepsin, which is secreted by the chief cells of the gastric glands (mainly under cholinergic control), generally falls in parallel with the reduction in volume of the gastric juice. Secretion of intrinsic factor is also reduced, but it is normally secreted in great excess, and absorption of vitamin B12 is usually adequate even during long-term therapy with H₂ blockers.

Concentrations of gastrin in plasma are not significantly altered under fasting conditions; however, the normal prandial elevation of gastrin concentration may be augmented, apparently as a consequence of a reduction in the negative feedback that is normally provided by acid.

Cimetidine is rapidly and virtually completely absorbed from the gastro-intestinal tract. Absorption is little impaired by food or by antacids. Peak plasma concentrations are obtained about an hour after administration on an empty stomach, and about 2 hours after administration with food. The duration of action is reported to be prolonged by administration with food. Peak concentrations in plasma are attained in about 1 to 2 hours. Hepatic first-pass metabolism results in bioavailabilities of about 60% for cimetidine. The elimination half-life is about 2-3 hours. Cimetidine is eliminated primarily by the kidneys, and 60% or more may appear in the urine unchanged; much of the rest is oxidation products. Small amounts are recovered in the stools.

Cimetidine crosses the placental barrier and is excreted in milk. It does not readily cross the blood-brain barrier.

There are no preclinical data.