The pharmacology of cimetidine, a new histamine H2-receptor antagonist

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  • Republished from Br J Pharmacol (1975), 53, 435–436

Burimamide and metiamide which have been described previously (Black, Duncan, Durant, Ganellin & Parsons, 1972; Black, Duncan, Emmett, Ganellin, Hesselbo, Parsons & Wyllie, 1973) are histamine H2-receptor antagonists. This communication describes some aspects of the pharmacology of cimetidine (N-cyano-N′-methyl-N″[2-(5- methyl-4-imidazolyl-methylthio)ethyl] guanidine; SK&F 92334), a new H2-receptor antagonist. In vitro the compound antagonizes the actions of histamine on isolated guinea-pig atrium and isolated electrically-stimulated rat uterus with KB values of 7.9 × 10−7m and 8.1 × 10−7m respectively, corresponding to pA2 values of 6.1 on each tissue. At very high concentrations cimetidine antagonizes the actions of isoprenaline on atrium and uterus and the actions of histamine and carbachol on isolated guinea-pig ileum but the results are not consistent with competitive antagonism at β-adrenoceptors, histamine H1-receptors or muscarinic receptors.

The effects of cimetidine on gastric acid secretion have been studied in a number of preparations. The results are summarized in Table 1. In all preparations cimetidine was approximately equiactive in inhibiting histamine and pentagastrin-stimulated acid secretion but less effective in inhibiting carbachol-stimulated secretion. Basal secretion was also inhibited. In Heidenhain pouch dogs the blood levels to give 50% inhibition of maximally-stimulated gastric secretion (EC50) were approximately 1–2 µm and the half-life of the compound about one hour.

Table 1.  The effects of cimetidine on gastric acid secretion
PreparationStimulantEffect of Cimetidine
Rat: Lumen-perfused stomachHistamine 15 µmol kg−1 h−1ID50 (rapid i.v. injection) 1.37 µmol/kg
ID50 (intraduodenal administration) 5.5 µmol/kg
i.v. infusion of 3 µmol kg−1 h−1 produced mean inhibition of 71%
Pentagastrin 60 µg kg−1 h−1ID 50 (rapid i.v. injection) 1.4 µmol/kg
Carbachol 30 µg kg−1 h−1Variable effect. Significant inhibition at 8 µmol/kg
Approximately 50% inhibition at 128–256 µmol/kg
Rat: Gastric fistulaBasal secretioni.v. infusion of 6 µmol kg−1 h−1 produced mean inhibition of 20% in first hour and 30% in second hour. With 60 µmol kg−1 h−1 inhibitions were 71% and 96% respectively.
Cat: Lumen-perfused stomachHistamine 3 µmol kg−1 h−1ID50 (rapid i.v. injection) 0.85 µmol/kg
Pentagastrin 10 µg kg−1 h−1ID50 (rapid i.v. injection) 1.45 µmol/kg
Dog: Heidenhain pouchHistamine 1.3 µmol kg−1 h−1ID50 (rapid i.v. injection) 1.7 µmol/kg
IE50 (i.v. infusion) 4.7 µmol kg−1 h−1
Oral administration of 10 & 20 µmol/kg produced mean inhibitions of 70 & 90% respectively
Dog: Heidenhain pouchPentagrastrin 8 µg kg−1 h−1µmol/kg by rapid i.v. injection gave mean inhibition of 55%
Carbachol 6.7 µg kg−1 h−1µmol/kg by rapid i.v. injection gave mean inhibition of 59%

In male human volunteers cimetidine given intravenously has been shown to inhibit histamineor pentagastrin-stimulated gastric secretion with an EC50 of about 2.5 µm and a half-life of about two hours.

In chronic toxicity studies metiamide has been shown at high doses to produce kidney damage and agranulocytosis in some dogs (Brimblecombe, Duncan & Walker, 1973). In tests so far carried out cimetidine at equivalent doses has not shown similar toxicity.

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