Cimetidine

Outline of Presentation History of Cimetidine Properties of H2 receptor antagonists Pharmacokinetics Mechanism of Action (Pharmacodynamics) Toxicity Improvements

History H1 receptor antagonists were discovered by chance. H2 receptor antagonists, however, resulted from extensive research by Smith, Kline, and French. Cimetidine was first marketed in the United Kingdom in 1976. It is used for the treatment of gastric hyperacidity.

Histamine, a stimulator of allergic reactions, triggers the release of acid when it binds to a receptor in the gut lining.

Existing antihistamines - used to treat hay fever - did not prevent this acid release. Therefore, the histamine was binding to a new receptor in the gut that was different from the H1 receptor. By modifying histamine, it was confirmed that a different histamine receptor did exist - H2 receptor. So, histamine acts as an H2 receptor agonist (stimulator) in the gut.

The goal was to find an H2 receptor antagonist to compete with histamine. After four years of research, guanylhistamine was found to act as an antagonist of histamine. However, it did stimulate some acid release as well. The acid release was due to the ability of the side chain to ionize and acquire a charge - just like histamine!

Structure of Guanylhistamine

Two years later, another molecule was created that still acted as a histamine antagonist. This molecule did not stimulate acid production. The molecule was made by replacing the charged guanidine moiety with a neutral thiourea. The molecule was called burimamide. However, it could not be given p.o.

Structure of Burimamide

To overcome the limits of burimamide, the electronic effects of influencing the hydrogen atom attached to one or other nitrogens in the imidazole ring was considered and the molecule metiamide was created. Metiamide was ten times more effective than burimamide and it could also be taken orally.

Metiamide has an electron releasing methyl group in the C5 position of the ring and an electron withdrawing sulfur atom in the side chain.

Researchers were worried about the thiourea group in metiamide because it had been known to produce toxic effects. A solution to this was to replace this group with a cyanoguanidine group. Thus, producing cimetidine.

Structure of Cimetidine

Structures of H2 receptor antagonists and Histamine

Properties of H2 receptors Hydrophilic molecules Determined by the imidazole ring Have low lipophilicity which limits access to the CNS Unable to mimic the stimulant actions of histamine because of the uncharged side chains

Equilibria between the Imidazole species

Pharmacokinetics Cimetidine is rapidly and completely absorbed in the GI tract. First pass metabolism reduces oral bioavailability to 60-70%. After cimetidine is absorbed, it produces blood and urine concentrations of unchanged cimetidine that are greater than the concentrations of any metabolite.

Cimetidine and possible metabolites

The rate but not the extent of absorption can be affected by food. The drug distributes throughout body tissues. 48% and 75% of an oral and IV dose, respectively, is excreted in the urine. Half life is roughly 2 hours - with normal renal function.

Metabolic Pathway

Mechanism of Action Cimetidine blocks the effects of histamine at the receptor located on the basolateral membrane of the parietal cell. This results in reduction of gastric volume and acidity. It also decreases the amount of gastric acid released in response to other stimuli.

Toxicity Cimetidine has been shown to have low acute toxicity. In repeated doses in rats studied for 12 months, no important adverse effects were observed. In dogs, having the same treatment, some tachycardia was observed at high doses.

Acute LD50 values of Cimetidine

Improvements Obviously there have been improvements upon cimetidine because the drugs Zantac, Axid, and Pepcid have been developed. These drugs are among the second generation of H2 antagonists that were introduced in the 1980’s. These drugs use aromatic groups in place of the imidazole functionality.

In Zantac, the methylimidazolyl ring of cimetidine is replaced by a dimethylaminomethylfuryl ring. The cyanoguanidine functionality is replaced by an isosteric methylnitroethenediamide moiety. Zantac is 4 to 10 times more potent than cimetidine.

Production of Zantac from the substituted form of Cimetidine

Replacement of the furan ring in Zantac by a thiazole group gives the drug Axid. Axid is 5 to 18 times more potent than cimetidine. In Pepcid, the N-methyl-2-nitro-1,1-ethenediamine group of axid is replaced by the aminosulfonylimidamide function, and the dimethylaminomethyl group is replaced by the guanidino functionality.

Structures of Tagamet, Zantac, Pepcid, and Axid

There have been more recent improvements in the field of gastric hyperacidity. The latest “drug of choice” is Protonix. In conclusion, Cimetidine was an excellent building block for the advancement of H2 antagonists.

Mechanisms regulating the actual histamine concentration in the vicinity of the parietal cell and at H2 receptors