The H2-receptor antagonists (H2RA, often shortened to H2 antagonist) are a class of drugs used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells. In the United States, all four FDA-approved members of the group Cimetidine, Ranitidine, Famotidine, and Nizatidine are available over the counter in relatively low doses.
History and development:
Cimetidine was the prototypical histamine H2-receptor antagonist from which the later members of the class were developed. Cimetidine was the culmination of a project at Smith, Kline & French (SK&F; now GlaxoSmithKline) by James W. Black, C. Robin Ganellin, and others to develop a histamine receptor antagonist that would suppress stomach acid secretion.
In 1964 it was known that histamine stimulated the secretion of stomach acid, but also that traditional antihistamines had no effect on acid production. From these facts the SK&F scientists postulated the existence of two histamine receptors. They designated the one acted on by the traditional antihistamines H1, and the one acted on by histamine to stimulate the secretion of stomach acid H2.
The SK&F team used a rational drug design process starting from the structure of histamine. Hundreds of modified compounds were synthesized in an effort to develop a model of the then-unknown H2 receptor. One of the compounds that showed weak H2-antagonist activity, guanylhistamine, was the point of departure in the development of these drugs. Extension of the side chain was found to increase the H2-antagonist activity, but some agonist effects were retained. When the very basic guanidino group was replaced by the neutral thiourea, Burimamide, a specific competitive antagonist at the H2 receptor 100-times more potent than Nα-guanylhistamine was obtained, proving the existence of the H2 receptor.
Although an effective drug, it cannot be absorbed orally. The addition of a 4-methyl group further improved binding to the H2 receptor. Introduction of the electron-withdrawing sulfur atom into the side chain reduced the ring pKa. The proportion of the cationic form was also decreased, and the tele tautomer became predominant. Reduced ionization improved the membrane permeability of the molecule; the oral absorption of the resulting compound, Metiamide had an activity 10 times higher than that of burimamide. However, metiamide still showed some side effects in the form of hematological and kidney damage, which were attributed to the thiourea group.
A satisfactory replacement was found by substituting another electron-withdrawing
group on guanidine while retaining the appropriate pKa. A cyano group proved suitable,
and the safe and effective cimetidine resulted.
It then became clear that an Imidazole nucleus was not absolutely necessary for H2-antagonist activity. The furan derivative ranitidine is even more active than cimetidine, and famotidine is seven times more active still. Since none of these compounds is lipid soluble (their average partition coefficient is only 2, compared with coefficients of up to 1000 for typical H1 antagonists), they do not produce any sedative CNS action since they cannot cross the blood–brain barrier.
| Structure Activity Relationship | structure | |||
| Histamine: H1=H2 Agonism |
| |||
| 5-metylhistamine: H2>H1 Agonism | A methyl group is added at position # 5 of histamine. | |||
| Nα-guanylhistamine: Partial H2-Receptor Agonist (weak Antagonist) | A highly basic Guanidine group is added at terminal chain Amino group. | |||
| Full H2-Receptor Antagonist But with low potency, poor oral bioavailability |  | |||
| Metiamide: Full H2-Receptor Antagonist Higher potency, improved oral bioavailability, toxic(Thiourea) |  | |||
| Cimetidine: Full H2-Receptor Antagonist Higher potency, High oral bioavailability, low toxicity |  |
Quantitative Structure-Activity Relationships (QSAR):
1) Examination of the structures of all the H2 antagonists shows that Imidazole ring of histamine is not necessary for activity.
2) Other heterocyclic may be added in place of Imidazole ring hence giving more potent, selective and safe compounds.
3) Replacing the Imidazole ring of cimetidine with a furan-ring with a nitrogen-containing substituent, giving the compound Ranitidine. Ranitidine was found to have a far-improved tolerability profile (i.e. fewer adverse drug reactions), longer-lasting action, and ten times the activity of cimetidine.
 |
4) 
The famotidine is seven times more active still. It contains a highly basic guanidine group directly attached to ring. It is the most potent member and dose not interfere with the liver Enzymes.
The famotidine is seven times more active still. It contains a highly basic guanidine group directly attached to ring. It is the most potent member and dose not interfere with the liver Enzymes.5)
 |
If thiazole-ring is added in place of the furan-ring in ranitidine the compound becomes Nizatidine. It was developed by Eli Lilly and company and marketed in 1987 by Reliant Pharmaceuticals. It is considered to be equipotent with ranitidine.
6) If Imidazole ring containing member is used then N-H tatumer should be the predominant species for maximum activity. The electronic effects of the ring substituents and side chain structural features determine the tatumerism.
7) For optimal antagonist activity the Nitrogen group and the Hetero ring should be separated by four carbon distance.
8) The isosteric thioether linkage is present in all the members of this class hence necessary for activity.
9) The terminal Nitrogen containing functionality should be polar, non basic substituents for maximal activity.
10) Groups that are positively charged at physiological pH appear to confer antagonist activity. In general, antagonistic activity varies inversely with the hydrophilic character of the Nitrogen group.
11) Ranitidine and Nizatidine are exception to above mentioned point as they are much more active then is predicted by relative solubility effects.
Pharmacology:
The H2 antagonists are competitive antagonists of histamine at the parietal cell H2 receptor. They suppress the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid. They accomplish this by two mechanisms:
Histamine released by ECL cells in the stomach is blocked from binding on parietal cell H2 receptors, which stimulate acid secretion; therefore, other substances that promote acid secretion (such as gastrin and acetylcholine) have a reduced effect on parietal cells when the H2 receptors are blocked.
Like the H1-antihistamines, the H2 antagonists are inverse agonists rather than true receptor antagonists.
Clinical uses:
H2-antagonists are clinically used in the treatment of acid-related Gastrointestinal conditions. Specifically, these indications may include: - Peptic ulcer disease (PUD)
- Gastro esophageal reflux disease (GERD/GORD)
- Dyspepsia
- Prevention of stress ulcer (a specific indication of ranitidine)
- Some studies suggest that H2-antagonists might be effective in treating herpes viruses, such as shingles and herpes simplex.
- People that suffer from heartburn infrequently may take either antacids or H2-receptor antagonists for treatment.
- The H2-antagonists offer several advantages over antacids, including longer duration of action (6–10 hours vs. 1–2 hours for antacids), greater efficacy, and ability to be used prophylactically before meals to reduce the chance of heartburn occurring
Adverse effects:
H2 antagonists are generally well-tolerated, except for cimetidine where all of the following adverse drug reactions (ADRs) are common. Infrequent ADRs include hypotension.
Rare ADRs include: headache, tiredness, dizziness, confusion, diarrhea, constipation, and rash. Additionally, cimetidine may also cause gynecomastia in males, loss of libido, and impotence, which are reversible upon discontinuation.
References
- Katzung, Bertram G. (2004). Basic and Clinical Pharmacology, 9th ed.
Potent human MC1 receptor antagonist (IC50 = 17 nM), and alsoMC3 and MC5 partial agonist (EC50 values are 59 and 1300 nM, respectively). Exhibits binding affinity for A375 melanoma. MSG 606
ReplyDelete