H2 antagonists, sometimes referred to asH2RAs[1] and also calledH2 blockers, are a class ofmedications that block the action ofhistamine at thehistamine H2 receptors of theparietal cells in thestomach. This decreases the production ofstomach acid. H2 antagonists can be used in the treatment ofdyspepsia,peptic ulcers andgastroesophageal reflux disease. They have been surpassed byproton pump inhibitors (PPIs). The PPIomeprazole was found to be more effective at both healing and alleviating symptoms of ulcers andreflux oesophagitis than the H2 blockersranitidine andcimetidine.[2]
H2 antagonists, which all end in "-tidine", are a type ofantihistamine. In general usage, however, the term "antihistamine" typically refers toH1 antagonists, which relieveallergic reactions. Like the H1 antagonists, some H2 antagonists function asinverse agonists rather thanreceptor antagonists, due to theconstitutive activity of these receptors.[3]
The prototypical H2 antagonist, calledcimetidine, was developed bySir James Black[4] at Smith, Kline & French – nowGlaxoSmithKline – in the mid-to-late 1960s. It was first marketed in 1976 and sold under the trade nameTagamet, which became the firstblockbuster drug. The use ofquantitative structure-activity relationships (QSAR) led to the development of other agents – starting withranitidine, first sold asZantac, which was thought to have a better adverse effect profile (later disproven), fewerdrug interactions and be more potent.
Cimetidine was the prototypical histamine H2 receptor antagonist from which later drugs were developed. Cimetidine was the culmination of a project at Smith, Kline & French (SK&F; now GlaxoSmithKline) byJames W. Black,C. Robin Ganellin, and others to develop ahistamine receptor antagonist that would suppress stomach acid secretion.
In 1964, it was known that histamine stimulated the secretion of stomach acid, and also thattraditional antihistamines had no effect on acid production. From these facts the SK&F scientists postulated the existence of two different types of histamine receptors. They designated the one acted upon by the traditional antihistamines as H1, and the one acted upon by histamine to stimulate the secretion of stomach acid as H2.
The SK&F team used a classical design process starting from the structure of histamine. Hundreds of modified compounds were synthesised in an effort to develop a model of the then-unknown H2 receptor. The first breakthrough wasNα-guanylhistamine, a partial H2receptor antagonist. From this lead, the receptor model was further refined, which eventually led to the development ofburimamide, a specificcompetitive antagonist at the H2 receptor. Burimamide is 100 times more potent thanNα-guanylhistamine, proving its efficacy on the H2 receptor.
The potency of burimamide was still too low for oral administration. And efforts on further improvement of the structure, based on the structure modification in the stomach due to theacid dissociation constant of the compound, led to the development ofmetiamide. Metiamide was an effective agent; however, it was associated with unacceptablenephrotoxicity andagranulocytosis. It was proposed that the toxicity arose from thethiourea group, and similarguanidine analogues were investigated until the discovery of cimetidine, which would become the first clinically successful H2 antagonist.
Ranitidine (common brand name Zantac) was developed by Glaxo (also nowGlaxoSmithKline), in an effort to match the success of Smith, Kline & French with cimetidine. Ranitidine was also the result of a rational drug design process utilising the by-then-fairly-refined model of the histamine H2 receptor andquantitative structure-activity relationships (QSAR). Glaxo refined the model further by replacing theimidazole-ring of cimetidine with afuran-ring with anitrogen-containing substituent, and in doing so developed ranitidine, which was found to have a much better tolerability profile (i.e. feweradverse drug reactions), longer-lasting action, and ten times the activity of cimetidine.
Ranitidine was introduced in 1981 and was the world's biggest-selling prescription drug by 1988. The H2 receptor antagonists have since largely been superseded by the even more effective proton pump inhibitors (PPIs), withomeprazole becoming the biggest-selling drug for many years.
The H2 antagonists are competitive antagonists of histamine at the parietal cell'sH2 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 byenterochromaffin-like cells (ECL) in the stomach is blocked from binding on parietal cell H2 receptors, which stimulate acid secretion; therefore, other substances that promote acid secretion (such asgastrin andacetylcholine) have a reduced effect on parietal cells when the H2 receptors are blocked.
H2 antagonists are used by clinicians in the treatment of acid-relatedgastrointestinal conditions, including:[7]
People who suffer from infrequent heartburn may take eitherantacids 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. Proton pump inhibitors, however, are the preferred treatment for erosiveesophagitis since they have been shown to promote healing better than H2antagonists.[citation needed]
H2 antagonists are generally well tolerated, with the exception of cimetidine, which more commonly elicits the following adverse drug reactions (ADRs) than other H2 antagonists:
Infrequent ADRs includehypotension. Rare ADRs includeheadache, tiredness, dizziness, confusion,diarrhea, constipation, and rash.[7] In addition,gynecomastia occurred in 0.1% to 0.5% of men treated for non-hypersecretory conditions with cimetidine for 1 month or longer and in about 2% of men treated for pathologic hypersecretory conditions; in even fewer men, cimetidine may also cause loss of libido, andimpotence, all of which are reversible upon discontinuation.[9]
A 31-study review found that the overall risk of pneumonia is about 1 in 4 higher among H2 antagonist users.[10]
According to a 2022 umbrella review of meta-analyses, the use of H2 receptor antagonist is associated with pneumonia, peritonitis, necrotizing enterocolitis,Clostridioides difficile infection,liver cancer,gastric cancer, andhip fracture diseases.[11]
Famotidine has been associated with agranulocytosis, the destruction of white blood cells.[12]
Histamine can cause bladder inflammation and contribute to the symptoms of such bladder diseases as cystitis (inflammation of the bladder) or painful bladder disease. Histamine binds to H2 receptors in the bladder smooth muscle, leading to relaxation[contradictory] of the bladder muscle and promotion of urine storage. Histamine does not seem to have a direct role in the development of bladder diseases, but it can contribute to bladder inflammation and associated symptoms.
H2 receptors in the bladder play a role in regulating bladder contraction.
H2 receptor antagonists have been shown to reduce bladder contractions and improve bladder function in animal studies.[13][14][15] Blocking the activation of H2 receptors in the bladder leads to decreased bladder contractions and improved urine storage. While H2 receptor antagonists may have a potential role in managing bladder conditions such as overactive bladder, they are not typically used in treating cystitis or painful bladder disease, and their mechanism of action in bladder diseases is still not fully understood. There is limited research that histamine H2 receptor antagonists can potentially alleviate symptoms of cystitis[16][17] or painful bladder disease.[18][19][20]
With regard topharmacokinetics, cimetidine in particular interferes with some of the body's mechanisms ofdrug metabolism and elimination through the livercytochrome P450 (CYP) pathway. To be specific, cimetidine is an inhibitor of the P450 enzymesCYP1A2,CYP2C9,CYP2C19,CYP2D6,CYP2E1,CYP3A4. By reducing the metabolism of drugs through these enzymes, cimetidine may increase theirserumconcentrations totoxic levels. Many drugs are affected, includingwarfarin,theophylline,phenytoin,lidocaine,quinidine,propranolol,labetalol,metoprolol,methadone,tricyclic antidepressants, somebenzodiazepines, dihydropyridinecalcium channel blockers,sulfonylureas,metronidazole,[21] and some recreational drugs such asethanol andmethylenedioxymethamphetamine (MDMA).
The more recently developed H2receptor antagonists are less likely to alter CYP metabolism. Ranitidine is not as potent a CYP inhibitor as cimetidine, although it still shares several of the latter's interactions (such as with warfarin, theophylline, phenytoin, metoprolol, and midazolam).[22]Famotidine has negligible effect on the CYP system, and appears to have no significant interactions.[21]
