H2 receptor antagonist

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Ball-and-stick model of cimetidine, the prototypical H2 receptor antagonist Cimetidine-xtal-3D-balls.png
Ball-and-stick model of cimetidine, the prototypical H2 receptor antagonist

H2 antagonists, sometimes referred to as H2RAs [1] and also called H2 blockers, are a class of medications that block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach. This decreases the production of stomach acid. H2 antagonists can be used in the treatment of dyspepsia, peptic ulcers and gastroesophageal reflux disease. They have been surpassed by proton pump inhibitors (PPIs). The PPI omeprazole was found to be more effective at both healing and alleviating symptoms of ulcers and reflux oesophagitis than the H2 blockers ranitidine and cimetidine. [2]

Contents

H2 antagonists, which all end in "-tidine", are a type of antihistamine. In general usage, however, the term "antihistamine" typically refers to H1 antagonists, which relieve allergic reactions. Like the H1 antagonists, some H2 antagonists function as inverse agonists rather than receptor antagonists, due to the constitutive activity of these receptors. [3]

The prototypical H2 antagonist, called cimetidine, was developed by Sir James Black [4] at Smith, Kline & French – now GlaxoSmithKline – in the mid-to-late 1960s. It was first marketed in 1976 and sold under the trade name Tagamet, which became the first blockbuster drug. The use of quantitative structure-activity relationships (QSAR) led to the development of other agents – starting with ranitidine, first sold as Zantac, which was thought to have a better adverse effect profile (later disproven), fewer drug interactions and be more potent.

Class members

History and development

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) 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, and also that traditional 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 was Nα-guanylhistamine, a partial H2receptor antagonist. From this lead, the receptor model was further refined, which eventually led to the development of burimamide, a specific competitive antagonist at the H2 receptor. Burimamide is 100 times more potent than Nα-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 the acid dissociation constant of the compound, led to the development of metiamide. Metiamide was an effective agent; however, it was associated with unacceptable nephrotoxicity and agranulocytosis. It was proposed that the toxicity arose from the thiourea group, and similar guanidine 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 now GlaxoSmithKline), 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 and quantitative structure-activity relationships (QSAR). Glaxo refined the model further by replacing the imidazole-ring of cimetidine with a furan-ring with a nitrogen-containing substituent, and in doing so developed ranitidine, which was found to have a much better tolerability profile (i.e. fewer adverse 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), with omeprazole becoming the biggest-selling drug for many years.

Pharmacology

The H2 antagonists are competitive antagonists of histamine at the parietal cell's 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 enterochromaffin-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 as gastrin and acetylcholine) have a reduced effect on parietal cells when the H2 receptors are blocked.

Clinical uses

H2 antagonists are used by clinicians in the treatment of acid-related gastrointestinal conditions, including: [7]

People who suffer from infrequent heartburn 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. Proton pump inhibitors, however, are the preferred treatment for erosive esophagitis since they have been shown to promote healing better than H2antagonists.[ citation needed ]

Adverse effects

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 include hypotension. Rare ADRs include: headache, 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, and impotence, all of which are reversible upon discontinuation. [9]

A 31-study review found that 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, Clostridium difficile infection, liver cancer, gastric cancer, and hip fracture diseases. [11]

Research

Bladder diseases

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. [12] [13] [14] 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 [15] [16] or painful bladder disease. [17] [18] [19]

Drug interactions

Skeletal formula of famotidine. Unlike cimetidine, famotidine has no significant interactions with other drugs. Famotidine.svg
Skeletal formula of famotidine. Unlike cimetidine, famotidine has no significant interactions with other drugs.

With regard to pharmacokinetics, cimetidine in particular interferes with some of the body's mechanisms of drug metabolism and elimination through the liver cytochrome P450 (CYP) pathway. To be specific, cimetidine is an inhibitor of the P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4. By reducing the metabolism of drugs through these enzymes, cimetidine may increase their serum concentrations to toxic levels. Many drugs are affected, including warfarin, theophylline, phenytoin, lidocaine, quinidine, propranolol, labetalol, metoprolol, methadone, tricyclic antidepressants, some benzodiazepines, dihydropyridine calcium channel blockers, sulfonylureas, metronidazole, [20] and some recreational drugs such as ethanol and methylenedioxymethamphetamine (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). [21] Famotidine has negligible effect on the CYP system, and appears to have no significant interactions. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Proton-pump inhibitor</span> Class of drugs for reducing stomach acid

Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump.

Peptic ulcer disease is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines is a duodenal ulcer. The most common symptoms of a duodenal ulcer are waking at night with upper abdominal pain, and upper abdominal pain that improves with eating. With a gastric ulcer, the pain may worsen with eating. The pain is often described as a burning or dull ache. Other symptoms include belching, vomiting, weight loss, or poor appetite. About a third of older people with peptic ulcers have no symptoms. Complications may include bleeding, perforation, and blockage of the stomach. Bleeding occurs in as many as 15% of cases.

<span class="mw-page-title-main">Zollinger–Ellison syndrome</span> Condition in which tumours stimulate excessive gastric acid production

Zollinger–Ellison syndrome is rare disease in which tumors cause the stomach to produce too much acid, resulting in peptic ulcers. Symptoms include abdominal pain and diarrhea.

<span class="mw-page-title-main">Histamine</span> Organic compound involved in immune responses

Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in 1910, it has been considered a local hormone (autocoid) because it lacks the classic endocrine glands to secrete it; however, in recent years, histamine has been recognized as a central neurotransmitter. Histamine is involved in the inflammatory response and has a central role as a mediator of itching. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues. It consists of an imidazole ring attached to an ethylamine chain; under physiological conditions, the amino group of the side-chain is protonated.

<span class="mw-page-title-main">Parietal cell</span> Epithelial cell in the stomach

Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions of the stomach. They contain an extensive secretory network of canaliculi from which the HCl is secreted by active transport into the stomach. The enzyme hydrogen potassium ATPase (H+/K+ ATPase) is unique to the parietal cells and transports the H+ against a concentration gradient of about 3 million to 1, which is the steepest ion gradient formed in the human body. Parietal cells are primarily regulated via histamine, acetylcholine and gastrin signalling from both central and local modulators.

<span class="mw-page-title-main">Famotidine</span> Medication that reduces stomach acid

Famotidine, sold under the brand name Pepcid among others, is a histamine H2 receptor antagonist medication that decreases stomach acid production. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome. It is taken by mouth or by injection into a vein. It begins working within an hour.

<span class="mw-page-title-main">Cimetidine</span> Medication

Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers.

<span class="mw-page-title-main">Ranitidine</span> Medication that decreases stomach acid

Ranitidine, sold under the brand name Zantac among others, is a medication used to decrease stomach acid production. It is commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellison syndrome. It can be given by mouth, injection into a muscle, or injection into a vein. In September 2019, the probable carcinogen N-nitrosodimethylamine (NDMA) was discovered in ranitidine products from a number of manufacturers, resulting in recalls.

<span class="mw-page-title-main">Dermatographic urticaria</span> Skin disorder

Dermatographic urticaria is a skin disorder and one of the most common types of urticaria, affecting 2–5% of the population.

Histamine H<sub>2</sub> receptor Mammalian protein found in Homo sapiens

H2 receptors are positively coupled to adenylate cyclase via Gs alpha subunit. It is a potent stimulant of cAMP production, which leads to activation of protein kinase A. PKA functions to phosphorylate certain proteins, affecting their activity. The drug betazole is an example of a histamine H2 receptor agonist.

<span class="mw-page-title-main">Betazole</span> Histamine H2 receptor agonist

Betazole (also known as ametazole) is a histamine H2 receptor agonist. Betazole hydrochloride is known as gastramine and histalog.

<span class="mw-page-title-main">Burimamide</span> Chemical compound

Burimamide is an antagonist at the H2 and H3 histamine receptors. At physiological pH, it is largely inactive as an H2 antagonist, but its H3 affinity is 100x higher. It is a thiourea derivative.

Gastric hydrogen potassium ATPase, also known as H+/K+ ATPase, is an enzyme which functions to acidify the stomach. It is a member of the P-type ATPases, also known as E1-E2 ATPases due to its two states.

<span class="mw-page-title-main">Antihistamine</span> Drug that blocks histamine or histamine agonists

Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic drug that can be bought without a prescription and provides relief from nasal congestion, sneezing, or hives caused by pollen, dust mites, or animal allergy with few side effects. Antihistamines are usually for short-term treatment. Chronic allergies increase the risk of health problems which antihistamines might not treat, including asthma, sinusitis, and lower respiratory tract infection. Consultation of a medical professional is recommended for those who intend to take antihistamines for longer-term use.

Lafutidine (INN) is a second generation histamine H2 receptor antagonist having multimodal mechanism of action and used to treat gastrointestinal disorders. It is marketed in South Korea, Japan and India.

Charon Robin Ganellin FRS is a British medicinal chemist, and Emeritus Smith Kline and French Professor of Medicinal Chemistry, at University College London.

Proton pump inhibitors (PPIs) block the gastric hydrogen potassium ATPase (H+/K+ ATPase) and inhibit gastric acid secretion. These drugs have emerged as the treatment of choice for acid-related diseases, including gastroesophageal reflux disease (GERD) and peptic ulcer disease. PPIs also can bind to other types of proton pumps such as those that occur in cancer cells and are finding applications in the reduction of cancer cell acid efflux and reduction of chemotherapy drug resistance.

There are several classes of drugs for acid-related disorders, such as dyspepsia, peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD/GERD), or laryngopharyngeal reflux.

<span class="mw-page-title-main">Acid peptic diseases</span> Overview of the acid peptic diseases of the stomach and gastrointestinal tract

Acid peptic diseases, such as peptic ulcers, Zollinger-Ellison syndrome, and gastroesophageal reflux disease, are caused by distinct but overlapping pathogenic mechanisms involving acid effects on mucosal defense. Acid reflux damages the esophageal mucosa and may also cause laryngeal tissue injury, leading to the development of pulmonary symptoms.

Ranitidine bismuth citrate - drug, which has antisecretory and bactericidal action.

References

  1. ↑ Francis KL Chan (21 April 2017). "ASP (PPI_H2RA) Study-H2RA Versus PPI for the Prevention of Recurrent UGIB in High-risk Users of Low-dose ASA". ClinicalTrials.gov. Retrieved 1 November 2017.
  2. ↑ Eriksson S, Långström G, Rikner L, Carlsson R, Naesdal J (1995). "Omeprazole and H2-receptor antagonists in the acute treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis: a meta-analysis". Eur J Gastroenterol Hepatol. 7 (5): 467–75. PMID   7614110.. A correction was published in European Journal of Gastroenterology & Hepatology 1996;8:192.
  3. ↑ Panula P, Chazot PL, Cowart M, et al. (2015). "International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors". Pharmacological Reviews. 67 (3): 601–55. doi:10.1124/pr.114.010249. PMC   4485016 . PMID   26084539.
  4. ↑ "Sir James W. Black - Biographical". Nobelprize.org. Retrieved 7 April 2015.
  5. ↑ Guengerich FP (2011). "Mechanisms of drug toxicity and relevance to pharmaceutical development". Drug Metabolism and Pharmacokinetics. 26 (1): 3–14. doi:10.2133/dmpk.dmpk-10-rv-062. PMC   4707670 . PMID   20978361.
  6. ↑ Gasbarrini G, Gentiloni N, Febbraro S, Gasbarrini A, Di Campli C, Cesana M, Miglio F, Miglioli M, Ghinelli F, d'Ambrosi A, Amoroso P, Pacini F, Salvadori G (1997). "Acute liver injury related to the use of niperotidine". Journal of Hepatology. 27 (3): 583–586. doi:10.1016/s0168-8278(97)80365-0. PMID   9314138.
  7. 1 2 Rossi S (Ed.) (2005). Australian Medicines Handbook 2005. Adelaide: Australian Medicines Handbook. ISBN   0-9578521-9-3.[ page needed ]
  8. ↑ Miller RD, Eriksson L, Fleisher LA, Wiener-Kronish JP (25 November 2014). Miller's Anesthesia Airway management in the Adult (8th ed.). Elsevier. pp. 1647–1681.
  9. ↑ Drugs.com "Cimetidine Side Effects"
  10. ↑ Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS (2011). "Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis". CMAJ. 183 (3): 310–9. doi:10.1503/cmaj.092129. PMC   3042441 . PMID   21173070. (adjusted odds ratio [OR] 1.22)
  11. ↑ Meng R, Chen L, Zhang M, Cai W, Yin S, Fan Y, Zhou T, Huang Y, He G (2023). "Effectiveness and Safety of Histamine H2 Receptor Antagonists: An Umbrella Review of Meta-Analyses". The Journal of Clinical Pharmacology. 63 (1): 7–20. doi:10.1002/jcph.2147. PMID   36039014. S2CID   251931004.
  12. ↑ Aizawa N, Fujita T (2023). "Physiological Role of Histamine H2 Receptor on Bladder Sensory Function in Rats". Continence. 7: 100808. doi: 10.1016/j.cont.2023.100808 .
  13. ↑ Stromberga Z, Chess-Williams R, Moro C (2019). "Histamine modulation of urinary bladder urothelium, lamina propria and detrusor contractile activity via H1 and H2 receptors". Scientific Reports. 9 (1): 3899. Bibcode:2019NatSR...9.3899S. doi:10.1038/s41598-019-40384-1. PMC   6405771 . PMID   30846750.
  14. ↑ Rudick CN, Schaeffer AJ, Klumpp DJ (2009). "Pharmacologic attenuation of pelvic pain in a murine model of interstitial cystitis". BMC Urology. 9: 16. doi: 10.1186/1471-2490-9-16 . PMC   2781023 . PMID   19909543.
  15. ↑ Zhou H, Zhou Y, Ping Y, Tian S, Li G, Cui Y, Zheng B (2019). "The combination of loratadine with famotidine to relieve the symptoms of urinary frequency in female patients with bladder function disorders：First report of three cases". Journal of Clinical Pharmacy and Therapeutics. 44 (5): 796–799. doi: 10.1111/jcpt.12845 . PMID   31049996. S2CID   143433911.
  16. ↑ Thilagarajah R, Witherow RO, Walker MM (2001). "Oral cimetidine gives effective symptom relief in painful bladder disease: A prospective, randomized, double-blind placebo-controlled trial". BJU International. 87 (3): 207–212. doi: 10.1046/j.1464-410x.2001.02031.x . PMID   11167643. S2CID   41415547.
  17. ↑ Thilagarajah R, Witherow RO, Walker MM (2001). "Oral cimetidine gives effective symptom relief in painful bladder disease: A prospective, randomized, double-blind placebo-controlled trial". BJU International. 87 (3): 207–212. doi: 10.1046/j.1464-410x.2001.02031.x . PMID   11167643. S2CID   41415547.
  18. ↑ Dasgupta P, Sharma SD, Womack C, Blackford HN, Dennis P (2001). "Cimetidine in painful bladder syndrome: A histopathological study". BJU International. 88 (3): 183–186. doi:10.1046/j.1464-410x.2001.02258.x. PMID   11488726. S2CID   19989194.
  19. ↑ Shan H, Zhang EW, Zhang P, Zhang XD, Zhang N, Du P, Yang Y (2019). "Differential expression of histamine receptors in the bladder wall tissues of patients with bladder pain syndrome/Interstitial cystitis - significance in the responsiveness to antihistamine treatment and disease symptoms". BMC Urology. 19 (1): 115. doi: 10.1186/s12894-019-0548-3 . PMC   6852726 . PMID   31718622.
  20. 1 2 Humphries TJ, Merritt GJ (August 1999). "Review article: drug interactions with agents used to treat acid-related diseases". Alimentary Pharmacology & Therapeutics. 13 (Suppl 3): 18–26. doi:10.1046/j.1365-2036.1999.00021.x. PMID   10491725. S2CID   2089156.
  21. ↑ Kirch W, Hoensch H, Janisch HD (1984). "Interactions and non-interactions with ranitidine". Clinical Pharmacokinetics. 9 (6): 493–510. doi:10.2165/00003088-198409060-00002. PMID   6096071. S2CID   10715649.
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