H2 receptor antagonist

{{Short description|Class of medications}} {{cs1 config|name-list-style=vanc}} [[Image:Cimetidine-xtal-3D-balls.png|thumb|[[Ball-and-stick model]] of [[cimetidine]], the prototypical H2 receptor antagonist]] '''H2 antagonists''', sometimes referred to as '''H2RAs'''<ref>{{cite journal |url=https://clinicaltrials.gov/ct2/show/NCT01408186 |title=ASP (PPI_H2RA) Study-H2RA Versus PPI for the Prevention of Recurrent UGIB in High-risk Users of Low-dose ASA |website=ClinicalTrials.gov |date=21 April 2017 |author=Francis KL Chan |access-date=1 November 2017 |archive-date=1 December 2018 |archive-url=https://web.archive.org/web/20181201135908/https://clinicaltrials.gov/ct2/show/NCT01408186 |url-status=live }}</ref> and also called '''H2 blockers''', are a class of [[pharmaceutical drug|medications]] that block the action of [[histamine]] at the [[histamine H2 receptor|histamine H2 receptors]] of the [[parietal cell]]s in the [[stomach]]. This decreases the production of [[gastric acid|stomach acid]]. H2 antagonists can be used in the treatment of [[dyspepsia]], [[peptic ulcer]]s and [[gastroesophageal reflux disease]]. They have been surpassed by [[proton pump inhibitor]]s (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]].<ref>{{cite journal | pmid = 7614110 | volume=7 | title=Omeprazole and H2-receptor antagonists in the acute treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis: a meta-analysis | year=1995 | journal=Eur J Gastroenterol Hepatol | pages=467–75 | vauthors=Eriksson S, Långström G, Rikner L, Carlsson R, Naesdal J| issue=5 }}. A correction was published in ''European Journal of Gastroenterology & Hepatology'' 1996;8:192.</ref> H2 antagonists, which all end in "-tidine", are a type of [[antihistamine]]. In general usage, however, the term "antihistamine" typically refers to [[H1 antagonist|H1 antagonists]], which relieve [[Allergy|allergic reactions]]. Like the H1 antagonists, H2 antagonists function as [[inverse agonist]]s rather than [[receptor antagonist]]s (with the exception of [[burimamide]]), due to the [[constitutive activity]] of these receptors.<ref name="Histamine receptors">{{cite journal | vauthors = Panula P, Chazot PL, Cowart M, et al. | title = International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors | journal = Pharmacological Reviews | volume = 67 | issue = 3 | pages = 601–55 | year = 2015 | pmid = 26084539 | doi = 10.1124/pr.114.010249 | pmc=4485016}}</ref>

The prototypical H2 antagonist, called [[cimetidine]], was developed by [[Sir James Black]]<ref>{{cite web|title=Sir James W. Black - Biographical|url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1988/black-bio.html|publisher=Nobelprize.org|access-date=7 April 2015|archive-date=23 April 2015|archive-url=https://web.archive.org/web/20150423004703/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1988/black-bio.html|url-status=live}}</ref> 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 relationship]]s (QSAR) led to the development of other agents – starting with [[ranitidine]], first sold as [[Ranitidine|Zantac]], which was thought to have a better adverse effect profile (later disproven), fewer [[drug interaction]]s and be more potent.

==Class members== {{Hatnote|This list may not be exhaustive.}}

* [[cimetidine]] (Tagamet) * [[ranitidine]] (Zantac) (withdrawn in the US, suspended in EU and Australia for carcinogenic contaminants) * [[famotidine]] (Pepcid) * [[nizatidine]] (Tazac, Axid) * [[roxatidine]] * [[lafutidine]] (Stogar, Lafaxid, Ildong Lafutidine) * [[lavoltidine]] (discontinued as carcinogen) * [[niperotidine]] (withdrawn<ref>{{cite journal|pmid=20978361 |year=2011 |last1=Guengerich |first1=F. P. |title=Mechanisms of drug toxicity and relevance to pharmaceutical development |journal=Drug Metabolism and Pharmacokinetics |volume=26 |issue=1 |pages=3–14 |doi=10.2133/dmpk.dmpk-10-rv-062 |pmc=4707670 }}</ref> as causing liver damage<ref>{{cite journal|pmid=9314138 |year=1997 |last1=Gasbarrini |first1=G. |last2=Gentiloni |first2=N. |last3=Febbraro |first3=S. |last4=Gasbarrini |first4=A. |last5=Di Campli |first5=C. |last6=Cesana |first6=M. |last7=Miglio |first7=F. |last8=Miglioli |first8=M. |last9=Ghinelli |first9=F. |last10=d'Ambrosi |first10=A. |last11=Amoroso |first11=P. |last12=Pacini |first12=F. |last13=Salvadori |first13=G. |title=Acute liver injury related to the use of niperotidine |journal=Journal of Hepatology |volume=27 |issue=3 |pages=583–586 |doi=10.1016/s0168-8278(97)80365-0 }}</ref>) * [[sufotidine]]

== 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 [[H1 antagonist|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 relationship|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 reaction]]s), 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 [[histamine H2 receptor|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 cell|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 condition]]s, including:<ref name="Rossi">Rossi S (Ed.) (2005). ''[[Australian Medicines Handbook]]'' 2005. Adelaide: Australian Medicines Handbook. {{ISBN|0-9578521-9-3}}.{{pn|date=May 2021}}</ref>

* [[Peptic ulcer]] disease (PUD) * [[Gastroesophageal reflux disease]] (GERD/GORD) * [[Dyspepsia]] * Prevention of [[stress ulcer]] (a specific indication of ranitidine) * Prevention of [[Aspiration pneumonia#Prevention|aspiration pneumonitis]] during surgery. Oral H2 antagonists reduce gastric acidity and volume and have shown to reduce the frequency of aspiration pneumonitis; however, this aspiration benefit has not been shown with IV H2antagonists.<ref name="Miller2014">{{cite book |last1=Miller |first1=Ronal D |last2=Eriksson |first2=Lars |last3=Fleisher |first3=Lee A |last4=Wiener-Kronish |first4=Jeanine P |title=Miller's Anesthesia Airway management in the Adult |date=25 November 2014 |edition = 8th|publisher=Elsevier |pages=1647–1681}}</ref>

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.<ref>{{cite journal|last1=Katz|first1=Philip O|last2=Gerson|first2=Lauren B|last3=Vela|first3=Marcelo F|title=Guidelines for the Diagnosis and Management of Gastroesophageal Reflux Disease|journal=American Journal of Gastroenterology|volume=108|issue=3|pages=308–328|date=March 2013|doi=10.1038/ajg.2012.444|pmid=23419381}}</ref>

== 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.<ref name="Rossi"/> In addition, [[gynecomastia]] occurred in 0.1–0.5% 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.<ref>Drugs.com [https://www.drugs.com/sfx/cimetidine-side-effects.html "Cimetidine Side Effects"] {{Webarchive|url=https://web.archive.org/web/20171107113455/https://www.drugs.com/sfx/cimetidine-side-effects.html |date=2017-11-07 }}</ref>

A 31-study review found that the overall risk of pneumonia is about 1 in 4 higher among H2 antagonist users.<ref>{{cite journal|title=Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis|doi=10.1503/cmaj.092129|pmc=3042441|pmid=21173070|journal=CMAJ|vauthors=Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS|year=2011|volume=183|issue=3|pages=310–9}} (adjusted odds ratio [OR] 1.22)</ref>

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]], and [[hip fracture]] diseases.<ref>{{cite journal |title=Effectiveness and Safety of Histamine H2 Receptor Antagonists: An Umbrella Review of Meta-Analyses |year=2023 |doi=10.1002/jcph.2147 |last1=Meng |first1=Rui |last2=Chen |first2=Li-Rong |last3=Zhang |first3=Man-Li |last4=Cai |first4=Wen-Ke |last5=Yin |first5=Sun-Jun |last6=Fan |first6=Yu-Xin |last7=Zhou |first7=Tao |last8=Huang |first8=Yan-Hua |last9=He |first9=Gong-Hao |journal=The Journal of Clinical Pharmacology |volume=63 |issue=1 |pages=7–20 |pmid=36039014 |s2cid=251931004 }}</ref>

Famotidine has been associated with agranulocytosis, the destruction of white blood cells.<ref>{{cite journal |last1=Marcus |first1=E. L. |last2=Clarfield |first2=A. M. |last3=Kleinman |first3=Y. |last4=Bits |first4=H. |last5=Darmon |first5=D. |last6=Da'as |first6=N. |title=Agranulocytosis associated with initiation of famotidine therapy |journal=Annals of Pharmacotherapy |date=February 2002 |volume=36 |issue=2 |pages=267–271 |doi=10.1345/aph.1A045 |pmid=11847947 }}</ref>

== 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 inline|date=November 2023|reason=The text later states that *blocking* those receptors reduces contractions.}} 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.<ref>{{cite journal|doi=10.1016/j.cont.2023.100808 |title=Physiological Role of Histamine H2 Receptor on Bladder Sensory Function in Rats |year=2023 |last1=Aizawa |first1=N. |last2=Fujita |first2=T. |journal=Continence |volume=7 |article-number=100808 |doi-access=free }}</ref><ref>{{cite journal|pmid=30846750 |year=2019 |last1=Stromberga |first1=Z. |last2=Chess-Williams |first2=R. |last3=Moro |first3=C. |title=Histamine modulation of urinary bladder urothelium, lamina propria and detrusor contractile activity via H1 and H2 receptors |journal=Scientific Reports |volume=9 |issue=1 |page=3899 |doi=10.1038/s41598-019-40384-1 |pmc=6405771 |bibcode=2019NatSR...9.3899S }}</ref><ref>{{cite journal|doi=10.1186/1471-2490-9-16 |title=Pharmacologic attenuation of pelvic pain in a murine model of interstitial cystitis |year=2009 |last1=Rudick |first1=Charles N. |last2=Schaeffer |first2=Anthony J. |last3=Klumpp |first3=David J. |journal=BMC Urology |volume=9 |article-number=16 |pmid=19909543 |pmc=2781023 |doi-access=free }}</ref> 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<ref>{{cite journal|doi=10.1111/jcpt.12845 |title=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 |year=2019 |last1=Zhou |first1=Haiyan |last2=Zhou |first2=Ying |last3=Ping |first3=Yaodong |last4=Tian |first4=Shuohan |last5=Li |first5=Guohui |last6=Cui |first6=Yimin |last7=Zheng |first7=Bo |journal=Journal of Clinical Pharmacy and Therapeutics |volume=44 |issue=5 |pages=796–799 |pmid=31049996 |s2cid=143433911 |doi-access=free }}</ref><ref>{{cite journal|pmid=11167643 |year=2001 |last1=Thilagarajah |first1=R. |last2=Witherow |first2=R. O. |last3=Walker |first3=M. M. |title=Oral cimetidine gives effective symptom relief in painful bladder disease: A prospective, randomized, double-blind placebo-controlled trial |journal=BJU International |volume=87 |issue=3 |pages=207–212 |doi=10.1046/j.1464-410x.2001.02031.x |s2cid=41415547 |doi-access=free }}</ref> or painful bladder disease.<ref>{{cite journal|pmid=11167643 |year=2001 |last1=Thilagarajah |first1=R. |last2=Witherow |first2=R. O. |last3=Walker |first3=M. M. |title=Oral cimetidine gives effective symptom relief in painful bladder disease: A prospective, randomized, double-blind placebo-controlled trial |journal=BJU International |volume=87 |issue=3 |pages=207–212 |doi=10.1046/j.1464-410x.2001.02031.x |s2cid=41415547 |doi-access=free }}</ref><ref>{{cite journal|pmid=11488726 |year=2001 |last1=Dasgupta |first1=P. |last2=Sharma |first2=S. D. |last3=Womack |first3=C. |last4=Blackford |first4=H. N. |last5=Dennis |first5=P. |title=Cimetidine in painful bladder syndrome: A histopathological study |journal=BJU International |volume=88 |issue=3 |pages=183–186 |doi=10.1046/j.1464-410x.2001.02258.x |s2cid=19989194 }}</ref><ref>{{cite journal|pmid=31718622 |year=2019 |last1=Shan |first1=H. |last2=Zhang |first2=E. W. |last3=Zhang |first3=P. |last4=Zhang |first4=X. D. |last5=Zhang |first5=N. |last6=Du |first6=P. |last7=Yang |first7=Y. |title=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 |journal=BMC Urology |volume=19 |issue=1 |page=115 |doi=10.1186/s12894-019-0548-3 |pmc=6852726 |doi-access=free }}</ref>

== Drug interactions ==

[[Image:Famotidine.svg|thumb|[[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 [[blood plasma|serum]] [[concentration]]s to [[toxic]] levels. Many drugs are affected, including [[warfarin]], [[theophylline]], [[phenytoin]], [[lidocaine]], [[quinidine]], [[propranolol]], [[labetalol]], [[metoprolol]], [[methadone]], [[tricyclic antidepressants]], some [[benzodiazepines]], dihydropyridine [[calcium channel blocker]]s, [[sulfonylureas]], [[metronidazole]],<ref name=Humphries>{{cite journal |vauthors=Humphries TJ, Merritt GJ |title=Review article: drug interactions with agents used to treat acid-related diseases |journal=Alimentary Pharmacology & Therapeutics |volume=13 |pages=18–26 |date=August 1999 |issue=Suppl 3 |pmid=10491725 |doi=10.1046/j.1365-2036.1999.00021.x |doi-access= |s2cid=2089156 }}</ref> and some recreational drugs such as [[Ethanol#Recreational|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).<ref>{{cite journal |vauthors=Kirch W, Hoensch H, Janisch HD |title=Interactions and non-interactions with ranitidine |journal=Clinical Pharmacokinetics |volume=9 |issue=6 |pages=493–510 |year=1984 |pmid=6096071 |doi=10.2165/00003088-198409060-00002|s2cid=10715649 }}</ref> [[Famotidine]] has negligible effect on the CYP system, and appears to have no significant interactions.<ref name=Humphries/>

== See also == * [[H1 antagonist|H1-receptor antagonist]] * [[H3 antagonist|H3-receptor antagonist]]

== References == {{Reflist}}

[[Category:H2 receptor antagonists| ]] {{DISPLAYTITLE:H2 receptor antagonist}}