{{DISPLAYTITLE:H2 receptor antagonist}}

H2 antagonists, sometimes referred to as H2RAs 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.
 
H2 antagonists are a type of antihistamine, although in common use the term "antihistamine" is often reserved for 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.

The prototypical H2 antagonist, called cimetidine, was developed by Sir James Black 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.

H2 blockers, which all end in "-tidine", are not the same as H1 receptor antagonists, which relieve allergy symptoms.

Class members

 cimetidine (Tagamet)
 ranitidine (Zantac) (withdrawn in USA, suspended in EU and Australia for carcinogenic metabolites)
 famotidine (Pepcid)
 nizatidine (Tazac, Axid)
 roxatidine 
 lafutidine (Stogar, Lafaxid, Ildong Lafutidine)
 lavoltidine (discontinued as carcinogen)
 niperotidine (withdrawn as causing liver damage)
 sufotidine

History and development 
Cimetidine was the prototypical histamine H2receptor 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 H2receptor 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:

 Peptic ulcer disease (PUD)
 Gastroesophageal reflux disease (GERD/GORD)
 Dyspepsia
 Prevention of stress ulcer (a specific indication of ranitidine)
 Prevention of aspiration pneumonitis during surgery. Oral H2antagonists 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.

People who suffer from infrequent heartburn may take either antacids or H2receptor antagonists for treatment. The H2antagonists 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.

Adverse effects 
H2 antagonists are, in general, well tolerated, except for cimetidine, wherein 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. 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.

A 31-study review found that overall risk of pneumonia is about 1 in 4 higher among H2 antagonist users.

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.

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 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. 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 or painful bladder disease.

Drug interactions 

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, 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). Famotidine has negligible effect on the CYP system, and appears to have no significant interactions.

See also 
 H1-receptor antagonist
 H3-receptor antagonist

References
H2 수용체 길항제(H2 receptor antagonist, H2RAs,) 또는 H2 차단제(H2 blockers)는 위의 벽세포에 있는 히스타민 H2 수용체에 히스타민이 작용하는 것을 막는 약물이다. 이로 인해 위산의 생산이 감소한다. 소화성 궤양, 소화불량, 위 식도 역류병(GERD) 등의 치료에 쓰일 수 있다. 현재는 양성자 펌프 억제제(PPI)가 H2 수용체 길항제보다 보통 우월하다고 알려져 있다. 양성자 펌프 억제제의 일종인 오메프라졸은 궤양과 역류성 식도염의 치료와 증상 완화, 두 측면 모두에서 H2 수용체 길항제인 라니티딘과 시메티딘보다 효과가 좋다.

H2 길항제는 항히스타민제의 한 종류이지만, 항히스타민제는 알레르기 반응을 완화하는 H1 수용체 길항제만을 가리키는 용어로도 흔히 사용된다. H1 길항제와 마찬가지로 일부 H2 길항제는 수용체 길항제가 아닌 역작용제로 작용하기도 한다.

최초의 H2 길항제인 시메티딘은 1960년대 중후반 제임스 화이트 블랙이 스미스, 클라인 & 프렌치(현재 글락소스미스클라인)에서 개발하였다. 이후 시메티딘은 1976년에 상품명 '타가메트'(Tagamet)로 처음 시장에 출시되며 최초로 1년에 10억 달러 매출을 올린 약물이 되었다. 구조-활성의 정량적 관계(QSAR) 모델이 쓰이면서 라니티딘부터 시작하여 여러 다른 약제가 개발되었다. 라니티딘과 같은 다른 약물들은 시메티딘에 비해 부작용과 약물 상호작용이 적고 효능은 더 크다.

H2 길항제는 모두 그 이름이 '-티딘'(-tidine)으로 끝나며, 알레르기 증상을 완화하는 H1 수용체 길항제와는 효과가 구분된다.

종류 
 시메티딘
 라니티딘 - 2020년 4월 기준, 제조 과정에서 발암물질에 오염되었다는 이유로 미국에서는 철수, EU와 호주에서는 판매 중단되었다.
 파모티딘
 니자티딘
 록사티딘
 라푸티딘
 라볼티딘 - 설치류에서 위유암종을 일으켜, 발암물질이라는 이유로 생산이 중단되었다.
 니페로티딘 - 간독성을 유발하여 시장에서 철수하였다.

약리학 
H2 길항제는 위의 벽세포에 존재하는 H2 수용체에서 히스타민에 대한 경쟁적 저해제로 작용한다. 따라서 장크롬친화성유사세포(ECL 세포)가 방출한 히스타민이 위산 분비를 자극하는 H2 수용체에 결합할 수 없게 된다. 또한 위산 분비를 촉진하는 다른 물질인 가스트린과 아세틸콜린은 그 효과가 완전히 차단되지는 않으나 H2 수용체가 차단되면 효과가 감소한다. 이러한 두 가지 기전으로 인해 벽세포가 평상시와 식후에 위산을 분비하는 것이 억제된다.

임상적 사용 
H2 길항제는 위산과 관련된 여러 위장관계 질환을 치료하기 위해 사용된다. 그 예로는 다음과 같은 질환들이 있다.

 소화성 궤양 (PUD)
 위 식도 역류병 (GERD)
 소화불량
 스트레스성 궤양 예방 (라니티딘의 특이적인 적응증)
 수술 도중 흡인성 폐렴의 예방. 경구 H2 길항제는 위의 산성과 부피를 줄여 흡인성 폐렴의 빈도를 줄인다고 알려져 있다. 그러나 IV H2 길항제에 대해서는 흡인성 폐렴에 대한 효과를 밝히지 못했다.

부작용 
H2 길항제는 시메티딘을 제외하면 일반적으로 부작용이 거의 없이 복용할 수 있다. 흔하지 않은 약물 부작용에는 저혈압이 있다. 드문 부작용에는 두통, 피로감, 어지럼증, 혼란, 설사, 변비, 발진이 있다. 시메티딘은 앞선 부작용이 비교적 흔하게 나타날 수 있다. 또한 위산 과다분비 상태가 아닌 남성의 0.1~0.5%, 병적인 과다분비 상태인 남성의 2% 가량에서 시메티딘으로 1개월 이상 치료할 시 여성형유방증이 발생하였다. 이보다 더 드물게 시메티딘은 남성에서 성욕 상실과 발기부전을 일으킬 수 있는데, 모두 약물 복용을 중단하면 정상으로 돌아온다.

31개의 연구를 문헌 고찰한 논문에서는 H2 길항제를 사용한 환자에서 폐렴의 전반적인 위험이 그렇지 않은 환자의 1.22배 정도로 증가했다고 밝혔다.

2022년 메타분석의 분석(엄브렐라 리뷰)에 따르면 H2 길항제의 사용은 폐렴, 복막염, 괴사성 장염, 디피실리균 감염, 간암, 위암, 고관절 골절 등과 관련이 있다.

약물 상호작용 

약동학과 관련하여, 시메티딘은 특히 간의 사이토크롬 P450(CYP) 경로를 통한 약물 대사와 제거에 일부 간섭한다. 구체적으로 시메티딘은 P450 효소인 CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4의 억제제 역할을 하여, 앞의 효소들을 통한 약물의 대사를 감소시킨다. 따라서 시메티딘은 여러 약물의 혈장 농도를 유독한 수준까지 올릴 수 있다. 농도가 올라갈 수 있는 약물에는 와파린, 테오필린, 페니토인, 리도카인, 퀴니딘, 프로프라놀롤, 라베탈롤, 메토프롤롤, 메타돈, 삼환계 항우울제, 일부 벤조디아제핀, 디히드로피리딘계 칼슘 통로 차단제, 설폰요소제, 메트로니다졸, 그 외 에탄올이나 메틸렌디옥시메스암페타민(MDMA) 등 몇몇 치료 목적이 아닌 기분전환용 약물이 있다.

시메티딘 이후에 개발된 H2 수용체 길항제는 CYP 대사를 변화시킬 가능성이 더 적다. 라니티딘은 시메티딘처럼 강력한 CYP 억제제는 아니지만 여전히 시메티딘과 비슷하게 여러 약물 상호작용을 일으킬 수 있다. 라니티딘과 상호작용하는 약물로는 와파린, 테오필린, 페니토인, 메토프롤롤, 미다졸람 등이 있다. 파모티딘은 CYP 대사에 거의 영향을 미치지 않으며 중요한 상호작용은 일으키지 않는 것으로 보인다.

참고 문헌 

H2 수용체 길항제