H2-receptor antagonist - AbsoluteAstronomy.com

The H₂ receptor antagonists are a class of drugs

Medication

A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

used to block the action of histamine

Histamine

Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...

on parietal cell

Parietal cell

Parietal cells, or oxyntic cells, are the stomach epithelium cells that secrete gastric acid and intrinsic factor.Acetylcholine and gastrin . The histamine receptors act by increasing intracellular cAMP, whereas the muscarinic and gastrin receptors increase intracellular Ca2+ levels...

s in the stomach

Stomach

The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...

, decreasing the production of acid

Acid

An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...

by these cells. H₂ antagonists are used in the treatment of dyspepsia

Dyspepsia

Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...

, although they have been surpassed in popularity by the more effective proton pump inhibitor

Proton pump inhibitor

Proton-pump inhibitors are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. The group followed and has largely superseded another group of pharmaceuticals with similar...

s. In the United States, all four FDA

Food and Drug Administration

The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

-approved members of the group—cimetidine

Cimetidine

Cimetidine INN is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers. It is marketed by GlaxoSmithKline under the trade name Tagamet...

, ranitidine

Ranitidine

Ranitidine is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in treatment of peptic ulcer disease and gastroesophageal reflux disease . Ranitidine is also used alongside fexofenadine and other antihistamines for the treatment of skin conditions...

, famotidine

Famotidine

Famotidine is a histamine H2-receptor antagonist that inhibits stomach acid production, and it is commonly used in the treatment of peptic ulcer disease and gastroesophageal reflux disease . It is commonly marketed by Johnson & Johnson/Merck under the trade names Pepcidine and Pepcid and by...

, and nizatidine

Nizatidine

Nizatidine is a histamine H2-receptor antagonist that inhibits stomach acid production, and commonly used in the treatment of peptic ulcer disease and gastroesophageal reflux disease...

—are available over the counter

Over-the-counter drug

Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...

in relatively low doses.

The prototypical H₂ antagonist was cimetidine, developed by Smith, Kline & French (now GlaxoSmithKline

GlaxoSmithKline

GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...

) in the mid-to-late 1960s and first marketed in 1976; sold under the trade name Tagamet, cimetidine would later become the first ever blockbuster drug. The use of quantitative structure-activity relationship

Quantitative structure-activity relationship

Quantitative structure–activity relationship or QSPR is the process by which chemical structure is quantitatively correlated with a well defined process, such as biological activity or chemical reactivity.For example, biological activity can be expressed quantitatively as the concentration of a...

s (QSAR) led to the development of other agents—starting with ranitidine, first sold as Zantac—which has fewer adverse effects

Adverse drug reaction

An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

and drug interaction

Drug interaction

A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...

s and is more potent.

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

GlaxoSmithKline

GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...

) by James W. Black

James W. Black

Sir James Whyte Black, OM, FRS, FRSE, FRCP was a Scottish doctor and pharmacologist. He spent his career both as researcher and as an academic at several universities. Black established the physiology department at the University of Glasgow, where he became interested in the effects of adrenaline...

, C. Robin Ganellin

C. Robin Ganellin

Charon Robin Ganellin is a British born medicinal chemist. He has contributed much to the field of drug discovery and development. His most outstanding achievement was the discovery of cimetidine, a drug used to combat stomach ulcers, when he was working at Smith Kline and French...

, and others to develop a histamine receptor

Histamine receptor

The histamine receptors are a class of G protein-coupled receptors with histamine as their endogenous ligand.There are four known histamine receptors:*H1 receptor*H2 receptor*H3 receptor*H4 receptor-Comparison:...

antagonist

Receptor antagonist

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

that would suppress stomach acid secretion.

In 1964 it was known that histamine

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 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 N^α-guanylhistamine, a partial H₂-receptor antagonist. From this lead the receptor model was further refined and eventually led to the development of burimamide

Burimamide

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

, a specific competitive antagonist

Competitive antagonist

A competitive antagonist is a receptor antagonist that binds to a receptor but does not activate the receptor. The antagonist will compete with available agonist for receptor binding sites on the same receptor...

at the H₂ receptor 100-times more potent than N^α-guanylhistamine, proving the existence of the H₂ receptor.

Burimamide was still insufficiently potent for oral administration and further modification of the structure, based on modifying the pKa

PKA

PKA, pKa, or other similar variations may stand for:* pKa, the symbol for the acid dissociation constant at logarithmic scale* Protein kinase A, a class of cAMP-dependent enzymes* Pi Kappa Alpha, the North-American social fraternity...

of the compound, led to the development of metiamide

Metiamide

Metiamide is a histamine H2-receptor antagonist developed from another H2 antagonist, burimamide. It was an intermediate compound in the development of the successful anti-ulcer drug cimetidine .-Development of metiamide from burimamide:...

. Metiamide was an effective agent; however, it was associated with unacceptable nephrotoxicity

Nephrotoxicity

Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...

and agranulocytosis

Agranulocytosis

Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...

. It was proposed that the toxicity arose from the thiourea

Thiourea

Thiourea is an organosulfur compound of with the formula SC2 . It is structurally similar to urea, except that the oxygen atom is replaced by a sulfur atom, but the properties of urea and thiourea differ significantly. Thiourea is a reagent in organic synthesis. "Thioureas" refers to a broad...

group, and similar guanidine

Guanidine

Guanidine is a crystalline compound of strong alkalinity formed by the oxidation of guanine. It is used in the manufacture of plastics and explosives. It is found in urine as a normal product of protein metabolism. The molecule was first synthesized in 1861 by the oxidative degradation of an...

analogues were investigated until the discovery of cimetidine

Cimetidine

, which would become the first clinically successful H₂ antagonist.

Ranitidine

Ranitidine

(common brand name Zantac) was developed by Glaxo (also now GlaxoSmithKline

GlaxoSmithKline

GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...

) 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

Imidazole

Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...

-ring of cimetidine with a furan

Furan

Furan is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen. The class of compounds containing such rings are also referred to as furans....

-ring with a nitrogen

Nitrogen

Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

-containing substituent, and in doing so developed ranitidine. Ranitidine was found to have a far-improved tolerability profile (i.e. fewer adverse drug reaction

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 inhibitor

Proton pump inhibitor

s, with omeprazole

Omeprazole

Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...

becoming the biggest-selling drug for many years.

Pharmacology

The H₂ antagonists are competitive antagonists of histamine

Histamine

at the parietal cell

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

Gastrin

In humans, gastrin is a peptide hormone that stimulates secretion of gastric acid by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the antrum of the stomach, duodenum, and the pancreas...

and acetylcholine

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

) have a reduced effect on parietal cells when the H₂ receptors are blocked.

Like the H₁-antihistamines, the H₂ antagonists are inverse agonist

Inverse agonist

In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....

s rather than true receptor antagonist

Receptor antagonist

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

Clinical use

H₂-antagonists are used by clinicians in the treatment of acid-related Gastrointestinal conditions. To be specific, these indications may include:

Peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...

disease (PUD)
Gastroesophageal reflux disease
Gastroesophageal reflux disease
Gastroesophageal reflux disease , gastro-oesophageal reflux disease , gastric reflux disease, or acid reflux disease is chronic symptoms or mucosal damage caused by stomach acid coming up from the stomach into the esophagus...

(GERD/GORD)
Dyspepsia
Dyspepsia
Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
Prevention of stress ulcer
Stress ulcer
Stress ulcers are single or multiple mucosal defects which can become complicated by upper gastrointestinal bleeding during the physiologic stress of serious illness...

(a specific indication of ranitidine)

People that 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

Esophagitis

Esophagitis is inflammation of the esophagus. It may be acute or chronic. The acute esophagitis can be catarrhal or phlegmonous, whereas the chronic esophagitis may be hypertrophic or atrophic.-Infectious:...

since they have been shown to promote healing better than H₂-antagonists.

Histamine H2 receptor blockers may have therapeutic benefits for CHF

Congestive heart failure

Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...

by blocking the action of histamine in the heart.

The H2 antagonist Ranitidine is prescribed by some urologists for patients with interstitial cystitis. Interstitial cystitis (IC) patients have been found to have significantly more mast cells than non-IC individuals. Mast cells explode with histamine. Studies have suggested that antihistamines improve IC-related pelvic pain.

Adverse effects

H₂ antagonists are, in general, well-tolerated, except for cimetidine

Cimetidine

, wherein all of the following adverse drug reaction

Adverse drug reaction

s (ADRs) are common. Infrequent ADRs include hypotension

Hypotension

In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

. Rare ADRs include: headache

Headache

A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...

, tiredness, dizziness, confusion, diarrhea

Diarrhea

Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

, constipation, and rash. In addition, cimetidine may also cause gynecomastia

Gynecomastia

Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...

in males, loss of libido, and impotence, which are reversible upon discontinuation.

In a longitudinal study

Longitudinal study

A longitudinal study is a correlational research study that involves repeated observations of the same variables over long periods of time — often many decades. It is a type of observational study. Longitudinal studies are often used in psychology to study developmental trends across the...

of elderly African American

African American

African Americans are citizens or residents of the United States who have at least partial ancestry from any of the native populations of Sub-Saharan Africa and are the direct descendants of enslaved Africans within the boundaries of the present United States...

s published in 2007, long-term use of H₂ blockers appeared to increase the risk of cognitive decline.

Drug interactions

With regard to pharmacokinetics

Pharmacokinetics

Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...

, cimetidine in particular interferes with some of the body's mechanisms of drug metabolism

Drug metabolism

Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...

and elimination through the liver cytochrome P450 pathway. To be specific, cimetidine is an inhibitor of the P450 enzymes CYP1A2

CYP1A2

Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...

, CYP2C9

CYP2C9

Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...

, CYP2C19

CYP2C19

Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...

, CYP2D6

CYP2D6

Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...

, CYP2E1

CYP2E1

Cytochrome P450 2E1 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. In humans, the CYP2E1 enzyme is encoded by the CYP2E1 gene...

, and CYP3A4

CYP3A4

Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...

. By reducing the metabolism of drugs through these enzymes, cimetidine may increase their serum

Blood plasma

Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

concentration

Concentration

In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...

s to toxic levels. Many drugs are affected, including warfarin

Warfarin

Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

, theophylline

Theophylline

Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...

, phenytoin

Phenytoin

Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...

, lidocaine

Lidocaine

Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...

, quinidine

Quinidine

Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...

, propranolol, labetalol

Labetalol

Labetalol is a mixed alpha/beta adrenergic antagonist, which is used to treat high blood pressure.-Indications:...

, methadone

Methadone

Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...

, metoprolol

Metoprolol

Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate...

, tricyclic antidepressants, some benzodiazepines, dihydropyridine calcium channel blocker

Calcium channel blocker

A calcium channel blocker is a chemical that disrupts the movement of calcium through calcium channels.CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with...

s, sulfonylureas, metronidazole

Metronidazole

Metronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....

, and some recreational drugs such as ethyl alcohol and methylenedioxymethamphetamine

Methylenedioxymethamphetamine

MDMA is an entactogenic drug of the phenethylamine and amphetamine class of drugs. In popular culture, MDMA has become widely known as "ecstasy" , usually referring to its street pill form, although this term may also include the presence of possible adulterants...

.

The more recently developed H₂-receptor antagonists are less likely to alter CYP metabolism. Ranitidine

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

Famotidine

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

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