Indomethacin (USAN) or indometacin (INN) is a non-steroidal anti-inflammatory drug commonly used to reduce fever, pain, stiffness, and swelling. It works by inhibiting the production of prostaglandins, molecules known to cause these symptoms. It is marketed under many trade names, including Indocin, Indocid, Indochron E-R, and Indocin-SR. CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... A chemical formula (also called molecular formula) is a concise way of expressing information about the atoms that constitute a particular chemical compound. ... The molecular mass of a substance (less accurately called molecular weight and abbreviated as MW) is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... Smile (album), for the musical, see Smile (Musical) and for the bank, see smile (bank) Smile was also the name of the band later known as Queen. ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of medication that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... The elimination half-life of a drug (or any xenobiotic agent) refers to the timecourse necessary for the quantity of the xenobiotic agent in the body (or plasma concentration) to be reduced to half of its original level through various elimination processes. ... Excretion is the biological process by which an organism chemically separates waste products from its body. ... The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother. ... The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... A United States Adopted Name (USAN) is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the United States Pharmacopeia (USP). ... An International Nonproprietary Name (INN) is the official non-proprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization. ... Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. ... See Fever for the Kylie Minogue album; Fever is also a song by Otis Blackwell. ... Look up Pain in Wiktionary, the free dictionary. ... Inflammation is the first response of the immune system to infection or irritation and may be referred to as the innate cascade. ... Chemical structure of prostaglandin E1 (PGE1). ...

Chemical properties

Indomethacin is a methylated indole derivative and a member of the arylalkanoic acid class of NSAIDs. In biochemistry, methylation refers to the replacement of a hydrogen atom (H) with a methyl group (CH3), regardless of the substrate. ... Indole is an aromatic heterocyclic organic compound. ...

Indications

Clinical indications for indomethacin include:

• ankylosing spondylitis
• rheumatoid arthritis
• arthritic gout
• osteoarthritis
• juvenile arthritis
• psoriatic arthritis
• Reiter's syndrome
• Paget's disease of bone
• Bartter syndrome
• pseudogout
• dysmenorrhea (menstrual cramps)
• pericarditis
• bursitis
• tendinitis
• nephrogenic diabetes insipidus (prostaglandin inhibits vasopressin's action in the kidney)
• fever and pain associated with malignant diseases (tumors, bony metastasis, lymphogranulomatosis)

Indomethacin has also been used clinically to delay premature labor, reduce amniotic fluid in polyhydramnios, and to treat patent ductus arteriosus. Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints. ... Gout (also called gouty arthritis, Greek name: podagra, from pod - foot and agra - trap) is a form of arthritis caused by the accumulation of uric acid crystals in joints. ... Osteoarthritis (OA, also known as degenerative arthritis or degenerative joint disease, and sometimes referred to as arthrosis or osteoarthrosis), is a condition in which low-grade inflammation results in pain in the joints, caused by wearing of the cartilage that covers and acts as a cushion inside joints. ... Psoriatic arthritis (or Arthropathic psoriasis) is a type of inflammatory arthritis that affects around 20% of people suffering from the chronic skin condition Psoriasis. ... It has been suggested that this article or section be merged with Reactive arthritis. ... Bold text X-ray of Pagets disease Pagets disease, otherwise known as osteitis deformans, is a chronic disorder that typically results in enlarged and deformed bones. ... Bartter syndrome is a rare genetic disease characterized by low potassium levels (hypokalemia), decreased acidity of blood (alkalosis), and normal to low blood pressure. ... It has been suggested that this article or section be merged with Calcium pyrophosphate deposition disease. ... Dysmenorrhea (or dysmenorrhoea), cramps or painful menstruation, involves menstrual periods that are accompanied by either sharp, intermittent pain or dull, aching pain, usually in the pelvis or lower abdomen. ... Pericarditis is inflammation of the pericardium. ... Inflammation of the bursa in a male human shoulder Bursitis is the inflammation of one or more bursa, or small sacks of oil, in the body. ... Tendonitis (also tenonitis or tendinitis) is an inflammation of a tendon. ... Diabetes insipidus (DI) is a disease characterized by excretion of large amounts of severely diluted urine, which cannot be reduced when fluid intake is reduced. ... Human kidneys viewed from behind with spine removed The kidneys are bean-shaped excretory organs in vertebrates. ... See Fever for the Kylie Minogue album; Fever is also a song by Otis Blackwell. ... Look up Pain in Wiktionary, the free dictionary. ... Premature birth is defined medically as a birth occurring earlier than 37 weeks. ... The amniotic sac is a tough but thin transparent pair of membranes which holds a developing embryo (and later fetus) until shortly before birth. ... The amniotic sac is a tough but thin transparent pair of membranes which holds a developing embryo (and later fetus) until shortly before birth. ... Patent ductus arteriosus (PDA) is a congenital heart defect wherein a childs ductus arteriosus fails to close after birth. ...

Indomethacin is a potent drug with many serious side effects and should not be considered an analgesic for minor aches and pains or fever. The drug is more potent than Aspirin, but the usually tolerated doses of Indomethacin do not allow a superior efficiency compared to Aspirin. In mild to moderate pain a usual oral dose of Indomethacin proved as efficient as 600mg Aspirin.

Contraindications

• acutely existing Ulcus ventriculi and/or duodeni, or history of Ulcus
• allergy against Indomethacin, Aspirin, or other NSAIDs
• patients with nasal polyps reacting with an angioedema to other NSAIDS
• children under 2 years of age
• severe preexisting renal and liver damage
• caution : preexisting bone marrow damage (frequent blood cell counts indicated)
• caution : bleeding tendencies of unknown origin (Indomethacin inhibits platelet aggregation)
• caution : Morbus Parkinson, epilepsy, psychic disorders (Indomethacin may worsen these conditions)

Endoscopic images of a duodenal ulcer. ... This article is about the cnidarian polyps. ... Angioedema (BE: angiooedema), also known by its eponym Quinckes edema and the older term angioneurotic edema, is the rapid swelling (edema) of the skin, mucosa and submucosal tissues. ... A 250 ml bag of newly collected platelets. ... Parkinsons disease (paralysis agitans or PD) is a movement disorder often characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia), and in extreme cases, a loss of physical movement (akinesia). ...

Mechanism of action

Main article: Non-steroidal anti-inflammatory drug

Indomethacin is a nonselective inhibitor of cyclooxygenase (COX) 1 and 2, enzymes that participate in prostaglandin synthesis from arachidonic acid. Prostaglandins are hormone-like molecules normally found in the body, where they have a wide variety of effects, some of which lead to pain, fever, and inflammation. Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. ... Cyclooxygenase (COX) is an enzyme (EC 1. ... Arachidonic acid is a polyunsaturated fatty acid with twenty carbons and four cis double bonds, the first at the omega-6 position (20:4n-6). ... A hormone (from Greek horman - to set in motion) is a chemical messenger from one cell (or group of cells) to another. ...

Prostaglandins also cause uterine contractions in pregnant women. Indomethacin is an effective tocolytic agent, able to delay premature labor by reducing uterine contractions through inhibition of PG synthesis in the uterus and possibly through calcium channel blockade. In medicine (obstetrics), a contraction is a forceful motion of the uterus, generated by the release of oxytocin (quick labor) by the pituitary gland, culminating in childbirth. ... Ion channels are present in the membranes that surround all biological cells. ...

Indomethacin has 2 additional modes of actions with clinical importance:

• It inhibits motility of polymorphonuclear leucocytes, like colchicine.
• It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, like salicylates.

These additional effects account as well for the analgesic and the antiinflammative properties.

Indomethacin easily crosses the placenta, and can reduce fetal urine production to treat polyhydramnios. It does so by reducing renal blood flow and increasing renal vascular resistance, possibly by enhancing the effects of vasopressin on the fetal kidneys. The placenta is an ephemeral (temporary) organ present only in female placental mammals during gestation (pregnancy). ... Fetus at eight weeks Foetus redirects here. ... Urine is liquid waste excreted by the kidneys and is produced by the process of filtration. ... Arginine vasopressin (AVP), also known as argipressin or antidiuretic hormone (ADH), is a human hormone that is mainly released when the body is low on water; it causes the kidneys to conserve water by concentrating the urine and reducing urine volume. ...

Adverse effects

Since indomethacin inhibits both COX-1 and COX-2, it inhibits the production of prostaglandins in the stomach and intestines which maintain the mucous lining of the gastrointestinal tract. Indomethacin, therefore, like other nonselective COX inhibitors, can cause ulcers. The ulcers can result in serious bleeding and/or perforation requirering hospitilization of the patient. Some even die from these complications. To reduce the possibility of peptic ulcers, indomethacin should be prescribed at the lowest dosage needed to achieve a therapeutic effect, usually between 50–200 mg/day. It should always be taken after a meal. Nearly all patients benefit from an ulcer protective drug (e.g. highly dosed antacids, ranitidine 150mg at bedtime, or omeprazole 20mg at bedtime). Other common seen gastrointestinal complaints as dyspepsia, heartburn and mild diarrhea are harmless in nature and rarely require discontinuation of Indomethacin. Cyclooxygenase (COX) is an enzyme (EC 1. ... Cyclooxygenase (COX) is an enzyme that is responsible for formation of important biological mediators called prostanoids (including prostaglandins, prostacyclin and thromboxane). ... In anatomy, the stomach (in ancient Greek στόμαχος) is an organ in the gastrointestinal tract used to digest food. ... The intestine is the portion of the alimentary canal extending from the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine. ... Mucus is a slippery secretion of the lining of various membranes in the body (mucous membranes). ... The gastrointestinal tract or digestive tract, also referred to as the GI tract or the alimentary canal or the gut, is the system of organs within multicellular animals which takes in food, digests it to extract energy and nutrients, and expels the remaining waste. ... Endoscopic images of a duodenal ulcer. ... Ranitidine is a histamine H2-receptor antagonist that inhibits stomach acid production, and commonly used in the treatment of peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD). ... Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease (PUD), GORD and Zollinger-Ellison syndrome. ... Diarrhea or diarrhoea (see spelling differences) is a condition in which the sufferer has frequent loose bowel movements (from the ancient Greek word διαρροή = leakage; lit. ...

Many NSAIDs, but particularly indomethacin, cause lithium retention by reducing its excretion by the kidneys. Thus indomethacin users have an elevated risk of lithium toxicity. For patients taking lithium supplements (e.g. for treatment of depression or bipolar disorder), less toxic NSAIDs such as sulindac or aspirin, are preferred. General Name, Symbol, Number lithium, Li, 3 Chemical series alkali metals Group, Period, Block 1, 2, s Appearance silvery white/gray Atomic mass 6. ... Human kidneys viewed from behind with spine removed The kidneys are bean-shaped excretory organs in vertebrates. ... Clinical depression is a state of sadness, melancholia or despair that has advanced to the point of being disruptive to an individuals social functioning and/or activities of daily living. ... Bipolar disorder (previously known as manic depression) is a diagnostic category describing a class of mood disorders where the person experiences states or episodes of depression and/or mania, hypomania, and/or mixed states. ... Sulindac is a non-steroidal anti-inflammatory drug of the arylalkanoic acid class that is marketed in the U.S. as Clinoril. ... Aspirin or acetylsalicylic acid is a drug in the family of salicylates, often used as an analgesic (against minor pains and aches), antipyretic (against fever), and anti-inflammatory. ...

Indomethacin also reduces plasma renin activity and aldosterone levels, and increases sodium and potassium retention. It also enhances the effects of vasopressin. Together these may lead to: Renin, also known as angiotensinogenase, is a circulating enzyme (EC 3. ... Aldosterone is a steroid hormone synthesized from cholesterol by the enzyme aldosterone synthase. ... General Name, Symbol, Number sodium, Na, 11 Chemical series alkali metals Group, Period, Block 1, 3, s Appearance silvery white Atomic mass 22. ... General Name, Symbol, Number potassium, K, 19 Chemical series alkali metals Group, Period, Block 1, 4, s Appearance silvery white Atomic mass 39. ... Arginine vasopressin (AVP), also known as argipressin or antidiuretic hormone (ADH), is a human hormone that is mainly released when the body is low on water; it causes the kidneys to conserve water by concentrating the urine and reducing urine volume. ...

• edema (swelling due to fluid retention)
• hyperkalemia (high potassium levels)
• hypernatremia (high sodium levels)
• hypertension (high blood pressure)

The drug may also cause elevations of serum creatinine and more serious renal damage such as acute renal failure, chronic nephritis and nephrotic syndrome. These conditions also often begin with edema and hyperkalema. Edema (BE: oedema, formerly known as dropsy) is swelling of any organ or tissue due to accumulation of excess fluid. ... Hyperkalemia (hyper is high, kalium is the Latin name for potassium) is an elevated blood level (above 5. ... Hypernatremia is a medical condition in which there is excess sodium, urea, and other electrolytes in the body relative to the amount of water. ... For other forms of hypertension see hypertension (disambiguation). ... Creatinine is a breakdown product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body (depending on muscle mass). ... Nephritis is inflammation of the kidney. ...

Additionally, Indomethacin quite often causes headache (10 to 20%), sometimes with vertigo and dizziness, hearing loss, tinnitus, blurred vision with or without retinal damage and worsens Parkinson's disease, epilepsy, and psychic disorders. Cases of life-threatening shock (including angioedema, sweating, severe hypotension and tachycardia as well as acute bronchospasm), severe or lethal hepatitis and severe bone marrow damage have all been seen. Skin reactions and photosensitivity are also possible side effects. Angioedema (BE: angiooedema), also known by its eponym Quinckes edema and the older term angioneurotic edema, is the rapid swelling (edema) of the skin, mucosa and submucosal tissues. ... In physiology and medicine, hypotension refers to an abnormally low blood pressure. ... Tachycardia is an abnormally rapid beating of the heart, defined as a resting heart rate of 100 or more beats per minute in an average adult. ... Difficulty in breathing caused by a sudden constriction of the muscles in the wall of the bronchi. ... Hepatitis is a gastroenterological disease, featuring inflammation of the liver. ... Photosensitivity is the amount to which an object reacts upon receiving photons of light. ...

Due to its strong antipyretic activity Indomethacin may obscure the clinical course of serious infections. Antipyretics are drugs that prevent or reduce fever by lowering the body temperature from a raised state. ...

The frequency and severity of side effects and the availability of better tolerated alternatives make Indomethacin today a drug of second choice. Its use in acute gout attacks and in dysmenorrhea is well established because in these indications the duration of treatment is limited to a few days only, therefore serious side effects are not likely to occur. Dysmenorrhea (or dysmenorrhoea), cramps or painful menstruation, involves menstrual periods that are accompanied by either sharp, intermittent pain or dull, aching pain, usually in the pelvis or lower abdomen. ...

Necessary Examinations during Longterm Treatment

Patients should have general examinations to detect edemas and signs of central nervous side effects. Blood presssure checks will reveal development of hypertension. Periodic serum electrolyte (sodium, potassium, chloride) measurements, complete blood cell counts and assessment of liver enzymes as well as of creatinine (renal function) should be performed. This is particular important if Indomethacin is given together with an ACE-Inhibitor or with potassium sparing diuretics, because these combinations can lead to hyperkalema and/or serious kidney failure. No examinations are necessary, if only the local forms (spray or gel) are applied.

Animal Toxicity and Human Overdose

Indomethacin has a high acute toxicity both for animals (12 mg/kg in rats and 50 mg/kg in mice) and for humans. Exact human data does not exist, but some fatal human cases, particular in children and adolescents, have been seen.

Generally, overdose in humans causes drowsiness, dizziness, severe headache, mental confusion, paraesthesia, numbness of limbs, nausea and vomiting. Severe gastrointestinal bleeding is also possible. Cerebral edema, and cardiac arrest with fatal outcome have been seen in children.

The treatment is symptomatic and largely the same as with diclofenac. However, the possibility of severe GI tract symptoms should be particularly noted. Diclofenac (marketed as Voltaren®, Voltarol®, Diclon® and Cataflam®) is a non-steroidal anti-inflammatory drug (NSAID) taken to reduce inflammation, such as in arthritis or acute injury. ...

The risk of overdose after exaggerated local treatment with gel or spray is very limited.

Usual Dosage Forms

• Tablets or Capsules 25 and 50mg
• Suppositories 50 and 100mg
• SR Capsules 75mg
• Syrup (25mg/5ml)
• injectable concentrate 50mg for i.m. injection
• Spray or Gel
• Patches containing 0.5% by weight
• 1% topical liquid

History

Indomethacin was discovered in 1963 and it was first approved for use in the U.S. by the Food and Drug Administration in 1965. Its mechanism of action, along with several other NSAIDs that inhibit COX, was described in 1971. 1963 (MCMLXIII) was a common year starting on Tuesday (the link is to a full 1963 calendar). ... This article or section is in need of attention from an expert on the subject. ... 1965 (MCMLXV) was a common year starting on Friday (the link is to a full 1965 calendar). ... 1971 (MCMLXXI) was a common year starting on Friday (the link is to a full 1971 calendar). ...

References

• Lum GM, Aisenbrey GA, Dunn MJ, Berl T, Schrier RW, McDonald KM. "In vivo effect of indomethacin to potentiate the renal medullary cyclic AMP response to vasopressin". J Clin Invest. 1977 January; 59(1): 8–13.
• Akbarpour F, Afrasiabi A, Vaziri ND. "Severe hyperkalemia caused by indomethacin and potassium supplementation". South Med J. 1985 Jun;78(6):756-7.
• Ragheb M. "The clinical significance of lithium-nonsteroidal anti-inflammatory drug interactions". J Clin Psychopharmacol. 1990 Oct;10(5):350-4.
• Phelan KM, Mosholder AD, Lu S. "Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs". J Clin Psychiatry. 2003 Nov;64(11):1328-34.
• Hart FD, Boardman PL. "Indomethacin: A new non-steroid anti-inflammatory agent". Br Med J. 1963 Oct 19;5363:965-70.
• Ferreira SH, Moncada S, Vane JR. "Indomethacin and aspirin abolish prostaglandin release from the spleen". Nat New Biol. 1971 Jun 23;231(25):237-9.
• Scherzer P, Wald H, Rubinger D, Popovtzer MM. "Indomethacin and sodium retention in the rat: role of inhibition of prostaglandin E2 synthesis". Clin Sci (Lond). 1992 Sep;83(3):307-11.

External links

• Effects of Perinatal Indomethacin Treatment on Preterm Infants, academic dissertation (PDF)
• Indomethacin, from MedicineNet
• Indomethacin, from Drugs.com
• Indocin: Description, chemistry, ingredients, from RxList.com
• Japanese Indomethacin patches

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