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Indomethacin (also indometacin) 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.
Chemical properties
Indomethacin is a methylated indole derivative and a member of the arylalkanoic acid class of NSAIDs.
Indications
Clinical indications for indomethacin include:
Indomethacin has also been used clinically to delay premature labor, reduce amniotic fluid in polyhydramnios, and to treat patent ductus arteriosus.
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.
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.
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.
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. 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.
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.
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:
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.
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.
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