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| {{drugbox |
| | #REDIRECT [[Indomethacin]] |
| | IUPAC_name = 1-(4-chlorobenzoyl)-5-methoxy-<BR>2-methyl-1-H-indole-3-acetic acid
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| | image = Indometacin skeletal.svg
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| | width = 220
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| | CAS_number = 53-86-1
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| | ATC_prefix = C01
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| | ATC_suffix = EB03
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| | ATC_supplemental = {{ATC|M01|AB01}}, {{ATC|M02|AA23}}, {{ATC|S01|BC01}}
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| | PubChem = 3715
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| | DrugBank = APRD00109
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| | C=19|H=16|Cl=1|N=1|O=4
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| | molecular_weight = 357.79 g.mol<sup>-1</sup>
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| | bioavailability = ~100% (oral), 80–90% (rectal)
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| | protein_bound = 99%
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| | metabolism = [[Hepatic]]
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| | elimination_half-life = 4.5 hours
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| | excretion = [[Renal]] 60%, [[Feces|faecal]] 33%
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| | pregnancy_category = C <small>([[Australia|Au]])</small>, C/D <small>[[(US)]]</small>
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| | legal_status = Rx-only
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| | routes_of_administration = Oral, [[suppository|rectal]], [[intravenous|IV]], topical
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| }}
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| '''Indometacin''' ([[International Nonproprietary Name|INN]]) or '''Indomethacin''' ([[United States Approved Name|USAN]] and former [[British Approved Name|BAN]]) is a [[non-steroidal anti-inflammatory drug]] commonly used to reduce [[fever]], [[Pain and nociception|pain]], stiffness, and [[inflammation|swelling]]. It works by inhibiting the production of [[prostaglandin]]s, molecules known to cause these symptoms. It is marketed under many trade names, including '''Indocin''', '''Indocid''', '''Indochron E-R''', and '''Indocin-SR'''.
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| == Chemical properties ==
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| Indometacin is a [[methylation|methylated]] [[indole]] derivative and a member of the arylalkanoic acid class of NSAIDs, which includes [[diclofenac]].
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| == Indications ==
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| Clinical indications for indometacin include:
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| * [[ankylosing spondylitis]]
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| * [[rheumatoid arthritis]]
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| * [[arthritic gout]]
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| * [[osteoarthritis]]
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| * [[childhood arthritis|juvenile arthritis]]
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| * [[psoriatic arthritis]]
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| * [[Reiter's syndrome]]
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| * [[Paget's disease of bone]]
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| * [[Bartter syndrome]]
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| * [[Chondrocalcinosis|pseudogout]]
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| * [[dysmenorrhea]] (menstrual cramps)
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| * [[pericarditis]]
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| * [[bursitis]]
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| * [[tendinitis]]
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| * nephrogenic [[diabetes insipidus]] (prostaglandin inhibits [[vasopressin]]'s action in the [[kidney]])
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| * [[fever]] and [[Pain and nociception|pain]] associated with malignant diseases (tumors, bony metastases, lymphogranulomatosis)
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| * [[paroxysmal hemicrania]], [[hemicrania continua]] and [[migraine]]
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| * [[renal colic]] (pain due to [[kidney stones]])
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| Indometacin has also been used clinically to delay [[premature labor]], reduce [[amniotic fluid]] in [[polyhydramnios]], and to treat [[patent ductus arteriosus]].
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| Indometacin 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 is not a better analgesic. In mild to moderate pain a standard oral dose of indometacin proved as effective as 600mg aspirin.
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| == Contraindications ==
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| * concurrent [[peptic ulcer]], or history of ulcer disease
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| * allergy to indometacin, aspirin, or other NSAIDs
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| * patients with nasal [[polyp]]s reacting with an [[angioedema]] to other NSAIDs
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| * children under 2 years of age (with the exception of neonates with patent ductus arteriosus)
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| * severe pre-existing renal and liver damage
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| * caution: pre-existing bone marrow damage (frequent blood cell counts are indicated)
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| * caution: bleeding tendencies of unknown origin (indometacin inhibits [[platelet]] aggregation)
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| * caution: [[Parkinson's disease]], [[epilepsy]], psychotic disorders (indometacin may worsen these conditions)
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| == Mechanism of action ==
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| {{main|Non-steroidal anti-inflammatory drug}}
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| 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.
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| Prostaglandins also cause [[uterine contraction]]s in pregnant women. Indometacin 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.
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| Indometacin has two additional modes of actions with clinical importance:
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| * It inhibits motility of polymorphonuclear leukocytes, similar to [[colchicine]].
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| * It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, like salicylates.
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| These additional effects account as well for the analgesic and the anti-inflammatory properties.
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| Indometacin readily crosses the [[placenta]], and can reduce [[fetus|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.
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| == Adverse effects ==
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| Since indomethacin inhibits both [[COX-1]] and [[COX-2]], it inhibits the production of prostaglandins in the [[stomach]] and [[intestines]] which maintain the [[mucus|mucous lining]] of the [[gastrointestinal tract]]. Indometacin, therefore, like other nonselective COX inhibitors, can cause [[peptic ulcer]]s. The ulcers can result in serious bleeding and/or perforation requiring hospitalization of the patient. Some even die from these complications.
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| To reduce the possibility of peptic ulcers, indometacin should be prescribed at the lowest dosage needed to achieve a therapeutic effect, usually between 50–200 mg/day. It should always be taken with food. Nearly all patients benefit from an ulcer protective drug (e.g. highly dosed antacids, [[ranitidine]] 150 mg at bedtime, or [[omeprazole]] 20 mg at bedtime). Other common gastrointestinal complaints, including [[dyspepsia]], [[heartburn]] and mild [[diarrhea]] are less serious and rarely require discontinuation of indometacin.
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| Many NSAIDs, but particularly indometacin, cause [[lithium]] retention by reducing its excretion by the [[kidney]]s. Thus indometacin users have an elevated risk of lithium toxicity. For patients taking lithium (e.g. for treatment of [[clinical depression|depression]] or [[bipolar disorder]]), less toxic NSAIDs such as [[sulindac]] or [[aspirin]], are preferred.
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| Indometacin also reduces [[renin|plasma renin activity]] and [[aldosterone]] levels, and increases [[sodium]] and [[potassium]] retention. It also enhances the effects of [[vasopressin]]. Together these may lead to:
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| * [[edema]] (swelling due to fluid retention)
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| * [[hyperkalemia]] (high potassium levels)
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| * [[hypernatremia]] (high sodium levels)
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| * [[hypertension]] (high blood pressure)
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| 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.
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| Additionally, indometacin 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 psychiatric 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 reported. Skin reactions and [[photosensitivity]] are also possible side effects.
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| Due to its strong [[antipyretic]] activity indometacin may obscure the clinical course of serious infections.
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| The frequency and severity of side effects and the availability of better tolerated alternatives make indometacin 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.
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| == Necessary examinations during longterm treatment ==
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| Patients should undergo regular physical examination to detect edema and signs of central nervous side effects. Blood pressure 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 particularly important if indometacin is given together with an [[ACE inhibitor]] or with potassium-sparing [[diuretic]]s, because these combinations can lead to hyperkalemia and/or serious kidney failure. No examinations are necessary if only the topical preparations (spray or gel) are applied.
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| == Animal toxicity and human overdose ==
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| 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, particularly in children and adolescents, have been seen.
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| Generally, overdose in humans causes drowsiness, dizziness, severe headache, mental confusion, [[paresthesia]], 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.
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| The treatment is symptomatic and largely the same as with [[diclofenac]]. However, the possibility of severe GI tract symptoms should be particularly noted.
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| The risk of overdose after exaggerated local treatment with gel or spray is very limited.
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| == Usual dosage forms ==
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| * tablets or capsules 25 and 50mg
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| * suppositories 50 and 100mg
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| * modified-release Capsules 75mg
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| * syrup (25mg/5ml)
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| * injectable concentrate 50mg for i.m. injection
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| * spray or gel
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| * patches containing 0.5% by weight
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| * 1% topical liquid
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| == History ==
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| Indometacin 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]].
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| == References ==
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| * {{cite journal | author = Lum G, Aisenbrey G, Dunn M, Berl T, Schrier R, McDonald K | title = In vivo effect of indomethacin to potentiate the renal medullary cyclic AMP response to vasopressin. | journal = J Clin Invest | volume = 59 | issue = 1 | pages = 8-13 | year = 1977 | month=Jan | id = PMID 187624 | url=http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=187624 | format=PDF or scanned copy}}
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| * {{cite journal | author = Akbarpour F, Afrasiabi A, Vaziri N | title = Severe hyperkalemia caused by indomethacin and potassium supplementation. | journal = South Med J | volume = 78 | issue = 6 | pages = 756-7 | year = 1985 | id = PMID 4002013}}
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| * {{cite journal | author = Ragheb M | title = The clinical significance of lithium-nonsteroidal anti-inflammatory drug interactions. | journal = J Clin Psychopharmacol | volume = 10 | issue = 5 | pages = 350-4 | year = 1990 | month=Oct | id = PMID 2258452}}
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| * {{cite journal | author = Phelan K, Mosholder A, Lu S | title = Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. | journal = J Clin Psychiatry | volume = 64 | issue = 11 | pages = 1328-34 | year = 2003 | month=Nov | id = PMID 14658947}}
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| * {{cite journal | author = Hart F, Boardman P | title = Indomethacin: A new non-steroid anti-inflammatory agent. | journal = Br Med J | volume = 5363 | issue = | pages = 965-70 | year = 1963 | month=Oct | id = PMID 14056924}}
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| * {{cite journal | author = Ferreira S, Moncada S, Vane J | title = Indomethacin and aspirin abolish prostaglandin release from the spleen. | journal = Nat New Biol | volume = 231 | issue = 25 | pages = 237-9 | year = 1971 | month=Jun 23 | id = PMID 5284362}}
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| * {{cite journal | author = Scherzer P, Wald H, Rubinger D, Popovtzer M | title = Indomethacin and sodium retention in the rat: role of inhibition of prostaglandin E2 synthesis. | journal = Clin Sci (Lond) | volume = 83 | issue = 3 | pages = 307-11 | year = 1992 | month=sep | id = PMID 1327647}}
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| == External links ==
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| * [http://acta.uta.fi/pdf/951-44-5007-8.pdf Effects of Perinatal Indomethacin Treatment on Preterm Infants], academic dissertation ([[portable document format|PDF]])
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| * [http://www.medicinenet.com/indomethacin/article.htm Indomethacin, from MedicineNet]
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| * [http://www.drugs.com/MMX/Indomethacin.html Indomethacin, from Drugs.com]
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| * [http://www.rxlist.com/cgi/generic/indometh.htm Indocin: Description, chemistry, ingredients], from RxList.com
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| {{NSAIDs}}
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| {{Anti-inflammatory and antirheumatic products}}
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| {{Topical products for joint and muscular pain}}
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| [[de:Indometacin]]
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| [[fa:ایندومتاسین]]
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| [[fr:Indométacine]]
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| [[hu:Indometacin]]
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| [[ja:インドメタシン]]
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| [[nl:Indometacine]]
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| [[pt:Indometacina]]
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| [[ro:Indometacin]]
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| [[ru:Индометацин]]
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| [[th:อินโดเมตทาซิน]]
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| [[Category:Non-steroidal anti-inflammatory drugs]]
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| [[Category:Indoles]]
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| [[Category:Tocolytics| ]]
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| [[Category:Drugs]]
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| [[pl:Indometacyna]]
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| [[tr:İndometazin]]
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| {{WikiDoc Sources}}
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