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| Pronunciation | /ɪndoʊˈmɛtəsɪn/ |
| Trade names | Indocid, Indocin |
| Other names | Indomethacin (USANUS) |
| AHFS/Drugs.com | Monograph |
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| Routes of administration | By mouth,rectal,intravenous,topical |
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| Bioavailability | ~100% (oral), 80–90% (rectal) |
| Protein binding | 99%[2] |
| Metabolism | Liver |
| Eliminationhalf-life | 2.6-11.2 hours (adults), 12-28 hours (infants)[2] |
| Excretion | Kidney (60%),fecal (33%) |
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| ECHA InfoCard | 100.000.170 |
| Chemical and physical data | |
| Formula | C19H16ClNO4 |
| Molar mass | 357.79 g·mol−1 |
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Indometacin, also known asindomethacin, is anonsteroidal anti-inflammatory drug (NSAID) commonly used as aprescription medication to reducefever,pain,stiffness, andswelling frominflammation. It works by inhibiting the production ofprostaglandins,endogenoussignaling molecules known to cause these symptoms. It does this by inhibitingcyclooxygenase, anenzyme thatcatalyzes the production of prostaglandins.[2][3]
It was patented in 1961 and approved for medical use in 1963.[4][5] It is on theWorld Health Organization's List of Essential Medicines.[6] In 2022, it was the 256th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[7][8]
As an NSAID, indometacin is ananalgesic,anti-inflammatory, andantipyretic. Clinical indications for indometacin include:
Joint diseases
Headaches
Others
In general, the adverse effects of indometacin are similar to those of all other NSAIDs. For instance, indometacin inhibits bothcyclooxygenase-1 andcyclooxygenase-2, which then inhibits the production ofprostaglandins in thestomach andintestines responsible for maintaining themucous lining of thegastrointestinal tract. Indometacin, therefore, like other non-selective COX inhibitors, can causepeptic ulcers. These ulcers can result in serious bleeding or perforation, requiring hospitalization of the patient.
To reduce the possibility of peptic ulcers, indometacin should be prescribed at the lowest dosage needed to achieve a therapeutic effect, usually between 50 and 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, oromeprazole 20 mg at bedtime). Other common gastrointestinal complaints, includingdyspepsia,heartburn and milddiarrhea are less serious and rarely require discontinuation of indometacin.
Many NSAIDs, but particularly indometacin, causelithium retention by reducing its excretion by thekidneys. Thus indometacin users have an elevated risk of lithium toxicity. For patients taking lithium (e.g. for treatment ofdepression orbipolar disorder), less toxic NSAIDs such assulindac oraspirin are preferred.
All NSAIDs, including indometacin, also increaseplasma renin activity andaldosterone levels, and increasesodium andpotassium retention.Vasopressin activity is also enhanced. Together these may lead to:
Elevations of serumcreatinine and more serious renal damage such as acutekidney failure, chronicnephritis andnephrotic syndrome, are also possible. These conditions also often begin with edema andhigh potassium levels in the blood.
Paradoxically yet uncommonly, indometacin can cause headache (10 to 20%), sometimes with vertigo and dizziness, hearing loss, tinnitus, blurred vision (with or without retinal damage). There are unsubstantiated reports of worsening Parkinson's disease, epilepsy, and psychiatric disorders. Cases of life-threatening shock (includingangioedema, sweating, severehypotension andtachycardia as well as acutebronchospasm), severe or lethalhepatitis and severe bone marrow damage have all been reported. Skin reactions andphotosensitivity are also possible side effects.
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 acutegout attacks and indysmenorrhea 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.
People 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 anACE inhibitor or with potassium-sparingdiuretics, because these combinations can lead tohyperkalemia and/or serious kidney failure. No examinations are necessary if only the topical preparations (spray or gel) are applied.
Rare cases have shown that use of this medication by pregnant women can have an effect on the fetal heart, possibly resulting in fetal death via premature closing of theDuctus arteriosus.[14]
In October 2020, the U.S.Food and Drug Administration (FDA) required thedrug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.[15][16] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.[15][16]
Indometacin, a non-steroidal anti-inflammatory drug (NSAID), has similar mode of action when compared to other drugs in this group. It is a nonselective inhibitor ofcyclooxygenase (COX) 1 and 2, the enzymes that participate inprostaglandinsynthesis fromarachidonic acid. Prostaglandins arehormone-like molecules normally found in the body, where they have a wide variety of effects, some of which lead to pain, fever, and inflammation. By inhibiting the synthesis of prostaglandins, indometacin can reduce pain, fever, and inflammation.[9] Mechanism of action of indomethacin, along with several other NSAIDs that inhibit COX, was described in 1971.[17]
Additionally, indometacin has recently been found to be apositive allosteric modulator (PAM) of theCB1 cannabinoid receptor. By enhancing thebinding and signalling ofendogenous cannabinoids such asanandamide, PAMs may elicit increased cannabinergic signalling in atissue specific manner, reducing the incidence of problematic side effects such aspsychoactivity while maintaining someantinociceptive activity.[18]
Indometacin has a logarithmicpKa of 3 to 4.5. Since the physiologic body pH is well above the pKa range of indometacin, most of the indometacin molecules will be dissociated into ionized form, leaving very little un-ionized form of indometacin to cross a cell membrane. If the pH gradient across a cell membrane is high, most of the indometacin molecules will be trapped in one side of the membrane with higher pH. This phenomenon is called "ion trapping". The phenomenon of ion trapping is particularly prominent in the stomach as pH at the stomach mucosa layer is extremely acidic, while theparietal cells are more alkaline. Therefore, indometacin are trapped inside the parietal cells in ionized form, damaging the stomach cells, causing stomach irritation. This stomach irritation can reduce if the stomach acidity is reduced, as the GI side effects from NSAIDs are generally reduced by decreasing stomach acidity.[9]
Indometacin's role in treating certain headaches is unique compared to other NSAIDs. In addition to the class effect of COX inhibition, there is evidence that indometacin has the ability to reduce cerebral blood flow not only through modulation of nitric oxide pathways but also via intracranial precapillary vasoconstriction.[19] The indometacin property of reducing cerebral blood flow is useful in treating raised intracranial pressure. A case report has shown that an intravenous bolus dose of indometacin given with 2 hours of continuous infusion is able to reduce intracranial pressure by 37% in 10 to 15 minutes and increases cerebral perfusion pressure by 30% at the same time.[9] This reduction in cerebral pressure may be responsible for the remarkable efficacy in a group of headaches that is referred to as "indometacin-responsive headaches", such as idiopathic stabbing headache, chronic paroxysmal hemicranial, and exertional headaches.[20] On the other hand, the activation ofsuperior salivary nucleus in thebrainstem is used to stimulate the trigeminal autonomic reflex arc, causing a type of headache calledtrigeminal autonomic cephalgia. Indometacin inhibits the superior salivatory nucleus, thus relieving this type of headache.[9]
Prostaglandins also causeuterine contractions in pregnant women. Indometacin is an effectivetocolytic agent,[21] able to delay premature labor by reducing uterine contractions through inhibition of prostaglandin synthesis in the uterus and possibly throughcalcium channel blockade.
Indometacin readily crosses theplacenta and can reducefetalurine production to treatpolyhydramnios. It does so by reducing renal blood flow and increasing renal vascular resistance, possibly by enhancing the effects ofvasopressin on the fetal kidneys.
Other modes of action for indometacin are:
Indometacin is theINNTooltip International Nonproprietary Name,BANTooltip British Approved Name, andJANTooltip Japanese Accepted Name of the drug while indomethacin is theUSANTooltip United States Approved Name, and formerAANTooltip Australian Approved Name andBANTooltip British Approved Name.[23][24][25]
This article incorporates text from this source, which is in thepublic domain. This article incorporates text from this source, which is in thepublic domain.| pyrazolones / pyrazolidines | |
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| salicylates | |
| acetic acid derivatives and related substances | |
| oxicams | |
| propionic acid derivatives (profens) |
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| n-arylanthranilic acids (fenamates) | |
| COX-2 inhibitors (coxibs) | |
| other | |
| NSAID combinations | |
Key:underline indicates initially developed first-in-class compound of specific group;#WHO-Essential Medicines;†withdrawn drugs;‡veterinary use. | |
