Indometacin: Difference between revisions

{{Short description|Anti-inflammatory drug}}

{{Use dmy dates|date=January 2024}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| verifiedrevid = 460769466

| image = Indometacin.svg

| width = 225

| alt =

| image2 = Indometacin-from-xtal-2003-ball-and-stick.png

| alt2 =

| USAN = Indomethacin

| pronounce = {{IPAc-en|ɪ|n|d|oʊ-|ˈ|m|ɛ|t|ə|s|ᵻ|n}}

| tradename = Indocid, Indocin

| DailyMedID = Indomethacin

| Drugs.com = {{drugs.com|monograph|indomethacin}}

| pregnancy_AU = C

| pregnancy_category =

| routes_of_administration = [[Oral administration|By mouth]], [[Rectal administration|rectal]], [[intravenous]], [[Topical administration|topical]]

| ATC_prefix = C01

| ATC_suffix = EB03

| ATC_supplemental = {{ATC|M01|AB01}}, {{ATC|M02|AA23}}, {{ATC|S01|BC01}}

| legal_AU = Schedule 4

| legal_CA = Rx-only

| legal_UK = POM

| legal_US = Rx-only

| protein_bound = 99%<ref name = MD/>

| metabolism = [[Liver]]

| elimination_half-life = 2.6-11.2 hours (adults), 12-28 hours (infants)<ref name = MD/>

| excretion = [[Kidney]] (60%), [[Feces|fecal]] (33%)

| PDB_ligand = IMN

| IUPAC_name = 2-<nowiki/>{1-[(4-Chlorophenyl)carbonyl]-5-methoxy-2-methyl-1''H''-indol-3-yl}acetic acid

| C=19 | H=16 | Cl=1 | N=1 | O=4

| SMILES = Cc1c(c2cc(ccc2n1C(=O)c3ccc(cc3)Cl)OC)CC(=O)O

}}

<!-- Please do not change "indometacin" to "indomethacin". "Indometacin" is not a typo, it is the International Nonproprietary Name. -->

'''Indometacin''', also known as '''indomethacin''', is a [[nonsteroidal anti-inflammatory drug]] (NSAID) commonly used as a [[prescription drug|prescription medication]] to reduce [[fever]], [[pain]], [[joint stiffness|stiffness]], and [[swelling (medical)|swelling]] from [[inflammation]]. It works by inhibiting the production of [[prostaglandin]]s, [[endogenous]] [[signaling molecule]]s known to cause these symptoms. It does this by inhibiting [[cyclooxygenase]], an [[enzyme]] that [[catalyzes]] the production of prostaglandins.<ref name = MD>{{cite web|title=Indometacin|work=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|date=14 January 2014|access-date=22 June 2014|url= http://www.medicinescomplete.com/mc/martindale/current/ms-2658-m.htm| veditors = Brayfield A |location=London, UK}}</ref><ref>{{cite web | title=TGA Approved Terminology for Medicines, Section 1 – Chemical Substances | date=July 1999 | publisher=Therapeutic Goods Administration, Department of Health and Ageing, Australian Government | page=70 | url=http://www.tga.gov.au/pdf/medicines-approved-terminology-chemical.pdf }}</ref>

It was patented in 1961 and approved for medical use in 1963.<ref>{{cite journal | vauthors = Hart FD, Boardman PL | title = Indomethacin: A New Non-steroid Anti-inflammatory Agent | journal = British Medical Journal | volume = 2 | issue = 5363 | pages = 965–70 | date = October 1963 | pmid = 14056924 | pmc = 1873102 | doi = 10.1136/bmj.2.5363.965 }}</ref><ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=517 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA517 |language=en}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> In 2021, it was the 253rd most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Indomethacin - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Indomethacin | access-date = 14 January 2024}}</ref>

==Medical uses==

As an NSAID, indometacin is an [[analgesic]], [[anti-inflammatory]], and [[antipyretic]]. Clinical indications for indometacin include:<br>

'''Joint diseases'''

*[[rheumatoid arthritis]]<ref name="Lucas 2016">{{cite journal | vauthors = Lucas S | title = The Pharmacology of Indomethacin | journal = Headache | volume = 56 | issue = 2 | pages = 436–46 | date = February 2016 | pmid = 26865183 | doi = 10.1111/head.12769 | s2cid = 205160729 }}</ref>

*[[ankylosing spondylitis]]<ref name="Lucas 2016"/>

*[[osteoarthritis]]<ref name="Lucas 2016"/>

*[[gouty arthritis]]<ref name="Lucas 2016"/>

*acute painful shoulder [[bursitis]] or [[tendinitis]]<ref name="Lucas 2016"/>

'''Headaches'''

*[[Trigeminal autonomic cephalgia]]s<ref name="Dodick 2004">{{cite journal | vauthors = Dodick DW | title = Indomethacin-responsive headache syndromes | journal = Current Pain and Headache Reports | volume = 8 | issue = 1 | pages = 19–26 | date = February 2004 | pmid = 14731379 | doi = 10.1007/s11916-004-0036-6 | s2cid = 24393617 }}</ref>

*[[Paroxysmal hemicrania]]s<ref name="Dodick 2004"/>

*Chronic paroxysmal hemicrania<ref name="Dodick 2004"/>

*Episodic paroxysmal hemicrania<ref name="Dodick 2004"/>

*[[Hemicrania continua]]<ref name="Dodick 2004"/>

*Valsalva-induced headaches<ref name="Dodick 2004"/>

*Primary cough headache<ref name="Dodick 2004"/>

*Primary exertional headache<ref name="Dodick 2004"/>

*Primary headache associated with sexual activity (preorgasmic and orgasmic)<ref name="Dodick 2004"/>

*Primary stabbing headache (jabs and jolts syndrome)<ref name="Dodick 2004"/>

*[[Hypnic headache]]<ref name="Dodick 2004"/>

'''Others'''

*[[Patent ductus arteriosus]]<ref>{{cite journal | vauthors = Sekar KC, Corff KE | title = Treatment of patent ductus arteriosus: indomethacin or ibuprofen? | journal = Journal of Perinatology | volume = 28 | issue = Suppl 1 | pages = S60-2 | date = May 2008 | pmid = 18446180 | doi = 10.1038/jp.2008.52 | doi-access = | s2cid = 5553768 }}</ref>

==Contraindications==

* Concurrent [[peptic ulcer]], or history of ulcer disease

* Allergy to indometacin, aspirin, or other NSAIDs

* [[Roux-en-Y]] gastric bypass and [[gastric sleeve]] patients

* Patients with nasal [[polyp (medicine)|polyps]] reacting with an [[angioedema]] to other NSAIDs

* Children under 2 years of age (with the exception of neonates with [[patent ductus arteriosus]])

* Severe pre-existing renal and liver damage

* Caution: pre-existing bone marrow damage (frequent blood cell counts are indicated)

* Caution: bleeding tendencies of unknown origin (indometacin inhibits [[platelet]] aggregation)

* Caution: [[Parkinson's disease]], [[epilepsy]], psychotic disorders (indometacin may worsen these conditions)<ref>{{cite web|title=INDOMETHACIN|url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+53-86-1|work=Hazardous Substances Data Bank (HSDB)|publisher=National Library of Medicine's TOXNET|access-date=4 April 2013}}</ref>

* Concurrent with potassium sparing diuretics

* Patients who have a [[patent ductus arteriosus]] dependent heart defect (such as [[transposition of the great vessels]])

* Significant [[hypertension]] (high blood pressure)

* Concomitant administration of [[Lithium (medication)|lithium salts]] (such as lithium carbonate)

==Adverse effects==

{{see also|Nonsteroidal anti-inflammatory drug}}

In general, the adverse effects of indometacin are similar to those of all other NSAIDs. For instance, indometacin inhibits both [[PTGS1|cyclooxygenase-1]] and [[Prostaglandin-endoperoxide synthase 2|cyclooxygenase-2]], which then inhibits the production of [[prostaglandin]]s in the [[stomach]] and [[intestines]] responsible for maintaining the [[mucus|mucous lining]] of the [[gastrointestinal tract]]. Indometacin, therefore, like other non-selective COX inhibitors, can cause [[peptic ulcer]]s. 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&nbsp;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&nbsp;mg at bedtime, or [[omeprazole]] 20&nbsp;mg at bedtime). Other common gastrointestinal complaints, including [[dyspepsia]], [[heartburn]] and mild [[diarrhea]] are less serious and rarely require discontinuation of indometacin.

Many NSAIDs, but particularly indometacin, cause [[Lithium (medication)|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.

All NSAIDs, including indometacin, also increase [[renin|plasma renin activity]] and [[aldosterone]] levels, and increase [[sodium]] and [[potassium]] retention. [[Vasopressin]] activity is also enhanced. Together these may lead to:

* [[Edema]] (swelling due to fluid retention)

* [[Hyperkalemia]] (high potassium levels)<ref>{{cite journal | vauthors = Akbarpour F, Afrasiabi A, Vaziri ND | title = Severe hyperkalemia caused by indomethacin and potassium supplementation | journal = Southern Medical Journal | volume = 78 | issue = 6 | pages = 756–7 | date = June 1985 | pmid = 4002013 | doi = 10.1097/00007611-198506000-00039 }}</ref>

* [[Hypernatremia]] (high sodium levels)

* [[Hypertension]]

Elevations of serum [[creatinine]] and more serious renal damage such as acute [[kidney failure]], chronic [[nephritis]] and [[nephrotic syndrome]], are also possible. These conditions also often begin with edema and [[hyperkalemia|high 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 (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.

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.

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 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.

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 the [[Ductus arteriosus]].<ref>{{cite journal | vauthors = Enzensberger C, Wienhard J, Weichert J, Kawecki A, Degenhardt J, Vogel M, Axt-Fliedner R | title = Idiopathic constriction of the fetal ductus arteriosus: three cases and review of the literature | journal = Journal of Ultrasound in Medicine | volume = 31 | issue = 8 | pages = 1285–91 | date = August 2012 | pmid = 22837295 | doi = 10.7863/jum.2012.31.8.1285 | s2cid = 6798504 }}{{dead link|date=December 2017 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

In October 2020, the U.S. [[Food and Drug Administration]] (FDA) required the [[Drug labelling|drug 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.<ref name="FDA PR 20201015" /><ref name="FDA safety 20201015" /> They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.<ref name="FDA PR 20201015">{{cite press release | title=FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications | website=U.S. [[Food and Drug Administration]] (FDA) | date=15 October 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-warns-using-type-pain-and-fever-medication-second-half-pregnancy-could-lead-complications | access-date=15 October 2020}} {{PD-notice}}</ref><ref name="FDA safety 20201015">{{cite web | title=NSAIDs may cause rare kidney problems in unborn babies | website=U.S. Food and Drug Administration | date=21 July 2017 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic | access-date=15 October 2020}} {{PD-notice}}</ref>

==Mechanism of action==

{{Main|Non-steroidal anti-inflammatory drug}}

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 of [[cyclooxygenase]] (COX) 1 and 2, the enzymes that participate in [[prostaglandin]] [[biosynthesis|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. By inhibiting the synthesis of prostaglandins, indometacin can reduce pain, fever, and inflammation.<ref name="Lucas 2016"/> Indometacin mechanism of action, along with several other NSAIDs that inhibit COX, was described in 1971.<ref>{{cite journal | vauthors = Ferreira SH, Moncada S, Vane JR | title = Indomethacin and aspirin abolish prostaglandin release from the spleen | journal = Nature | volume = 231 | issue = 25 | pages = 237–9 | date = June 1971 | pmid = 5284362 | doi = 10.1038/newbio231237a0 }}</ref>

Additionally, indometacin has recently been found to be a [[Allosteric modulator#Classes|positive allosteric modulator (PAM)]] of the [[Cannabinoid receptor type 1|CB₁ cannabinoid receptor]]. By enhancing the [[Ligand (biochemistry)#Receptor.2Fligand binding affinity|binding]] and signalling of [[Endocannabinoid system|endogenous cannabinoids]] such as [[anandamide]], PAMs may elicit increased cannabinergic signalling in a [[Allosteric modulator#Medical importance|tissue specific manner]], reducing the incidence of problematic side effects such as [[Psychoactive drug|psychoactivity]] while maintaining some [[Nociception|antinociceptive]] activity.<ref>{{cite journal | vauthors = Laprairie RB, Mohamed KA, Zagzoog A, Kelly ME, Stevenson LA, Pertwee R, Denovan-Wright EM, Thakur GA | title = Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling | journal = Frontiers in Molecular Neuroscience | volume = 12 | pages = 257 | date = 18 October 2019 | pmid = 31680861 | pmc = 6813218 | doi = 10.3389/fnmol.2019.00257 | doi-access = free }}</ref>

Besides, indometacin has logarithmic [[acid dissociation constant]] pKa 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 the [[parietal cell]]s 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.<ref name="Lucas 2016"/>

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.<ref name="pmid9876886">{{cite journal | vauthors = Castellano AE, Micieli G, Bellantonio P, Buzzi MG, Marcheselli S, Pompeo F, Rossi F, Nappi G | title = Indomethacin increases the effect of isosorbide dinitrate on cerebral hemodynamic in migraine patients: pathogenetic and therapeutic implications | journal = Cephalalgia | volume = 18 | issue = 9 | pages = 622–30 | date = November 1998 | pmid = 9876886 | doi = 10.1046/j.1468-2982.1998.1809622.x | doi-broken-date = 7 February 2024 }}</ref> 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.<ref name="Lucas 2016"/> 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.<ref>{{cite book | vauthors = Dowd FJ, Johnson B, Mariotti A | chapter = Chapter 23, Drugs for Treating Orofacial Pain Syndromes. | pages = 384–5 | title = Pharmacology and Therapeutics for Dentistry-E-Book. Elsevier Health Sciences; 2016 Sep 3. }}</ref> On the other hand, the activation of [[superior salivary nucleus]] in the [[brainstem]] is used to stimulate the trigeminal autonomic reflex arc, causing a type of headache called [[trigeminal autonomic cephalgia]]. Indometacin inhibits the superior salivatory nucleus, thus relieving this type of headache.<ref name="Lucas 2016"/>

Prostaglandins also cause [[uterine contraction]]s in pregnant women. Indometacin is an effective [[tocolytic agent]],<ref name="pmid17459777">{{cite journal | vauthors = Giles W, Bisits A | title = Preterm labour. The present and future of tocolysis | journal = Best Practice & Research. Clinical Obstetrics & Gynaecology | volume = 21 | issue = 5 | pages = 857–68 | date = October 2007 | pmid = 17459777 | doi = 10.1016/j.bpobgyn.2007.03.011 }}</ref> able to delay premature labor by reducing uterine contractions through inhibition of prostaglandin synthesis in the uterus and possibly through [[calcium channel]] blockade.

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.

Other modes of action for indometacin are:

* it inhibits motility of polymorphonuclear leukocytes, similar to [[colchicine]]

* it uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, like salicylates

* it has been found to specifically inhibit MRP (multidrug resistance proteins) in murine and human cells<ref name="pmid9062400">{{cite journal | vauthors = Draper MP, Martell RL, Levy SB | title = Indomethacin-mediated reversal of multidrug resistance and drug efflux in human and murine cell lines overexpressing MRP, but not P-glycoprotein | journal = British Journal of Cancer | volume = 75 | issue = 6 | pages = 810–5 | date = 1997 | pmid = 9062400 | pmc = 2063393 | doi = 10.1038/bjc.1997.145 }}</ref>

==Nomenclature==

Indometacin is the {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|JAN|Japanese Accepted Name}} of the drug while indomethacin is the {{abbrlink|USAN|United States Approved Name}}, and former {{abbrlink|AAN|Australian Approved Name}} and {{abbrlink|BAN|British Approved Name}}.<ref name="Elks2014">{{cite book | vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA684|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=684–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA550|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=550–}}</ref><ref name="MortonHall2012">{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA153|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=153–}}</ref>

{{Reflist}}

{{Prostanoid signaling modulators}}

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[[Category:3α-Hydroxysteroid dehydrogenase inhibitors]]

[[Category:Antigout agents]]

[[Category:Carboxamides]]

[[Category:Chloroarenes]]

[[Category:Hepatotoxins]]

[[Category:Indole ethers at the benzene ring]]

[[Category:Nonsteroidal anti-inflammatory drugs]]

[[Category:Aromatic ketones]]

[[Category:Methoxy compounds]]