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Indometacin (INN) or indomethacin (USAN and former BAN) is a non-steroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication 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 more than seventy different trade names.^[1]

Indications[edit]

Clinical indications for indometacin include:

Hemicrania continua^[2]^{[unreliable medical source?]}
ankylosing spondylitis
arthritic gout
Bartter syndrome
bursitis
cluster headache prophylaxis
cryoglobulinemia
dysmenorrhea (menstrual cramps)
exertion headache
fever and pain associated with malignant diseases (especially tumor fever associated with liver involvement, lymphogranulomatosis)
juvenile arthritis
nephrogenic diabetes insipidus (prostaglandin inhibits vasopressin's action in the kidney)
osteoarthritis
Paget's disease of bone
paroxysmal hemicrania, hemicrania continua and migraine
patent ductus arteriosus^[3]
pericarditis
pseudogout
psoriatic arthritis
Reactive arthritis
renal colic (pain due to kidney stones)
retinopathy of prematurity
rheumatoid arthritis
tendinitis

Indomethacin has also been used clinically to delay premature labor, reduce amniotic fluid in polyhydramnios, and to close patent ductus arteriosus.

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 medication is better described as an anti-inflammatory, rather than an analgesic. Indomethacin can also affect warfarin and subsequently raise INR.

Contraindications[edit]

concurrent peptic ulcer, or history of ulcer disease
allergy to indomethacin, aspirin, or other NSAIDs
patients with nasal 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 (indomethacin inhibits platelet aggregation)
caution: Parkinson's disease, epilepsy, psychotic disorders (indomethacin may worsen these conditions)^[4]
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)

Mechanism of action[edit]

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,^[5] able to delay premature labor by reducing uterine contractions through inhibition of PG synthesis in the uterus and possibly through calcium channel blockade.

Indomethacin has two additional modes of actions with clinical importance:

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

These additional effects account as well for the analgesic and the anti-inflammatory properties.

Indomethacin readily 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[edit]

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 non-selective COX inhibitors can cause peptic ulcers. These ulcers can result in serious bleeding and/or perforation requiring hospitalization of the patient.

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 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 indomethacin.

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 (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:

edema (swelling due to fluid retention)
hyperkalemia (high potassium levels)^[6]
hypernatremia (high sodium levels)
hypertension

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 hyperkalemia.

Additionally, indomethacin quite often causes headache (10 to 20%), sometimes with vertigo and dizziness, hearing loss, tinnitus, blurred vision (with or without retinal damage). There were reports of worsening Parkinson's disease, epilepsy, and psychiatric disorders but these are not substantiated. 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.

Due to its strong antipyretic activity indomethacin may obscure the clinical course of serious infections.

Psychosis has also been reported with prolonged use.

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.

Necessary examinations during long term treatment[edit]

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 Indomethacin is given together with an ACE inhibitor or with potassium-sparing diuretics, 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.

Animal toxicity and human overdose[edit]

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.

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.

The treatment is symptomatic and largely the same as with diclofenac. However, the possibility of severe GI tract symptoms should be particularly noted.

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

Usual dosage forms[edit]

tablets or capsules 25 and 50 mg
suppositories 50 and 100 mg
modified-release Capsules 75 mg
syrup (25 mg/5ml)
injectable concentrate 50 mg for i.m. injection
spray or gel
patches containing 0.5% by weight
1% topical liquid

History[edit]

Indomethacin was discovered in 1963^[7] 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.^[8]

References[edit]

^ Trade names are listed on DrugBank.ca entry DB00328
^ Sanders, Lisa (6 January 2012). "Think Like a Doctor: Ice Pick Pain Solved!". The New York Times.
^ Smyth JM, Collier PS, Darwish M et al. (September 2004). "Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study". Br J Clin Pharmacol 58 (3): 249–58. doi:10.1111/j.1365-2125.2004.02139.x. PMC 1884560. PMID 15327584.
^ "INDOMETHACIN". Hazardous Substances Data Bank (HSDB). National Library of Medicine's TOXNET. Retrieved April 4, 2013.
^ Giles W, Bisits A (October 2007). "Preterm labour. The present and future of tocolysis". Best Pract Res Clin Obstet Gynaecol 21 (5): 857–68. doi:10.1016/j.bpobgyn.2007.03.011. PMID 17459777.
^ Akbarpour F, Afrasiabi A, Vaziri N (1985). "Severe hyperkalemia caused by indomethacin and potassium supplementation". South Med J 78 (6): 756–7. doi:10.1097/00007611-198506000-00039. PMID 4002013.
^ Hart F, Boardman P (October 1963). "Indomethacin: A New Non-steroid Anti-inflammatory Agent". Br Med J 2 (5363): 965–70. doi:10.1136/bmj.2.5363.965. PMC 1873102. PMID 14056924.
^ Ferreira S, Moncada S, Vane J (Jun 23 1971). "Indomethacin and aspirin abolish prostaglandin release from the spleen". Nat New Biol 231 (25): 237–9. doi:10.1038/231237a0. PMID 5284362.

External links[edit]

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
Indomethacin bound to proteins in the PDB

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 発作性片側頭痛：臨床的特徴および診断 paroxysmal hemicrania clinical features and diagnosis
2. 早産児における動脈管開存症のマネージメント management of patent ductus arteriosus in premature infants
3. 発作性片側頭痛：治療および予後 paroxysmal hemicrania treatment and prognosis
4. 持続性片側頭痛 hemicrania continua
5. 一次性咳嗽性頭痛 primary cough headache

English Journal

Baeckeins F-I, four novel C-methylated biflavonoids from the roots of Baeckea frutescens and their anti-inflammatory activities.

Jia BX1, Zeng XL2, Ren FX3, Jia L2, Chen XQ4, Yang J4, Liu HM5, Wang Q6.Author information 1Department of Pharmacognosy, College of Pharmacy, Zhengzhou University, No. 100 of Science Road, Zhengzhou 450001, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, PR China. Electronic address: jiabeixi_2003_123@163.com.2Department of Pharmacognosy, College of Pharmacy, Zhengzhou University, No. 100 of Science Road, Zhengzhou 450001, PR China.3Henan Zhongshuai Pharmaceutical Science and Technology Development Co., Ltd, Zhengzhou 450001, PR China.4State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, PR China.5Department of Pharmacognosy, College of Pharmacy, Zhengzhou University, No. 100 of Science Road, Zhengzhou 450001, PR China. Electronic address: liuhm@zzu.edu.cn.6State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, PR China. Electronic address: qwang49@163.com.AbstractBaeckea frutescens is an aromatic shrub used in South China as an ornamental and as a spice. Four unusual C-methylated biflavonoids named baeckeins F-I (1-4) were isolated from the roots of B. frutescens. The baeckeins F-I possessed a unique carbon skeleton, a flavonol conjugated with a coumaronochromone molecule via the unusual linkages of C-2-C-8 and C-3-O-C-7. Their structures were elucidated by analysis of the 1D ((1)H/(13)C) and 2D NMR (HSQC/HMBC/NOESY) and HR-ESI-MS spectroscopic data, and the absolute stereochemistry for chiral carbons of C-2 and C-3 was established by CD spectrometry combined with quantum chemical calculations. Baeckeins F-I (1-4) were also evaluated for their anti-inflammatory activities by detecting the NO production of LPS-induced RAW264.7 murine macrophage cell line; baeckein I (4) with the β-d-glucose unit and configuration of (2R,3R) exhibited the highest NO inhibitory activity (IC50=15.2 μM), which was similar to that of the positive control indomethacin.
Food chemistry.Food Chem.2014 Jul 15;155:31-7. doi: 10.1016/j.foodchem.2014.01.022. Epub 2014 Jan 24.
Baeckea frutescens is an aromatic shrub used in South China as an ornamental and as a spice. Four unusual C-methylated biflavonoids named baeckeins F-I (1-4) were isolated from the roots of B. frutescens. The baeckeins F-I possessed a unique carbon skeleton, a flavonol conjugated with a coumaronochr
PMID 24594150

Biological evaluation of bismuth non-steroidal anti-inflammatory drugs (BiNSAIDs): Stability, toxicity and uptake in HCT-8 colon cancer cells.

Hawksworth EL1, Andrews PC2, Lie W1, Lai B3, Dillon CT4.Author information 1School of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522, Australia.2School of Chemistry, Monash University, Clayton, Victoria, 3168, Australia.3X-Ray Science Division, Advanced Photon Source, Argonne National Laboratory, Argonne, IL 60439, USA.4School of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522, Australia. Electronic address: carolynd@uow.edu.au.AbstractRecent studies showed that the metal-coordinated non-steroidal anti-inflammatory drug (NSAID), copper indomethacin, reduced aberrant crypt formation in the rodent colon cancer model, while also exhibiting gastrointestinal sparing properties. In the present study, the stability and biological activity of three BiNSAIDs of the general formula [Bi(L)3]n, where L=diflunisal (difl), mefenamate (mef) or tolfenamate (tolf) were examined. NMR spectroscopy of high concentrations of BiNSAIDs (24h in cell medium, 37°C) indicated that their structural stability and interactions with cell medium components were NSAID specific. Assessment of cell viability using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium]bromide (MTT) assay showed that the toxicity ranking of the BiNSAIDs paralleled those of the respective free NSAIDs: diflH<mefH<tolfH. While the IC50 values of the BiNSAIDs (ranging between 16 and 81μM) were lower than the free NSAIDs, it was apparent that the toxicity of the BiNSAIDs was due to the molar ratio of the three NSAID molecules contained in the BiNSAIDs, with the exception of [Bi(difl)3]. The highest cellular bismuth content was observed following treatment with [Bi(tolf)3]. Since NMR studies indicated that [Bi(tolf)3] was the most stable BiNSAID and that cellular uptake of bismuth correlated with structural stability it appears that bismuth uptake is assisted by the NSAID. Microprobe SR-XRF imaging showed that the intracellular fate of bismuth was independent of the specific BiNSAID treatment whereby all BiNSAID-treated cells showed bismuth accumulation in the cytoplasm within 24-h exposure. The size and location of the hot spots (0.3-5.8μm(2)), were consistent with cellular organelles such as lysosomes.
Journal of inorganic biochemistry.J Inorg Biochem.2014 Jun;135:28-39. doi: 10.1016/j.jinorgbio.2014.02.012. Epub 2014 Mar 1.
Recent studies showed that the metal-coordinated non-steroidal anti-inflammatory drug (NSAID), copper indomethacin, reduced aberrant crypt formation in the rodent colon cancer model, while also exhibiting gastrointestinal sparing properties. In the present study, the stability and biological activit
PMID 24650572

Effect of storage conditions on the recrystallization of drugs in solid dispersions with crospovidone.

Shibata Y1, Fujii M, Suzuki A, Koizumi N, Kanada K, Yamada M, Watanabe Y.Author information 1Pharmaceutical Research Laboratories, Kissei Pharmaceutical Co, Ltd , Azumino-city, Nagano , Japan and.AbstractThe physical stability of amorphous solid dispersions (SDs) is influenced by their storage conditions. The goal of this work was to investigate the factors affecting the recrystallization of drugs in SDs after storage under conditions of high temperature and high humidity. SDs of three drugs (dipyridamole, nifedipine and indomethacin) with different functional groups (amino, carbonyl and hydroxyl) and onset times for crystallization of the amorphous state were prepared using crospovidone (CrosPVP). All of the drugs in the SDs remained in an amorphous state at 25 °C/50% relative humidity (RH) in closed glass bottles for at least six months. Under conditions of high temperature (40 °C/75%RH/closed and 60 °C/open), differences in interactions between the hydrogen bond donors of the drugs and the amide carbonyl group of CrosPVP are essential factors for recrystallization of the drugs in the SDs. On the other hand, under condition of high humidity (40 °C/75%RH/open), in addition to the difference in the interaction between the drug and CrosPVP, the rate of increase in moisture content affects their recrystallization in SDs.
Pharmaceutical development and technology.Pharm Dev Technol.2014 Jun;19(4):468-74. doi: 10.3109/10837450.2013.795168. Epub 2013 May 17.
The physical stability of amorphous solid dispersions (SDs) is influenced by their storage conditions. The goal of this work was to investigate the factors affecting the recrystallization of drugs in SDs after storage under conditions of high temperature and high humidity. SDs of three drugs (dipyri
PMID 23682860

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リンク元

「インドメタシン」

Indometacin
Systematic (IUPAC) name
	2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy cat.	C (Au), C/D (US)
Legal status	Prescription Only (S4) (AU) ℞ Prescription only
Routes	Oral, rectal, IV, topical
Pharmacokinetic data
Bioavailability	~100% (oral), 80–90% (rectal)
Protein binding	99%
Metabolism	Hepatic
Half-life	4.5 hours
Excretion	Renal 60%, faecal 33%
Identifiers
CAS number	53-86-1
ATC code	C01EB03 M01AB01, M02AA23, S01BC01
PubChem	CID 3715
IUPHAR ligand	1909
DrugBank	DB00328
ChemSpider	3584
UNII	XXE1CET956
KEGG	D00141
ChEBI	CHEBI:49662
ChEMBL	CHEMBL6
Chemical data
Formula	C19H16ClNO4
Mol. mass	357.787 g.mol-1
	SMILES Cc1c(c2cc(ccc2n1C(=O)c3ccc(cc3)Cl)OC)CC(=O)O;
	InChI InChI=1S/C19H16ClNO4/c1-11-15(10-18(22)23)16-9-14(25-2)7-8-17(16)21(11)19(24)12-3-5-13(20)6-4-12/h3-9H,10H2,1-2H3,(H,22,23) ; Key:CGIGDMFJXJATDK-UHFFFAOYSA-N ;
(what is this?) (verify);

　　[★]

英: indomethacin、indometacin？
ラ: indometacinum
化: インドメタシンナトリウム
商: アコニップ、イドメシン、インサイド、インダシン、インテナース、インテナシン、インテバン、インデラニック、インドノール、インドメロール、インナミット、インフリー、インメシン、カトレップ、ゼムパック、セラスター、テンポラル、トラップオン、ハップスター、プロアリシン、ミカメタン、ラクティオン, Indocin
関: (プロドラッグ)インドメタシンファルネシル; 鎮痛，鎮痒，収歛，消炎剤

インドール酢酸系の非ステロイド性抗炎症薬

[1] Trade names are listed on DrugBank.ca entry DB00328

[2] Sanders, Lisa (6 January 2012). "Think Like a Doctor: Ice Pick Pain Solved!". The New York Times.

[pmid15327584-3] Smyth JM, Collier PS, Darwish M et al. (September 2004). "Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study". Br J Clin Pharmacol 58 (3): 249–58. doi:10.1111/j.1365-2125.2004.02139.x. PMC 1884560. PMID 15327584.

[4] "INDOMETHACIN". Hazardous Substances Data Bank (HSDB). National Library of Medicine's TOXNET. Retrieved April 4, 2013.

[pmid17459777-5] Giles W, Bisits A (October 2007). "Preterm labour. The present and future of tocolysis". Best Pract Res Clin Obstet Gynaecol 21 (5): 857–68. doi:10.1016/j.bpobgyn.2007.03.011. PMID 17459777.

[6] Akbarpour F, Afrasiabi A, Vaziri N (1985). "Severe hyperkalemia caused by indomethacin and potassium supplementation". South Med J 78 (6): 756–7. doi:10.1097/00007611-198506000-00039. PMID 4002013.

[7] Hart F, Boardman P (October 1963). "Indomethacin: A New Non-steroid Anti-inflammatory Agent". Br Med J 2 (5363): 965–70. doi:10.1136/bmj.2.5363.965. PMC 1873102. PMID 14056924.

[8] Ferreira S, Moncada S, Vane J (Jun 23 1971). "Indomethacin and aspirin abolish prostaglandin release from the spleen". Nat New Biol 231 (25): 237–9. doi:10.1038/231237a0. PMID 5284362.

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