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Indometacin ( INN ; or USAN indomethacin ) is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of prostaglandins, endogenous signaling molecules known to cause these symptoms. It does this by inhibiting cyclooxygenase, an enzyme that catalyzes the production of prostaglandins.
It is marketed under more than twelve different trade names.
Contents
1 Medical uses
2 Contraindications
3 Adverse effects
4 Toxicity
5 Mechanism of action
6 History
7 Society and culture
7.1 Generic names
8 See also
9 References
10 External links
Medical uses
As an NSAID, indometacin is an analgesic, anti-inflammatory, and antipyretic. Clinical indications for indometacin include:
Joint diseases
rheumatoid arthritis
ankylosing spondylitis
osteoarthritis
gouty arthritis
acute painful shoulder bursitis or tendinitis
Headaches
Trigeminal autonomic cephalgias
Paroxysmal hemicranias
Chronic paroxysmal hemicrania
Episodic paroxysmal hemicrania
Hemicrania continua
Valsalva-induced headaches
Primary cough headache
Primary exertional headache
Primary headache associated with sexual activity (preorgasmic and orgasmic)
Primary stabbing headache (jabs and jolts syndrome)
Hypnic headache
Others
Patent ductus arteriosus
Indometacin has also been used clinically to delay premature labor, reduce amniotic fluid in polyhydramnios, and to close patent ductus arteriosus.
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 medication is better described as an anti-inflammatory, rather than an analgesic. Indometacin can also affect warfarin and subsequently raise INR.
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 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)
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 salts (such as lithium carbonate)
Adverse effects
See also: Nonsteroidal anti-inflammatory drug
In general, adverse effects seen with indometacin are similar to all other NSAIDs. For instance, indometacin inhibits both cyclooxygenase-1 and cyclooxygenase-2, which then inhibits the production of prostaglandins in the stomach and intestines responsible for maintaining the mucous lining of the gastrointestinal tract. Indometacin, 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, 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.
Many NSAIDs, but particularly indometacin, cause lithium retention by reducing its excretion by the kidneys. Thus indometacin 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.
All NSAIDs, including indometacin, also increase 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)
Hypernatremia (high sodium levels)
Hypertension
Elevations of serum creatinine and more serious renal damage such as acute renal failure, chronic nephritis and nephrotic syndrome, are also possible. These conditions also often begin with edema and hyperkalemia.
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 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.
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.
Toxicity
Indometacin has a high acute toxicity both for animals (in rats, 12 mg/kg) 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.
Mechanism of action
Main article: 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. Indometacin is a nonselective inhibitor of cyclooxygenase (COX) 1 and 2, the 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. By inhibiting the synthesis of prostaglandins, indometacin can reduce pain, fever, and inflammation.
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 disscociated into ionised form, leaving very little unionised 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 cells are more alkaline. Therefore, indometacin are trapped inside the parietal cells in ionised form, damaging the stomach cells, causing stomach irritation. This stomach irritation can reduce if the stomach acid pH is reduced.
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.
Prostaglandins also cause uterine contractions in pregnant women. Indometacin is an effective tocolytic agent, 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 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
History
Indometacin was created in 1963
Society and culture
Generic names
Indometacin is the INN, BAN, and JAN of the drug while indomethacin is the USAN, and former AAN and BAN.
See also
Indometacin farnesil
Indometacin morpholinylamide
Pravadoline
GW-405,833

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