Article: Indometacin

Indometacin
Systematic (IUPAC) name
1-(4-chlorobenzoyl)-5-methoxy- 2-methyl-1-H-indole-3-acetic acid
Identifiers
CAS number	53-86-1
ATC code	C01EB03 M01AB01, M02AA23, S01BC01
PubChem	3715
DrugBank	APRD00109
Chemical data
Formula	C19H16NClO4
Mol. weight	357.79 g.mol-1
Pharmacokinetic data
Bioavailability	~100% (oral), 80–90% (rectal)
Protein binding	99%
Metabolism	Hepatic
Half life	4.5 hours
Excretion	Renal 60%, faecal 33%
Therapeutic considerations
Pregnancy cat.	C (Au)
Legal status	℞ Prescription only
Routes	Oral, rectal, IV, topical

Indometacin (INN) or Indomethacin (USAN and former BAN) is a non-steroidal anti-inflammatory drug commonly used 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 many trade names, including Indocin, Indocid, Indochron E-R, and Indocin-SR.

Chemical properties

Indometacin is a methylated indole derivative and a member of the arylalkanoic acid class of NSAIDs.

Indications

Clinical indications for indometacin include:

• ankylosing spondylitis
• rheumatoid arthritis
• arthritic gout
• osteoarthritis
• juvenile arthritis
• psoriatic arthritis
• Reiter's syndrome
• Paget's disease of bone
• Bartter syndrome
• pseudogout
• dysmenorrhea (menstrual cramps)
• pericarditis
• bursitis
• tendinitis
• nephrogenic diabetes insipidus (prostaglandin inhibits vasopressin's action in the kidney)
• fever and pain associated with malignant diseases (tumors, bony metastasis, lymphogranulomatosis)
• Paroxysmal hemicrania

Indometacin has also been used clinically to delay premature labor, reduce amniotic fluid in polyhydramnios, and to treat 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 drug is more potent than Aspirin, but the usually tolerated doses of Indometacin do not allow a superior efficiency compared to Aspirin. In mild to moderate pain a usual oral dose of Indometacin proved as efficient as 600mg Aspirin.

Contraindications

• acutely existing Ulcus ventriculi and/or duodeni, or history of Ulcus
• allergy against Indomethacin, Aspirin, or other NSAIDs
• patients with nasal polyps reacting with an angioedema to other NSAIDS
• children under 2 years of age
• severe preexisting renal and liver damage
• caution : preexisting bone marrow damage (frequent blood cell counts indicated)
• caution : bleeding tendencies of unknown origin (Indomethacin inhibits platelet aggregation)
• caution : Morbus Parkinson, epilepsy, psychotic disorders (Indomethacin may worsen these conditions)

Mechanism of action

Main article: Non-steroidal anti-inflammatory drug

Indometacin 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. 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.

Indometacin has 2 additional modes of actions with clinical importance:

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

These additional effects account as well for the analgesic and the antiinflammative properties.

Indometacin easily 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

Since indometacin 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. Indometacin, therefore, like other nonselective COX inhibitors, can cause ulcers. The ulcers can result in serious bleeding and/or perforation requirering hospitilization of the patient. Some even die from these complications. 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 after a meal. Nearly all patients benefit from an ulcer protective drug (e.g. highly dosed antacids, ranitidine 150mg at bedtime, or omeprazole 20mg at bedtime). Other common seen gastrointestinal complaints as dyspepsia, heartburn and mild diarrhea are harmless in nature and rarely require discontinuation of Indomethacin.

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 supplements (e.g. for treatment of depression or bipolar disorder), less toxic NSAIDs such as sulindac or aspirin, are preferred.

Indometacin 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)
• hypernatremia (high sodium levels)
• hypertension (high blood pressure)

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.

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 psychic 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 seen. Skin reactions and photosensitivity are also possible side effects.

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

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.

Necessary Examinations during Longterm Treatment

Patients should have general examinations to detect edemas and signs of central nervous side effects. Blood presssure 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 hyperkalema and/or serious kidney failure. No examinations are necessary, if only the local forms (spray or gel) are applied.

Animal Toxicity and Human Overdose

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, paraesthesia, 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

• Tablets or Capsules 25 and 50mg
• Suppositories 50 and 100mg
• SR Capsules 75mg
• Syrup (25mg/5ml)
• injectable concentrate 50mg for i.m. injection
• Spray or Gel
• Patches containing 0.5% by weight
• 1% topical liquid

History

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.