Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic properties. It is thought to be mediated through potent and nonselective inhibition of the enzyme cyclooxygenase (COX), which is the main enzyme responsible for catalyzes the rate-limiting step in prostaglandin and thromboxane biosynthesis via the arachidonic acid (AA) pathway. It is one of the most potent NSAIDs in blocking prostaglandin synthesis and was among the first NSAIDs to be used in the symptomatic treatment of migraine and for headaches that eventually became known as “indomethacin-responsive” headache disorders.

Indication
● Acute Gouty Arthritis
● Moderate to Severe Osteoarthritis
● Moderate to Severe Rheumatoid Arthritis
● Moderate to severe ankylosing spondylitis
● Patent Ductus Arteriosus (PDA)
● Acute Shoulder Pain

Pharmacology

Mechanism of Action:
Indometacin is a nonspecific and reversible inhibitor of the cyclo-oxygenase (COX) enzyme, or prostaglandin G/H synthase. There are two identified isoforms of COX: COX-1 is universally present in most body tissues and is involved in the synthesis of the prostaglandins and thromboxane A2, while COX-2 is expressed in response to injury or inflammation. The COX-1 enzyme is involved in gastric mucosal protection, platelet, and kidney function. COX-2 also catalyzes the conversion of arachidonic acid to PGG2 and PGG2 to PGH2.  PGE2 is involved in mediating inflammation, pain, and fever. Decreasing levels of PGE2 leads to reduced inflammatory reactions. Indometacin is known to inhibit both isoforms of COX, however, with greater selectivity for COX-1, which accounts for its increased adverse gastric effects relative to other NSAIDs. It binds to the active site of the enzyme and prevents the interaction between the enzyme and its substrate, arachidonic acid. Indometacin, unlike other NSAIDs, also inhibits phospholipase A2, the enzyme responsible for releasing arachidonic acid from phospholipids. The analgesic, antipyretic and anti-inflammatory effects of indomethacin as well as adverse reactions associated with the drug occur as a result of decreased prostaglandin synthesis. Its antipyretic effects may be due to action on the hypothalamus, resulting in increased peripheral blood flow, vasodilation, and subsequent heat dissipation.

Pharmacokinetics
Absorption: Indometacin is readily and rapidly absorbed from the gastrointestinal tract. The bioavailability is virtually 100% following oral administration 1 and about 90% of the dose is absorbed within 4 hours.
Volume of distribution: The volume of distribution ranged from 0.34 to 1.57 L/kg following oral administration.
Indometacin has been shown to cross the blood-brain barrier (BBB)11, its extensive plasma protein binding allows only the small fraction of free or unbound indometacin to diffuse across the BBB
Protein binding: Indometacin is a weak organic acid that is 90-99% bound to protein in plasma
Metabolism: Indometacin undergoes hepatic metabolism involving glucuronidation, O-desmethylation, and N-deacylation.
Route of elimination: Indometacin is eliminated via renal excretion, metabolism, and biliary excretion. 

Side Effects
The common side effects include:
● Nausea
● Vomiting
● Heartburn
● Diarrhea
● Stomach pain
● Constipation
● Headache
● Dizziness
Immediately discontinue the use if any severe side effects are observed and consult your physician.

Interaction
Some products that may interact with this drug include:
● Angiotensin-converting enzyme (ACE) inhibitors
● Angiotensin II receptor blockers
● Diuretics), such as hydrochlorothiazide
● Aspirin
● Lithium
● Methotrexate
● Ibuprofen
● Meloxicam
● Naproxen
● Warfarin
● Clopidogrel
● Ticlopidine
● Rivaroxaban

Contraindication
This medication should not be consumed in following conditions:
● An increased risk of bleeding
● Depression
● High blood pressure
● Chronic heart failure
● Liver problems
● Stomach or intestinal ulcer
● Seizures
● Pregnancy
● History of gastric bypass surgery

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