WW INDO 25MG CAPSULES

Indications

• Rheumatoid arthritis
• Osteoarthritis
• Ankylosing spondylitis
• Acute gouty arthritis
• Pain relief in various inflammatory conditions
• Postoperative pain management

Mechanism of action

Indomethacin acts as a nonspecific and reversible inhibitor of the cyclo-oxygenase (COX) enzymes, specifically COX-1 and COX-2. By binding to the active site of these enzymes, it prevents the conversion of arachidonic acid into prostaglandins. The inhibition of COX-1 is associated with gastrointestinal protection, while COX-2 inhibition reduces inflammation and pain. Additionally, indomethacin inhibits phospholipase A2, limiting the release of arachidonic acid from membrane phospholipids, further contributing to its anti-inflammatory effects.

Pharmacodynamics

As an NSAID, indomethacin provides relief from pain, reduces fever, and alleviates inflammation. Its efficacy has been demonstrated in conditions such as rheumatoid arthritis and acute gouty arthritis. Indomethacin reduces symptoms such as joint swelling, tenderness, and morning stiffness, while also improving functional capabilities like grip strength and mobility. However, its use may be associated with serious cardiovascular and gastrointestinal risks, including the potential for thrombotic events and severe gastric complications.

Pharmacokinetics

Indomethacin is well absorbed after oral administration, with peak plasma concentrations typically reached within 2 to 4 hours. It has a half-life of approximately 4.5 hours and is extensively metabolized in the liver, with metabolites primarily excreted in urine. The drug exhibits a high protein binding capacity, which may influence its distribution and efficacy. Dosage adjustments may be necessary in individuals with hepatic impairment.

Contra-indications

• Active peptic ulcer disease
• History of gastrointestinal bleeding or perforation related to prior NSAID therapy
• Severe heart failure
• Untreated hypertension
• Hypersensitivity to indomethacin or other NSAIDs

Adverse effects

• Gastrointestinal bleeding
• Peptic ulcers
• Nausea
• Vomiting
• Diarrhea
• Dizziness
• Headache
• Tinnitus
• Renal impairment
• Cardiovascular thrombotic events (myocardial infarction, stroke)

Interactions

• Increased risk of bleeding with anticoagulants
• Increased toxicity with methotrexate
• Reduced effectiveness of antihypertensive agents
• Increased risk of nephrotoxicity with other NSAIDs

Precautions

• Use with caution in patients with cardiovascular disease
• Monitor renal function in at-risk patients
• Avoid concurrent use with other NSAIDs
• Assess gastrointestinal history before prescribing

Pregnancy

Indomethacin is contraindicated during the third trimester due to the risk of premature closure of the ductus arteriosus.

Breast-feeding

Indomethacin is excreted in breast milk. Caution is advised if administered to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Capsules
• Suppositories
• Oral suspension

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. Constitutively expressed, the COX-1 enzyme is involved in gastric mucosal protection, platelet, and kidney function by catalyzing the conversion of arachidonic acid to prostaglandin (PG) G2 and PGG2 to PGH2. COX-2 is constitutively expressed and highly inducible by inflammatory stimuli. It is found in the central nervous system, kidneys, uterus, and other organs. COX-2 also catalyzes the conversion of arachidonic acid to PGG2 and PGG2 to PGH2. In the COX-2-mediated pathway, PGH2 is further converted to PGE2 and PGI2 (also known as prostacyclin). 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 enzyme's active site 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. The exact mechanism of action of indometacin in inducing closure of a patent ductus arteriosus is not fully understood; however, it is thought to be through inhibition of prostaglandin synthesis. At birth, the ductus arteriosus is normally closed as the tension of the oxygen increases significantly after birth. Patent ductus arteriosus in premature infants is associated with congenital heart malformations where PGE1 mediates an opposite effect to that of oxygen. PGE1 dilates the ductus arteriosus through smooth muscle relaxation and prevents the closure of the ductus arteriosus. By inhibiting the synthesis of prostaglandins, indometacin promotes the closure of ductus arteriosus. Indometacin has been described as possessing anticancer and antiviral properties through activation of protein kinase R (PKR) and downstream phosphorylation of eIF2α, inhibiting protein synthesis. The anti-inflammatory, analgesic, and antipyretic effects of indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2) (e.g., celecoxib), appear to result from inhibition of prostaglandin synthesis. While the precise mechanism of the anti-inflammatory and analgesic effects of NSAIAs continues to be investigated, these effects appear to be mediated principally through inhibition of the COX-2 isoenzyme at sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors. This effect may be related to inhibition of the synthesis of prostaglandins that are believed to play a role in modulating the rate and extent of leukocyte infiltration during inflammation. Indomethacin also inhibits lysosomal enzyme release from polymorphonuclear leukocytes. Although the mechanism has not been determined, this effect appears to depend on the nature of the stimulus and may not be related to inhibition of prostaglandin synthesis. It has also been postulated that indomethacin, as an inhibitor of phosphodiesterase, may increase intracellular concentrations of cyclic adenosine monophosphate (AMP) which may play a role in the inflammatory response. In supratherapeu

Pharmacodynamics

Indometacin is an NSAID with analgesic and antipyretic properties that exerts its pharmacological effects by inhibiting the synthesis of factors involved in pain, fever, and inflammation. Its therapeutic action does not involve pituitary-adrenal stimulation. Indometacin primarily works by suppressing inflammation in rheumatoid arthritis by providing relief of pain as well as reducing fever, swelling, and tenderness. This effectiveness has been demonstrated by a reduction in the extent of joint swelling, the average number of joints displaying symptoms of inflammation, and the severity of morning stiffness. Increased mobility was demonstrated by a decrease in total walking time and by improved functional capability seen as an increase in grip strength. In clinical trials, indometacin was shown to be effective in relieving the pain, reducing the fever, swelling, redness, and tenderness of acute gouty arthritis. Due to its pharmacological actions, the use of indometacin is associated with the risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, as well as gastrointestinal effects such as bleeding, ulceration, and perforation of the stomach or intestines. In a study of healthy individuals, acute oral and intravenous indometacin therapy resulted in a transiently diminished basal and CO2 stimulated cerebral blood flow; this effect disappeared in one study after one week of oral treatment. The clinical significance of this effect has not been established. Compared to other NSAIDs, it is suggested that indometacin is a more potent vasoconstrictor that is more consistent in decreasing cerebral blood flow and inhibiting CO2 reactivity. There have been studies that show indometacin directly inhibiting neuronal activity to some extent in the trigeminocervical complex after either superior salivatory nucleus or dural stimulation.