METHACIN

Indications

• Pain and inflammation in musculoskeletal disorders
• Rheumatoid arthritis
• Osteoarthritis
• Acute gouty arthritis
• Dysmenorrhea

Dosage

Adults: The typical adult dosage for indometacin is 50 mg to 200 mg daily, divided into 2-3 doses. In acute cases, a higher starting dose may be used, followed by a maintenance dose. D

Mechanism of action

Indometacin is a nonspecific and reversible inhibitor of the cyclo-oxygenase (COX) enzymes, primarily COX-1 and COX-2. By inhibiting these enzymes, indometacin reduces the production of prostaglandins, which are responsible for mediating pain, inflammation, and fever. Indometacin also inhibits phospholipase A2, which is involved in the release of arachidonic acid from cell membrane phospholipids, further contributing to its anti-inflammatory effects.

Pharmacodynamics

Indometacin's pharmacological effects include the reduction of pain, fever, and inflammation. It alleviates symptoms associated with rheumatoid arthritis, such as joint swelling, tenderness, and stiffness. Its use has been linked to increased mobility and improved functional capabilities in patients suffering from inflammatory conditions. However, indometacin is associated with risks of gastrointestinal complications and cardiovascular events due to its mechanism of action.

Pharmacokinetics

Indometacin is well absorbed after oral administration, with peak plasma concentrations typically occurring within 2-4 hours. It is metabolized in the liver and has a half-life of approximately 4.5 hours. The drug is primarily excreted in the urine, with a significant portion as metabolites. Indometacin's pharmacokinetics may be affected by factors such as age, liver function, and concurrent medications.

Contra-indications

• Active gastrointestinal bleeding
• Active gastrointestinal ulceration
• History of gastrointestinal bleeding related to previous NSAID therapy
• History of gastrointestinal perforation related to previous NSAID therapy
• History of recurrent gastrointestinal hemorrhage (two or more distinct episodes)
• Severe renal impairment

Adverse effects

• Gastrointestinal bleeding
• Peptic ulcers
• Agranulocytosis
• Allergic reactions
• Headache
• Dizziness
• Tinnitus
• Nausea
• Vomiting
• Abdominal pain
• Renal impairment
• Cardiovascular thrombotic events

Interactions

• Increased concentration of digoxin
• Increased risk of gastrointestinal bleeding when used with other NSAIDs or anticoagulants
• May reduce the effectiveness of antihypertensive medications

Precautions

• Caution in patients with a history of allergic disorders
• Caution in patients with cardiac impairment
• Caution in patients with renal impairment
• Caution in patients with coagulation defects
• Caution in patients with connective tissue disorders
• Monitor for signs of gastrointestinal bleeding

Pregnancy

Indometacin should be avoided during pregnancy, particularly in the third trimester, due to the risk of premature closure of the ductus arteriosus and potential harm to the fetus.

Breast-feeding

Indometacin is excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

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

Formulations

• Capsules
• Oral suspension
• Rectal suppositories
• Topical gel

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.