Etodolac

Etodolac is Non- Steroidal Anti inflammatory Drugs belonging to Analgesic and Anti inflammatory agents.

Etodolac is used in the treatment of Acute pain and Arthritis.

Etodolac is Rapidly absorbed with Bioavailability of ≥80%. Volume of distribution: Approx 390 mL/kg with Plasma protein binding: >99%, primarily to albumin.

It is Extensively metabolised in the liver to hydroxylated metabolites and etodolac glucuronide; hydroxylated metabolites undergo further glucuronidation and get excreted Mainly via urine (73%); faeces (16%).

The Duration of action of Etodolac was found to be about 4 to 6 hours.

The onset of action for Etodolac for Oral was 0.5 hours

The Tmax of Etodolac was within 2 hours and Cmax of Etodolac was found within 1200 mg to 3200 mg

Etodolac shows common side effects like Oedema, HTN, cardiac failure, nausea, epigastric pain, diarrhea, indigestion, heartburn, flatulence, abdominal pain, constipation, vomiting, ulcerative stomatitis, dyspepsia, hematemesis, melaena, rectal bleeding, exacerbation of colitis, vasculitis, headaches

Etodolac is available in India, Germany, Canada, France, USA

Etodolac binds to the upper portion of the COX enzyme active site and prevents its substrate, arachidonic acid, from entering the active site. Etodolac was previously thought to be a non-selective COX inhibitor, but it is now known to be 5 – 50 times more selective for COX-2 than COX-1. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss.

Etodolac is available in the form of Capsule, tablet.

Etodolac is used in the treatment of Acute pain and Arthritis.

Etodolac is an NSAID derived from pyrano-indoleacetic acid which inhibits cyclooxygenase 2 (COX-2), resulting in decreased prostaglandin precursor formation.

Etodolac is approved for use in the following clinical indications

Acute pain (immediate release): Management of acute pain.

Arthritis: Relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis (immediate and extended release) and juvenile arthritis (extended release only).

Acute pain: Oral: Immediate release: 200 to 400 mg every 6 to 8 hours; maximum: 1 g daily.

Osteoarthritis, rheumatoid arthritis

Osteoarthritis, rheumatoid arthritis: Oral:

Immediate release: 400 mg 2 times daily or 300 mg 2 to 3 times daily or 500 mg 2 times daily

Extended release: Initial: 400 mg to 1 g once daily.

Etodolac is available in the dosage strength of 500mg, 160mg/5 ml, 500 mg/15 mL, 160 mg/5 mL, 160 mg/5 mL, 500 mg/15 mL, 50 mL, 100 mL, 5 mL, 10.15 mL, 20.3 mL, 118 mL, 473 mL); 325 mg/10.15 mL (10.15 mL); 650 mg/20.3 mL.

Take after eating and with a full glass of water to decrease gastric upset.

Etodolac is contraindicated in patients with:

Hypersensitivity (e.g, anaphylactic reaction) to Etodolac or any component of the formulation.

Concerns related to adverse effects:

• Anaphylactoid reactions: Even in patients without prior exposure anaphylactoid reactions may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Contraindicated in patients who experience bronchospasm, asthma, rhinitis, or urticaria with nonsteroidal anti-inflammatory drug (NSAID) or aspirin therapy.

• Cardiovascular events: NSAIDs cause an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including MI and stroke. Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of serious cardiovascular thrombotic events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors and in those receiving higher doses. New onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to ACE inhibitors, thiazide diuretics, or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention; use with caution in patients with edema. Avoid use in heart failure . Avoid use in patients with recent MI unless benefits outweigh risk of cardiovascular thrombotic events. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.

• CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

• Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.

• GI events: NSAIDs cause increased risk of serious GI inflammation, ulceration, bleeding, and perforation (may be fatal). Avoid use in patients with active GI bleeding. In patients with a history of acute lower GI bleeding, avoid use of non-aspirin NSAIDs, especially if due to angioectasia or diverticulosis . Use caution with a history of GI ulcers, concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), advanced hepatic disease, coagulopathy, smoking, use of alcohol, or in elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of gastrointestinal complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended.

• Hematologic effects: Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Anemia may occur; patients on long-term NSAID therapy should be monitored for anemia. Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, thrombocytopenia, aplastic anemia).

• Hepatic effects: Transaminase elevations have been reported with use; closely monitor patients with any abnormal LFT. Rare (sometimes fatal) severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue immediately if clinical signs or symptoms of liver disease develop or if systemic manifestations occur.

• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in the elderly, diabetics, renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE-inhibitors). Monitor potassium closely.

• Renal effects: NSAID use may compromise existing renal function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow which may cause renal decompensation (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, hepatic impairment, those taking diuretics, and ACE inhibitors, and the elderly are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Long-term NSAID use may result in renal papillary necrosis and other renal injury.

• Skin reactions: NSAIDs may cause potentially fatal serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN); may occur without warning; discontinue use at first sign of skin rash (or any other hypersensitivity).

Disease-related concerns:

• Aseptic meningitis: May increase the risk of aseptic meningitis, especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders.

• Asthma: Contraindicated in patients with aspirin-sensitive asthma; severe and potentially fatal bronchospasm may occur. Use caution in patients with other forms of asthma.

• Bariatric surgery: Gastric ulceration: Avoid chronic use of oral nonselective NSAIDs after bariatric surgery; development of anastomotic ulcerations, perforations, and leaks may occur. Short-term use of celecoxib or IV ketorolac are recommended as part of a multimodal pain management strategy for postoperative pain.

• Coronary artery bypass graft surgery: Risk of MI and stroke may be increased with use following coronary artery bypass graft surgery.

• Hepatic impairment: Use with caution in patients with hepatic impairment; reduced doses may be required due to extensive hepatic metabolism. Patients with advanced hepatic disease are at an increased risk of GI bleeding and kidney failure with NSAIDs.

• Renal impairment: Avoid use in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function; monitor closely if therapy must be initiated.

Etodolac may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

It is not known if etodolac is present in breast milk.

Nonopioid analgesics are preferred for breastfeeding patients who require pain control peripartum or for surgery outside of the postpartum period .Nonsteroidal anti-inflammatory drugs are considered compatible for the treatment of rheumatic and musculoskeletal diseases in lactating patients; agents with a short half-life and established safety data in infants may be preferred.

Due to the potential for serious adverse reactions in the breastfeeding infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, considering the importance of treatment to the mother. Maternal use of NSAIDs should be avoided if the breastfeeding infant has platelet dysfunction, thrombocytopenia, or a ductal-dependent cardiac lesion.

May decrease GI upset and serum peak levels when taken w/ food. Alcohol enhances gastric mucosal irritation.

Common Adverse effects:

• Oedema, HTN, cardiac failure, nausea, epigastric pain, diarrhea, indigestion, heartburn, flatulence, abdominal pain, constipation, vomiting, ulcerative stomatitis, dyspepsia, hematemesis, melaena, rectal bleeding, exacerbation of colitis, vasculitis, headaches

Less Common Adverse effects:

• Dizziness, abnormal vision, pyrexia, drowsiness, tinnitus, rash, pruritus, fatigue, depression, insomnia, confusion, paresthesia, tremor, weakness, dyspnea

Rare Adverse effects

• Hepatic function abnormalities, jaundice, urinary frequency, Crohn's disease, photosensitivity, asthma, nephritis, anemia.

May increase the effect of lithium, warfarin and methotrexate. Increased risk of adverse effect w/ aspirin or other NSAIDs. May reduce the effect of diuretics, mifepristone and antihypertensives. Increased risk of nephrotoxicity w/ ciclosporin, diuretics and tacrolimus, Increased risk of GI bleeding w/ SSRIs, anti-platelets and corticosteroids. Increased risk of convulsions w/ quinolone antibiotics. Increased risk of hematological toxicity when given w/ zidovudine. May exacerbate cardiac failure, reduce GFR and increase serum level w/ of cardiac glycoside.

The common side effects of Etodolac include the following :

• Oedema, HTN, cardiac failure, nausea, epigastric pain, diarrhoea, indigestion, heartburn, flatulence, abdominal pain, constipation, vomiting, ulcerative stomatitis, dyspepsia, haematemesis, melaena, rectal bleeding, exacerbation of colitis, vasculitis, headaches.

Symptoms: Lethargy, drowsiness, nausea, vomiting, epigastric pain, GI bleeding, coma, HTN, acute renal failure, resp depression.

Management: Symptomatic and supportive treatment. Perform emesis and/or administer activated charcoal or osmotic cathartic w/in 4 hr of ingestion.

• Pharmacodynamic

Etodolac is an anti-inflammatory agent with analgesic and antipyretic properties. It is used to treat osteoarthritis, rheumatoid arthritis and control acute pain. The therapeutic effects of etodolac are achieved via inhibition of the synthesis of prostaglandins involved in fever, pain, swelling and inflammation. Etodolac is administered as a racemate. As with other NSAIDs, the S-form has been shown to be active while the R-form is inactive. Both enantiomers are stable and there is no evidence of R- to S- conversion in vivo.

• Pharmacokinetics

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
2. https://reference.medscape.com/drug/colestid-Etodolac -342452
3. https://go.drugbank.com/drugs/DB00375
4. https://www.sciencedirect.com/topics/medicine-and-dentistry/Etodolac
5. https://europepmc.org/article/med/6988203