indication

For the acute and chronic treatment of signs and symptoms of osteoarthritis and rheumatoid arthritis.

pharmacology

Diclofenac is an acetic acid nonsteroidal antiinflammatory drug (NSAID) with analgesic and antipyretic properties. Diclofenac is used to treat pain, dysmenorrhea, ocular inflammation, osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and actinic keratosis

mechanism of action

The antiinflammatory effects of diclofenac are believed to be due to inhibition of both leukocyte migration and the enzyme cylooxygenase (COX-1 and COX-2), leading to the peripheral inhibition of prostaglandin synthesis. As prostaglandins sensitize pain receptors, inhibition of their synthesis is responsible for the analgesic effects of diclofenac. Antipyretic effects may be due to action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat dissipation.

toxicity

Symptoms of overdose include loss of consciousness, increased intracranial pressure, and aspiration pneumonitis. LD₅₀=390mg/kg (orally in mice)

biotransformation

Hepatic

absorption

Completely absorbed from the gastrointestinal tract.

half life

2 hours

route of elimination

Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites.

drug interactions

Alendronate: Increased risk of gastric toxicity

Anisindione: The NSAID, diclofenac, may increase the anticoagulant effect of anisindione.

Colesevelam: Bile acid sequestrants may decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Monitor for decreased serum concentrations/therapeutic effects of nonsteroidal anti-inflammatory agents (NSAID) if coadministered with bile acid sequestrants. Separating the administration of doses by 2 or more hours may reduce (but not eliminate) the risk of interaction. The manufacturer of colesevelam recommends that drugs should be administered at least 1 hour before or 4 hours after colesevelam.

Cyclosporine: Monitor for nephrotoxicity

Dicumarol: The NSAID, diclofenac, may increase the anticoagulant effect of dicumarol.

Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.

Lithium: The NSAID, diclofenac, may decrease the renal excretion of lithium. Increased risk of lithium toxicity.

Methotrexate: The NSAID, diclofenac, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Rifampin: Rifampin, a CYP2C9 inducer, may increase the metabolism of diclofenac.

Tacrine: The metabolism of Tacrine, a CYP1A2 substrate, may be reduced by Diclofenac, a CYP1A2 inhibitors. Monitor the efficacy and toxicity of Tacrine if Diclofenac is initiated, discontinued or if the dose is changed.

Telmisartan: Concomitant use of Telmisartan and Diclofenac may increase the risk of acute renal failure and hyperkalemia. Monitor renal function at the beginning and during treatment.

Timolol: The NSAID, Diclofenac, may antagonize the antihypertensive effect of Timolol.

Tizanidine: Diclofenac may decrease the metabolism and clearance of Tizanidine. Consider alternate therapy or use caution during co-administration.

Trandolapril: The NSAID, Diclofenac, may reduce the antihypertensive effect of Trandolapril. Consider alternate therapy or monitor for changes in Trandolapril efficacy if Diclofenac is initiated, discontinued or dose changed.

Treprostinil: The prostacyclin analogue, Treprostinil, may increase the risk of bleeding when combined with the NSAID, Diclofenac. Monitor for increased bleeding during concomitant thearpy.

Vilazodone: Increased risk of bleeding with concomitant use of NSAIDs with vilazodone.

Voriconazole: Voriconazole, a strong CYP2C9 inhibitor, may increase the serum concentration of diclofenac by decreasing its metabolism. Renal impairment may increase the risk of diclofenac adverse effects. Monitor for changes in therapeutic and adverse effects of diclofenac if voriconazole is initiated, discontinued or dose changed.

Warfarin: The antiplatelet effects of oral diclofenac may increase the bleed risk associated with warfarin. Consider alternate therapy or monitor for signs and symptoms of bleeding during concomitant therapy.