Diclofenac Stats & Data
Pharmacology
DrugBankDescription
Diclofenac is a phenylacetic acid derivative and non-steroidal anti-inflammatory drug (NSAID). NSAIDs inhibit cyclooxygenase (COX)-1 and-2 which are the enzyme responsible for producing prostaglandins (PGs). PGs contribute to inflammation and pain signalling. Diclofenac, like other NSAIDs, is often used as first line therapy for acute and chronic pain and inflammation from a variety of causes. Diclofenac was the product of rational drug design based on the structures of phenylbutazone, mefenamic acid, and indomethacin. The addition of two chlorine groups in the ortho position of the phenyl ring locks the ring in maximal torsion which appears to be related to increased potency. It is often used in combination with misoprostol to prevent NSAID-induced gastric ulcers. Diclofenac was first approved by the FDA in July 1988 under the trade name Voltaren, marketed by Novartis (previously Ciba-Geigy).
Mechanism of Action
Diclofenac inhibits cyclooxygenase-1 and -2, the enzymes responsible for production of prostaglandin (PG) G2 which is the precursor to other PGs. These molecules have broad activity in pain and inflammation and the inhibition of their production is the common mechanism linking each effect of diclofenac. PGE2 is the primary PG involved in modulation of nociception. It mediates peripheral sensitization through a variety of effects. PGE2 activates the Gq-coupled EP1 receptor leading to increased activity of the inositol trisphosphate/phospholipase C pathway. Activation of this pathway releases intracellular stores of calcium which directly reduces action potential threshold and activates protein kinase C (PKC) which contributes to several indirect mechanisms. PGE2 also activates the EP4 receptor, coupled to Gs, which activates the adenylyl cyclase/protein kinase A (AC/PKA) signaling pathway. PKA and PKC both contribute to the potentiation of transient receptor potential cation channel subfamily V member 1 (TRPV1) potentiation, which increases sensitivity to heat stimuli. They also activate tetrodotoxin-resistant sodium channels and inhibit inward potassium currents. PKA further contributes to the activation of the P2X3 purine receptor and sensitization of T-type calcium channels.
Pharmacodynamics
Diclofenac reduces inflammation and by extension reduces nociceptive pain and combats fever. It also increases the risk of developing a gastrointestinal ulcer by inhibiting the production of protective mucus in the stomach.
Metabolism
Diclofenac undergoes oxidative metabolism to hydroxy metabolites as well as conjugation to glucuronic acid, sulfate, and taurine. The primary metabolite is 4'-hydroxy diclofenac which is generated by CYP2C9. This metabolite is very weakly active with one thirtieth the activity of diclofenac. Other metabolites include 3'-hydroxy diclofenac, 3'-hydroxy-4'methoxy diclofenac, 4',5-dihydroxy diclofenac, an acylglucuronide conjugate, and other conjugate metabolites.
Absorption
Diclofenac is completely absorbed from the GI tract but likely undergoes significant first pass metabolism with only 60% of the drug reaching systemic circulation unchanged . Many topical formulations are absorbed percutaneous and produce clinically significant plasma concentrations. Absorption is dose proportional over the range of 25-150 mg. Tmax varies between formulations with the oral solution reaching peak plasma concentrations in 10-40min, the enteric coated tablet in 1.5-2h, and the sustained- and extended-release formulations prolonging Tmax even further. Administration with food has no significant effects on AUC but does delay Tmax to 2.5-12h.
Toxicity
Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain, and gastrointestinal bleeding. Hypertension, acute renal failure, respiratory depression and coma occur rarely. In case of overdose, provide supportive care and consider inducing emesis and administering activated charcoal if overdose occurred less than 4 hours prior.
Indication
Diclofenac is indicated for use in the treatment of pain and inflammation from varying sources including inflammatory conditions such as osteoarthritis, rheumatoid arthritis, and akylosing spondylitis, as well as injury-related inflammation due to surgery and physical trauma. It is often used in combination with misoprostol as a gastro-protective agent in patients with high risk of developing NSAID-induced ulcers.
Half-life
The terminal half-life of diclofenac is approximately 2 h, however the apparent half-life including all metabolites is 25.8-33 h.
Protein Binding
Diclofenac is over 99.7% bound to serum proteins, primarily albumin. It is undergoes limited binding to lipoproteins as well with 1.1% bound to HDL, 0.3% to LDL, and 0.15% to VLDL.
Elimination
Diclofenac is mainly eliminated via metabolism. Of the total dose, 60-70% is eliminated in the urine and 30% is eliminated in the feces. No significant enterohepatic recycling occurs.
Volume of Distribution
Diclofenac has a total volume of distribution of 5-10 L or 0.1-0.2 L/kg. The volume of the central compartment is 0.04 L/kg. Diclofenac distributes to the synovial fluid reaching peak concentration 2-4h after administration. There is limited crossing of the blood brain barrier and cerebrospinal fluid concentrations only reach 8.22% of plasma concentrations. Doses of 50 mg delivered via intramuscular injection produced no detectable diclofenac concentrations in breast milk, however metabolite concentrations were not investigated. Diclofenac has been shown to cross the placenta in mice and rats but human data is unavailable.