RiteMED Diclofenac Mechanism of Action

Pharmacology: Pharmacodynamics: Diclofenac sodium exhibits anti-inflammatory, analgesic and antipyretic activities by inhibiting cyclooxygenase (COX)-1 and COX-2 isoenzymes. These enzymes are found throughout the body and produce prostaglandins, which are important mediators of pain, fever, and adaptive and protective reactions in many organs and (inflamed) tissues.
When used concomitantly with opioids for the management of post-operative pain, diclofenac significantly reduces the need for opioids.
Pharmacokinetics: Diclofenac sodium is almost completely absorbed from the gastrointestinal (GI) tract after oral administration. However, the drug undergoes extensive first pass metabolism in the liver with only about 50 to 60% of a diclofenac dose reaching the systemic circulation as unchanged drug. Peak plasma concentrations occur within 2 to 3 hours (range: 1 to 4 hours) after oral intake. The area under the plasma concentration-time curve (AUC) increases linearly with single diclofenac sodium doses of 25 to 150 mg.
Food decreases the onset and rate of absorption of enteric-coated diclofenac sodium resulting in a delayed and decreased peak plasma concentration but the extent of absorption is not affected substantially. When single doses of diclofenac sodium enteric-coated tablets are taken with food, the onset of absorption is usually delayed by 1 to 4.5 hours but may be delayed for up to 12 hours in some patients.
After administration of 75 mg diclofenac by IM injection, absorption sets in immediately, and mean plasma concentrations of about 2.558 ± 0.96 mcg/mL (8 mcmol/L) are reached after about 20 minutes. When 75 mg diclofenac is administered as an IV infusion over 2 hours, mean peak plasma concentrations are about 1.875 + 0.436 mcg/mL (5.9 mcmol/L). Shorter infusions result in higher peak plasma concentrations, while longer infusions give plateau concentrations proportional to the infusion rate after 3 to 4 hours. This is in contrast to the rapid decline in plasma concentrations seen after peak levels have been achieved with oral, rectal or IM administration.
The AUC after IM or IV administration is about twice as large as it is following oral or rectal administration as this route avoids "first-pass" metabolism. Pharmacokinetic behavior does not change after repeated administration. No accumulation occurs provided the recommended dosage interval is observed.
Diclofenac is distributed into synovial fluid, achieving peak synovial fluid concentrations about 60 to 70% of those attained in plasma after oral administration; however, synovial fluid concentrations of diclofenac and its metabolites substantially exceed those in plasma after 3 to 6 hours. Diclofenac appears to be eliminated from synovial fluid less rapidly than from plasma. The apparent total volume of distribution of diclofenac is 1.3 to 1.4 L/kg.
Diclofenac was detected in a low concentration (100 ng/mL) in breast milk. The estimated amount ingested by the infant consuming breast milk is equivalent to 0.03 mg/kg/day dose.
Diclofenac is extensively but reversibly bound to plasma proteins, mainly albumin. In vitro studies showed that the drug is 99 to 99.8% protein bound. In patients with rheumatoid arthritis, protein binding of diclofenac in synovial fluid appears to be lower than in plasma.
Following IV administration of diclofenac sodium in healthy adults, the half-life of diclofenac is approximately 3 minutes in the initial distribution phase, 16 minutes in the intermediate phase, and 1 to 2 hours in the terminal phase.
Oral diclofenac is rapidly and extensively metabolized in the liver. Its elimination half-life was approximately 1.2 to 2 hours. In humans the major metabolite is the 4'-hydroxy compound. About 20 to 30% of an oral dose is excreted in the urine while 10 to 20% is excreted in the bile. In mice and rats, diclofenac and its metabolites were shown to cross the placenta.
Special Population: Hepatic Insufficiency: Patients with hepatic disease may require reduced doses of diclofenac compared to patients with normal hepatic function since hepatic metabolism accounts for almost 100% of diclofenac elimination.
Renal Insufficiency: The elimination half-life in patients with moderate renal impairment appears to be similar to that in patients with normal renal function.