Inflaryl Mechanism of Action

Pharmacology: Pharmacodynamics: Diclofenac is a nonsteroidal anti-inflammatory agent with potent anti-inflammatory, analgesic, and antipyretic properties. Chemically it is a phenylacetic acid derivative. Diclofenac is a potent inhibitor of cyclooxygenase activity, which causes a sharp reduction in the formation of prostaglandin, prostacyclin and thromboxane product, all of which are mediators of inflammation. In addition, diclofenac also regulates the lipoxygenase pathway. Proinflammatory cytokine IL-6 and substance P levels in synovial fluid and plasma of 24 patients with rheumatoid arthritis were reduced after seven days of treatment with diclofenac compared to placebo, suggesting that these are factors in NSAID anti-inflammatory mechanism of action.
Diclofenac has been found to decrease the signs and symptoms of ocular inflammation following cataract removal. It may prevent the effects of prostaglandins on eye structures.
PREVENTION OF COLORECTAL CANCER: In vitro, animal, clinical and epidemiological studies lend support for the role of nonsteroidal anti-inflammatory drugs (NSAIDs) in preventing colorectal cancer. Four mechanisms have been proposed for the chemopreventative effects of NSAIDs: (1) cyclooxygenase (COX)-mediated carcinogen activation, (2) cell proliferation, (3) apoptosis and (4) immune surveillance. Some mechanisms are believed to occur independently of cyclooxygenase inhibition. COX-1 or COX-2 or both may initiate carcinogenesis by the following mechanisms: (1) direct activation of carcinogens, (2) production of MDA, a mutagen and carcinogen and (3) production of peroxyl radicals. NSAIDs inhibit the first 2 of the previously mentioned processes. In addition, colon carcinogens increase COX-1 and COX-2 expression which may increase carcinogen activation. In all tissues, a balance exists between cell renewal and cell loss which is lost in neoplasia. In cell culture, NSAIDs inhibit cell division and alter cell cycle phase distribution of colon cancer cells; it has NOT been definitively determined whether prostaglandin synthesis is necessary for this effect. Apoptosis, programmed cell death, is inhibited during development of colorectal cancer. NSAIDs induce apoptosis in the colon and rectum. In clinical studies, use of sulindac restored normal apoptosis in the flat rectal mucosa of patients with familial adenomatous polyposis. In cell culture and animal models, colon tumors produce increased quantities of prostaglandin E2 which reduces gene expression of HLA antigens and recognition by immune cells. NSAIDs increase gene expression in colon cancer cells which increases recognition by immune cells.
Pharmacokinetics: Onset of Duration: ONSET: Analgesia, immediate release: 30 minutes.
DRUG CONCENTRATION LEVELS: BIOAVAILABILITY (F): Oral, delayed release: 50% after first-pass metabolism.
Oral, immediate release: 50% after first-pass metabolism.
Intramuscular, regular release: complete.
Ophthalmic drops: minimal.
Rectal suppositories: complete.
Topical gel: 6% percutaneous absorption.
Distribution: TOTAL PROTEIN BINDING: 99.7%.
OTHER DISTRIBUTION SITES: SYNOVIAL FLUID, 70%: The synovial fluid concentration was 70% of the plasma concentration 2 hours after injecting diclofenac 75 mg. At 4 hours and beyond, synovial fluid concentrations were higher than plasma concentrations. Accumulation may occur after multiple doses, with synovial fluid concentrations rising 3 to 5 times higher than plasma.
Distribution Kinetics: VOLUME OF DISTRIBUTION (Vd): 550 mL/kg.
Metabolism: METABOLISM SITES AND KINETICS: Liver, extensive.
Diclofenac undergoes first-pass metabolism which decreases systemic bioavailability to 50%.
METABOLITES: Aromatic hydroxylated metabolite, inactive. Conjugated metabolite, inactive.
Excretion: BREAST MILK: BREASTFEEDING: Unknown.
Limited data from two studies indicate that diclofenac is undetectable in breast milk. However, the presence or absence of diclofenac metabolites in breast milk was not assessed.
KIDNEY: RENAL EXCRETION: 65%.
Diclofenac is eliminated primarily by the kidney as conjugated metabolites; little unchanged drug is detected in the urine.
Other: OTHER EXCRETION: Bile, 35%.
Little or no unchanged diclofenac is excreted in the bile.
Half-Life: PARENT COMPOUND: ELIMINATION HALF-LIFE: 2 hours.
The synovial fluid half-life is 3 times longer than the plasma half-life.
Toxicology: Preclinical Safety Data: Preclinical Data reveal no special hazard for humans based on conventional studies of pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.