Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

Mechanism of action
Diclofenac is a non-steroidal compound with pronounced antirheumatic, anti- inflammatory, analgesic, and antipyretic properties. Inhibition of prostaglandin biosynthesis, which has been demonstrated in experiments, is considered to be fundamental to its mechanism of action. Prostaglandins play an important role in causing inflammation, pain and fever.
Diclofenac in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in humans.

Pharmacodynamic effects
In rheumatic diseases, the anti-inflammatory and analgesic properties of diclofenac elicit a clinical response characterized by marked relief from signs and symptoms such as pain at rest, pain on movement, morning stiffness, and swelling of the joints, as well as by an improvement in function.
Diclofenac has also been found to exert a pronounced analgesic effect in moderate and severe pain of non-rheumatic origin, an effect which sets in within 15 to 30 minutes.

Diclofenac has also been shown to have a beneficial effect in migraine attacks.
In post-traumatic and post-operative inflammatory conditions, diclofenac rapidly relieves both spontaneous pain and pain on movement and reduces inflammatory swelling and wound edema.

When used concomitantly with opioids for the management of post-operative pain, diclofenac significantly reduces the need for opioids.
Abitren injection is particularly suitable for initial treatment of inflammatory and degenerative rheumatic diseases, and of painful conditions due to inflammation of non-rheumatic origin.

Pharmacokinetic Properties

Pharmacokinetic properties
Absorption
After administration of 75 mg diclofenac by intramuscular injection, absorption sets in immediately, and mean peak plasma concentrations of about 2.5 micrograms/mL (8 micromol/L) are reached after about 20 minutes. The amount absorbed is in linear proportion to the size of the dose.

When 75 mg diclofenac is administered as an intravenous infusion over 2 hours, mean peak plasma concentrations are about 1.9 micrograms/mL (5.9 micromol/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. In contrast, plasma concentrations decline rapidly once peak levels have been reached following intramuscular injection or administration of tablets or suppositories.
ABITREN INJECTION July 2014,      28 7. 2014, RH                   Page 11 of 13 The area under the concentration curve (AUC) after intramuscular or intravenous administration is about twice as large as it is following oral or rectal administration, because about half the active substance is metabolised during its first passage through the liver ("first pass" effect) when administered via the oral or rectal routes.
Pharmacokinetic behavior does not change after repeated administration. No accumulation occurs provided the recommended dosage intervals are observed.

Distribution
99.7% of diclofenac binds to serum proteins, mainly to albumin (99.4%). The apparent volume of distribution calculated is 0.12 to 0.17 L/kg.
Diclofenac enters the synovial fluid, where maximum concentrations are measured 2 to 4 hours after peak plasma values have been reached. The apparent half-life for elimination from the synovial fluid is 3 to 6 hours. Two hours after reaching peak plasma levels, concentrations of the active substance are already higher in the synovial fluid than in the plasma, and they remain higher for up to 12 hours.

Biotransformation
Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites (3'-hydroxy-, 4'-hydroxy-, 5-hydroxy-, 4',5-dihydroxy-, and 3'- methoxy-diclofenac), most of which are converted to glucuronide conjugates.
Two of these phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.
Elimination
Total systemic clearance of diclofenac from plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1 to 2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1 to 3 hours. One metabolite, 3'-hydroxy- 4'-methoxy-diclofenac, has a much longer plasma half-life.
However, this metabolite is virtually inactive.
About 60% of the administered dose is excreted in the urine as the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the feces.
Characteristics in patients
No relevant age-dependent differences in the drug’s absorption, metabolism, or excretion have been observed. However, in a few elderly patients a 15-minute intravenous infusion resulted in 50% higher plasma concentrations than expected from the data on young healthy subjects.
In patients suffering from renal impairment, no accumulation of the unchanged active substance can be inferred from the single-dose kinetics when applying the usual dosage schedule. At a creatinine clearance of less than 10 mL/min, the calculated steady-state plasma levels of the hydroxy metabolites are about 4 times higher than in normal subjects. However, the metabolites are ultimately cleared through the bile.
In patients with chronic hepatitis or non-decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.