Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Topical products for joint and muscular pain. Anti- inflammatory preparations, non-steroids for topical use, ATC code: M02A A15 
Mechanism of action and pharmacodynamic effects: Diclofenac is a potent non- steroidal anti-inflammatory drug (NSAID) with pronounced analgesic, anti- inflammatory and antipyretic properties. Diclofenac exerts its therapeutic effects primarily through inhibition of prostaglandin synthesis by cyclo-oxygenase 2 (COX-2).

This medicine is an anti-inflammatory and analgesic preparation designed for topical application. In inflammation and pain of traumatic or rheumatic origin, this medicine relieves pain, decreases swelling, and shortens the time to return to normal function.
In one ankle sprain study (VOPO-P-307), this medicine significantly decreased pain on movement scores verus placebo treated subjects within three days of starting treatment, including a subject of patients with severe pain. In addition treatment this medicine also significantly improved ankle joint function within 3 days of beginning treatment.

Due to an aqueous-alcoholic base the gel also exerts a soothing and cooling effect.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
The quantity of diclofenac absorbed through the skin is proportional to the size of the treated area, and depends on both the total dose applied and the degree of skin hydration. After topical application to approximately 400 cm2 of skin, the extent of systemic exposure as determined by plasma concentration of this medicine (2 applications/day) was equivalent to diclofenac 1.16% (4 applications/day). The relative bioavailability of diclofenac (AUC ratio) for this medicine versus tablet was 4.5% on day 7 (for equivalent diclofenac sodium dose). Absorption was not modified by a moisture and vapour permeable bandage.

Distribution
Diclofenac concentrations have been measured from plasma, synovial tissue and synovial fluid after application of topical diclofenac to hand and knee joints. Maximum plasma concentrations were approximately 100 times lower than after oral administration of the same quantity of diclofenac. 99.7% of diclofenac is bound to serum proteins, mainly albumin (99.4%).

From the skin and underlying tissue, diclofenac penetrates inflamed areas, preferentially distributing to and persisting in deep inflamed tissues (such as joints) rather than in the bloodstream. Diclofenac is found in concentrations up to 20 times higher than in plasma.

Biotransformation
Biotransformation of diclofenac involves partly glucuronidation of the intact molecule, but mainly single and multiple hydroxylation resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of the phenolic metabolites are biologically active, however, to a much smaller extent than diclofenac.

Elimination
The total systemic clearance of diclofenac from plasma is 263 ± 56 ml/min. The terminal plasma half-life is 1-2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1-3 hours. One metabolite, 3'-hydroxy-4'- methoxy-diclofenac, has a longer half-life but is virtually inactive. Diclofenac and its metabolites are excreted mainly in the urine.
Characteristics in patients
No accumulation of diclofenac and its metabolites is to be expected in patients suffering from renal impairment. In patients with chronic hepatitis or non- decompensated cirrhosis, the kinetics and metabolism of diclofenac are the same as in patients without liver disease.