Dalyx Mechanism of Action

Pharmacotherapeutic group: Propionic acid derivatives.
Pharmacology: Pharmacodynamics: Dexketoprofen trometamol is the tromethamine salt of S-(+)-2-(3-benzoylphenyl)propionic acid, an analgesic, anti inflammatory and antipyretic medicinal product, which belongs to the non-steroidal anti-inflammatory group of drugs (M01AE).
Mechanism of action: The mechanism of action of non-steroidal anti inflammatory medicinal products is related to the reduction of prostaglandin synthesis by the inhibition of cyclooxygenase pathway. Specifically, there is an inhibition of the transformation of arachidonic acid into cyclic endoperoxides, PGG2 and PGH2, which produce prostaglandins PGE1, PGE2, PGF2α and PGD2 and also prostacyclin PGI2 and thromboxanes (TxA2 and TxB2). Furthermore, the inhibition of the synthesis of prostaglandins could affect other inflammation mediators such as kinins, causing an indirect action which would be additional to the direct action.
Pharmacodynamic effects: Dexketoprofen has been demonstrated to be an inhibitor of COX-1 and COX-2 activities in experimental animals and humans.
Clinical efficacy and safety: Clinical studies performed on several pain models demonstrated effective analgesic activity of dexketoprofen. The analgesic efficacy of intramuscular and intravenous dexketoprofen in the management of moderate to severe pain was investigated in several surgical pain models (orthopaedic and gynaecologic/abdominal surgery) as well as in musculo-skeletal pain (acute low back pain model) and renal colic.
In the studies performed, the onset of analgesic effect was rapid, and within the first 45 minutes the peak analgesic effect occurred. Duration of analgesic effect after the administration of 50 mg of dexketoprofen is usually 8 hours.
Clinical studies in postoperative pain management have demonstrated that dexketoprofen trometamol when used in combination with opioids significantly reduced opioid consumption. In the post-operative pain studies where patients received morphine by a patient controlled analgesia device, patients treated with dexketoprofen required significantly less morphine (between 30 - 45% less) than patients in the placebo group.
Pharmacokinetics: Absorption: After intramuscular administration of dexketoprofen trometamol to humans, the peak concentrations are reached at 20 minutes (range 10 to 45 min). For 25 to 50 mg single doses the area under the curve has been shown to be dose proportional after both intramuscular and intravenous administration.
Distribution: In multiple-dose pharmacokinetic studies, it was observed that Cmax and AUC after the last intramuscular or intravenous administration were not different from that obtained following a single dose, indicating that no drug accumulation occurs.
As with other medicinal products with a high plasma protein binding (99%), the volume of distribution has a mean value below 0.25 L/kg. The distribution half-life was approximately 0.35 hours and the elimination half-life ranged between 1 - 2.7 hours.
Biotransformation and elimination: After administration of dexketoprofen trometamol only the S-(+) enantiomer is obtained in urine, demonstrating that no conversion to the R-(-) enantiomer occurs in humans. The main elimination route for dexketoprofen is glucuronide conjugation followed by renal excretion.
Elderly: In healthy elderly subjects (65 years and older), exposure was significantly higher than in young volunteers after single and repeated oral doses (up to 55%) whereas there was no statistically significant difference in peak concentrations and time to reach peak concentration. The mean elimination half-life was prolonged after single and repeated doses (up to 48%), and the apparent total clearance was reduced.
Toxicology: Preclinical safety data: Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and immunopharmacology. The chronic toxicity studies carried out in mice and monkeys gave a No Observed Adverse Effect Level (NOAEL) at 3 mg/kg/day. The main adverse effect observed at high doses was gastrointestinal erosions and ulcers that developed dose dependently.
As it has been recognised for the whole pharmacological class of NSAIDs, dexketoprofen may cause changes of embryo-foetal survival in animal models, both indirectly, through the gastrointestinal toxicity on the pregnant mothers, and directly upon the development of the foetus.