Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
ATC Code: M01AE51 – Musculoskeletal system, anti-inflammatory and antirheumatic products, non- steroids, propionic acid derivatives. Ibuprofen combinations.

Mechanism of action
Although the exact site and mechanism of analgesic action of paracetamol is not clearly defined, it appears that it induces analgesia by elevation of the pain threshold. The potential mechanism may involve inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptors including N- methyl-D-aspartate and substance P.
Ibuprofen is a propionic acid derivative with analgesic, anti-inflammatory and antipyretic activity. The drug's therapeutic effects as an NSAID result from its inhibitory effect on the enzyme cyclo-oxygenase, leading to reduction in prostaglandin synthesis.
Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Some pharmacodynamic studies show that when single doses of ibuprofen 400 mg were taken within 8 h before or within 30 min after immediate release acetylsalicylic acid dosing (81mg), a decreased effect of acetylsalicylic acid on the formation of thromboxane or platelet aggregation occurred. Although there are uncertainties regarding extrapolation of these to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 4.5).

Clinical trials
Randomized, double-blind studies were conducted with the combination using the acute dental pain model of post-operative pain. The studies showed that:
• Over the 48 hours, this product had a faster onset than either of its two active ingredients and provided superior analgesia than the same daily dose of paracetamol (p=0.007 at rest, p=0.006 on activity) and ibuprofen (p=0.003 at rest, p=0.007 on activity).
• All three doses evaluated (half caplet or one caplet or two caplets) were effective when compared with placebo (p=0.004-0.002) and the highest dose [two caplets] had the greatest response rate (50%), lowest maximum VAS pain scores, longest time to rescue medication and lowest % of patients requiring rescue medication. All these measures were significantly different to placebo (p<0.05).

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Absorption
Both paracetamol and ibuprofen, are readily absorbed from the gastrointestinal tract with peak plasma concentration occurring about 10 to 60 minutes after oral administration.
The rate and absorption of both paracetamol and ibuprofen from the combination product is slightly delayed following administration after food.

Distribution
As for any product containing paracetamol, it is distributed into most body tissues. Ibuprofen is highly bound (90-99%) to plasma proteins.

Metabolism
Paracetamol is metabolized extensively in the liver and excreted in the urine, mainly as inactive glucuronide and sulphate conjugates. Less than 5% is excreted unchanged. The metabolites of paracetamol include a minor hydroxylated intermediate which has hepatotoxic activity. This active intermediate is detoxified by conjugation with glutathione, however, it can accumulate following paracetamol overdose and if left untreated has the potential to cause severe and even irreversible liver damage.
Paracetamol is metabolized differently by premature infants, newborns, and young children compared with adults, the sulphate conjugate being most predominant.
Ibuprofen is extensively metabolized to inactive compounds in the liver, mainly by glucuronidation.
The metabolic pathways of paracetamol and ibuprofen are distinct and there should be no drug interactions where the metabolism of one affects the metabolism of the other. A formal study using human liver enzymes to investigate such a possibility failed to find any potential drug interaction on the metabolic pathways.
In another study, the effect of ibuprofen on the oxidative metabolism of paracetamol was evaluated in healthy volunteers under fasting conditions. The study results indicated that ibuprofen did not alter the amount of paracetamol undergoing oxidative metabolism, as the amount of paracetamol and its metabolites (glutathione-, mercapturate-, cysteine-, glucuronide- and sulfate-paracetamol) were similar when administered alone, as paracetamol, or with the concomitant administration of ibuprofen (as a fixed combination) This study clears any added hepatic risks from the hepatotoxic metabolite, NAPQI, from paracetamol if administered with Ibuprofen.

Elimination
Paracetamol elimination half-life varies from about 1 to 3 hours.
Both the inactive metabolites and a small amount of unchanged ibuprofen are excreted rapidly and completely by the kidney, with 95% of the administered dose eliminated in the urine within four hours of ingestion. The elimination half-life of ibuprofen is around 2 hours.

Pharmacokinetic relationship
A specific study to investigate possible effects of paracetamol on the plasma clearance of ibuprofen and vice versa did not identify any drug interactions.