Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Natural opium alkaloids
ATC code: NO2A AO5

Oxycodone is a full opioid agonist with no antagonist properties. It has an affinity for kappa, mu and delta opiate receptors in the brain and spinal cord. The therapeutic effect is mainly analgesic, anxiolytic and sedative.

Gastrointestinal System
Opioids may induce spasm of the sphincter of Oddi.
Endocrine system
See section 4.4.
Other pharmacological effects
In- vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown. Whether oxycodone, a semisynthetic opioid, has immunological effects similar to morphine is unknown.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
The release of oxycodone from OxyContin tablets is biphasic with an initial relatively fast release providing an early onset of analgesia followed by a more controlled release, which determines the 12 hour duration of action.
Release of oxycodone from OxyContin tablets is independent of pH.

OxyContin tablets have an oral bioavailability comparable with conventional oral oxycodone, but the former achieve maximal plasma concentrations at about 3 hours rather than about 1 to 1.5 hours.
Peak and trough concentrations of oxycodone from OxyContin tablets 10 mg administered 12-hourly are equivalent to those achieved from conventional oxycodone 5 mg administered 6-hourly.

The strengths of OxyContin tablets are bioequivalent in terms of both rate and extent of absorption.

Distribution
Following absorption, oxycodone is distributed throughout the entire body. Approximately 45% is bound to plasma protein.

Metabolism
Oxycodone is metabolised in the liver via CYP3A4 and CYP2D6 to noroxycodone, oxymorphone and noroxymorphone, which are subsequently glucuronidated. Noroxycodone and noroxymorphone are the major circulating metabolites. Noroxycodone is a weak mu opioid agonist. Noroxymorphone is a potent mu opioid agonist; however, it does not cross the blood-brain barrier to a significant extent.
Oxymorphone is a potent mu opioid agonist but is present at very low concentrations following 
oxycodone administration. None of these metabolites are thought to contribute significantly to the analgesic effect of oxycodone.

Elimination
The mean apparent elimination half-life of OxyContin is 4.5 hours, which leads to steady-state being achieved in about one day. The active drug and its metabolites are excreted in urine.


Elderly
The AUC in elderly subjects is 15% greater when compared with young subjects.
Gender
Female subjects have, on average, plasma oxycodone concentrations up to 25% higher than males on a body weight adjusted basis. The reason for this difference is unknown.

Patients with renal impairment
Preliminary data from a study of patients with mild to moderate renal dysfunction show peak plasma oxycodone and noroxycodone concentrations approximately 50% and 20% higher, respectively and AUC values for oxycodone, noroxycodone and oxymorphone approximately 60%, 60% and 40% higher than normal subjects, respectively. There was an increase in t½ of elimination for oxycodone of only 1 hour.

Patients with mild to moderate hepatic impairment
Patients with mild to moderate hepatic dysfunction showed peak plasma oxycodone and noroxycodone concentrations approximately 50% and 20% higher, respectively, than normal subjects. AUC values were approximately 95% and 75% higher, respectively. Oxymorphone peak plasma concentrations and AUC values were lower by 15% to 50%. The t½ elimination for oxycodone increased by 2.3 hours.