Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antidotes, ATC code: V03AB15

Mechanism of action and pharmacodynamic effects

Naloxone, a semisynthetic morphine derivative (N-allyl-nor-oxymorphone), is a specific opioid antagonist that acts competitively at opioid receptors. It reveals very high affinity for the opioid receptor sites and therefore displaces both opioid agonists and partial antagonists. Naloxone does not possess the "agonistic" or morphine-like properties characteristic of other opioid antagonists.
In the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity. Naloxone has not been shown to produce tolerance or cause physical or mental dependence.


As the duration of action of some opioid agonists may be longer than that of naloxone, the effects of the opioid agonist may return as the effects of naloxone disappear. This may necessitate repeat doses of naloxone – though the need for repeat naloxone doses is dependent on the quantity, type and route of administration of the opioid agonist that is being treated.

Paediatric population

No data are available.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption

Intranasal administration of naloxone has demonstrated naloxone to be rapidly absorbed, as evidenced by very early appearance (as early as 1 minute after administration) of the active substance in systemic circulation.

A study investigating intranasal naloxone at doses of 1, 2, 4 mg (MR903-1501) shows that the median (range) tmax associated with intranasal administration of naloxone was 15 (10, 60) minutes for 1 mg, 30 (8, 60) minutes for 2 mg and 15 (10, 60) minutes for 4 mg intranasal doses. Onset of action following intranasal administration can reasonably be expected to occur in each individual before the tmax is reached.

The half value duration (HVD) values for intranasal administration were longer than for IM administration (intranasal, 2 mg, 1.27h, IM, 0.4 mg 1.09h) from which we can infer a longer duration of action of naloxone given by the intranasal rather than the IM route. If the duration of action of the opioid agonist exceeds that of intranasal naloxone, the effects of the opioid agonist may return, necessitating a second intranasal naloxone administration.

A study demonstrated mean absolute bioavailability of 47% and mean half-lives of 1.4 h from intranasal doses of 2 mg.

Biotransformation

Naloxone is rapidly metabolized in the liver and excreted in the urine. It undergoes extensive hepatic metabolism mainly by glucuronide conjugation. The principal metabolites are naloxone-3-glucuronide, 6-beta-naloxol and its glucuronide.

Elimination

There are no data available on the excretion of naloxone following intranasal administration, however, the disposition of labelled naloxone following IV administration was studied in healthy volunteers and opioid-dependent patients. Following an IV dose of 125 µg, 38% of the dose was recovered in the urine within 6 hours in healthy volunteers compared with 25% of the dose being recovered in opioid-dependent patients in the same time period. After a period of 72 hours, 65% of the injected dose was recovered in urine in the healthy volunteers compared with 68% of the dose in opiate-dependent patients.
 Paediatric population

No data are available.