Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

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

Mechanism of action and pharmacodynamic effects
Naloxone hydrochloride, a semisynthetic morphine derivative (N-allyl-noroxymorphone), 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, such as pentazocine, for example, but also nalorphine. Naloxone hydrochloride does not counteract central depression caused by hypnotics or other non-opioids and does not possess the "agonistic" or morphine-like properties characteristic of other opioid antagonists. Even high doses of the drug (10 times the usual therapeutic dose) produce insignificant analgesia, only slight drowsiness, and no respiratory depression, psychotomimetic effects, circulatory changes, or miosis. In the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity. Because naloxone hydrochloride, unlike nalorphine, does not exacerbate the respiratory depression caused by other substances, it can therefore also be used for differential diagnosis.
Naloxone hydrochloride has not been shown to produce tolerance or cause physical or mental dependence.
In case of opioid dependence, administration of naloxone hydrochloride will enhance the symptoms of physical dependence. When administered intravenously, the pharmacological effect of naloxone hydrochloride will usually be visible within two minutes. The duration of the antagonistic effect depends on dose, but in general is in the range of 1-4 hours. The need for repeated doses depends on the quantity, type and route of administration of the opioid to be antagonised.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Naloxone hydrochloride is rapidly absorbed from the gastrointestinal tract but it is subject to considerable first-pass metabolism and is rapidly inactivated following oral administration. Although the drug is effective orally, doses much larger than those required for parenteral administration are required for complete opioid antagonism.
Therefore, naloxone hydrochloride is administered parenterally.

Distribution
Following parenteral administration, naloxone hydrochloride is rapidly distributed into body tissues and fluids, especially into the brain, because the drug is highly lipophilic.
The diffusion of naloxone at the cerebral level is good: at the maximum serum concentrations (i.e. 15 minutes after injection), the cerebral concentrations are one and a half times higher than the plasma concentrations.
In adult humans, the distribution volume at steady-state is reported to be about 2 l/kg.
Protein binding is within the range of 32 to 45%.
Naloxone hydrochloride readily crosses the placenta; however, it is not known whether naloxone hydrochloride is distributed into breast milk.

Biotransformation
Naloxone hydrochloride is rapidly metabolised in the liver, mainly by conjugation with glucuronic acid, and excreted in urine.
After i.v. injection, naloxone undergoes rapid degradation: only small quantities of non-metabolized naloxone are found in plasma.
The degradation of naloxone takes place according to an enterohepatic cycle: dealkylation with reduction of group 6 keto and glycuroconjugation give rise to different metabolites including, in particular, 2-naloxone-glycuronide.

Elimination
Naloxone hydrochloride has a short plasma half-life of approximately 45-90 minutes after parenteral administration. The plasma half-life for neonates is approximately 3 hours.
The total body clearance amounts to 22 ml/min/kg.
The elimination of naloxone and its metabolites is urinary (70% in 72 hours).