Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2023 Publisher: hameln pharma ltd, Nexus, Gloucester Business Park, Gloucester, GL3 4AG, United Kingdom
Pharmacotherapeutic group: Antidotes
ATC code: V03AB15
Naloxone hydrochloride, 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, 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.
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.
Following parenteral administration, naloxone hydrochloride is rapidly distributed into body tissues and fluids, especially into the brain, because the drug is highly lipophilic. 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.
Naloxone hydrochloride is rapidly metabolised in the liver, mainly by conjugation with glucuronic acid, and excreted in urine.
Naloxone hydrochloride has a short plasma half-life of approximately 1-1.5 hours after parenteral administration. The plasma half-life for neonates is approximately 3 hours. The total body clearance amounts to 22 ml/min/kg.
Non-clinical data revealed no special hazard for humans based on conventional studies of acute and repeated dose toxicity.
Naloxone hydrochloride was weakly positive in the Ames mutagenicity and in vitro human lymphocyte chromosome aberration tests and was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in an in vivo rat bone marrow chromosome aberration study.
Studies to determine the carcinogenic potential of naloxone hydrochloride have not been performed to date.
Dose-dependent changes in the speed of postnatal neurobehavioral development and abnormal cerebral findings have been reported in rats after in utero exposure. In addition, increases in neonatal mortality and reduced body weights have been described after exposure during late gestation in rats.
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