Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Aurum Pharmaceuticals Ltd, Bampton Road, Harold Hill, Romford, Essex, RM3 8UG, United Kingdom
Pharmacotherapeutic group: Antidotes
ATC-Code: V03AB15
Naloxone is a competitive antagonist of µ, δ and κ-opioid receptors. Naloxone is most potent at the µ-receptor. Naloxone, given on its own, produces very little effect. However, if it is given in higher doses it rapidly reverses the effect of morphine and other opioids, including pentazocine and nalorphine. Naloxone has little effect on the pain threshold in normal conditions, but causes hyperalgesia in stressful conditions where endogenous opioids are produced.Naloxone also inhibits acupuncture analgesia, which is associated with the release of opioid peptides. Naloxone also prevents analgesia produced by PAG (periaqueductal grey matter) stimulation. PAG is one site of action in pain transmission. Naloxone is given intravenously and its effects are produced immediately. It is rapidly metabolised by the liver, and its effect lasts only 1-2 hours, which is a lot shorter than that of most morphine- like drugs. Thus it may have to be given repeatedly.
Naloxone is rapidly absorbed following oral administration but high presystemic metabolism makes this route unreliable. 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.
Naloxone is highly lipid soluble and is thus rapidly distributed throughout the body, with a volume of distribution of 5.1kg -1. High concentrations occur in brain, kidney, lung, heart and skeletal muscle. The brain/serum ratio has been estimated to be 1.5-4.6, approximately 15 times that of morphine. 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%.
Levels of naloxone in the central nervous system are short-lived as rapid redistribution occurs and this could account for the short duration of action. About 50% of naloxone is bound to plasma proteins, principally albumin. The plasma half-life is 1-2 hours. Naloxone hydrochloride readily crosses the placenta; however, it is not known whether naloxone hydrochloride is distributed into breast milk.
When naloxone reaches the liver it undergoes extensive biotransformation, mainly by conjugation with glucuronic acid, almost none of the drug excreted being unchanged and excreted in urine.
Metabolites are excreted largely in the urine, 70% of the dose being recoverable over 72 hours. In the neonate the elimination half-life is prolonged because of reduced hepatic metabolism. The total body clearance amounts to 22 ml/min/kg.
Preclinical data did not reveal a 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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