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Mechanism of action
Naloxone is a competitive inhibitor of the µ-opioid receptor. Naloxone antagonizes the action of opioids, reversing their effects. If a patient has not taken opioids, naloxone does not have a significant effect on patients.
Naloxone hydrochloride is essentially a pure opiate antagonist. The precise mechanism of action of the opiate antagonist effects of naloxone is not fully understood. Naloxone is thought to act as a competitive antagonist at mu, kappa, and sigma opiate receptors in the CNS; it is thought that the drug has the highest affinity for the mu receptor. In contrast to levallorphan or nalorphine, naloxone has little or no agonistic activity. When administered in usual doses to patients who have not recently received opiates, naloxone exerts little or no pharmacologic effect. Even extremely 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 patients who have received large doses of morphine or other analgesic drugs with morphine-like effects, naloxone antagonizes most of the effects of the opiate. There is an increase in respiratory rate and minute volume, arterial PCO2 decreases toward normal, and blood pressure returns to normal if depressed. Unlike nalorphine or levallorphan, naloxone antagonizes mild respiratory depression caused by small doses of opiates. Because the duration of action of naloxone is generally shorter than that of the opiate, the effects of the opiate may return as the effects of naloxone dissipate. Naloxone antagonizes opiate-induced sedation or sleep. Reports are conflicting on whether or not the drug modifies opiate-induced excitement or seizures.
Heat shock protein (HSP)60 is primarily a mitochondrial protein. Previous experiments have found that changes in the location of intracellular HSP60 have been associated with apoptosis. Extracellular HSP60 mediates apoptosis via its ligand, Toll-like receptor (TLR)-4. TLR-4 is an important factor expressed on microglia, with a central role in generating neuroimmune responses in the pathogenesis of neurodegenerative disorders. Naloxone is a highly effective nonselective opioid receptor antagonist, and has been reported to be pharmacologically beneficial for the treatment of brain diseases through inhibiting microglia activation. However, the mechanisms underlying these beneficial effects of naloxone remain poorly understood. The present study aimed to investigate the role of HSP60 in the neuroprotective effects of naloxone on the production of proinflammatory mediators in lipopolysaccharide (LPS)-stimulated BV2 murine microglial cells and the possible signaling pathways involved. The results demonstrated that naloxone significantly inhibited the expression and release of HSP60 in BV2 cells. The expression levels of heat shock factor (HSF)-1 were upregulated in LPS-activated BV2 cells, which indicated that the increased expression of HSP60 was driven by HSF-1 activation. However, increased HSF-1 levels may be downregulated by naloxone. The levels of TLR-4 were elevated in activated BV2 cells, and then inhibited by naloxone. Activation of TLR-4 is characterized by activation of nuclear factor-kB (NF-kB) followed by the production of various proinflammatory and neurotoxic factors. Data from the present study demonstrated that naloxone reduced the expression levels of NF-kB and its upstream protein caspase-3, and reduced the LPS-induced production of nitric oxide, inducible nitric oxide synthase, tumor necrosis factor a, interleukin-1beta and interleukin-6 in BV2 microglia. In light of this data, it was concluded that naloxone may exert its neuroprotective and anti-inflammatory effects by inhibiting microglia activation through a HSP60-TLR-4-NF-kB signaling pathway.
Phosphoinositide 3-kinase (PI3K) delta and gamma (the p110delta and p110gamma isoforms of PI3K) actively participate in the process of inflammation. We sought to elucidate the possible roles of PI3Kdelta and PI3Kgamma in mediating the anti-inflammation effects of naloxone. MATERIALS AND METHODS: Murine macrophages were treated with endotoxin, endotoxin plus naloxone, or endotoxin plus naloxone plus the PI3K inhibitors (the PI3Kdelta inhibitor IC87114, the PI3Kgamma inhibitor AS252424, or IC87114 plus AS252424) and denoted as the LPS, LPS + N, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS group, respectively. Differences in inflammatory molecules and levels of nuclear factor-kB (NF-kB) activation and Akt activation (indicator of PI3K activity) among these groups were compared. The concentrations of inflammatory molecules (macrophage inflammatory protein 2, tumor necrosis factor-alpha, interleukin-1beta, andd cyclooxygenase-2/prostaglandin E2) and the levels of NF-kB activation (p-NF-kB p65 and p-inhibitor-kB concentrations and NF-kB-DNA binding activity) of the LPS + N group were significantly lower than those of the LPS group (all P < 0.001). These data confirmed the anti-inflammation effects of naloxone. Moreover, the anti-inflammation effects of naloxone could be counteracted by the inhibitors of PI3Kdelta and PI3Kgamma, as the concentrations of inflammatory molecules and the levels of NF-?B activation of the LPS + N group were significantly lower than those of the LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05). In contrast, the concentration of phosphorylated Akt of the LPS + N group was significantly higher than those of the LPS, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05). PI3Kdelta and PI3Kgamma play crucial roles in mediating the anti-inflammation effects of naloxone.
For more Mechanism of Action (Complete) data for NALOXONE (7 total), please visit the HSDB record page.
Pharmacodynamics
Naloxone is an opioid receptor antagonist indicated in the reversal of opioid overdoses. Naloxone has a shorter duration of action than opioids and multiple doses may be required. The therapeutic window of naloxone is wide, as it has no effect if a patient has not taken opioids. Patients treated with naloxone may experience opioid withdrawal and a person administering naloxone should be aware that reversal of opioid overdoses may not resolve all the symptoms a patient is experiencing if other drugs are involved.
Pharmacokinetics
Half-life
The mean half life of naloxone hydrochloride is 1.8-2.7 hours intranasally, 1.4 hours intramuscularly, and 1.2 hours intravenously. In neonates, the mean half life is 3.1 ± 0.5 hours.
The mean plasma half-life of naloxone was 1.28 hours following IM or subcutaneous injection of naloxone hydrochloride using an auto-injector, compared with 1.36 hours following IM or subcutaneous injection using a standard syringe.
The half-life of naloxone has been reported to be 30-81 minutes in adults and about 3 hours in neonates.
Plasma naloxone levels were determined by RIA over a period of 6--36 hr in three groups of neonates, (1) those given 35 microgram iv (n = 6), (2) those given 70 microgram iv (n = 6) and (3) those given 200 microgram im (n = 17) naloxone HCl within 1 min of birth. After intravenous administration of 35 and 70 microgram of naloxone peak levels of 4--15 ng/mL and 9--20 ng/mL respectively were reached in 5--40 min and the mean plasma half-life after both doses was 3.1 +/- 0.5 hr.
Absorption
An intranasal dose of naloxone is 42-47% bioavailable. An 8 mg dose of nasal naloxone reaches a Cmax of 12.3-12.8 ng/mL, with a Tmax of 0.25 hours, and an AUC of 16.7-19.0 h\*ng/mL. A 0.4 mg intramuscular dose reaches a Cmax of 0.876-0.910 ng/mL, with a Tmax of 0.25 hours, and an AUC of 1.94-1.95 h\*ng/mL. A 2 mg intravenous dose reaches a Cmax of 26.2 ng/mL with an AUC of 12.8 h\*ng/mL.
After oral or intravenous administration, naloxone is 25-40% eliminated in the urine within 6 hours, 50% in 24 hours, and 60-70% in 72 hours. The metabolites naloxone-3-glucuronide, noroxymorphone, and naloxol are all detected in the urine.
The volume of distribution of naloxone is 200 L. Naloxone distributes into tissues rapidly. It can also cross the placenta and blood-brain barrier.
The clearance of naloxone is 2500 L/day.
Naloxone is distributed rapidly throughout the body with high levels found in the brain, kidneys, spleen, skeletal muscle, lung, and heart. The drug also readily crosses the placenta.
Naloxone is only minimally absorbed when given orally as it is rapidly destroyed in the GI tract. Much higher doses are required if using this route of administration for any pharmacologic effect. When given IV, naloxone has a very rapid onset of action (usually 1-2 minutes). If given IM, the drug generally has an onset of action with 5 minutes of administration. The duration of action usually persists from 45-90 minutes, but may act for up to 3 hours.
Metabolism
Naloxone primarily undergoes glucuronidation to form naloxone-3-glucuronide. Naloxone is also N-dealkylated to noroxymorphone or undergoes 6-keto reduction to naloxol.
Naloxone is rapidly metabolized in the liver, principally by conjugation with glucuronic acid. The major metabolite is naloxone-3-glucuronide. Naloxone also undergoes N-dealkylation and reduction of the 6-keto group followed by conjugation.
Yields N-allyl-7,8-dihydro-14-hydroxynormorphine, 7,8-dihydro-14-hydroxynormorphinone in man; Weinstein, SH, Pfeffer, M, Schor, JM, Indindoli, L, & Mintz, M, J Pharm Sci, 60, 1567 (1971). Yields naloxone-3-beta-d-glucuronide in man; Fujimoto, JM, J Pharmac Exp Ther, 168, 180(1969). /From table/
... Oxidative N-deallylation, redn of 6-keto-group, and glucuronidation occur in man.
... Naloxone-3-glucuronide (major), 3-sulfate (minor), naloxol and conjugated naloxol (minor), 7,8-dihydro-14-hydroxynormorphine, 7,8-dihydro-14-hydroxynormorphine and their conjugates were shown to be the metabolites of naloxone. In addition, tentative evidence was obtained for two polar hydroxylated metabolites (with hydroxylation presumably in the 17-side chain or in position 2 of the aromatic nucleus). 7,8-Dihydro-14-hydroxynormorphinone and 2-polar metabolites were also observed in brain. ...
Protein binding
Naloxone is approximately 45% bound to albumin, but there is significant binding to other proteins.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.