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Details

Stereochemistry ABSOLUTE
Molecular Formula C19H21NO4
Molecular Weight 327.3743
Optical Activity UNSPECIFIED
Defined Stereocenters 4 / 4
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of NALOXONE

SMILES

[H][C@@]12OC3=C4C(C[C@H]5N(CC=C)CC[C@@]14[C@@]5(O)CCC2=O)=CC=C3O

InChI

InChIKey=UZHSEJADLWPNLE-GRGSLBFTSA-N
InChI=1S/C19H21NO4/c1-2-8-20-9-7-18-15-11-3-4-12(21)16(15)24-17(18)13(22)5-6-19(18,23)14(20)10-11/h2-4,14,17,21,23H,1,5-10H2/t14-,17+,18+,19-/m1/s1

HIDE SMILES / InChI

Molecular Formula C19H21NO4
Molecular Weight 327.3743
Charge 0
Count
MOL RATIO 1 MOL RATIO (average)
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 4 / 4
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

Naloxone, sold under the brand name Narcan among others, is a medication used to block the effects of opioids, especially in overdose. Naloxone has an extremely high affinity for μ-opioid receptors in the central nervous system (CNS). Naloxone is a μ-opioid receptor (MOR) inverse agonist, and its rapid blockade of those receptors often produces rapid onset of withdrawal symptoms. Naloxone also has an antagonist action, though with a lower affinity, at κ- (KOR) and δ-opioid receptors (DOR). If administered in the absence of concomitant opioid use, no functional pharmacological activity occurs (except the inability for the body to combat pain naturally). In contrast to direct opiate agonists, which elicit opiate withdrawal symptoms when discontinued in opiate-tolerant people, no evidence indicates the development of tolerance or dependence on naloxone. The mechanism of action is not completely understood, but studies suggest it functions to produce withdrawal symptoms by competing for opiate receptor sites within the CNS (a competitive antagonist, not a direct agonist), thereby preventing the action of both endogenous and xenobiotic opiates on these receptors without directly producing any effects itself. When administered parenterally (e.g. intravenously or by injection), as is most common, naloxone has a rapid distribution throughout the body. The mean serum half-life has been shown to range from 30 to 81 minutes, shorter than the average half-life of some opiates, necessitating repeat dosing if opioid receptors must be stopped from triggering for an extended period. Naloxone is primarily metabolized by the liver. Its major metabolite is naloxone-3-glucuronide, which is excreted in the urine. Naloxone is useful both in acute opioid overdose and in reducing respiratory or mental depression due to opioids. Whether it is useful in those in cardiac arrest due to an opioid overdose is unclear. Naloxone is poorly absorbed when taken by mouth, so it is commonly combined with a number of oral opioid preparations, including buprenorphine and pentazocine, so that when taken orally, just the opioid has an effect, but if misused by injecting, the naloxone blocks the effect of the opioid. In a meta-analysis of people with shock, including septic, cardiogenic, hemorrhagic, or spinal shock, those who received naloxone had improved blood flow. Naloxone is also experimentally used in the treatment for congenital insensitivity to pain with anhidrosis, an extremely rare disorder (one in 125 million) that renders one unable to feel pain or differentiate temperatures. Naloxone can also be used as an antidote in overdose of clonidine, a medication that lowers blood pressure.

CNS Activity

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
7.3 nM [IC50]
49.8 nM [IC50]
138.0 nM [IC50]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
NARCAN
Primary
NARCAN
Primary
NARCAN

Cmax

ValueDoseCo-administeredAnalytePopulation
1.09 ng/mL
10 mg/kg single, nasal
NALOXONE plasma
Homo sapiens
4.83 ng/mL
4 mg single, nasal
NALOXONE plasma
Homo sapiens
0.87 ng/mL
0.4 mg single, intramuscular
NALOXONE plasma
Homo sapiens
9.62 ng/mL
8 mg single, nasal
NALOXONE plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
37.1 ng × min/mL
10 mg/kg single, nasal
NALOXONE plasma
Homo sapiens
7.9 ng × h/mL
4 mg single, nasal
NALOXONE plasma
Homo sapiens
1.68 ng × h/mL
0.4 mg single, intramuscular
NALOXONE plasma
Homo sapiens
15 ng × h/mL
8 mg single, nasal
NALOXONE plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
28.2 min
10 mg/kg single, nasal
NALOXONE plasma
Homo sapiens
1.2 h
0.4 mg single, intramuscular
NALOXONE plasma
Homo sapiens
2.1 h
8 mg single, nasal
NALOXONE plasma
Homo sapiens

Doses

AEs

Overview

Drug as victim

PubMed

Sample Use Guides

In Vivo Use Guide
Opioid Overdose–Known or Suspected: An initial dose of 0.4 mg to 2 mg of NARCAN may be administered intravenously. If the desired degree of counteraction and improvement in respiratory functions are not obtained, it may be repeated at two- to three-minute intervals. If no response is observed after 10 mg of NARCAN have been administered, the diagnosis of opioid-induced or partial opioid-induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if the intravenous route is not available. Postoperative Opioid Depression: For the partial reversal of opioid depression following the use of opioids during surgery, smaller doses of NARCAN are usually sufficient. The dose of NARCAN should be titrated according to the patient’s response. For the initial reversal of respiratory depression, NARCAN should be injected in increments of 0.1 to 0.2 mg intravenously at two- to three-minute intervals to the desired degree of reversal, i.e., adequate ventilation and alertness without significant pain or discomfort. Larger than necessary dosage of NARCAN may result in significant reversal of analgesia and increase in blood pressure. Similarly, too rapid reversal may induce nausea, vomiting, sweating or circulatory stress. Repeat doses of NARCAN may be required within one- to two-hour intervals depending upon the amount, type (i.e., short or long acting) and time interval since last administration of an opioid. Supplemental intramuscular doses have been shown to produce a longer lasting effect.
Route of Administration: Other
In Vitro Use Guide
MDCKII-MDR1 assay. Stock solutions of Naloxone (20 mM) were prepared in 100% DMSO and then diluted to the final concentration of 10 mkM, in Dulbecco’s PBS. Naloxone were tested in both directions, apicalto-basolateral (A→B) and basolateral-to-apical (B→A), in duplicate. The ratio BA/AB >2 indicates an efflux phenomena. Permeability studies were conducted at 37 ◦C in incubator for 60 min. The monolayer integrity was evaluated by measuring the TransEpithelial Electrical Resistance (TEER) by using the Millicell-ERS system (Millipore Corporation) and it was considered integer if the resistancewas between 200 and 300 cm2. After the transport study the monolayer integrity was measured in each well by adding a 0.02 mg/mL solution of lucifer yellow (LY); the test was conducted at 37 ◦C for 60 min, and the fluorescence (RFU) was measured at 485/535 nm.
Substance Class Chemical
Record UNII
36B82AMQ7N
Record Status Validated (UNII)
Record Version