Naloxone

Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts.

The combined admin of flunitrazepam and naloxone to volunteers incr resp frequency and resp min vol but did not alter endexpired pCO2 pressure, resp inhalation vol, or alveolar ventilation when compared with naloxone treatment alone.

Therapy with naloxone has not been linked to serum enzyme elevations or to idiosyncratic acute, clinically apparent liver injury. Patients with opioid overdose often have underlying chronic liver diseases such as alcoholic liver disease, hepatitis B or C, but treatment with naloxone does not appear to exacerbate those conditions. Naloxone is extensively metabolized in the liver, but largely by conjugation with glucuronide followed by its urinary excretion.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 560(SRC), determined from a structure estimation method(2), indicates that naloxone is expected to have low mobility in soil(SRC). The estimated pKa1 and pKa2 of naloxone are 7.84 (amine) and 10.07 (phenol), respectively(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Naloxone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.3X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 560(SRC), determined from a structure estimation method(2), indicates that naloxone is expected to adsorb to suspended solids and sediment(SRC). The estimated pKa1 and pKa2 of naloxone are 7.84 (amine) and 10.07 (phenol), respectively(3), indicating that naloxone will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 11(SRC), from its log Kow of 2.09(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), naloxone, which has an estimated vapor pressure of 4.3X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase naloxone may be removed from the air by wet and dry deposition(SRC). Naloxone contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

The most common adverse effects associated with naloxone occur after acute withdrawal from opioids. These include anxiety, aggression, nausea, vomiting, diarrhea, abdominal pain, and rhinorrhea. In rare cases, the use of naloxone can precipitate noncardiogenic pulmonary edema. The incidence of naloxone-induced noncardiogenic pulmonary edema is estimated to be between 0.2% and 3.6% of patients who have received naloxone and are transported to the emergency department. Symptoms include persistent hypoxia despite the resolution of respiratory depression secondary to acute overdose. Patients may also have a cough productive of the classic "pink, frothy sputum," which indicates pulmonary edema. Chest radiography will be consistent with the findings of pulmonary edema. The onset of noncardiogenic pulmonary edema occurs within 4 hours in most patients. However, there have been case reports of delayed onset up to 8 hours after naloxone administration. Naloxone is listed in the Key Potentially Inappropriate Drugs in Pediatrics: The KIDs List due to the increased risk of seizure. Therefore, it should be administered with extreme caution in neonates for postpartum resuscitation.

IDENTIFICATION AND USE: Naloxone is composed of crystals. Naloxone hydrochloride is used for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids (both human and veterinary cases). It may also be useful as an adjunctive agent to increase blood pressure in the management of septic shock. A formulation for wildlife use (Trexonil) is more concentrated and used to reverse tranquilization in wild animals. HUMAN EXPOSURE AND SYMPTOMS: Adverse effects associated with naloxone use have included seizures, severe hypertension, and hypotension and/or bradycardia. A total of 1.2 mg administered intravenously as 0.2, 0.4, and 0.6 mg at 11, 22, and 33 minutes respectively to nonaddicts caused miosis, decreased core temperature, and systolic blood pressure. Naloxone-induced acute pulmonary edema is an extremely rare but lethal complication. Endogenous opioids appear to regulate blood pressure in some hypertensive patients and opiate antagonists such as naloxone must be administered with caution to these individuals. Moderate increases in respiratory rate, heart rate, and blood pressure occur after naloxone administration to children, but development of more serious complications is rare. Naloxone was weakly positive in the in vitro human lymphocyte chromosome aberration test. Naloxone may affect some functions of the immune system in humans, but its action is transient. ANIMAL STUDIES: The injection of naloxone into the medial septal nucleus of rats produced a marked increase in hippocampal ACh release in a dose-dependent manner. It was also found that rats given an injection of naloxone showed an increase in motor activity and occasionally exhibited behavioral seizures. Subcutaneous injection of 100 mg/kg/day in rats for 3 weeks produced only transient salivation and partial ptosis following injection. Administration of naloxone to rats from day 17 of pregnancy significantly increased neonatal death. Body weight increase was slightly retarded by administration of naloxone. Naloxone was weakly positive in the Ames mutagenicity test and was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and the in vivo rat bone marrow chromosome aberration study.

Signs and Symptoms of Overdose

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of December 17, 2015: http://actor.epa.gov/dashboard/]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of naloxone can be estimated to be 560(SRC). According to a classification scheme(2), this estimated Koc value suggests that naloxone is expected to have low mobility in soil. The estimated pKa1 and pKa2 of naloxone are 7.84 (amine) and 10.07 (phenol), respectively(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ ... Clinical administration of the opiate receptor antagonist naloxone hydrochloride has had little or inconsistent behavioral effects in normals. This may be attributable to the use of doses insufficient to yield a complete endogenous opioid system (EOS) blockade. To assess this explanation, normals were administered increasing doses of naloxone hydrochloride (0.3 to 4 mg/kg) in a single-blind design. Significant dose-dependent behavioral, hormonal, and physiological effects were found. With increasing doses of naloxone, volunteers demonstrated increasingly dysphoric affects, a deterioration of performance on memory testing, increasing systolic BP and respiratory rate, and increasing plasma cortisol and growth hormone levels. These results are consistent with the expected effects of increasing EOS blockade, and thus suggest that lower doses of naloxone used in previous clinical studies may not have been sufficient to produce a complete EOS blockade. ...

/HUMAN EXPOSURE STUDIES/ 1.2 mg administered iv as 0.2, 0.4, and 0.6 mg at 11, 22, and 33 min respectively to nonaddict caused miosis, decr core temp, and systolic blood pressure. Hand tremor, resp, and heart rates unaffected. May possess slight opiate agonist properties. Interaction with endogenous opiate is possibility

/SIGNS AND SYMPTOMS/ In /a/ study, 36 patients with acute stroke received a loading dose of 4 mg/kg (10 mg/sq m/min) of naloxone hydrochloride injection followed immediately by 2 mg/kg/hr for 24 hours. Twenty-three patients experienced adverse events associated with naloxone use, and naloxone was discontinued in seven patients because of adverse effects. The most serious adverse events were: seizures (2 patients), severe hypertension (1), and hypotension and/or bradycardia (3).

/SIGNS AND SYMPTOMS/ Although a causal relationship to the drug has not been established, severe cardiopulmonary effects (eg, hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, cardiac arrest) resulting in death, coma, and encephalopathy have been reported in patients following postoperative administration of naloxone hydrochloride. Adverse cardiopulmonary effects have occurred most frequently in postoperative patients with preexisting cardiovascular disease or in those receiving other drugs that produce similar adverse cardiovascular effects.

For more Human Toxicity Excerpts (Complete) data for NALOXONE (24 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

naloxone

DILI Negative

Intravenous

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 11 was calculated in fish for naloxone(SRC), using a log Kow of 2.09(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

The estimated pKa1 and pKa2 of naloxone are 7.84 (amine) and 10.07 (phenol), respectively(1), indicating that naloxone will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. Naloxone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.3X10-11 mm Hg(SRC), determined from a fragment constant method(2).

The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Naloxone hydrochloride is included on this list. /Naloxone hydrochloride/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including naloxone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Naloxone hydrochloride/

MEDICATION

MEDICATION (VET)

Narcotic Antagonists

Use (kg; approx.) in Germany (2009): >2500

3-O-allylnaloxone

10alpha-hydroxynaloxone

10beta-hydroxynaloxone

2,2'-binaloxone

For more Impurities (Complete) data for NALOXONE (7 total), please visit the HSDB record page.

14-Hydroxydihydronormorphinone is N-alkylated with allyl bromide.

Oxymorphone is demethylated and resulting 4,5alpha-epoxy-3,14-dihydroxymorphinan-6-one is n-allylated by reaction in ethanol with allyl bromide in presence of NaHCO3. Resulting naloxone is reacted with ethanolic hydrochloride. US Patent 3,254,088. /Naloxone hydrochloride/

Oral: Tablets: Pentazocine hydrochloride 50 mg (of pentazocine) and Naloxone hydrochloride 0.5 mg (of naloxone); Pentazocine and Naloxone Hydrochloride Tablets, C-IV (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)

Table: Naloxone Hydrochloride Preparations [Table#4524]

Table: Naloxone Hydrochloride DihydrateCombinations Preparations [Table#4525]

Naloxone is available in injectable vials with preservatives in 0.4 or 1 mg/mL, without preservatives in 0.02 mg (20 ug) 0.4 mg or 1 mg per mL, as Trexonil in 50 mg/mL.

Incompatibilities - physical: long-chain or high-mol wt anions (forms relatively insol salts) and with alkaline soln (base PPT if concn is high enough); however, injection is compatible with bulk in soln that are slightly alkaline. Chemical: oxygen, oxidizing agents, bisulfites, and metabisulfites. /Naloxone hydrochloride/

Naloxone is an antagonist at the mu-opioid receptor