4-Hydroxybutyric Acid

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Potential pharmacologic interaction (additive sedative effects). Sodium oxybate is contraindicated in patients receiving sedative-hypnotic agents. Sodium oxybate should not be used concomitantly with alcohol or other CNS depressants. /Sodium oxybate/

gamma-Hydroxybutyrate may potentiate other endogenous opiates or exogenous narcotics, and it is potentiated by alcohol, benzodiazepines, and other neuroleptics. While dextroamphetamine, naloxone, trimethadone, and valproate antagonize the electroencephalographic changes produced by GHB, no clinically effective GHB antagonists are consistently described in the published literature.

Gamma-hydroxybutyrate (GHB) is often abused together with other 'club drugs', such as the N-methyl-D-aspartate (NMDA) receptor antagonists ketamine and phencyclidine (PCP). We recently found that the NMDA antagonist dizocilpine markedly enhanced GHB-induced catalepsy in rats. The present studies explored the generality of this interaction. Different groups of rats were trained to discriminate 2 mg/kg PCP or 3.2 mg/kg of the gamma-aminobutyric acid B receptor agonist baclofen from saline. In the PCP-trained rats, the dose-response (DR) curve for the discriminative stimulus (DS) effects of PCP was shifted 2.5-fold to the left by 178 mg/kg GHB, but not by baclofen. In the baclofen-trained rats, 2 mg/kg PCP shifted the DR curve for the baclofen-like DS effects of GHB 2.2-fold to the left, but did not shift the DR curve for baclofen. These results suggest that (i) NMDA antagonists potentiate not only the cataleptic effects of high doses of GHB, but also the DS effects of low doses, (ii) PCP and GHB enhance one another's DS effects, and (iii) this enhancement might be specific for GHB, because it did not occur with PCP and baclofen. These findings suggest that NMDA antagonists might potentiate the subjective effects of GHB in humans, and are further evidence that glutamatergic systems modulate effects of drugs of abuse.

Gamma-hydroxybutyrate (GHB) and ethanol are often co-ingested in settings of drug-facilitated rape and recreational abuse. Little is known about the effects of ethanol on GHB plasma kinetics. Our objective was to evaluate the pharmacokinetic interactions of ethanol and GHB. Method: GHB plasma pharmacokinetic evaluation was conducted as part of a double-blind, placebo-controlled, 4-arm crossover study in eight healthy human volunteers (four men). Subjects ingested 50 mg/kg GHB, 0.6 g/kg ethanol in two doses, or both drugs combined. Serial plasma GHB samples were obtained over a 24 hr period. Primary outcomes were area under the curve (AUC) from 0-24 hr, elimination half-life (t 1/2) and maximum drug concentration (Cmax). Data were analyzed using a paired two-tailed t test. Results: A new gas chromatography-mass spectrometer (GC-MS) method was developed to quantitate GHB in human plasma. Ethanol coadministration increased the AUC and decreased the t 1/2 of GHB. The Cmax of GHB was also increased in the presence of ethanol, although the difference was not statistically significant. Conclusion: The alteration of GHB AUC and clearance by ethanol may be the result of both increased bioavailability and diminished elimination of GHB. These results may help in part to explain the additive effect of GHB and ethanol on cognitive impairment in humans.

For more Interactions (Complete) data for 4-HYDROXYBUTANOIC ACID (9 total), please visit the HSDB record page.

In preregistration clinical trials, serum enzyme elevations were reported in small numbers of treated patients, but no instance of clinically apparent liver injury was reported. Since the approval and more widespread use of oxybate, there have been no published cases of liver injury due to oxybate, and in postmarketing overviews of adverse events hepatotoxicity was not listed. Thus, despite use in high doses (3 to 9 g daily), acute liver injury from oxybate must be very rare, if it occurs at all.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of less than 1(SRC), determined from a structure estimation method(2), indicates that 4-hydroxybutanoic acid is expected to have very high mobility in soil(SRC). The pKa of 4-hydroxybutanoic acid is 4.72(3), indicating that this compound will primarily exist in the anion form in the environment, and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). The pKa also indicates that volatilization of 4-hydroxybutanoic acid from moist soil surfaces is not expected to be an important fate process(SRC). 4-Hydroxybutanoic acid is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.13 mm Hg(SRC), determined from a fragment constant method(6). Biodegradation data were not available(SRC, 2008).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of less than 1(SRC), determined from a structure estimation method(2), indicates that 4-hydroxybutanoic acid is not expected to adsorb to suspended solids and sediment(SRC). A pKa of 4.72(3) indicates 4-hydroxybutanoic acid will exist almost entirely in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(4). 4-Hydroxybutanoic acid is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(5). According to a classification scheme(6), an estimated BCF of 3.2(SRC), from an estimated log Kow of -0.40(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2008).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 4-hydroxybutanoic acid, which has an estimated vapor pressure of 0.13 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 4-hydroxybutanoic acid is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4.6 days(SRC), calculated from its rate constant of 7.0X10-12 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). 4-Hydroxybutanoic acid does not contain chromophores that absorb at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

GHB reaches much higher concentrations in the brain and activates GABAB receptors, which are primarily responsible for its sedative effects. GHB receptors are densely expressed in many areas of the brain, including the cortex and hippocampus, and these are the receptors that GHB displays the highest affinity for. There has been somewhat limited research into the GHB receptor; however, there is evidence that activation of the GHB receptor in some brain areas results in the release of glutamate, the principal excitatory neurotransmitter. Activation of both the GHB receptor and GABA(B) is responsible for the addictive profile of GHB. GHB's effect on dopamine release is biphasic,[19] low concentrations stimulate dopamine release via the GHB receptor.[20] Higher concentrations inhibit dopamine release via GABA(B) receptors as do other GABA(B) agonists such as baclofen and phenibut.[21] After an initial phase of inhibition, dopamine release is then increased via the GHB receptor. This explains the paradoxical mix of sedative and stimulatory properties of GHB, as well as the so-called "rebound" effect, experienced by individuals using GHB as a sleeping agent, wherein they awake suddenly after several hours of GHB-induced deep sleep. That is to say that, over time, the concentration of GHB in the system decreases below the threshold for significant GABAB receptor activation and activates predominantly the GHB receptor, leading to wakefulness.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of 4-hydroxybutanoic acid can be estimated to be less than 1(SRC). According to a classification scheme(2), this estimated Koc value suggests that 4-hydroxybutanoic acid is expected to have very high mobility in soil. The pKa of 4-hydroxybutanoic acid is 4.72(3), indicating that this compound will primarily exist in the anion form in the environment, and anions generally adsorb less strongly to soils containing organic carbon and clay than their neutral counterparts(4).

RURAL/REMOTE: 4-Hydroxybutanoic acid was detected in fine aerosols collected from July 5 to August 25, 1995 at the Great Smoky National Park, Tennessee at concns of 5.4-178.4 ng/ cu m during the daytime and 21.2-364.7 ng/cu m during the nighttime(1). Atmospheric photooxidation of 1,4-dihydroxybutane is a potential source of 4-hydroxybutanoic acid in aerosols(1).

/SIGNS AND SYMPTOMS/ To describe the clinical features of gamma-hydroxybutyrate (GHB) and gamma-butyrolactone (GBL) toxicity /a/ retrospective case-study of 65 GHB and GBL intoxications seen in an urban emergency department /were reviewed/. 63% of intoxications occurred in male patients. The median age was 24 years (range 16-41 years). 65% co-ingested alcohol or illicit drugs, mostly MDMA and cocaine. 83% presented with coma. The mean+/-S.D. time to regain consciousness among comatose patients was 111+/-61 min and was significantly longer in patients who co-abused illicit drugs such as cocaine or MDMA (155+/-60 min). Bradycardia occurred in 38%, hypotension in 6% and hypothermia in 48%. Agitation was observed in 17% of all patients and was significantly more frequent in patients with alcohol co-use (29%). Vomiting occurred in 31% of all patients and tended to be more frequent in patients who co-used alcohol (39%). Management of GHB and GBL overdose was supportive. Four patients needed admission to an intensive care unit for mechanical ventilation (6%). Overdosing of GHB and GBL frequently results in non-reactive coma reflecting the severity of poisoning. Multiple drug use is common and significantly influences the clinical presentation.

/SIGNS AND SYMPTOMS/ GHB produces a wide range of central nervous system effects, including dose-dependent drowsiness, dizziness, nausea, amnesia, visual hallucinations, hypotension, bradycardia, severe respiratory depression, and coma. The use of alcohol in combination with GHB greatly enhances its depressant effects. Overdose frequently requires emergency room care, and many GHB-related fatalities have been reported.

/SIGNS AND SYMPTOMS/ Gamma-Hydroxybutyrate (GHB)-related compounds are most commonly described as depressants, with emphasis on somnolence, obtundation, stupor, and coma (SOSC). /Investigators/ sought to demonstrate the full spectrum of clinical presentations of GHB intoxication, including agitation and other nonsedative effects. /This/ observational study identified 66 patients with GHB toxicity, 40 of whom manifested agitation; 25 had agitation before or after SOSC, 10 had agitation alternating abruptly with SOSC, and 5 had agitation only. Fourteen presentations also included "bizarre" or self-injurious behaviors. Of 40 presentations with agitation, 19 had stimulant co-intoxicants confirmed by screen (14) or history (5). The remaining 21 patients with agitation were negative for stimulants by screen (12) or history (9). Gas chromatography/mass spectrometry detected GHB in 25 cases; 12 manifested agitation, 4 of which also screened negative for stimulants. ...

/SIGNS AND SYMPTOMS/ Information about signs and symptoms associated with overdosage with sodium oxybate derives from reports of its illicit use. Patient presentation following overdose is influenced by the dose ingested, the time since ingestion, the co-ingestion of other drugs and alcohol, and the fed or fasted state. Patients have exhibited varying degrees of depressed consciousness that may fluctuate rapidly between a confusional, agitated combative state with ataxia and coma. Emesis (even when obtunded), diaphoresis, headache, and impaired psychomotor skills may be observed. No typical pupillary changes have been described to assist in diagnosis; pupillary reactivity to light is maintained. Blurred vision has been reported. An increasing depth of coma has been observed at higher doses. Myoclonus and tonic-clonic seizures have been reported. Respiration may be unaffected or compromised in rate and depth. Cheyne-Stokes respiration and apnea have been observed. Bradycardia and hypothermia may accompany unconsciousness, as well as muscular hypotonia, but tendon reflexes remain intact. /Sodium oxybate/

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

gamma hydroxybutyric acid

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl sodium oxybate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Sodium Oxybate/

/DEA/ Schedule I shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a depressant effect on the central nervous system, including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation. gamma-Hydroxybutyric acid (DEA Code Number: 2010) is included on this list.

/DEA/ Schedule III shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Narcotic drugs. Unless specifically excepted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of the following substances having a depressant effect on the central nervous system: Any drug product containing gamma hydroxybutyric acid, including its salts, isomers, and salts of isomers, for which an application is approved under section 505 of the Federal Food, Drug, and Cosmetic Act. DEA Code Number: 2012.

This is a Schedule I controlled substance.

This is a Schedule III controlled substance.

Intermediate

Therapeutic Category: Anesthetic (intravenous). In treatment of narcolepsy; in treatment of alcoholism.

For more Uses (Complete) data for 4-HYDROXYBUTANOIC ACID (7 total), please visit the HSDB record page.

Use (kg; approx.) in Germany (2009): >750

gamma-Hydroxybutyric acid is obtained from gamma-butyrolactone by alkaline hydrolysis and isolated as the alkali-metal salt. gamma-Butyrolactone is produced by dehydrocyclization of 1,4-butanediol.

Endogenous constituent of mammalian brain ... Biosynthesized from gamma-aminobutyric acid.