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Gamma Hydroxybutyrate

Gamma Hydroxybutyrate
30.May.2017-Expires: 7 days - Do not archive

DESCRIPTION

SUBSTANCE NAME

Gamma Hydroxybutyrate
 

USES

This substance may be used either therapeutically but can also be subject to abuse.

Treatment for narcolepsy
Treatment for alcoholism
Anesthetic agent
Euphoric
“Date rape” agent
“Growth Hormone booster”
“Aphrodisiac”
“Muscle builder” (although effectiveness has never been proven)
 

INTERVENTION CRITERIA

The correct identification of the substance is important. If the symptoms are inconsistent with those described in the literature, or the history is considered unreliable, other substances may need to be considered.
 

Intervention Level

Child

Medical observation is recommended:
- For any suspected ingestion in children
 
The risks of decontamination outweigh any benefits, and should not be attempted.
 

Adult

Medical observation is recommended:
- For any suspected ingestion
 
The risks of decontamination outweigh any benefits, and should not be attempted.
 
History of dose ingested is not a reliable guide to management.
 

Observation Period

Observation at Home

All patients require medical attention.
 

Medical Observation

If medical observation is required the patient must be monitored for 6 hours following exposure for onset or worsening of symptoms.
 
If the patient is asymptomatic at the end of the observation period, and provided that appropriate assessment and investigations have been carried out, they may be:
Discharged into the care of a reliable observer, or
Referred for psychological assessment if the overdose or exposure was with intent to self-harm
 

Investigations

Levels

Serum concentrations do not aid management.
 

Monitoring

Monitor:
Level of consciousness
Heart rate
Blood pressure
Respirations
Seizure activity
 

Admission Criteria

Admission to an intensive care environment is recommended for patients who develop significant signs of toxicity including:
CNS depression requiring intubation
Respiratory depression
Aspiration pneumonitis
Hemodynamic instability
 

TREATMENT

TREATMENT SUMMARY

Emergency stabilization may be required for respiratory depression and/or pulmonary aspiration, immediate assessment and management of respiratory compromise is a priority. Due to fast onset of action, gastrointestinal decontamination is not recommended.
 
There is no proven antidote for poisoning. Extracorporeal elimination techniques would not be anticipated to be of clinical benefit in the majority of patients as most will satisfactorily recover with adequate airways management alone.
 
Supportive care is the mainstay of management, with primary emphasis on airway management and cardiovascular support. Airway protection including endotracheal intubation and/or assisted ventilation may be necessary due to respiratory depression and aspiration risk. Seizures may rarely occur and, in the presence of coma, indicate anoxia: manage the airway and ensure adequate ventilation. Should repetitive seizure occur in a well ventilated patient treat with a benzodiazepine, or if still refractory, a barbiturate. Myoclonic jerking is a recognized re-emergence phenomenon and single episodes do not require treatment. Other complications such as bradycardia, hypotension, hypothermia, and gastrointestinal upset should be treated along usual guidelines.
 
A withdrawal syndrome is recognized after chronic abuse of this compound and may last 3 to 21 days. Benzodiazepines are usually effective to relieve symptoms. Weakness, headache, fatigue and nausea lasting 3 days after ingestion may occur. However, if significant CNS depressant effects persist beyond 8 hours, alternative causes should be investigated.
 
Emergency Stabilization
Decontamination
Ingestion
Antidote(s)
Enhanced Elimination
Supportive Care
Respiratory
Neurologic
Cardiovascular
Metabolic
Other
 

EMERGENCY STABILIZATION

Ensure Adequate Cardiopulmonary Function

Ensure the airway is protected if compromised (intubation may be necessary).
 

Cardiovascular

Establish secure intravenous access if hypotensive.
 

Emergency Monitoring

Airway
Breathing
Blood pressure
Heart rate/rhythm
Core body temperature
Blood oximetry
 

DECONTAMINATION

Ingestion

Decontamination Not Recommended

Absorption is too rapid for decontamination to be effective.

Supportive care is likely to be successful without decontamination.

ANTIDOTE(S)

There Are No Antidotes For This Substance

There are no specific antidotes for this overdose.[1]
 
Agents including naloxone, flumazenil, and physostigmine have been investigated as potential antidotes. None have shown consistent results in reversing intoxication.
 
Physostigmine is viewed as an unproven experimental antidote for this intoxication. It was initially investigated as a reversal agent in patients under GHB-induced anesthesia.[2][3] However, use following poisoning has produced differing results, with the majority of patients not showing response.[4][5][6] Reviews of the literature have shown there is not sufficient evidence to support the use of physostigmine in acute GHB overdose.[6][7] At this stage physostigmine is not recommended.[1]
 
Additionally, naloxone and flumazenil have been used following human poisoning, both have had limited effect on reversing toxicity.[8][9][10][11][12] Neither of these compounds can be recommended.[1]
 

ENHANCED ELIMINATION

Enhanced Elimination Not Recommended

There is limited information regarding use of hemodialysis, hemoperfusion, hemodiafiltration, or hemofiltration to enhance elimination. GHB has minimal protein binding, a low molecular weight,[13] and a relatively small volume of distribution,[14][15][16] suggesting use of extra-corporal techniques may enhance its elimination. However, it would not be anticipated to be of benefit in the majority of patients as GHB has a rapid clearance and short duration of clinical effects.
 

SUPPORTIVE CARE

Monitoring

Closely monitor:
Level of consciousness
Respiratory function
Gag reflex
For signs of withdrawal
 

Respiratory

Respiratory Failure

Respiratory compromise is the most critical problem in severe poisoning. Intense respiratory support, when needed, constitutes the most vital supportive measure. Rapid sequence induction with endotracheal intubation and/or assisted ventilation may be required.[1]
 
Monitoring for respiratory failure should include:
Chest auscultation
Oxygen saturation
Arterial blood gases
 
Treat using standard protocols for respiratory failure.
 

Pulmonary Aspiration

Aspiration is a significant risk. Protection and careful monitoring of the airway is required if aspiration is suspected. Oxygen should be administered and artificial ventilation may be required.[1]
 
Monitor:
Airway
Breathing
Pulse oximetry
Arterial blood gases
Chest x-ray
 

Neurologic

Coma

Profound coma is characteristic and generally short-term. Airway protection may be required, endo-tracheal intubation and even ventilation may on occasion be necessary.[17]
 
Closely monitor level of consciousness.
 
Follow standard protocols for the management of coma.
 

Seizures

Myoclonic jerking is recognized as a re-emergence phenomenon (sometime mistaken for seizure activity) and does not require treatment. However, tonic-clonic seizures may occur and should be treated with standard protocols. Anoxia is an important precipitant and adequate airways and ventilation must be ensured.
 
Observe the patient closely for onset of seizure activity.
 

Cardiovascular

Bradycardia

Bradycardia may occur in moderate to severe intoxication. Pharmacological intervention is rarely required in patients with hemodynamically stable bradycardia. Atropine may be useful in the presence of hemodynamically-unstable bradycardia.[1]
 
Monitor:
Heart rate/rhythm
Blood pressure
ECG
 
Manage bradycardia following standard treatment protocols.
 

Metabolic

Metabolic Acidosis

Metabolic acidosis is reported in severe cases. Acid-base abnormalities should be sought and appropriately treated. In severe, refractory acidosis, hemodialysis may be required.[18]
 
Monitor:
Arterial blood gases (pH, bicarbonate, pCO2, pO2)
Plasma lactate
Base excess
 
Follow standard protocols for the management of metabolic acidosis.
 

Other

Withdrawal Syndrome

A withdrawal syndrome related to gamma hydroxybutyrate is recognized with symptoms resolving in some 3 to 21 days.[19][20][21][22][23][24] Treatment with benzodiazepines has been reported as being sufficient to achieve regression of symptoms.[25] The initial treatment of choice appears to be benzodiazepine administration; if necessary, second line management options include barbiturates, baclofen, or propofol.[21][23][26][27][28][29]
 
Monitor for:
Insomnia
Confusion
Hallucinations
Autonomic instability
Tachycardia
Hypertension
Diaphoresis
Tremor
Increased creatine phosphokinase
 
Follow standard protocols for the management of withdrawal.
 

DISCHARGE CRITERIA

Patients may, if initially symptomatic, be discharged following 6 hours of observation. Symptomatic patients may discharged subsequent to becoming stable and asymptomatic.[30]
 

FOLLOW UP

Medical follow-up is unlikely to be required, as long as recovery from any complications is complete. Psychiatric intervention may be necessary depending on the circumstances of the exposure.
 

PROGNOSIS

Following appropriate supportive care the prognosis is good.
 

SIGNS AND SYMPTOMS

The correct identification of the substance is important. If the symptoms are inconsistent with those described in the literature, or the history is considered unreliable, other substances may need to be considered.
 
Other drug/compounds are commonly co-ingested with this substance and may significantly influence the clinical picture.[1]
 
With mild toxicity, gastrointestinal upset may occur and CNS effects predominate including CNS depression, euphoria, ataxia, disorientation, dizziness, and occasionally miosis and nystagmus. Sudden drowsiness followed by profound coma is a characteristic presentation; a GCS of 3 is not uncommon. Recovery is sometimes accompanied by emergence phenomena including myoclonic jerking, transient confusion, and agitation and combativeness.[1]
 
With severe toxicity, sudden, profound coma, seizures, and respiratory arrest may occur. Further complications may include bradycardia, hypotension, and hypothermia. Deaths are reported.[1][31][32][33]
 
Persistent symptoms of weakness, headache, fatigue, and nausea lasting three days after ingestion has been noted,[34] and a withdrawal syndrome is described.[19][20]
 

Onset/Duration of Symptoms

In the majority of cases signs and symptoms develop within 1 hour of ingestion and resolve within 4 to 8 hours of onset.[8][35][36][37][38][39] Recovery from coma, if it occurs, is typically rapid, and may be indicated by initial GCS score.[35] Weakness, headache, fatigue, and nausea lasting three days after ingestion has been noted.[34]
 
A withdrawal syndrome which may begin within 1 to 12 hours of the last dose and may continue for 3 to 21 days is described.[19][20][21][22][23][24]
 

Severity of Poisoning

Mild Gamma-Hydroxybutyrate ToxicityModerate Gamma-Hydroxybutyrate ToxicitySevere Gamma-Hydroxybutyrate Toxicity
Euphoria
Drowsiness
Dizziness
Confusion
Disorientation
Vomiting
Bradycardia
Hypotension
Myoclonic jerking
Hypothermia (mild)
Agitation
Ataxia
Miosis
Respiratory depression
Profound coma
Rhabdomyolysis
Seizure
Respiratory arrest
 

ACUTE EFFECTS (ORGAN SYSTEM)

Neurologic

Disorientation[51][59][60][61][62]
Hallucinations[37][62][63][65]
Hyporeflexia[4][67][68][69]
Slurred speech[56][62][65]
Confusion[38][62][70]
Incoordination[37][56]
Dysarthria[33][60]
Headache[55][60]
Euphoria[20][51]
Amnesia[33][51]
Vertigo[17]
Disinhibition[60]
Delusions[61]
Bruxism (teeth grinding)[5]
Extrapyramidal side effects[65]
Dystonias[65]
Athetoid posturing[5]
Tremor[17][56]
 

Cardiovascular

Chest tightness[60][63]
Palpitations[60]
ECG changes
U waves[10]
Transient P-wave inversion[83]
Elevation of the ST segments[69]
QTc prolongation[69]
Right bundle-branch block[10][69]
First-degree atrioventricular block[10]
Atrial fibrillation[5][35]
Asystole[18]
 

Respiratory

Gastrointestinal

Metabolic

Ocular

Fluid and Electrolytes

Hypokalemia[41][42][59][84]
Hypernatremia (if large doses of the sodium salt ingested)[92]
 

Musculoskeletal

 

Dermatologic

Other

Withdrawal Syndrome

Nausea and vomiting[21][25]
Diarrhea[21][93]
Abdominal pain[94]
Aggression/combativeness[21][96][99][106][112]
Depression[29][103][113]
Cardiac palpitations[94][107][113]
Dyspnea[107]
Tachypnea[100]
Miosis[101]
 

TOXICITY

The correct identification of the substance is important. If the symptoms are inconsistent with those described in the literature, or the history is considered unreliable, other substances may need to be considered.
 

HUMAN

Child

The acute toxic dose in children has not been determined.

Adult

Toxicity of gamma hydroxybutyrate:[17][20][26][30][92]
 
10 mg/kg
Anterograde amnesia, hyptonia, and euphoria
20 to 30 mg/kg
Drowsiness, a normal sequence of REM and non-REM sleep, and myoclonus
50 mg/kg
Anesthesia and unconsciousness
>50 mg/kg
Decreased cardiac output, severe respiratory depression, seizure-like activity, coma
 
Other substances may be abused concomitantly with this compound greatly increasing toxicity.[1][116][117]
 
Sodium hydroxide may be inappropriately used in the preparation of gamma hydroxybutyrate forming a caustic mixture.[32]
 

ANIMAL

Sodium Gamma Hydroxybutyrate:
LD50 Oral, Rat
9,690 mg/kg9,690 mg/kg/[118]
LD50 IP, Rat
1,650 mg/kg1,650 mg/kg/[118]
LD50 IP, Mouse
3,330 mg/kg3,330 mg/kg/[118]

BIOLOGICAL LEVELS - TOXIC

Blood concentrations do not aid patient management.
 

REPRODUCTION

PREGNANCY

GHB crosses the placenta.[119] Therapeutic GHB/sodium oxybate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[120]
 
There are no adequate and well-controlled studies in pregnant women. Animal studies in rats and rabbits have shown no clear evidence of developmental toxicity. In rats administration of 150, 350, or 1,000 mg/kg/day throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and body weight gain at the highest dose tested.[120]Gamma hydroxybutyrate is not reported as teratogenic when injected into fertile chicken eggs.[121]
 

LACTATION

GHB is excreted into human breast milk.[122] GHB may affect the infant. Taking GHB is not considered acceptable when breastfeeding. The manufacturers of therapeutic GHB/sodium oxybate only recommend use while breast feeding when the potential benefit out weighs the risk.[120]
 

TOXIC MECHANISM

Gamma hydroxybutyrate (GHB) is a water-soluble four carbon molecule normally found in the human body. It is formed from the precursor molecule gamma butyrolactone (GBL) and is metabolized to succinic semialdehyde and the neurotransmitter gamma-aminobutyric acid (GABA).[30] The greatest concentration of GHB in humans is in the basal ganglia.
 
Mechanism of Action
 
HUMAN
Gamma hydroxybutyrate (GHB) acts as:
- An inhibitory neurotransmitter regulating dopaminergic neurons
- A central nervous system depressant with euphoria-inducing capabilities
Has a general anesthetic effect caused via:
- Suppression of the entire cerebrospinal axis, and
- Muscular relaxation by direct action on the spinal cord, rather than neuromuscular junction.[123]
 
ANIMAL
GHB alters dopaminergic activity:
Either by reducing dopaminergic activity in the basal ganglia
- Possibly due to the inhibition of dopamine-releasing nerve cells
Or by stimulating dopamine release
However, the direction is dependent on several undefined variables.
 
GHB has binding affinity for two receptor sites in the central nervous system
- GHB-specific receptor
- The GABAB receptor
GHB might mediate some of its effects (alteration in dopaminergic activity) through interaction with the GABAB receptor.[124]
 

THERAPEUTIC DRUG INFORMATION

KINETICS

ABSORPTION

Oral Absorption
Yes, rapidly
Effect of Food
Reduces mean peak plasma concentrations, increases median time to peak concentration, and decreases the area under the plasma concentration-time curve[125]
Bioavailability
First Pass Metabolism
Extensive[126][127]
Onset of Action
15 to 45 minutes[38][59][66]
Effects typically peak at 30 to 60 minutes post ingestion[13][128][129]
Duration of Action
~ 1 to 8 hours[30][35][38][39][57]
Time to Peak Plasma Levels
 

DISTRIBUTION

Distribution
  1. Rapid[135]
Volume of Distribution
  1. 192 to 741 mL/kg[14][16][130]
Plasma Protein Binding
  1. Limited[13]
Lipid Solubility
Crosses the blood brain barrier[136][137][138]
Crosses the placenta[119]
Is excreted in breast milk[120]
 

METABOLISM

Metabolism
  1. Hepatic[1]
Major Metabolic Pathways
Parent:
  1. Following oxidation to succinate and entry into the Krebs cycle, gamma hydroxybutyrate is almost completely metabolized to water and carbon dioxide.[92][123]
First Pass Metabolism
  1. Significant[127]
 

ELIMINATION

Excretion
Urine
  1. 2 to 5% excreted unchanged[37][128]
Lungs
  1. Excreted as carbon dioxide
Half-life
Clearance Rate
  1. 3.7 to 15.8 mL/min/kg[13][14][125]
Time to Completion
  1. 4 to 8 hours[133][134]
 

IDENTIFICATION

PRODUCT INFORMATION

This substance may be available in a stated dosage, however this should be treated with some caution particularly if obtained illicitly, due to variables such as uncontrolled manufacturing process, inappropriate packaging, and product bulking.
 

OTHER NAME(S)

Chemical Name

Gamma hydroxybutyric acid:
4-hydroxy butyrate
 

Common Names

4-hydroxy butyrate4-hydroxybutanoic acid
Gamma-hydrategamma-Hydroxybutyrate
Gamma-hydroxybutyric acidGBH
GHB Sodium oxybate
Sodium oxybutyrate
 
 

“Street” Names

Alcover Aminos Blue Thunder
Cherry Menth Cherry Meth Date Rape Drug
Easy LayEverclearFantasy
Fingernail Polish Remover Flower Power G
G caps G juice Gamma 10
Gamma Date Rape Drug Gamma-OH GBH
Georgia Home BoyGH Buddy GHB
GHBees (GHB & 2C-B)Ghbers GHGold
Gina Goop Great Hormones
Great Hormones at BedtimeGrevious Bodily HarmGrievous Bodily Harm
G-Riffick H2O Ink Jet Cartridge Cleaner
Jib Liquid E Liquid Ecstasy
Liquid Fantasy Liquid G Liquid X
Max (GHB & Amphetamines)Nail Polish Remover Natural Sleep 500
Nectar Organic Quaalude Oxy-Sleep
Paint Stripper Phantasy Plant Food
PMSomax Puritech Rejoov
Salty water Scoop Sleep-500
Soap Somatomax Somsanit
Swirl Thundar Tranquili G
Vita-G Water White Magic Cleaner
Womans Viagra
 
 
 

CODES

ATC CLASSIFICATION

Anesthetics, General - Other General AnestheticsAnesthetics, General
N01A X11
Sodium Oxybate
N01A X
 
Other Nervous System Drugs - Other Nervous System DrugsOther Nervous System Drugs
N07X X04
Sodium Oxybate
N07X X
 

CAS NUMBER

Gamma Hydroxybutyrate:
591-81-1
Sodium Gamma Hydroxybutyrate:
502-85-2
 

MOLECULAR FORMULA

GHB:
C4H8O3
 

PHYSICOCHEMICAL PROPERTIES

GAMMA HYDROXYBUTYRATE:
Molecular Weight
104.10 104.10% degrees C[139]
 
GAMMA HYDROXYBUTYRATE SODIUM:
Crystals
 
Molecular Weight
127.09 127.09% degrees C[139]
Solubility
Water: highly soluble[139]
 
Attempts to avoid detection:
Artificial flavoring
Artificial coloring
Mixed in:
Fruit drinks
Bottled water
Sold as cleaning products, e.g. CD cleaner
 
Testing:
Gamma butyrolactone (GBL) and 1,4 butanediol are rapidly metabolized to gamma hydroxybutyrate (GHB), therefore:
Routine drug screen will not detect GHB
Tests must be targeted specifically for GHB
Urine testing should be used
 

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