Friday, December 7, 2007

GHB

Snead OC, Gibson KM. Gamma hydroxybutyric acid. NEJM 2005; 352:2721-2732.
Benarroch EE. Y-Hydroxybutyric acid and its relevance in neurology. Neurology 2009; 72: 282-286.

GHB is formed from endogenous GABA or exogenous dosing. Its effects are modulated both by GABA-B and GHB receptors. The former, within mesocorticolimbic dopamine pathways is probably responsible for the addictive nature. Effects of exogenous drug include triggering the onset of slow wave sleep (thus its use in cataplexy), intoxication, tolerance, withdrawal and addiction. It also may be used in alcohol withdrawal and intoxication. Accumulation may underlie some signs of SSADH deficiency in humans.

The sedative properties are similar to those previously seen in gamma butyrolactone 13 years ago, because that drug is metabolized to GHB. GHB occurs naturally from GABA and resembles neurotransmitters, and is released by neuronal depolarization in a calcium dependent fashion. The high affinity receptor is probably presynaptic and G protein coupled, and is located in the hippocampus, thalamus, and neocortex. GABA A receptors (not related here) result in influx of chloride ions and the generation of a fast inhibitory post-synaptic potential, whereas the GABA B receptor mediates a slow inhibitory postsynaptic potential. GABA B receptors mediate effects through voltage dependent inhibition of high voltage activated calcium channes. GHB and GABA B receptor may be one and the same (controversial). Natural GHB is present in micromolar quantities, can activate GHB receptors but not GABA B receptors. Exogenous GHB probably acts through GABA B receptor. GHB conversion to GABA (normal metabolism) can be inhibited by valproic acid and ethosiximide.

GHB has a half life of 20-30 minutes, peak levels occur at 40 minutes, and it can be detected in urine for 12 hours. The narrow margin of safety is such that doses up to 20-30 mg/kg lead to euphoria and memory loss, drowsiness and sleep. Twice this dose leads to coma.

The clinical hallmark is rapid onset of profound coma, myoclonus, respiratory depression, hypoventilation, and bradycardia. Hupothermia, vomiting, mydriasis, or miosis also may occur. The signs persist for a short time. The rapid/uneventful recovery creates a false sense of security in users. The level of consciousness does not correlate with the serum level of GHB. It should be considered in any young man with rapid onset of coma when head trauma, metabolic disorders, CNS infection and increased intracranial pressure are excluded. It can be considered in women as well (date rape drug).

Death due to overdose can occur to respiratory compromise, aspiration, positional asphyxia, pulmonary edema, accidental trauma, or injury. Over half of abusers also use other drugs, and alcohol is synergistic in causing respiratory depression and hypotension.

Management is supportive (airway, breathing, circulation) oxygen, and atropine for persistent bradycardia. Mucosal burns can occur as illicit forms are synthesized from gamma butyrolactone and sodium hydroxide. There are no specific antidotes. Charcoal is not indicated due to short half life and risk of aspiration. Physostigmine is not indicated.

GHB and its prodrugs (gammabutyrolactone and 1,4 butanediol) are abused by bodybuilders because they were thought to stimulate the production of growth hormone. The diol prodrug is metabolized by an alchohol dehyrogenase, and is made more toxic by alcohol, possibly because of competition by two drugs for that enzyme. GHB is available by schedule one prescription. Names for illicit forms include G, liquid ecstasy, grievous bodily harm, Georgia home boy, liquid X, soap, easy lay, salty water, scoop, cherry meth, and nitro. The two prodrugs are available on internet for sale, advertised for mood enhancement, sleep induction and bodybuilding (GBL, gamma butyrolactone).

The psychic effects include reduced anxiety, euphoria, enhanced sensuality, and emotional warmth. It is common at raves. Raves are all night dance parties attended by large number sof young people with clandestine venues, hynotic music and liberal use of drugs including GHB. Circuit parties differ in that they are usually attended by homosexual/bisexual men. This is a problem, because protease inhibitors, given for HIV infection, alter the metabolism of GHB through interaction on P-450 system. Even small doses can cause coma.

Rebound insomnia after 2-3 hours of sleep can lead to repeat dosing with an additive response. Chronic users may thus take doses every 2-4 hours around the clock, and suffer withdrawal when they stop taking it with symptoms similar to those of benzodiazepine or alcohol. Once daily GHB users (for narcolepsy) do not develop withdrawal. The minimum dose for withdrawal is 18 g (10g for precursor) but doses are variable. Symptoms are mild at onset and include tremor, tachycardia, restlessness, insomnia, anxiety, or vomiting and can build up, later causing delirium, frank psychosis, diaphoresis or death. Withdrawal can last weeks or even months and patients may abuse benzodiazepines or alcohol to self-medicate symptoms. Lorazepan or diazepam often in very high doses may be needed to treat withdrawal. Antipsychotics and antiepileptic drugs are not needed. Baclofen could be considered a potential drug for weaning as it is a GABA B receptor agonist and helps in other addictive drugs by decreasing reinforcement effects in dopaminergic mesocorticolimbic pathways,

Sexual assault (date rape drug) occurs with doses of 10-20 mg/kg, as drug causes increased libido, anterograde amnesia, suggestibility and passivity. In suspected patients, early collection of blood and urine is important for detection. It is not readily measurable and may need to be sent out to a state reference lab.

Potential legitimate uses include narcolepsy, alcohol dependence and withdrawal, stimulus induced paroxysmal drop attacks in Coffin-Lowry syndrome, tardive dyskinesia and bipolar affective disorder.

See discussion of metabolic disease SSADH (related) here :
http://www.blogger.com/post-edit.g?blogID=30837446&postID=3676676890024591264


Letters to editor were published in NEJM 2005; 353: 1632-33. One writer opined that rapid diagnosis through tox screens should be detectable by urinary organic acid analysis, similar to the way succinic dehydrogenase deficiency is diagnoses. Another writer opined that GHB is approved for alcohol detoxification in Europe, as well as maintenance of long term abstinence. No abuse occurs with greater fractioning of the dose. A third writer stresses the importance of assessing agitation as a sign of co-intoxicants. They plan to publish a series on 146 deaths with GHB, including 138 CP deaths, 4 drownings, 3 MVA fatalities, and 1 death to a fire while intoxicated.

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