Neuro GHB and Benzodiazepines

gamma-hydroxybutyrate

synthetic drug and naturally occurring chemical in the body

- wine, beef, small citrus fruit, almost all living creatures

GBL and 1,4-butanediol

GHB pro drugs found in household products

GHB naturally occur in CNS

- byproduct of GABA metabolism

- precursor to GABA, glutamate, glycine

- similar structure to GABA

- GABAb receptor agonist

schedule 1

GHB drug schedule

euphoria

GHB as a club drug produces

date rape drug

GHB soapy or salty taste OR undetectable

body builders

GHB growth hormone release during sleep

Xyrem (sodium oxybate)

schedule III, instrumental use: narcolepsy, opiate/alcohol detox

oral, rectal, injection nasal

GHB routes of administration

5-15 mg/kg

light GHB dosing

10-30 mg/kg

common GHB dosing

20-50 mg/kg

strong GHB dosing

GHB absorption

rapidly absorbed from GI tract

- significant first pass metabolism

- bioavailability 25%

- peak concentrations in 45 minutes

GHB distribution

readily crosses BBB no depot binding

GHB dehydrogenase enzyme

what metabolizes GHB in the liver

succicinic semialdehyde (SSA)

what is GHB metabolized into in the liver

30 minutes

what is GHB's half life

4-12 hours

GHB detectable in urine how long after consumption

GABA

once synthesized GHB is stored in the same synaptic vesicles as _____

GABA

_____ neurons release both GHB and GABA, and GHB is transported back into releasing neuron to be converted to GABA

GHB receptor

excitatory G-protein coupled receptor

- found in hippocampus, cortex, stratum, often on glutamate neurons

low doses of GHB

act as a GHB receptor agonist - stimulatory effects

high doses of GHB

acts as GABAb receptor agonist - depressant effects

GHB and alcohol

synergistic drug effects

- intoxication and memory loss "blackout"

- sexual predator victims appear drunk

alcohol

GHB effects are very similar to those of

GHB overdose

nausea, dec BP, dec heart rate, unconscious or coma, respiratory depression, ER visits often due to combined use with alcohol

GHB withdrawal

occur within hours of last use: weakness, tremor, inc anxiety, confusion, seizures

fear

emotional response to current threat

anxiety

apprehension about possible future events

amygdala, hypothalamus, PAG, PFC, hippocampus

anxiety may result from imbalance between emotion generating centers and higher cortical controls

amygdala

impaired GABA functions leads to overactive _____ activity

- indicates menacing/aversive event

GABA

_____ receptors found in high concentrations in amygdala, limbic system, and cerebral cortex

anxiolytics

drugs that relieve anxiety

- receive tension, worry, stress

- produce a calm and relaxed state, with drowsiness, mental clouding, and incoordination

sedative-hypnotic drugs

CNS depressants and include barbiturates, benzodiazepines, and alcohol

- sleep aides/sedation

- at the high doses CNS depressants induce coma and death

baribuates

schedule II, III, and IV drugs

- surgical anesthesia, sleep aid, anti-anxiety, anticonvulsant

barbiturates route of administration

short term: IV

long term: oral

intranasal: abuse

barbiturates absorption

absorbed rapidly from GI tract depending on lipid solubility

- readily pass BBB and placental barriers

- accumulates in skeletal muscles and adipose tissue (depot binding)

ultrashort acting

highest lipid solubility

- used for IV anesthetic/surgical preanesthetic

long acting

lowest lipid solubility

- used for chronic anxiety, seizures, or alcohol withdrawal

CYP450

barbiturates are broken down in the liver by what enzymes into inactive metabolites excreted in urine

metabolic tolerance

CYP450 enzyme induction associated with increased drug metabolism, lower blood concentration of drug, and reduced drug effectiveness (cross tolerance occurs)

GABA

barbiturates enhance ____ actions in the CNS

positive allosteric modulator

barbiturates act as a ______ by increasing affinity of the GABAA receptor for GABA

chloride

barbiturates can directly open ____ ion channels in GABAA receptor without GABA present allowing extreme sedation

antagonists

higher doses of barbiturates act as ____ for NMDA, AMPA and kainate glutamate receptors

withdrawal

barbiturates produce significant _____ and have high abuses potential

- can't quite cold turkey after chronic use

withdrawal syndrome

______ is associated with potentially fatal rebound hyperexcitability in brain similar to alcohol

high dose baribiturates

poor coordination, slurred speech, life threatening respiratory depression

benzodiazepines

account for 2/3rd of all medical prescriptions for psychoactive drugs

- help treat anxiety and panic disorder

- most are schedule IV drugs

short acting

used for anxiety disorders/ insomnia

midazolam (Versed)

example of an ultrashort-acting BDZ

alprazolam (xanax) and lorazepam (Ativan)

example of a short acting BDZ

diazepam (Valium)

example of a long acting BDZ

BZDs routes of administration

oral (xanax), IV and IM (Ativan; valium), intranasal used during abuse

absorption of BDZs

short acting BDZs more lipid soluble and reach brain faster than long acting BDZs

- high blood albumin protein binding

- redistribution form fat and muscle can extend time drug can be detected in system

inactive metabolites

short acting BDZs like lorazepam are metabolized in 1 step into

12 hours

what is Ativans half life

nordiazepam (major) and temazepam (minor)

long lasting BDZs like chlordiazepoxide (librium) or Diazepam (valium) metabolized in liver in multiple steps into what active metabolites

48 hours

what is Valiums half life

CYP liver

BDZs do not induce ______ enzymes which means there is less risk for metabolic tolerance (but behavior tolerance still occurs)

700%

since BDZs are a positive allosteric modulator of GABAA receptor they can enhance the activity of it by up to

adenosine

BDZs also increase actions of ____ in the brain by blocking its reuptake

sedative hypnotic/anticonvulsant effects

BZ1 receptor binding site

anxiety relief and cognitive impairment

BZ2 receptor binding site

mesolimbic DA release

dependence and reinforcing aspects of BDZs and barbiturates due to increased...

synergistic effects

severe CNS and respiratory depression if BDZs are combined with alcohol, narcotics, barburates

rohypnol (flunitrazepam)

DEA schedule IV, roofies, powerful benzodiazepine

- 10x the potency of valium

- easily dissolve in liquid

- odorless and tasteless

- effects in 30 mins and last for hours

CYP450 enzymes

what is rohypnol broken down by in the liver

20 hours

rohypnol half life

7-aminoflunitrazepam

what metabolite is rohypnol broken down into and is detectable in urine for 5 days

rohypnol with alcohol

blackout/amnesia, confusion, sedation, loss of muscle control, death

acute

_____ tolerance to BDZs can develop during a single drug administration

- limited to behavioral tolerance

chronic tolerance

repeated administration reduces BDZ efficacy

- anticonvulsant actions slow to develop tolerance

sedative hypnotic withdrawal

tremors, cramps, delirium, possible convulsions, generally seen in people who take the drug at high doses for over a month

- symptoms last 10 days

low dose withdrawal

seen in people taking low doses for about 6 months

- anxiety, terror, panic, irregular heartbeat, inc bp, memory impairment, distorted reality, light sensitivity, akathisia

akathisia

a state of inner restlessnesss with outer movement that compels one to pace/ move for hours on end

- feels like you are going to explode

BZD withdrawal treatment

detox with tapering drug concentration over 8-12 week period

- IV Flumazenil (BDZ receptor antagonist)

therapeutic index

BDZs have higher _____ than barbiturates

- little risk for respiratory depression