75% of US adults drink EtOH, only 10-13% have a problem with EtOH
EtOH Metabolism
EtOH is a small, H2O-soluble substance that is rapidly absorbed from the GI tract (even faster when fasted)
90-98% of EtOH is oxidized in the liver by zero-order kinetics (ability to metabolize is proportional to liver weight)
EtOH intoxication is dependent on the blood alcohol concentration, the rate of EtOH consumption, the rate of the rise in blood EtOH level, and the time during which the blood level is maintained.
EtOH is metabolized mainly by Alcohol Dehydrogenase and Aldehyde Dehydrogenase, however when large amounts of EtOH are consumed or during chronic use the Microsomal Oxidizing System plays a role.
Effects of Various Levels of blood EtOH:
50-100 mg/dL: Sedation, "high",
Ý reaction time
100-200 mg/dL: Impaired motor function, slurred speech, ataxia
200-300 mg/dL: Emesis, stupor
300-400 mg/dL: Coma
>500 mg/dL: Respiratory depression, Death
Effects of EtOH on Various Neurotransmitters
GABAA
- the major inhibitory neurotransmitter (NT) in the brain
Cl- fluxes through GABAA receptors are Ý with EtOH.
the inverse agonist Ro15-4513 attenuates EtOH-induced motor incoordination
GLUTAMATE
- the major excitatory neurotransmitter in the brain. 3 types of Glutamate receptors (2 ion channels, 1 G-protein)
NMDA receptor (an ion channel) is affected by EtOH, ethanol suppresses the excitatory effects of Glutamate in some brain regions.
NEUROPEPTIDE Y (NPY)
- a 36 amino acid peptide that works at G-coupled receptors to inhibit the production of cAMP
NPY deficient animals have Ý anxiety, are more susceptible to seizures, and demonstrate Ý EtOH consumption
EtOH Pharmacotherapy
Drugs that effect EtOH metabolism
Disulfiram (Anabuse)
- inhibits Aldehyde Dehydrogenase leading to acetaldehyde buildup and symptoms of a hangover (face and neck flushing, nausea and vomiting, headache, feelings of impending doom, etc.) when EtOH is consumed.
even without EtOH side effects include: cramps, drowsiness, psychosis in those predisposed, and birth defects
it takes weeks to resynthesize new aldehyde dehydrogenase
a metabolite, Diethyldithiocarbamate, blocks Dopamine b -hydroxylase (the enzyme that takes DA Þ NE)
Drugs that affect neurotransmitter synthesis
Benzodiazapines
(Oxazepam) - diminish EtOH withdrawl symptoms (ß motor system agitation, ß delirium, ß seizures)
work at the same site of action as EtOH, still need to withdrawl from benzodiazapines
Oxazepam is #1 prescribed because it doesn’t have active metabolites that could be a problem in liver disease
Naltrexone
- pure antagonist at opiod receptors, may be working downstream at pleasure centers,
decreases EtOH cravings and use
well absorped, T1/2 ~ 10 hrs, Tolerance does not develop
side effects: fatigue, N/V, headaches, dizziness, nervousness
Acomprosate
- Used in Europe, not FDA approved, rapidly absorbed
modulates activation of excitatory synapses operated by L-glutamate.
reduces signs of EtOH withdrawl (such as hyperactivity)
Ro15-4513
- an inverse agonist that attenuates EtOH induced motor incoordination