Alcohol Flashcards
What is the economic burden in the US of alcohol per drink?
$1.90 per drink
What is the earliest historical evidence?
Archaeological evidence of fermentation
from Neolithic period (10,000 BCE)
What is alcohol?
Colloquially alcohol refers to ethyl
alcohol or ethanol (EtOH).
Describe pharmacology
EtOH administered by oral dose has high bioavailability
Alcohol has high caloric content but little nutritive value
Describe alcohol. absorption
Higher concentration of alcohol is absorbed faster
Food in stomach slows passage to intestine –
slower uptake
* Carbonation (e.g. champagne) accelerates passage
– faster uptake
Alcohol dehydrogenase (ADH) is secreted in
gastric fluids
Describe alcohol distribution
- EtOH readily diffuses into all aqueous
fluids/tissues via passive diffusion - Easy access through BBB and placental
barrier - Excluded from fat tissues
Describe alcohol metabolism
Liver metabolism of alcohol depends
on the key enzymes alcohol
dehydrogenase and aldehyde
dehydrogenase.
- Drug interactions caused by competition for P450 → elevated drug concentration
- Induction of P450 with chronic use → decreased drug concentration
Describe specific effects of alcohol
- Specific effects – result of interactions with receptors
- Cause most of the acute and chronic effects of intoxication
- Responsible for most subjective effects of intoxication
describe nonspecific effects of alcohol
- Non-specific effects – result of interaction with
phospholipid membranes or bodily fluids - EtOH interacts with cell membranes causing changes in membrane protein function and cellular dysfunction
Describe GABAA
- EtOH acts as a positive allosteric
modulator of GABAA - CNS depressant and sedative effects of
EtOH moderated through GABA - EtOH can be cross-tolerant and cross-
dependent with benzodiazepines and
barbiturates
Describe NMDA and glutamate
- At low doses EtOH antagonizes NMDA
receptors - Decreases LTP
- Impairs learning and memory
- NMDAR responsible for amnesiac
effects of ethanol - Blackouts
Describe one chronic effect on NMDA
- Glutamate release increases as a result
of EtOH withdrawal - Rebound hyperactivity
Describe dopamine
- EtOH increases the firing rate of VTA
dopamine projections into the nucleus
accumbens - Dramatic decrease in VTA firing on
withdrawal– may cause dysphoria of
withdrawal
Describe opioid receptors and alcohol
- Acute administration of ethanol increases
endogenous opioid activity
NAc
* Opioid antagonists reduce EtOH self-
consumption in animal models
Describe physiological effects
At low doses:
* Diuretic (increased kidney output – dehydration)
* Inhibits antidiuretic hormone (vasopressin) release
* Sedative and hypnotic (sleep-inducing)
Describe alcohol, balance and coordination
- Non-specific effects on vestibular system
- Ethanol thins the fluid in the inner ear
- Fluid moves more rapidly leading to
overcompensation
Describe alcohol tolerance
- Cross-tolerance also develops with other sedative-hypnotic drugs, particularly benzodiazepines and barbiturates
Describe acute alcohol tolerance
Effects associated with intoxication –
euphoria, anxiolysis, and mild
stimulation occur when blood alcohol
levels are rising.
Describe alcohol metabolic tolerance
- Drug disposition tolerance occurs
relatively quickly – induction of liver
enzymes (ADH and P450) increases the
rate of alcohol metabolism
Describe pharmacodynamic tolerance
- Increased NMDA receptor function, increased glutamate release
- Decreased GABA receptor function
- Decreased synthesis and release of opioids
- Decreased firing of mesolimbic dopamine neurons
describe classical conditioning
- Classical conditioning:
- Similar to opiates
- Environmental cues induce compensatory
physiological changes - In rodent models alcohol administration
decreases body temperature - Conditioning leads to a compensatory increase in
body temperature based on expectancy - Tolerance diminished in novel environment
- May play a strong role in craving
Describe behavioural changes
- Behavioural changes:
- Practising behaviours under the influence of
alcohol leads to improved performance - Rats trained run on a treadmill while
intoxicated performed better with time - Rats trained on treadmill sober performed
poorly when tested after alcohol
administration
Describe physical alcohol dependence
- Prolonged intoxication can result in adaptive changes
- Mechanisms of tolerance esp. pharmacodynamics
- Restoration of homeostasis in presence of drug
- Can be readily demonstrated by the development of
symptoms of abstinence syndrome (withdrawal)
Describe acute alcohol withdrawal
Hangover is often described as an early
component of withdrawal
- May result from acute tolerance rather than
dependence
Describe contributors to hangovers
- Toxicity:
- Can be demonstrated by use of ALDH inhibitor -
disulfuram - Dehydration:
- Alcohol-induced gastric irritation:
- Rebound effects on blood sugar:
- Hypoglycemia, faintness, fatigue and malaise
- Congeners:
- Ingredients or fermentation byproducts that
exacerbate condition - Red wine – tannins, sulfates
- Distilled spirits – methanol
Describe early component of early withdrawal
- Early component (8-12 hours after last drink)
- Agitation, tremors, muscle cramps, vomiting, nausea, sweating, vivid dreams (rebound effects on REM), irregular heartbeat
- Typically lasts ~48 hours
- Less severe component of alcohol withdrawal
- Fewer than 5% of patients hospitalized for alcohol withdrawal go on to
develop the late stage of withdrawal
describe rebound effect at GABAA receptor
- Rebound effects lead to development of
hyperexcitability
Describe rebound effect at NMDA receptor
- Rebound effects lead to hyperexcitability
Describe late withdrawal
- Delirium tremens (DT)
Describe risk with DT
- Altered GABA homeostasis leads to
unopposed sympathetic activation - Management of DT involves
administration of benzodiazepines–
effective due to cross tolerance at
GABAA
Describe cognitive deficits
- Cognitive deficits occur with prolonged heavy drinking:
- Abstract problem solving
- Visuospatial abilities
- Verbal learning
- Perceptual motor skills
- Motor skills
- Memory
Describe brain damage mechanisms
- NMDA-mediated excitotoxicity
- Homocysteine accumulation
- Homocysteine is an agonist at glutamate and glycine sites of NMDAR (exacerbates excitotoxicity)
- Neurotrophic factors
Describe accumulation of toxic byproducts
- Acetaldehyde:
- Aldehydes are highly reactive with protein and DNA
- General damage to protein function and DNA
- Formation of aldehyde adducts correlates with liver damage
- Acetaldehyde also shown to cause increased reinforcing effects in the mesolimbic dopamine pathway
- Acetaldehyde microinjection to VTA can demonstrate self-administration in rats
Describe Korsakoff syndrome
- Alcoholism causes B1-vitamin deficiency
Describe effects on the liver
- At lower levels alcohol leads to fatty liver
- Metabolism of alcohol decreases fat metabolism
leading to reversible accumulation of fats - Prolonged use leads to alcoholic hepatitis
- Inflammation, fever, jaundice
- Potentially fatal
