Alcohol

Question 1

What is the economic burden in the US of alcohol per drink?

Answer 1

$1.90 per drink

Question 2

What is the earliest historical evidence?

Answer 2

Archaeological evidence of fermentation
from Neolithic period (10,000 BCE)

Question 3

What is alcohol?

Answer 3

Colloquially alcohol refers to ethyl
alcohol or ethanol (EtOH).

Question 4

Describe pharmacology

Answer 4

EtOH administered by oral dose has high bioavailability

Alcohol has high caloric content but little nutritive value

Question 5

Describe alcohol. absorption

Answer 5

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

Question 6

Describe alcohol distribution

Answer 6

• EtOH readily diffuses into all aqueous
  fluids/tissues via passive diffusion
• Easy access through BBB and placental
  barrier
• Excluded from fat tissues

Question 7

Describe alcohol metabolism

Answer 7

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

Question 8

Describe specific effects of alcohol

Answer 8

• Specific effects – result of interactions with receptors
• Cause most of the acute and chronic effects of intoxication
• Responsible for most subjective effects of intoxication

Question 9

describe nonspecific effects of alcohol

Answer 9

• 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

Question 10

Describe GABAA

Answer 10

• 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

Question 11

Describe NMDA and glutamate

Answer 11

• At low doses EtOH antagonizes NMDA
  receptors
• Decreases LTP
• Impairs learning and memory
• NMDAR responsible for amnesiac
  effects of ethanol
• Blackouts

Question 12

Describe one chronic effect on NMDA

Answer 12

• Glutamate release increases as a result
  of EtOH withdrawal
• Rebound hyperactivity

Question 13

Describe dopamine

Answer 13

• 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

Question 14

Describe opioid receptors and alcohol

Answer 14

• Acute administration of ethanol increases
  endogenous opioid activity

NAc
* Opioid antagonists reduce EtOH self-
consumption in animal models

Question 15

Describe physiological effects

Answer 15

At low doses:
* Diuretic (increased kidney output – dehydration)
* Inhibits antidiuretic hormone (vasopressin) release
* Sedative and hypnotic (sleep-inducing)

Question 16

Describe alcohol, balance and coordination

Answer 16

• Non-specific effects on vestibular system
• Ethanol thins the fluid in the inner ear
• Fluid moves more rapidly leading to
  overcompensation

Question 17

Describe alcohol tolerance

Answer 17

• Cross-tolerance also develops with other sedative-hypnotic drugs, particularly benzodiazepines and barbiturates

Question 18

Describe acute alcohol tolerance

Answer 18

Effects associated with intoxication –
euphoria, anxiolysis, and mild
stimulation occur when blood alcohol
levels are rising.

Question 19

Describe alcohol metabolic tolerance

Answer 19

• Drug disposition tolerance occurs
  relatively quickly – induction of liver
  enzymes (ADH and P450) increases the
  rate of alcohol metabolism

Question 20

Describe pharmacodynamic tolerance

Answer 20

• Increased NMDA receptor function, increased glutamate release
• Decreased GABA receptor function
• Decreased synthesis and release of opioids
• Decreased firing of mesolimbic dopamine neurons

Question 21

describe classical conditioning

Answer 21

• 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

Question 22

Describe behavioural changes

Answer 22

• 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

Question 23

Describe physical alcohol dependence

Answer 23

• 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)

Question 24

Describe acute alcohol withdrawal

Answer 24

Hangover is often described as an early
component of withdrawal

• May result from acute tolerance rather than
  dependence

Question 25

Describe contributors to hangovers

Answer 25

* 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

Question 26

Describe early component of early withdrawal

Answer 26

* 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

Question 27

describe rebound effect at GABAA receptor

Answer 27

* Rebound effects lead to development of hyperexcitability

Question 28

Describe rebound effect at NMDA receptor

Answer 28

* Rebound effects lead to hyperexcitability

Question 29

Describe late withdrawal

Answer 29

* Delirium tremens (DT)

Question 30

Describe risk with DT

Answer 30

* Altered GABA homeostasis leads to unopposed sympathetic activation * Management of DT involves administration of benzodiazepines– effective due to cross tolerance at GABAA

Question 31

Describe cognitive deficits

Answer 31

* Cognitive deficits occur with prolonged heavy drinking: * Abstract problem solving * Visuospatial abilities * Verbal learning * Perceptual motor skills * Motor skills * Memory

Question 32

Describe brain damage mechanisms

Answer 32

* NMDA-mediated excitotoxicity * Homocysteine accumulation * Homocysteine is an agonist at glutamate and glycine sites of NMDAR (exacerbates excitotoxicity) * Neurotrophic factors

Question 33

Describe accumulation of toxic byproducts

Answer 33

* 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

Question 34

Describe Korsakoff syndrome

Answer 34

* Alcoholism causes B1-vitamin deficiency

Question 35

Describe effects on the liver

Answer 35

* 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