Outline

• Pharmacokinetics
– Absorption
– Distribution
– Metabolism
• Pharmacodynamics
– CNS effects
– Tolerance
– Alcohol as a reinforcer
– Neuropharmacological effects

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 Pharmacokinetics: Absorption
• Rapidly absorbed primarily from duodenum
• Rate of absorption is extremely variable
• Peak blood alcohol concentration (BAC) depends on:
– Amount and alcohol concentration of beverage
– Rate of drinking
– Food consumption and composition
– Gastric emptying and gastric metabolism
– Hepatic first pass

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 Distribution
• Volume of distribution = Total Body Water
• Gender Differences in body composition

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 Metabolism
• Metabolism
– 90-98% metabolized in liver

Alcohol MEOS,P450 Aldehyde

Alcohol Acetaldehyde
dehydrogenase
Acetate
dehydrogenase

– Alcohol dehydrogenase saturates at low to moderate BACs

(Michaelis-Menten kinetics)
– Apparent zero-order kinetics at moderate BACs
• Alcohol Elimination Rate = 7 g per hr
• Disappearance Rate = 0.015% per hr

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 Metabolism
• Metabolism

Alcohol ,MEOS,P450 Aldehyde

Alcohol Acetaldehyde
dehydrogenase
Acetate
dehydrogenase

– Aldehyde dehydrogenase usually not rate-limiting

– Accumulation of acetaldehyde associated with headache,
gastritis, nausea, dizziness (hangover)
– Aldehyde dehydrogenase inhibition (disulfiram)

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 Metabolism: Genetic Variation
Genetic variation in alcohol metabolizing enzymes
• Alcohol Dehydrogenase (ADH)
– Polymorphism occurs at ADH2 and ADH3 loci

ADH2*1 ADH2*2 ADH2*3 ADH3*1 ADH3*2

White American 95% <5% <5% 50% 50%
Black American 85% <5% 15% 85% 15%
Asian 15% 85% <5% 95% 5%

– 15% of Black Americans have ADH2*3 allele  increased alcohol metabolic rate

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 Metabolism: Genetic Variation
Genetic variation in alcohol metabolizing enzymes
• Aldehyde Dehydrogenase (ALDH)
– Polymorphism at the ALDH2 gene
• 50% of Asians have ALDH2*2 allele
 decreased elimination of acetaldehyde (and alcohol)
 flushing response

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Pharmacokinetics: Gender Differences
• Gender Differences
– in absorption
• Differences in gastric ADH activity
– in volume of distribution
• Differences in body composition and total body water (TBW)
– in metabolism
• Differences in liver volume, ADH activity?
• Effect of menstrual cycle on alcohol pharmacokinetics
• Effect of sex hormones (OC) on alcohol PK

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 ACUTE EFFECTS: CNS Effects
• Alcohol is a CNS depressant SEDATION ,SLURRED
SPEECH ,ATAXIA.If >300mg/dl then loss of
conciousness,coma
• Apparent stimulatory effects result from depression of
inhibitory control mechanisms in the brain
• Characteristic response: euphoria, impaired thought
processes, decreased mechanical efficiency

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 Concentration-Effect Relationship

BAC [%] Effects

0.02-0.03 Mood elevation. Slight muscle relaxation.
0.05-0.06 Relaxation and Warmth. Increased reaction time. Decreased
fine muscle coordination.
0.08-0.09 Impaired balance, speech, vision, hearing, muscle coordination.
Euphoria.
0.14-0.15 Gross impairment of physical and mental control.
0.20-0.30 Severely intoxicated. Very little control of mind or body.
0.40-0.50 Unconscious. Deep coma. Death from respiratory depression

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 CHRONIC Tolerance: Definitions
• Tolerance: The phenomenon of decreased effect with
prolonged exposure to a drug
• Acute tolerance: during the time-course of a single
exposure to drug
• Chronic tolerance: over repeated use of drug

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 Tolerance: Significance
• Why is tolerance to alcohol important?
– One of the determinants of increased alcohol consumption
• maintains or aggravates alcohol dependence
• increases risk of organic complications of alcoholism
– Diagnostic criteria for alcoholism by DSM-IV
– Cross-tolerance to other depressant drugs
– Genetic determinants exist
– Low Response predicts alcoholism

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 Alcohol as a Reinforcer
• Reinforcer: a substance whose pharmacological effects
drive the user to continue to use it.
• Positive reinforcing effects:
– Gain pleasure
– Altered consciousness
– Conform to behavior of peers
• Negative reinforcing effects:
– Relief of stress and negative emotions
– Relief of withdrawal symptoms

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Alcohol as a Reinforcer: Neural Systems

Activation of mesocorticolimbic system

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Reinforcement: Neurochemical systems
Glutamate
Enkephalin or Excitatory Input
Dynorphin
Inhibitory Neuron

k Opioid Dopamine Receptors

Enkephalin Receptors
Inhibitory Dopamine Neuron GABA
Neuron Neuron

m Opioid REWARD
Receptors

GABA-A Receptors

GABA Inhibitory Feedback

GABA Presynaptic
Inhibitory Opioid
Neuron Receptors
(m, d?)

Ventral Tegmental Area Nucleus Accumbens

(VTA) (NAc)
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 Neuropharmacology: GABA
• Effects on GABA system
– Interaction with GABA-A receptor and facilitation of GABA
transmission
• Sedative and anxiolytic effects
• Withdrawal

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 Neuropharmacology: DA, Opioids
• Effects on Dopamine system
– Increase dopamine in mesocorticolimbic system
• Reinforcing, rewarding effects
• Effects on Opioid peptide system
– Activation of opioid peptide system
• Reinforcing and rewarding effects (Mu)
• Aversion (Kappa)
• Craving

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 Neuropharmacology: NMDA, 5HT
• Effects on NMDA Glutamate system
– Blockage of NMDA receptor (allosteric effect)
• Sedative/hypnotic effects
• Neuroadaptation
• Withdrawal
• Effects on Serotonin system
• Neuroadaptation, aversion
• Effects on stress hormones
• Stress response

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 Neuropharmacology: Summary
Experience Transmitter/Receptor
euphoria/pleasure Dopamine, Opioids
anxiolysis/ataxia  GABA
sedation/amnesia  GABA +  NMDA
nausea 5HT3
neuroadaptation NMDA, 5HT
stress CRF
withdrawal GABA, NMDA ( Ca, Mg)
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 Implications for Pharmacotherapy
• Disulfiram
• Naltrexone
• Acamprosate
• Benzodiazepines
• SSRIs

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Liver – fattyl iver, cirrosis
GIT- irritation, bleeding, absorption defects,
pancreatitis
Endocrine – gynecomastia, testicular atrophy
CVS- binge drinking, arrythmia
Fetal alcohal syndarome
Immune system- decreased function
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Program
Treatment
1. Accessive CNS depression- intravenous
dextrose, thiamine
2. Alcohol with drawl syndromes- corect
electrolyte imbalance, bensodile
3. Treatment of alcohol ism- naltrexone,
acamprosate, disulfiram

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Program