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Copyright Alcohol Medical Scholars Program
1
Alcohol: Pharmacology and Neurobiology
Vijay A. Ramchandani, Ph.D.
Indiana University School of Medicine
Copyright Alcohol Medical Scholars Program 2
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 Acetaldehyde Acetate
– 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
Alcoholdehydrogenase
Aldehydedehydrogenase
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Metabolism
• Metabolism
Alcohol Acetaldehyde Acetate
– Aldehyde dehydrogenase usually not rate-limiting
– Accumulation of acetaldehyde associated with headache, gastritis, nausea, dizziness (hangover)
– Aldehyde dehydrogenase inhibition (disulfiram)
Alcoholdehydrogenase
Aldehydedehydrogenase
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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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Pharmacodynamics: CNS Effects
• Alcohol is a CNS depressant• 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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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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Alcohol as a Reinforcer: Evidence
• Animal models of alcohol preference– Selectively bred animal lines show innate differences in limbic
structures and neurotransmitter function
• Animal models of self-administration– Animals trained to chronically self-administer alcohol show
differences in neurotransmitter levels in the mesolimbic system
– Animals will bar-press repeatedly for intra-cranial injections of alcohol into the VTA
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Reinforcement: Neurochemical systems
EnkephalinInhibitoryNeuron
REWARD
Glutamate Excitatory InputEnkephalin or
DynorphinInhibitory Neuron
GABAInhibitory
Neuron
GABA Inhibitory Feedback
Dopamine Neuron GABANeuron
Ventral Tegmental Area(VTA)
Nucleus Accumbens(NAc)
Dopamine Receptors
GABA-A Receptors
PresynapticOpioid
Receptors(, ?)
OpioidReceptors
OpioidReceptors
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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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