Thursday Feb 22

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Thursday - Feb 22 Alcohol (cont)
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• VII. Chronic Effects
• BRAIN
• With repeated use, cellular tolerance occurs
  changes at sites of action (highpoints only)
• 1. GABAA receptor system become less sensitive to
  alcohol via reduced number of receptors (fewer
  produced when action is constantly amplified by
  alcohol)
• 2. Since alcohol has been inhibiting the NMDA
  receptor, system adapts by building more to
  provide Glutamate binding sites (more to find
  what little Glutamate seems to be present)
• (In absence of alcohol, GABA does not produce
  enough inhibition and the excess Glutamate
  receptors cause increased excitation)
• 3. Threshold for release or action of Dopamine
  in reward pathway changes (no alcohol, not enough
  reward, craving)

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• B. Repeated use at high levels damages the brain.
• depresses synthesis of protein important to
  neuronal function and repair
• brain shrinkage occurs (death of neurons and
  glia)
• increases ventricular size (fluid fills in the
  space)
• reduces myelin content
• Particularly vulnerable brain areas hippocampus,
  cerebellum, prefrontal cortex
• increased risk for Wernicke-Korsakoff Syndrome
  (will discuss later)

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BODY C. Cardiovascular effects increased risk
for heart disease D. Alcoholic Fatty Liver
chronic fatty liver condition interferes with
general metabolism increases risk for
nutritional deficiencies and disease E. Cirrhosis
inflammation of liver 7th most common cause of
death in U.S. 75 of deaths caused by alcoholism
are due to cirrhosis F. Increased risk for cancer
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• VIII. Withdrawal
• Changes with chronic use produce symptoms of
  withdrawal when alcohol is not available
• extent of withdrawal symptoms varies with the
  pattern of alcohol use
• Chronic, daily repetitive, high use worst
  symptoms
• Binge drinkers, those who drink lesser amounts,
  and those who drink heavily for lesser period
  milder symptoms

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• General Symptoms of withdrawal (opposites of
  action)
• agitation
• tremor
• seizures
• insomnia
• discomfort and craving
• Not enough inhibition inhibitory systems dont
  work excitatory systems go unchecked
• Not enough reward reward systems not adequately
  activated (dopamine opiates)

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• VIII. Withdrawal
• Mild disturbed sleep nausea, weakness,
  anxiety, mild tremors occurring in lt 24 hours
  after alcohol was consumed (overlaps with
  hangover symptoms)
• Severe symptoms
• Tremulous syndrome
• Seizures can be life-threatening
• Delirium tremens - delirious, agitated, anxious

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• VIII. Withdrawal
• C. Timecourse for unassisted pattern of
  withdrawal
• For repeated use/withdrawal, withdrawal gets
  worse each time.
• 3-24 hours
• Tremors
• nausea, anxiety, sweating
• Sleep disturbances nightmares REM rebound
• Hallucination (alcoholic hallucinosis paranoid
  persecutory)
• Postural hypotension
• seizures

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• VIII. Withdrawal
• C. Timecourse
• By 3rd day
• Hyperthermia
• Continued hallucination delirium
• Cardiovascular collapse possible
• Death may occur
• If one survives, most recovery in 5-7 days
  (unassisted)
• Months later
• Abnormal EEG

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• VIII. Withdrawal
• C. Timecourse
• D. Possible permanent disorder Korsakoffs
  Psychosis Alcohol Amnestic Disorder
• Caused by long-term heavy drinking (5-15 years)
  accompanied by thiamine deficiency (vitamin B1)
• Rare thiamine now routinely administered during
  detox
• Initial symptoms
• Behavioral Symptoms - confusion, anterograde
  memory deficits some memory retrieval problems
• Visual problems - blurred vision, nystagmus gaze
  palsy
• Peripheral neuropathy ataxia muscle weakness
• Permanent effects less likely to develop when
  thiamine administered

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• VIII. Withdrawal
• D. Possible permanent disorder Korsakoffs
  Psychosis Alcohol Amnestic Disorder
• LongTerm Effects
• Memory deficits
• Hippocampal abnormalities
• Most affected require custodial care

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• IX. Drugs for the Treatment of Alcohol-Related
  Problems
• Drugs used to treat withdrawal
• Drugs used to promote avoidance
• Drugs used to reduce craving
• Drugs used to treat comorbid conditions and
  reduce dependence on alcohol

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• IX. Drugs for the Treatment of Alcohol-Related
  Problems
• Drugs used to treat acute withdrawal
• Benzodiazepines help facilitate actions of GABA
  in absence of alcohol continuing to potentiate
  GABA action
• Chlordiazepoxide (Librium)
• Diazepam (Valium)

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• IX. Drugs for the Treatment of Alcohol-Related
  Problems
• Drugs used to treat withdrawal
• Drugs used to promote avoidance
• Alcohol sensitizing drugs make you sick if you
  drink
• Antabuse (disulfiram) block aldehyde
  dehydrogenase and cause acetaldehyde (toxic
  metabolite) to build up
• Calcium carbimide (Canada Temposil) similar
  action
• Acetaldehyde syndrome flushing, throbbing
  headache, nausea, vomiting
• Can help but not much better than placebo
  agents.

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• IX. Drugs for the Treatment of Alcohol-Related
  Problems
• Drugs used to treat withdrawal
• Drugs used to promote avoidance
• Drugs used to reduce craving
• 1. opioid antagonists
• Naltrexone (ReVia, Trexan, Nalorex, Phaltrexia)
  Reduces reinforcement value of alcohol by
  preventing opioids from producing it, and
  preventing opioids from increasing release of
  dopamine
• Not much better than placebo
• Nalmefene (Revex) similar and works a little
  better

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• IX. Drugs for the Treatment of Alcohol-Related
  Problems
• Drugs used to treat withdrawal
• Drugs used to promote avoidance
• Drugs used to reduce craving
• 1. opioid antagonists
• 2. Dopaminergic agonists elevate dopamine and
  provide some reward
• Bupropion (Wellbutrin Odranol) antidepressant
  effects
• 3. Acamprosate GABAA agonist and antagonist at
  NMDA receptors

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• IX. Drugs for the Treatment of Alcohol-Related
  Problems
• Drugs used to treat withdrawal
• Drugs used to promote avoidance
• Drugs used to reduce craving
• Drugs used to treat comorbid conditions and
  reduce dependence on alcohol
• Serotonergic drugs used to treat depression and
  anxiety
• SSRIs selective serotonin reuptake inhibitors
  (Prozac Zoloft Paxil)
• Serotonergic agonist - buspirone (BuSpar)
• Ondansetron (Zofran) efficacy not yet
  documented marketed as antiemetic for radiation
  and chemotherapy patients Touted for anxiety,
  bulemia, Schizophrenia.

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• X. Alcohol and Prenatal Development
• Readily crosses the placental membrane
• Developing embryo/fetus lacks detoxifying enzymes
• Alcohol interferes with normal developmental
  processes (reduces folic acid levels alters
  Vitamin A actions)
• Effects occur over a continuum from death,
  malformation, growth retardation, behavioral
  dysfunction
• Most research has focused on the severe end of
  the spectrum Fetal Alcohol Syndrome
• Fetal Alcohol Effects lesser effects than full
  syndrome may be physically normal but have
  learning or behavioral problems

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• Variables Governing Susceptibility
• Gestational Age at Exposure
• Genotype
• Amount consumed
• drinking frequency
• Among chronic alcoholics, 30-50 of infants have
  FAS.

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• Diagnosis of Fetal Alcohol Syndrome
• Minimal criteria
• Abnormalities in three areas
• Prenatal and/or postnatal growth retardation
• Central nervous system involvement
• Characteristic facial dysmorphology

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CNS Dysfunction Infants feeding problems
sleep problems irritable difficult to soothe
abnormal muscle tone Permanent reduced
intelligence behavioral abnormalities (reduced
inhibitory control social difficulties
increased activity) Alcohol is the 1 preventable
cause of mental retardation. May have anatomical
malformations heart and brain