Pharmacology of Alcohol

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Pharmacology of Alcohol

• A Project CREATE Module

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Consumption Patterns

• Most frequently abused drug in North America and
  the world
• Consumed regularly by over one-half the adult
  population of Canada
• One million Canadians are alcoholics
• Per capita annual consumption of 10 L (2 drinks
  per day)

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Consequences of Use/Abuse

• In US, cirrhosis is fourth most frequent cause
  of death in persons 25-64 years of age
• 20-40 of patients admitted to general hospital
  in the US have alcohol-related problems
• Amongst the elderly, alcohol-related
  hospitalizations are as numerous as those due to
  myocardial infarctions

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PharmacologyAbsorption and Distribution

• Water soluble, readily diffuses through any
  mucous membrane
• Quickly absorbed from stomach and small
  intestines
• Absorption affected by
• delayed gastric emptying
• concentration of alcohol in a drink

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PharmacologyAbsorption and Distribution

• Diffuses quickly from bloodstream into aqueous
  compartment of all tissues, body fluids and
  alveolar air
• Volume of distribution volume of total body
  water
• Acohol in the alveolar space is proportional to
  that in pulmonary blood
• at equilibrium ratio between alveolar air and
  blood is approximately 12100
• breathblood ratio incorporated into devices such
  as breathalyzers

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Pharmacology Metabolism

• Small amounts excreted unchanged in breath, urine
  and sweat
• Small amounts removed by enzymes catalysing
  production of sulfate and glucuronide
• Remainder disposed by
• oxidative metabolism by alcohol dehydrogenase
• microsomal ethanol-oxidizing system (MEOS)
• catalase

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Pharmacology Metabolism

• Main enzyme is hepatic alcohol dehydrogenase
• Induction of MEOS with regular, heavy drinking
  likely responsible for metabolic tolerance
• Ethanol ? acetaldehyde ? acetate ? carbon dioxide
  and water
• Mitochondrial aldehyde dehydrogenase converts
  acetaldehyde to acetate

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Pharmacology Metabolism

• Oxidation of alcohol determined by
• activity of hepatic alcohol dehydrogenase
• concentration of NAD
• rate of NADH ? NAD
• 70 kg social drinker metabolizes 9-10 g of
  alcohol per hour

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Physiological Responses Behavioural Effects

• Ehanol causes intoxication
• Degree of impairment depends on
• blood alcohol concentration
• duration of drinking episode
• tolerance

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Physiological Responses Consumption and
Consequences

• One standard drink contains 13.4 g of alcohol
• 12 oz (341mL) beer (alcohol content 5 v)
• OR
• 1.5 oz liquor (alcohol content 40 v/v)
• OR
• 5 oz serving of wine (alcohol content 12 v/v)

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Physiological Responses Consumption and
Consequences

• 2-3 drinks
• effect on attention and mood, some impairment in
  judgement
• relaxation, pleasurable feelings of well-being
• minimal influence on motor skills

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Physiological Respnses Consumption and
Consequences

• 4-5 drinks preceding effects plus
• graded onset of disrupted motor function - slight
  difficulty with balance, some ataxia and slurring
  of speech
• decrements in skilled processes requiring
  attention, evaluation, judgement and motor
  responses (decline in driving abilities)
• decrements in reaction time to simple auditory
  or visual stimuli

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Physiological Responses Consumption and
Consequences

• 6-10 drinks
• blurry and tunnelled vision, onset of sensory
  disturbances, perception of pain obtunded, poor
  memory retention, blackouts
• motor function and behaviour continue to
  degenerate
• vomiting

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Physiological Responses Consumption and
Consequences

• 10-15 drinks
• irregularities in breathing, stupor, decreased
  reflexes and anaesthesia, coma, death
• fatalities due to inhalation of vomitus and
  respiratory failure due to depression of medulla

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Physiological Responses Consumption and
Consequences

• NMDA-receptor complex responds to glutamate
  (excitatory neurotransmitter)
• Alcohol inhibits NMDA receptor, causing CNS
  depression
• Chronic alcohol use compensatory up-regulation
  of NMDA receptors
• This causes tolerance to depressant effects of
  alcohol, and withdrawal symptoms (tremors,
  seizures) on cessation of alcohol

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Ethanol and Endocrine Function

• Defects in the hypothalamic-pituitary-testicular
  axis
• Decreased testosterone production
• Atrophic testes in patients with alcoholic
  cirrhosis
• Gynaecomastia in males and anovulation in females
• Pseudo-Cushings syndrome
• Decreased secretions of the posterior pituitary
  hormones

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Toxicological Responses

• Neuronal toxicity
• Wernickes encephalopathy
• Korsakoffs psychosis
• cerebral atrophy , enlarged ventricles, enlarged
  cortical sulci

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Toxicological Responses Cardiac Toxicity

• Acute ingestion causes vasodilation, a fall in
  peripheral arteriolar resistance, tachycardia and
  increased pulse pressure amplitude
• Binge drinking may result in supraventricular
  tachycardia and arrhythmias
• Heavy consumption over a decade may result in
  congestive cardiomyopathy
• Chronic abuse associated with arterial
  hypertension, increased incidence of myocardial
  infarctions, and strokes
• Moderate drinking lowers risk of myocardial
  infarction and ischemic stroke

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Toxicological Responses Gastrointestinal Toxicity

• High concentrations of alcohol irritate tissues
  and can cause stomatitis, esophagitis, gastritis,
  duodenitis
• Exacerbation of existing ulcers
• Acute and chronic pancreatitis
• Diabetes, malabsorption, fat-soluble vitamin
  deficiencies

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Toxicological Responses Hepatic Toxicity

• Fatty liver
• Alcoholic hepatitis
• Cirrhosis (10-20 of chronic alcoholics)
• Risk of cirrhosis if consume more than
• 80 g daily over 10 years (men)
• 40 g daily over 10 years (women)

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Toxicological Responses Musculoskeletal Toxicity

• Acute and chronic myopathy
• Increased falls and fractures
• Aseptic necrosis

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Toxicological ResponsesFetal Toxicity

• Ethanol readily crosses placenta
• Teratogen
• Fetal alcohol syndrome(FAS) growth retardation,
  facial abnormalities, CNS dysfunction
• Severity of FAS is dose-related and exposure
  period of greatest risk is first trimester of
  pregnancy
• Incidence in US is 2-6 per 1000 deliveries
• Most commonly identified cause of mental
  retardation

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Alcohol WithdrawalFirst Stage

• Anxiety, nausea, vomiting, tremor of hands
• Increasing agitation and psychomotor activity
• Sweating, hypertension and tachycardia
• Signs and symptoms appear within 6-12 hours after
  last drink
• Resolves within 2-3 days in most cases

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Alcohol WithdrawalSecond Stage

• Signs of first stage become more intense
• Begins 12-48 hours after the last drink
• Grand mal seizures
• Supraventricular or ventricular tachyarrhythmias
• Auditory and sometimes visual hallucinations

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Alcohol WithdrawalSecond Stage

• Seizures are grand-mal, non-focal, brief
• Seizures present between 12-72 hours after
  cessation of drinking
• Lifetime prevalence of seizures in alcohol
  dependent patients 10-20

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Alcohol WithdrawalStage Three (Delirium Tremens)

• Reversible psychosis, fluctuating level of
  consciousness
• Usually begins 3-5 days after the last drink and
  may continue for several days
• Autonomic signs and symptoms noted above more
  severe
• Hallucinations may be visual, olfactory, auditory
  and/or tactile
• Patients highly disoriented, anxious and fearful
• Emotional lability
• Measurable risk of morbidity and mortality

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Pharmacological InterventionsTreatment of
Withdrawal

• Stage one medication often not required
• Higher stages of withdrawal
• benzodiazepines (prevent seizures)
• haloperidol (treat hallucinations)
• digitalis, verapamil, lidocaine (for arrhythmias)
• NOTE thiamine should be given to patients in
  all stages (reduces risk of Wernicke-Korsakoff
  syndrome)

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Pharmacological InterventionsLong-term Treatment

• Disulfiram (Antabuse)
• inhibits aldehyde dehydrogenase
• patients must be warned not to drink alcohol
• if alcohol is ingested, accumulation of aldehyde
  causes hyperthermia, flushing, weakness, nausea,
  elevated pulse rate
• rate of synthesis of new enzyme is rate-limiting
  step

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Pharmacological Interventions

• Selective Serotonin Reuptake Inhibitors
• may reduce alcohol consumption in patients with
  mild or moderate alcohol dependence
• Opioid antagonists
• naltrexone has been approved for adjunctive
  therapy of alcoholics
• mechanism of action yet to be elucidated

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Pharmacological Interventions

• Acamprosate (calcium acetylhomotaurinate) thought
  to inhibit neuronal hyperexcitability by
  antagonizing excitatory amino acid activity as
  well as reduce neuronal calcium ion refluxes
• currently not available in Canada

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