Alcohol: Pharmacology, Toxicology and Medico-legal aspects

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AlcoholPharmacology, Toxicology and
Medico-legal aspects

• Teri Martin
• teri.martin_at_jus.gov.on.ca
• October 14, 2003

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Outline

• Pharmacology and toxicology of alcohol
• Absorption, distribution and elimination in the
  body
• Stages of alcohol intoxication
• Tolerance
• Alcohol in breath, blood, and urine
• Alcohol and driving impairment
• Effects of alcohol on memory

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Types of Alcohol

• Ethanol (ethyl alcohol, grain alcohol)
• Methanol (methyl alcohol, wood alcohol)
• Isopropanol (isopropyl alcohol, rubbing alcohol)
• Ethylene glycol

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Routes of Administration

• Topical
• Inhalation
• Intravenous injection
• Oral ingestion

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Absorption

• Absorption of ethanol is by simple diffusion
• 25 of an ingested dose of ethanol is absorbed
  from the stomach
• 75 of an ingested dose of ethanol is absorbed
  from the small intestine

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Factors affecting absorption

• Alcohol concentration of the ingested beverage
• Optimal absorption occurs for beverages with
  alcohol concentrations between 10 alc. v/v and
  30 alc. v/v
• Beverages lt10 alc. v/v do not present as large
  a concentration gradient
• Beverages gt30 alc. v/v will irritate the gastric
  mucosa and increase mucous production

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Factors affecting absorption

• Physiology
• Changes in blood supply to the GI tract
• Changes in motility will affect the speed with
  which ethanol enters the small intestine

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Factors affecting absorption

• Presence of food in the stomach
• Food in the stomach will prolong gastric emptying
  time, resulting in a lower, delayed peak blood
  alcohol concentration

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Effect of food on absorption
Empty stomach
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Distribution

• Alcohol is hydrophilic and will distribute into
  fluids and tissues according to water content
• Total body water (TBW) is dependent upon
• Age
• Sex
• Body weight

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Examples

• Effect of sex
• Man weighing 150 lbs
• Woman weighing 150 lbs
• Each consume 2 beer
• BAC of the man will be 57 mg/100 mL
• BAC of the woman will be 67 mg/100 mL

• Effect of weight
• Man weighing 150 lbs
• Man weighing 200 lbs
• Each consume 2 beer
• BAC of the lighter man will be 57 mg/100 mL
• BAC of the heavier man will be 43 mg/100 mL

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Alcohol Metabolism

• 5-10 of ingested ethanol is excreted
• Biotransformation occurs in the liver
• Commences as soon as EtOH is absorbed
• Alcohol dehydrogenase is primary enzyme

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Alcohol dehydrogenase
Aldehyde dehydrogenase
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Elimination

• Elimination of alcohol from the blood
• Follows zero-order kinetics
• Ranges from 10-20 mg/100 mL/hour
• Average rate of elimination is 15 mg/100 mL/hour
• Is fixed and unaffected by

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Fructose

• There is scientific agreement that fructose can
  increase the elimination rate of alcohol
• However the required intake of fructose is so
  high that vomiting and abdominal pains result
  from the ingestion

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Effects of Alcohol on the Body

• One day I stumbled across a case of bourbon and
  kept stumbling for several days
  thereafter. - W.C. Fields

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Effects of Alcohol on the Body

• Vasodilatation
• Creates a feeling of warmth when alcoholic
  beverages are consumed
• Contributes to paradoxical undressing in
  hypothermia deaths
• Disinhibition
• Responsible for the stimulant effects of
  alcohol
• Euphoria, ? talkativeness, ? sociability

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Effects of Alcohol on the Body

• Central nervous system depressant
• Non-selective depression of brain and spinal cord
• Effects occur on a continuum - with increased
  BAC, increased effects occur
• Sedated ? Sleepy ? Stuporous ? Unconscious
• Effects are additive with other CNS depressants

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Stages of Alcohol Intoxication

• See also Table 2, Chapter 10. Levine, 1999. p.
  177

1050 mg/100 mL Slight intoxication May be no observable signs of intoxication Laboratory testing may reveal some effects
30-120 mg/100 mL Mild euphoria, ? sociability, talkativeness Increased self confidence, ? inhibitions Sensory perception ? (e.g. hearing) Loss of fine motor skills Slowed information processing
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Stages of Alcohol Intoxication
90250 mg/100 mL Emotional instability (dissatisfaction) Mental confusion Memory impairment Impaired balance and coordination Sedation, drowsiness
180-300 mg/100 mL Disoriented to time and place, ? confusion Exaggerated emotional state Double-vision Motor incoordination worsens, apathy Anesthesia
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Stages of Alcohol Intoxication
250-400 mg/100 mL Loss of motor function Response to stimuli ? Stupor, unconsciousness Vomiting, incontinence Hypothermia
350-500 mg/100 mL Unconsciousness ? Coma Depression of reflexes Impairment of respiration, circulation Death
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Alcohol and Death

• Primary mechanism for death due to acute alcohol
  intoxication is respiratory depression
• Average BAC at which respiratory paralysis occurs
  is 350 mg/100 mL
• Death can occur at much lower BAC where
  aspiration of vomit occurs

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Positional Asphyxia

• Alcohol intoxication is the major risk factor for
  positional asphyxiation. Central nervous system
  depression causes relaxation of the muscles that
  keep the airway open during sleep
• Average BAC in 23 cases of positional
  asphyxiation was reported to be 240 mg/100 mL
  (Bell et al. 1992)

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Tolerance

• Chronic use of alcohol will result in a decreased
  susceptibility to the effects of alcohol
• Visible signs of intoxication are decreased
• Increased survivability even after consumption of
  large amounts of alcohol
• Tolerance to alcohol may be either functional
  and/or metabolic in nature

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Functional Tolerance

• Decreased sensitivity to the CNS depressant
  effects of EtOH
• e.g. Integrity of phospholipid bilayer ?
• e.g. Up-regulation of excitatory receptors
• Requires higher BAC and higher doses of EtOH to
  produce the same effect
• Learning by the chronic alcohol user

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Metabolic Tolerance

• Induction of enzymes in chronic, heavy users of
  alcohol can result in an enhanced metabolic rate
• Elimination rate in alcoholics has been measured
  at 40 mg/100 mL/hour and up
• Result is a comparatively lower BAC after
  equivalent doses of alcohol are ingested

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Example Tolerance
Urso et al. 1981. Life Sciences. 28 1053-1056.

• Measured range of BAC in 65 patients who had been
  deemed non-intoxicated by examining physician
• Ambulatory
• Alert, capable of passing mental status exam
• Responsible for self
• Blood alcohol concentrations ranged from
  undetectable to 540 mg/100 mL (average BAC was
  268 mg/100 mL)

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Alcohol in Blood, Breath and Urine
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Alcohol in Blood

• Plasma and serum are the watery components of
  whole blood
• Plasma and serum therefore have a higher alcohol
  content than whole blood
• Plasmawhole blood ratio ranges from
  approximately 1.0 to 1.3. Average plasmawhole
  blood ratio is 1.14

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Case Example

• An individual suspected of driving while impaired
  is brought to the hospital for medical treatment
  following a car accident in which his 2
  passengers were badly injured
• Blood is drawn at the hospital for medical
  purposes and hospital laboratory results reveal a
  serum alcohol concentration of 17 mmol/L
• Police would like to know if they can charge this
  individual with driving over the legal limit

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Over 80?

• 17.5 mmol/L ? 80 mg/100 mL
• Serumblood 1.14
• Therefore, a serum alcohol concentration of 80
  mg/100 mL indicates a whole blood alcohol
  concentration of 70 mg/100 mL
• This individual is not over 80 at the time the
  blood sample is drawn

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Alcohol in Urine

• Alcohol will pass from the blood into the urine
  as the blood is filtered in the kidneys
• Urine contains approximately 1.3x as much water
  as blood, therefore the UAC will be 1.3 times
  that of the BAC.

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Alcohol in Urine

• Urine is stored in the bladder for a period of
  time before it is voided.
• The UAC therefore represents the BAC sometime
  prior to collection of the urine sample.

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Analytical Considerations

• Ethanol losses during storage can occur by three
  mechanisms
• Diffusion from improperly sealed containers
• Metabolism of ethanol by microorganisms
• Oxidation of ethanol ? acetaldehyde

Proper storage conditions will minimize the loss
of ethanol
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Analytical Considerations

• Neo-formation of ethanol during storage can occur
  if there is a source of microbial contamination
  and a suitable substrate for fermentation (e.g.
  glucose)
• More likely to occur in postmortem cases but can
  also occur in samples taken from living subjects
• Sodium fluoride will prevent the neo-formation of
  ethanol during storage

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Example Case

• Woman, early 20s
• Sexually assaulted
• Blood alcohol level 0 mg/100 mL
• Urine alcohol level 105 mg/100 mL
• Blood alcohol sometime prior to collection of the
  urine sample was 80 mg/100 mL

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Further history

• Non-drinker, mentally challenged
• Lived in a group home, no access to alcohol
• Poorly controlled diabetic
• Yeast infection

Sugar Yeast ? Ethanol The woman had not
necessarily been drinking part or all of the
ethanol detected in the urine may have been
formed after collection of the sample.
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Alcohol in Breath

• Alcohol is volatile - at physiological
  temperatures alcohol will diffuse from the blood
  into the alveolar air of the lung and into the
  breath
• Breath analysis is rapid, non-invasive, and does
  not require specialized medical personnel for
  sampling

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Henrys Law

• At a given temperature, the ratio of the
  concentration of a volatile compound in solution
  and the concentration of the volatile compound in
  the air above the solution is fixed
• At 37C, the amount of alcohol in the blood will
  be 2300x greater than the amount of alcohol in
  the end-expiratory breath

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Issues in Breath TestingQuality of the breath
sample

• End-expiratory breath is the best reflection of
  the alcohol content of the blood
• A poor quality breath sample will result in an
  underestimate of blood alcohol concentration

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Issues in Breath TestingMouth alcohol effect

• Residual alcohol, temporarily trapped in the
  mouth may result in an elevated breath alcohol
  concentration
• Sources of mouth alcohol
• Recent ingestion of alcohol
• Regurgitation or vomiting
• Asthma inhalers
• Breath sprays and mouthwashes

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Mouth alcohol effect

• Since the mouth alcohol effect will dissipate
  within 15 minutes, observation of a subject for a
  minimum of 15 minutes will protect against
  artificially elevated breath alcohol results
• Duplicate breath testing is a further safeguard
  against mouth alcohol effect

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Behavioural Effects of Alcohol
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Alcohol and Driving

• Laboratory studies
• Simulator studies
• Closed-course studies
• Epidemiological studies

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Laboratory studies

• Test the effect of alcohol on skills that are
  related to the operation of a motor vehicle
• Choice reaction time
• Visual tracking
• Vigilance
• Glare recovery

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Closed-course studies

• Test the effect of alcohol on subjects driving
  real cars on closed-driving courses
• Parking tasks
• Emergency-braking tasks
• Pylons on curves
• Width judgment

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Epidemiological studies

• Compare the BAC in drivers who have had accidents
  with the BAC of drivers who have not had
  accidents
• Grand Rapids study by Robert Borkenstein,
  inventor of the Breathalyzer, conducted in 1964

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Grand Rapids Study
Borkenstein et al. 1974. Blutalkohol. 11 7-13

• Relative probability of causing an accident
  increases exponentially with ? BAC
• 80 mg/100 mL - 4x ?
• 100 mg/100 mL - 7x ?
• 150 mg/100 mL - 25x ?

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Effects of Alcohol on Driving

• At low BAC the faculties required for driving
  that are impaired are
• Judgment
• Ability to divide attention
• Choice reaction time

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Effects of Alcohol on Driving

• With increasing BAC, the nature and the extent of
  impairment will increase
• Impairment of other faculties, including
• Tracking
• Vision

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Alcohol and Driving

• In addition to the BAC, driving impairment will
  also be affected by
• Skills of the driver
• Driving task
• Tolerance to alcohol

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Alcohol and Memory

1. Memory loss may be characterized by forgotten
   events, later recoverable, either when brought to
   the individuals attention or spontaneously
2. Memory loss may be non-recoverable characterized
   by feelings of lost time, also known as an
   alcoholic blackout

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Alcohol Blackout

• Amnesia for events occurring during any part of a
  drinking episode
• Not associated with a loss of consciousness
• May vary in length from hours to days
• More common among alcoholics
• Typically associated with high BAC
• Rapid rise in BAC may contribute

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• Reminds me of my safari in Africa... Somebody
  forgot the corkscrew and for several days we had
  nothing to live on but food and water. -
  W.C. Fields