Alcohol: Pharmacology, Toxicology and Medico-legal aspects

1. Alcohol:Pharmacology, Toxicology and Medico-legal aspects Teri Martin teri.martin@jus.gov.on.ca October 14, 2003

2. 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

3. Types of Alcohol • Ethanol (ethyl alcohol, grain alcohol) • Methanol (methyl alcohol, wood alcohol) • Isopropanol (isopropyl alcohol, rubbing alcohol) • Ethylene glycol

4. Routes of Administration • Topical • Inhalation • Intravenous injection • Oral ingestion

5. 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

6. 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 <10 % alc. v/v do not present as large a concentration gradient • Beverages >30% alc. v/v will irritate the gastric mucosa and increase mucous production

7. 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

8. 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

9. 120 100 80 With food in stomach 60 Blood Alcohol Concentration 40 20 0 0 20 50 60 100 120 140 200 220 250 300 Time Effect of food on absorption Empty stomach

10. 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

11. 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 Examples

12. 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

13. Ethanol Acetaldehyde Acetic Acid CO2 + H2O Alcohol dehydrogenase Aldehyde dehydrogenase

14. showering • fresh air • coffee • sleep • exercise • eating 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:

15. 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

16. 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

17. 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

18. 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

19. See also: Table 2, Chapter 10. Levine, 1999. p. 177 Stages of Alcohol Intoxication

20. Stages of Alcohol Intoxication

21. Stages of Alcohol Intoxication

22. 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

23. 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)

24. 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

25. 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

26. 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

27. 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)

28. Alcohol in Blood, Breath and Urine

29. 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 • Plasma:whole blood ratio ranges from approximately 1.0 to 1.3. Average plasma:whole blood ratio is 1.14

30. 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

31. Over 80? • 17.5 mmol/L  80 mg/100 mL • Serum:blood =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

32. 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.

33. 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.

34. 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

35. 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

36. Example Case • Woman, early 20’s • 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

37. 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.

38. 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

39. Henry’s 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 37°C, the amount of alcohol in the blood will be 2300x greater than the amount of alcohol in the end-expiratory breath

40. 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

41. 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

42. 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

43. Behavioural Effects of Alcohol

44. Alcohol and Driving • Laboratory studies • Simulator studies • Closed-course studies • Epidemiological studies

45. 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

46. 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

47. 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

48. 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 

49. 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

50. Effects of Alcohol on Driving • With increasing BAC, the nature and the extent of impairment will increase • Impairment of other faculties, including: • Tracking • Vision