1. FSC402H Forensic Toxicology of Common Pharmaceuticals November 11, 2003

2. Common Pharmaceuticals Compendium of Pharmaceuticals and Specialties: The Canadian Drug Reference for Health Professionals Published by: The Canadian Pharmacists Association  146 pharmaceutical companies  63 pages listing brand and generic names

3. Forensic Issues  Delayed Toxicity  Toxicity at Low and High Concentrations  Degradation of Sample in vitro  High Toxicity vs Low Toxicity  Age dependant toxicity  Drug Interactions  Role of Metabolites  Impairment  Postmortem Redistribution

4. Delayed Toxicity Acetaminophen  Tylenol + + +  also found combined with great # of combined products  350-650 mg, oral, normal-release, sustained- release  Analgesic and Anti-pyretic  Therapeutic Concentrations  0.2 – 5.2 mg/dL

5. Delayed Toxicity Glucuronide  Acetaminophen  Sulfate  Reactive Intermediate  Glutathione Conjugate

6. Delayed Toxicity Acetaminophen Toxicity – Overdose  Glutathione becomes depleted  Reactive Intermediate builds up  Reversible damage to hepatocytes

7. Delayed Toxicity Rumack- Matthew Nomogram Adapted from Rumack BH, Matthew H: "Acetaminophen poisoning and toxicity." Pediatrics 55(6):871-876, 1975

8. Delayed Toxicity RUMACK – MATTHEW NOMOGRAM CAUTIONS  time refers to time from ingestion  serum (blood) levels drawn before 4 hours may not represent peak  used only for a single acute ingestion  if T 1/2 > 4 hours -  likelihood of hepatic injury

9. Delayed Toxicity Phase 1: 0-24 hours  asymptomatic  anorexia  nausea, vomiting  diaphoresis  malaise Phase 2: 18-72 hours   phase 1 symptoms  pain in upper right quadrant   liver enzymes Acetaminophen Toxicity – Overdose Phase 3: 72-96 hours  hepatic necrosis with abdominal pain  hepatic encephalopathy  jaundice  nausea & vomiting  renal failure  DEATH Phase 4: 4d – 3wks  complete resolution

10. Delayed Toxicity Acetaminophen Toxicity – Overdose hepatotoxicity – 24-48 hours peak hepatotoxicity – 72-96 hours death – 4-18 days Minimal Fatal Conc.: ?? 9 – 32 mg/dL

11. Delayed Toxicity AcetylSalicylic Acid  Aspirin + + +  also found combined with great # of combined products

12. Delayed Toxicity AcetylSalicylic Acid  Analegesia, Antipryresis  325-975 mg, oral  3.1 – 11.4 mg/dL  Antiinflammatory  3000-5000 mg, oral  4.4 – 33 mg/dL (50 mg/kg)

13. Delayed Toxicity AcetylSalicylic Acid – Toxicity  hyperventilation  mild confusion  tinnitus  nausea, vomiting  agitation or lethargy  seizures  respiratory alkalosis, metabolic acidosis  pulmonary edema, hemorrhage, acute renal failure, DEATH

14. Delayed Toxicity Done Nomogram (Adapted from Done, AK Pediatrics, 1978, 62:890)

15. Delayed Toxicity NOMOGRAM CAUTIONS  single, acute ingestion  serum (blood) level to be compared is at least 6 hours after time of ingestion MINIMAL FATAL CONCENTRATION  generally > 50 mg/dL  6.1 – 732 mg/dL

16. Toxicity at Low and High Anti-Convulsants TOO LITTLE is as bad as TOO MUCH  Phenobarbital  Phenytoin  Primidone  Valproic Acid  Gabapentin  Vigabatrin  Carbamazepine  Lamotrigine

17. Toxicity at Low and High Phenobarbital  used as an anticonvulsant since 1912  for epilepsy  60 – 120 mg/day  often given in combination with other anticonvulsants

18. Toxicity at Low and High Phenobarbital  Effective Concentration – Plasma  1 – 3 mg/dL  Effective Concentration – Blood  0.8 – 2.4 mg/dL

19. Toxicity at Low and High Phenobarbital - Toxicity Low Concentrations  Ineffective control of epilepsy  seizures, DEATH High Concentrations  CNS depression, coma, DEATH  Begin at plasma conc. > 4 mg/dL (3.2 mg/dL blood)  Coma  6.5 – 11.7 mg/dL plasma (5.2 – 9.4 mg/dL blood)  DEATH  as little as 5.5 mg/dL blood

20. Toxicity at Low and High Phenytoin  first use in 1938  considered by many to be drug of choice in epilepsy  300 – 400 mg/day oral  intravenous or intramuscular for acute seizure

21. Toxicity at Low and High Phenytoin Effective Concentration – Plasma  1 – 2 mg/dL  general guidelines  0.23 – 2.9 mg/dL  controlled study Effective Concentration – Blood  0.63 – 1.3 mg/dL  general guidelines  0.14 – 1.81 mg/dL  controlled study

22. Toxicity at Low and High Phenytoin - Toxicity Low Concentrations  Ineffective control of epilepsy  seizures, DEATH High Concentrations  Unintentional elevations may be due to inability to metabolize to p-hydroxyphenytoin (through drug interactions)  Few deaths  2 ½ yr boy – 11.2 mg/dL

23. Toxicity at Low and High Phenytoin – Toxicity  nystagamus  ataxia  slurred speech  confusion  hyperreflexia  somnelence, lethargy  blurred vision  nausea, vomiting  coma  death due to respiratory and circulatory depression

24. Toxicity at Low and High Lamotrigine  used as an anticonvulsant since 1992  often in conjunction with other anticonvulsants  maintenance dose  100 – 700 mg/day  Effective concentration  ??

25. Toxicity at Low and High Lamotrigine Therapeutic Concentrations  dependant on whether alone or with other anticonvulsants Lamotrigine doseOther drugConc. (mg/70 Kg)(mg/dL) 428None0.56 573Phenytoin0.23 491Phenobarbital0.34 364Carbamazepine0.27 197Valproic Acid0.90

26. Toxicity at Low and High Lamotrigine – Toxicity Low Concentrations  Ineffective control of epilepsy  seizures, DEATH  Difficult to determine  lack of information  often used with other anticonvulsants

27. Toxicity at Low and High Lamotrigine – Toxicity High Concentrations  skin rash  dizziness  headache  somnolence  ataxia  blurred vision  nausea, vomiting  coma  death

28. Toxicity at Low and High Lamotrigine – Toxicity  Minimal fatal concentration difficult to determine  lack of information  often used with other anticonvulsants  One reported fatality  5.2 mg/dL

29. Degradation of Sample In Vitro Bupropion Olanzapine Diltiazem Others ???

30. Degradation of Sample In Vitro Bupropion (Zyban, Wellbutrin)  used in U.S. since 1990  for treatment of depression, cessation of cigarette smoking  200 – 450 mg/day  Therapeutic Concentration  0.005 – 0.01 mg/dL  can achieve 0.04 mg/dL – no toxicity

31. Degradation of Sample In Vitro Bupropion – Toxicity  seizures  tachycardia  lethargy  confusion  tremors  vomiting  DEATH

32. Degradation of Sample In Vitro Bupropion – Toxicity  DEATH  minimal fatal concentration to date 0.4 mg/dL N = 5 (0.4 – 1.3 mg/dL)

33. Degradation of Sample In Vitro Bupropion – Interpretative Problem Bupropion breaks down in vitro – temp. & pH dependant High Concentration (> 0.4 mg/dL) - potentially fatal Low Concentration (0.03 – 0.4 mg/dL) - toxic - fatal with degradation

34. Degradation of Sample In Vitro Bupropion – Interpretative Problem Low Concentration (< 0.03 mg/dL) - therapeutic - toxic with degradation - fatal with degradation Not Detected - not present - therapeutic with degradation - toxic with degradation - fatal with degradation

35. Degradation of Sample In Vitro Olanzapine (Zyprexa)  used since 1996  anti-psychotic  10 – 20 mg/day  Therapeutic Concentration (chronic, trough)  0.0009 – 0.0026 mg/dL

36. Degradation of Sample In Vitro Olanzapine – Toxicity  drowsiness  slurred speech  ataxia  disorientation  hypotension  coma

37. Degradation of Sample In Vitro Olanzapine – Toxicity  DEATH  Minimal information available  N = 7 Overdose, survived serum conc. = 0.005 – 0.1 mg/dL  minimum fatal conc. to date  0.1 mg/dL

38. Degradation of Sample In Vitro Olanzapine – Interpretative Problem Olanzapine breaks down in vitro - undergoes oxidation 16% loss during extraction 40% loss during 1 week at 4 o C 45% loss during 1 day at RT - inhibited by addition of ascorbic acid Olesen & Linnet, 1998, J. Chrom. B714:309

39. Degradation of Sample In Vitro Olanzapine – Interpretative Problem  degradation is not consistent  by the time a sample is screened, significant degradation may have occurred

40. Degradation of Sample In Vitro Olanzapine – Interpretative Problem High Concentration (> 0.1) - potentially fatal Low Concentration (< 0.005 mg/dL) - therapeutic - toxic, degradation - fatal, degradation Not Detected - not present - therapeutic, degradation - toxic, degradation - fatal, degradation

41. High vs. Low Toxicity Barbiturates vs. Benzodiazepines Amobarbital (Amytal) vs. Diazepam (Valium) Tricyclic vs. SSRI Antidepressants Amitriptyline vs. Sertraline

42. High vs. Low Toxicity Amobarbital - 15 –200 mg oral - 65 – 500 mg i.v., i.m. - therapeutic conc. 0.18 – 1.2 mg/dL Amobarbital (Amytal) vs. Diazepam (Valium) - sedative, hypnotic Diazepam - 2 –40 mg oral - 2 – 40 mg i.v., i.m. - therapeutic conc. 0.01 – 0.15 mg/dL

43. High vs. Low Toxicity Amobarbital - tolerance - drowsiness - confusion - stupor - ataxia - coma Amobarbital vs. Diazepam - Toxicity Diazepam -tolerance - drowsiness - confusion - ataxia - muscle weakness - light coma (> 2.0 mg/dL)

44. High vs. Low ToxCicity Amobarbital - DEATH N = 55 amobarbital deaths 1.3 – 9.6 mg/dL (therapeutic < 1.2 mg/dL) Amobarbital vs. Diazepam - Toxicity Diazepam - few reported Deaths N = 67 diazepam cases N= 3, diazepam alone Mean conc. 4.8 mg/dL (therapeutic < 0.15 mg/dL)

45. High vs. Low Toxicity Amitriptyline - Tricyclic - oral, i.m., up to 150 mg - therapeutic conc. 0.004 – 0.016 mg/dL Amitriptyline (Elavil) vs. Sertraline (Zoloft) - antidepressant Sertraline - Selective-serotonin reuptake inhibitor - oral, 50 –200 mg - therapeutic conc. 0.002 – 0.03 mg/dL

46. High vs. Low Toxicity Amitriptyline - confusion, agitation - stupor, drowsiness - vomiting - cardiac dysrhythmias (0.04 mg/dL) - hypotension - convulsions - CNS depression - coma Amitriptyline vs. Sertraline Sertraline - sedation - nausea, vomiting - tachycardia - anxiety

47. High vs. Low Toxicity Amitriptyline - DEATH > 0.1 mg/dL (therapeutic < 0.02 mg/dL) Amitriptyline vs. Sertraline Sertraline -No reported Fatalities N = 5 sertraline unrelated 0.06 – 0.14 mg/dL (therapeutic < 0.03 mg/dL)

48. Age Dependant Toxicity The Very Young  Brompheniramine  Acetaminophen The Very Old  Diphenhydramine

49. Age Dependant Toxicity Brompheniramine  antihistamine  available in OTC preparations with other drugs - Dimetame; Dimetapp - Dimetapp Oral Infant Cold Drops  Therapeutic Concentrations - only adult information available - up to 0.002 mg/dL

50. Age Dependant Toxicity Brompheniramine – Toxicity  CNS depression  may cause stimulation in children  No reported fatalities in adults

51. Age Dependant Toxicity INFANTS  several cases, < 8 weeks old, male  Brompheniramine concentrations of 0.02 mg/dL  Is this fatal ??????  no other drugs detected  no anatomical cause of death  SIDS?

52. Age Dependant Toxicity Acetaminophen  analgesic, antipyretic  available in OTC preparations alone and with other drugs  Therapeutic Concentrations - Adults  0.2 – 5.2 mg/dL - Children  1.0 – 4.0 mg/dL

53. Age Dependant Toxicity Acetaminophen  Fetus and Neonate (< 2 months)  appear to metabolize acetaminophen through mixed oxidase system  reactive intermediate  at risk for liver toxicity

54. Age Dependant Toxicity Diphenhydramine  antihistamine  available in OTC preparations alone or with other drugs  oral  50 – 100 mg  also available for i.v. and i.m.  Therapeutic concentrations  up to 0.03 mg/dL

55. Age Dependant Toxicity Diphenhydramine – Toxicity Potential for toxicity is increased in those > 60 yrs  agitation  confusion  hallucination  coma  seizures  CNS depression

56. Age Dependant Toxicity Diphenhydramine – Toxicity  DEATH Minimal Fatal Concentrations Diphendydramine  0.5 mg/dL Diphenhydramine - Elderly  0.21 mg/dL

57. Drug Interactions  Metabolism Interactions - Inhibition of Enzymes - Induction of Enzymes  Serotonin Syndrome

58. Drug Interactions SEROTONIN SYNDROME  from excess serotonin - irritability- dysphoria - confusion- anxiety - delirium- hyperthermia - tachycardia- tremor - diaphoresis- hyperreflexia - shivering- muscle rigidity - tachypnea- ataxia - coma  DEATH

59. Drug Interactions SEROTONIN SYNDROME From Drug Interactions ***MAO Inhibitor + SSRI - MAO + Tricyclic Antidepressant (TCA) - MAO Inhibitor + Meperidine - MAO Inhibitor + Dextromethorphan

60. Role of Metabolites Drugs are metabolized to help increase elimination, not necessarily decrease action or toxicity.  Active Metabolites  Toxic Metabolites  Added Information  Acute vs. Chronic

61. Role of Metabolites Active Metabolites 1) Metabolite Activity = Parent Activity  Acebutolol  Diacetolol (anti-hypertensive)  Buspirone  1-pyrimidinylpiperazine (anxiolytic)  Clobazam  Desmethylclobazam (anticonvulsant; anxiolytic)  Diazepam  Nordiazepam* (anxiolytic; anticonvulsant)

62. Role of Metabolites Active Metabolites 1) Metabolite Activity = Parent Activity  Doxepin  Nordoxepin (antidepressant)  Fluoxetine  Norfluoxetine* (antidepressant)  Ketamine  Norketamine (induction agent)  Thioridazine  mesoridazine & sulforidazine (antipsychotics)

63. Role of Metabolites Active Metabolites 2) Metabolite is a drug itself  Amitriptyline  Nortriptyline* (anti-depressant)  Chlordiazepoxide  Demoxepam*; Oxazepam*; Nordiazepam *(sedative/hypnotic)  Oxazepam is a drug itself; demoxepam and nordiazepam are active metabolites  Imipramine  Desipramine *(antidepressant)

64. Role of Metabolites Active Metabolites 2) Metabolite is a drug itself  Oxycodone  Oxymorphone (potent drug itself) (narcotic analgesic)  Primidone  Phenobarbital* (minimal) (anticonvulsant)  Selegiline  Methamphetamine* (anti-Parkinson)  Temazepam  Oxazepam* (drug) (hypnotic)

65. Role of Metabolites Active Metabolites 3) Metabolite has same activity and longer half-life  Chloral Hydrate  Trichloroethanol*; major active component (sedative) - chloral hydrate transforms rapidly, not measured  Venlafaxine  O-desmethylvenlafaxine (same; longer halflife) (anitdepressant)

66. Role of Metabolites Active Metabolites 4) Metabolite has less activity but has longer half-life  Bupropion  3 metabolites; longer half-life; less activity than parent (anti-depressant)  Propoxyphene  norpropoxyphene (1/2-1/4) (narcotic analgesic)

67. Role of Metabolites Active Metabolites 5) Metabolite has less activity than parent  Amobarbital  3-Hydroxyamobarbital (1/3)(sedative, hypnotic; anticonvulsant)  Clonazepam  7-aminoclonazepam; conc. similar to parent but minimal activity (anticonvulsant; sedative)  Chlorpromazine  168 possible metabolites; 20 isolated; 2 confirmed less active (antipsychotic)

68. Role of Metabolites Active Metabolites 5) Metabolite has less activity than parent  Diltiazem  deaetyldiltiazem* (20%); nordiltiazem (45%) (anti-hypertensive)  Triazolam  Hydroxymethyltriazolam (50-100%) (hynotic)  Verapamil  Norverapamil (20%) (Anti-anginal)

69. Role of Metabolites OTHER  Codeine  Morphine* (significance of activity controversial; 10% conversion)

70. Role of Metabolites TOXIC Metabolites Meperidine (narcotic analgesic)  the metabolite Normeperidine is more toxic  has different toxicity than meperidine – seizure vs CNS depression

71. Role of Metabolites Added Information Chronic vs. Acute Ingestion Parent Concentration > Metabolite Concentration = Acute Parent Concentration = or < Metabolite Concentration = Chronic

72. Impairment Pharmaceutical Drugs Shown to Have Impairing Effects with respect to Driving Information is obtained through  Laboratory studies  Driving studies  Epidemiology

73. Impairment Challenges  Tolerance needs to be considered  Often information on dose, not plasma (blood) concentration is available  No means through law to obtain a blood sample from an individual – seized hospital samples from motor vehicle collisions

74. Impairment Drugs shown to impair motor and/or cognitive performance Benzodiazepines Barbiturates Tricyclic Antidepressants Anti-Histamines Some Anticonvulsants (Carbamazepine, Gabapentin, Phenytoin) Anti-psychotics (Chloripromazine, Haloperidol, Lithium, Thioridazine) Narcotic Analgesics

75. Post Mortem Redistribution  A phenomenon whereby increased concentrations of some drugs are observed in postmortem samples and/or site dependent differences in drug concentrations may be observed  Typically central blood samples are more prone to postmortem changes (will have greater drug concentrations than peripheral blood samples)