FSC402H Forensic Toxicology of Common Pharmaceuticals November 11, 2003

FSC402HForensic Toxicology of Common Pharmaceuticals

November 11, 2003

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

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

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

Delayed Toxicity

Glucuronide Acetaminophen Sulfate

Reactive Intermediate

Glutathione Conjugate

Delayed Toxicity

Acetaminophen Toxicity – Overdose

Glutathione becomes depleted

Reactive Intermediate builds up

Reversible damage to hepatocytes

Delayed Toxicity

Rumack-Matthew Nomogram

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

Delayed Toxicity

RUMACK – MATTHEWNOMOGRAM 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 T1/2 > 4 hours - likelihood of hepatic injury

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


Phase 3: 72-96 hours hepatic necrosis with abdominal pain hepatic encephalopathy jaundice nausea & vomiting renal failure DEATH

Phase 4: 4d – 3wks complete resolution

Delayed Toxicity


hepatotoxicity – 24-48 hours

peak hepatotoxicity – 72-96 hours

death – 4-18 days

Minimal Fatal Conc.: ??9 – 32 mg/dL

Delayed Toxicity

AcetylSalicylic Acid

Aspirin + + +

also found combined with great # of combined products

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)

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

Delayed Toxicity

Done Nomogram

(Adapted from Done, AK Pediatrics, 1978, 62:890)

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

Toxicity at Low and High

Anti-Convulsants

TOO LITTLE is as bad as TOO MUCH

Phenobarbital

Phenytoin

Primidone

Valproic Acid

Gabapentin

Vigabatrin

Carbamazepine

Lamotrigine


Phenobarbital used as an anticonvulsant since 1912

for epilepsy 60 – 120 mg/day

often given in combination with other anticonvulsants


Phenobarbital

Effective Concentration – Plasma 1 – 3 mg/dL

Effective Concentration – Blood 0.8 – 2.4 mg/dL


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


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


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


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

Toxicity at Low and HighPhenytoin – Toxicity

nystagamus ataxia slurred speech confusion hyperreflexia somnelence, lethargy blurred vision nausea, vomiting coma death due to respiratory and circulatory depression


Lamotrigine used as an anticonvulsant since 1992

often in conjunction with other anticonvulsants

maintenance dose 100 – 700 mg/day

Effective concentration ??


LamotrigineTherapeutic Concentrations dependant on whether alone or with other anticonvulsants

Lamotrigine dose Other drug Conc.(mg/70 Kg) (mg/dL) 428 None 0.56 573 Phenytoin 0.23 491 Phenobarbital 0.34 364 Carbamazepine 0.27 197 Valproic Acid 0.90


Lamotrigine – Toxicity

Low Concentrations

Ineffective control of epilepsy seizures, DEATH Difficult to determine

lack of information often used with other anticonvulsants



High Concentrations skin rash dizziness headache somnolence ataxia blurred vision nausea, vomiting coma death



Minimal fatal concentration difficult to determine lack of information often used with other anticonvulsants

One reported fatality 5.2 mg/dL

Degradation of Sample In Vitro

Bupropion

Olanzapine

Diltiazem

Others ???


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


Bupropion – Toxicity seizures

tachycardia

lethargy

confusion

tremors

vomiting

DEATH


Bupropion – Toxicity DEATH

minimal fatal concentration to date

0.4 mg/dL

N = 5 (0.4 – 1.3 mg/dL)


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


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


Olanzapine (Zyprexa) used since 1996

anti-psychotic

10 – 20 mg/day

Therapeutic Concentration (chronic, trough)

0.0009 – 0.0026 mg/dL


Olanzapine – Toxicity drowsiness

slurred speech

ataxia

disorientation

hypotension

coma


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


Olanzapine – Interpretative Problem

Olanzapine breaks down in vitro

- undergoes oxidation

16% loss during extraction40% loss during 1 week at 4oC45% loss during 1 day at RT- inhibited by addition of ascorbic acid

Olesen & Linnet, 1998, J. Chrom. B714:309


Olanzapine – Interpretative Problem

degradation is not consistent

by the time a sample is screened, significant degradation may have occurred


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

High vs. Low Toxicity

Barbiturates vs. Benzodiazepines

Amobarbital (Amytal) vs. Diazepam (Valium)

Tricyclic vs. SSRI Antidepressants

Amitriptyline vs. Sertraline


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.



Amobarbital

- tolerance

- drowsiness- confusion- stupor- ataxia- coma

Amobarbital vs. Diazepam - Toxicity

Diazepam

-tolerance

- drowsiness- confusion- ataxia- muscle weakness- light coma (> 2.0 mg/dL)

High vs. Low ToxCicity

Amobarbital

- DEATH

N = 55 amobarbital deaths1.3 – 9.6 mg/dL(therapeutic < 1.2 mg/dL)

Amobarbital vs. Diazepam - Toxicity

Diazepam

- few reported Deaths

N = 67 diazepam casesN= 3, diazepam aloneMean conc. 4.8 mg/dL(therapeutic < 0.15 mg/dL)


Amitriptyline- Tricyclic

- oral, i.m., up to 150 mg


Amitriptyline (Elavil) vs. Sertraline (Zoloft)

- antidepressant

Sertraline- Selective-serotonin reuptake inhibitor

- oral, 50 –200 mg



Amitriptyline- confusion, agitation- stupor, drowsiness- vomiting- cardiac dysrhythmias

(0.04 mg/dL)- hypotension- convulsions- CNS depression- coma


Sertraline- sedation

- nausea, vomiting

- tachycardia

- anxiety


Amitriptyline

- DEATH

> 0.1 mg/dL (therapeutic < 0.02 mg/dL)


Sertraline

-No reported Fatalities

N = 5 sertraline unrelated0.06 – 0.14 mg/dL(therapeutic < 0.03 mg/dL)

Age Dependant Toxicity

The Very Young

Brompheniramine

Acetaminophen

The Very Old

Diphenhydramine


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


Brompheniramine – Toxicity

CNS depression

may cause stimulation in children

No reported fatalities in adults


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?


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


Acetaminophen

Fetus and Neonate (< 2 months)

appear to metabolize acetaminophen through mixed oxidase system reactive intermediate

at risk for liver 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


Diphenhydramine – Toxicity

Potential for toxicity is increased in those > 60 yrs

agitation

confusion

hallucination

coma

seizures

CNS depression


Diphenhydramine – Toxicity

DEATH

Minimal Fatal Concentrations

Diphendydramine 0.5 mg/dL

Diphenhydramine - Elderly 0.21 mg/dL

Drug Interactions

Metabolism Interactions

- Inhibition of Enzymes

- Induction of Enzymes

Serotonin Syndrome

Drug Interactions

SEROTONIN SYNDROME from excess serotonin

- irritability - dysphoria- confusion - anxiety

- delirium - hyperthermia- tachycardia - tremor- diaphoresis - hyperreflexia- shivering - muscle rigidity- tachypnea - ataxia- coma

DEATH

Drug Interactions

SEROTONIN SYNDROMEFrom Drug Interactions

***MAO Inhibitor + SSRI

- MAO + Tricyclic Antidepressant (TCA)

- MAO Inhibitor + Meperidine

- MAO Inhibitor + Dextromethorphan

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

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)

Role of Metabolites

Active Metabolites

1) Metabolite Activity = Parent Activity

Doxepin Nordoxepin (antidepressant)

Fluoxetine Norfluoxetine* (antidepressant)

Ketamine Norketamine (induction agent)

Thioridazine mesoridazine & sulforidazine (antipsychotics)

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)

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)

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)

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)

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)

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)

Role of Metabolites

OTHER

Codeine Morphine* (significance of activity controversial; 10% conversion)

Role of Metabolites

TOXIC Metabolites

Meperidine (narcotic analgesic)

the metabolite Normeperidine is more toxic

has different toxicity than meperidine

– seizure vs CNS depression

Role of Metabolites

Added Information

Chronic vs. Acute Ingestion

Parent Concentration > Metabolite Concentration

= Acute

Parent Concentration = or < Metabolite Concentration

= Chronic

Impairment

Pharmaceutical Drugs Shown to Have Impairing Effects with respect to Driving

Information is obtained through

Laboratory studies

Driving studies

Epidemiology

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

Impairment

Drugs shown to impair motor and/or cognitive performance

BenzodiazepinesBarbituratesTricyclic AntidepressantsAnti-HistaminesSome Anticonvulsants (Carbamazepine, Gabapentin, Phenytoin)Anti-psychotics (Chloripromazine, Haloperidol, Lithium, Thioridazine)Narcotic Analgesics

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)

Documents

FSC402H Forensic Toxicology of Common Pharmaceuticals November 11, 2003