Case Studies In Forensic

Toxicology – Lessons for Living

in Today’s Toxic World

George B. Kudolo, PhD, FAIC, FACB

Distinguished Teaching Professor

Department of Clinical Laboratory Sciences

University of Texas HSC @ San Antonio

Objectives

Using case studies:

Describe selected sudden death fatalities in

children and adults associated with common

antidepressant and antipsychotic drugs

Discuss the dangers of direct-to-consumer

advertising, polypharmacy and prescription

cascade

Discuss how individual genetic variability may alter

the safety of frequently prescribed medications

BACKGROUND

Our Toxic World

Over 250,000 therapeutic & household

products

$10 billion on over-the-counter drugs

$11 billion spent on prescribed drugs

25-50% of patients make errors in self-

administration of properly prescribed

drugs

30% of “reliable patients” take <70% of prescribed medications

>22 drugs are found in the average U.S.

household

Forensic Toxicology

The application of chemical analytical procedures:

to isolate,

identify, and

determine the quantities of toxic materials

..in biological samples

Evaluate how the toxic substances could have produced toxicity or death

Results must be defensible in court

The Forensic Toxicologist

Cause of Death

The disease or injury

responsible for the death

Examples:

Diabetes

Stroke

Drowning

Fire

Gunshot wound

Drug

intoxication

Manner of Death

Explains how the cause

arose and the events

surrounding the death

Examples:

• Natural

• Accident

• Suicide

• Homicide

• Undetermined

Assist the Medical Examiner establish the Cause of Death & the Manner of Death

Pharmacokinetics (What the body does to the drug)

Pharmacodynamics (What the drug does to the body)

Metabolism/Enzymes Transport systems

Therapeutic Efficacy &

Adverse Reactions

Genetics

Drugs

Hormones

Diet

The Fate of Drugs

Fatal

Outcomes

Effect of Pharmacokinetics on

Drug Disposal

Water-soluble drugs: easy transportation

Lipid-soluble drugs: Easy cell entry

Vd: hypothetical volume in which the drug is dissolved

Vd =D/Cp (Vd in L/kg, D in mg/kg, in Cp mg/L)

Lipid-soluble drugs have large Vd

Effect of Metabolism on Drug Disposal

HEPATIC FIRST-PASS EFFECT

Phase I reactions - majority = Cyp450 enzymes Hydroxylation etc.

Drug “inactivated” but many may remain potent

E.g. Imipramine Desipramine

Phase II reactions - addition of functional groups to make water-soluble Glucuronic acid, sulfate, Glutathione

Genetics

HUMAN DRUG OXIDATION

More than 90% of human drug metabolism

is due to 6 CYP isoenzymes:

CYP1A2

CYP2C9

CYP2C19

CYP2D6

CYP2E1

CYP3A4

Antidepressants &

Antipsychotics

CYP2D6 Polymorphism in the Population

CYP450 Isoenzyme

deficiency

CYP2C19 CYP2D6

Caucasian PMs 3-5% 7-10%

Asian PMs 18-20% 1-3%

Important Pharmacokinetic

Parameters

Therapeutic

Range

TIME (hours)

MTC

Steady State MEC D

rug

co

nc

en

tra

tio

n

Terms:

t½

Cmax

Tmax

Peak

Trough

Clinical relevance of Drug Metabolizing

Enzyme Polymorphism - UM

Mutation - duplication or multiplication of functional gene

CYP2D6 Function - Enhanced drug metabolism - ultra rapid metabolizer (UM)

Clinical Effect - Ineffective therapy

Clinician response

Prescribe mega doses

Prescribe additional drugs (of CYP2D6 substrates) or

Avoid drugs that are substrates for CYP2D6

Clinical relevance of Drug Metabolizing

Enzyme Polymorphism - PM

Mutation - defective enzymes or complete deletions

CYP2D6 Function -Reduced or complete absence - Poor metabolizer (PM)

Clinical Effect - Toxicity & adverse drug effect

Clinician response

Reduce dose

Change medication (avoid substrates of CYP2D6)

Clinical Relevance of Drug

Metabolizing Enzyme Polymorphism -

EM

Mutation - homozygous or heterogygous wild type

CYP2D6 Function - normal to extensive metabolizer (EM)

Clinical Effect - desired concn. range & efficient therapy

Consequences “Don’t worry, be happy”

Clinical Relevance of Drug –Induced

Inhibition of CYP Enzymes In The EM

Mutation - homozygous or heterogygous wild type

CYP2D6 Function – Inhibited, converted to “Poor Metabolizer”

Clinical Effect – Increased drug concn. Range

Consequences Toxic reactions & Adverse

events appear

Acute Alcohol ingestion

Cimetidine

Danazol

Fluoxetine

Verapimil

Clinical Relevance of Drug-Induced

Induction of CYP Enzymes In The EM

Mutation - homozygous or heterozygous wild type

CYP2D6 Function - normal to extensive metabolizer (EM)

Clinical Effect – Therapeutic failure

Clinician response Prescribe mega doses of same

drug

Prescribe additional drugs

Prescribe completely different drugs

Barbiturates

Chronic alcohol use

Cigarette smoking

Glutethimide

Phenytoin

Primidone

Depression - No.1 psychological disorder in the western world

Found in all age groups, in every community

Will be 2nd most disabling condition in the world by 2020

Most Prescribed Drugs in The United

States

Prevalence of Overmedication in ED Visits*

Drug Percentage

Psychotherapeutic agents 52

Antidepressants 18

Antipsychotics 8.4

Anxiolytics, sedatives, hypnotics 33

Benzodiazepianes 25

CNS agents 52

Analgesics 42

Opiates/opioids 20

Nonsteroidal anti-inflammatory agents 7.5

Salicylates/combinations 5

Miscellaneous analgesics/combinations 15

Anticonvulsants 6.2

Muscle relaxants 7.6

*Drug Abuse Warning Network, Rockville, MD

Poisoning Deaths Involving

Opioid Analgesics

CDC/NCHS, National Vital Statistics System

Case 1

54 W/F, apparent natural.

Became dizzy at home and collapsed. Family called EMS.

Taken to ER-code 3. No trauma, no foul play.

Was admitted to ER at 1530 with FULL ARREST - was treated until expiration.

Seen previously at YY and ZZ Hospitals.

NOK refused tissue/organ donation - but first blood collected.

Toxicology Results

Desipramine Therapeutic range: 0.2-0.6 mg/L

Fatal levels: 6.0-15.0 mg/L

Drug Femoral Blood Drug

Concentration (mg/L)

Fluoxetine 0.41

Norfluoxetine 0.24

Trazodone 0.58

Desipramine 10.90

COD: Cardiomyopathy?

PRESCRIPTION RECORD

Date/Dr. Drug prescribed #Rx/#Left

Dec 11, Dr. X Desipramine, 50 mg 4/day 124/36

Trazadone 50 mg 3/day 100/44

Dec 24, Dr. Y Desipramine, 150 mg bedtime 30/19

Trazadone, 50 mg 3/day 90/82

Levothyroxine, 0.15mg 30/18

Fluoxetine, 20 mg/day 30/19

Jan 5 Collapse and sudden death

So, What Happened?

COD Desipramine OD

MOD Accidental

Mechanism:

Fluoxetine = inhibition of

CYP 2D6 & CYP 3A3/3A4

Rx desipramine

exceeded

recommended daily dose

(300 mg)

Desipramine PK properties

(e.g. Vd) increases resident

time

Case 2 - Sudden Death in a Child

7 year-old boy

Collapsed about 5 min

after walking home from

school

EMS arrived at the scene

within minutes but could

not revive the boy

Was transported to the ER

in cardiac arrest

Case 2

BACKGROUND

Boy was 1st grader under state custody for 4 years.

Had been living with current foster parents for 10 months.

Was diagnosed with behavioral problems:

“Adjustment disorder with mixed disturbance of emotions and conduct”

Articulation disorder

Severe stress

MEDICAL HISTORY

Was put on IMIPRAMINE (25 mg/d) about 7 months prior to death (ptd).

Dose 50 mg/d at 5 months ptd.

Dose 125 mg/d (a week later 150 mg/d) at 3.5 months ptd.

THIORIDAZINE (50 mg/d) added 2 months ptd.

THIORIDAZINE 75 mg/d 19 d ptd.

CASE 2: Toxicology Results

Desipramine TW: 0.2-0.6 mg/L

Fatal levels: >6.0 mg/L

Cause of Death Imipramine/desipramine OD

Manner of Death Accidental

Mechanism?

Sample Imipramine Desipramine

R. Femoral blood 1.2 mg/L 9.9 mg/L

L. Femoral blood 0.5 mg/L 6.7 mg/L

Aorta blood 1.0 mg/L 8.7 mg/L

Liver 68 mg/kg 400 mg/kg

CYP2D6 - hepatic imipramine & desipramine

metabolism

THIORIDAZINE is an inhibitor of CYP2D6 (50 mg/day

adults)

Boy 75 mg/day !

CONCLUSION:

Increased desipramine levels from thioridazine-

induced desipramine metabolism

Mechanism of

Death

Case 3

39 W/F found dead in vacant lot.

Upon paramedic arrival she was in full rigor.

DEC was found lying on her back on the ground

in the direct sun light, temp 80°F.

Numerous syringes/needles, drug paraphernalia,

and two methadone bottles (not the DEC’s name on them).

No obvious signs of trauma or needle marks

observed.

DEC had history of drug use and prostitution.

Case 3: Toxicology Results

Alkaline Drugs

Blood (GC) Blood (GC;GC/MS) Urine (GC;GC/MS)

0.25 mg/l

Thioridazine

0.32 mg/l

Mesoridazine

0.96 mg/l Doxepin

0.17 mg/l

Desmethyldoxepin

0.38 mg/l

Propoxyphene

+Norpropoxyphene

0.20 mg/l Methadone

+Methadone-M

+Cocaine

+Verapamil

+Diazepam

+Nordiazepam

+Doxepin

+Desmethyldoxepin

+Propoxyphene

+Norpropoxyphene

+Thioridazine

+Mesoridazine

+Methadone

+Methadone-M

+Cocaine

+Verapamil

+Norverapamil

Case 3: Toxicology Results, contd

Acid Neutral Drug screen:

Cocaine

Blood (GC;GC/MS) Urine (FPIA) Urine (GC;GC/MS)

+Salicylic acid

+Phenytoin

+Phenytoin

(unconfirmed)

Salicylic acid

(confirmed)

Blood (GC/MS) Urine (FPIA) Urine (GC/MS)

0.19 mg/l Cocaine

1.8 mg/l Benzoylecgonine

+Benzolecgonine

+Cocaine

+Benzoylecgonine

+Ecgnine methyl ester

Heroin & Codeine Metabolism

HEROIN

(Diacetylmorphine)

6-Monoacetylmorphine

(6-MAM) MORPHINE CODEINE

Blood (GC/MS) Urine

(FPIA)

Urine (GC/MS)

0.05 mg/l

Morphine

+ Opiate + Morphine

+ Codeine

+ Monoacetylmorphine

CYP P450 Enzymes Involved

Cytochrome P450

substrates inhibitors

CYP 3A4

METHADONE

COCAINE

DIAZEPAM

VERAPAMIL

CYP 2D6

MORPHINE

THIORIDAZINE

DOXEPIN

THIORIDAZINE

COCAINE

CYP 2C9

PHENYTOIN

DIAZEPAM

SALICYLATES

PRESCRIPTION CASCADE

Definition: Prescription of additional medications to

manage side effects created by other medications

Thioridazine seizures phenytoin insomnia

diazepam headache + depression

propoxyphene + doxepin

Methadone cardiac arrhythmia verapamil

Cocaine hypertension verapamil

Verapamil potent inhibitor of diazepam & cocaine

So, What Happened?

Cause of Death: Mixed

Drug Intoxication

Mechanism of Death:

Accidental

Mechanism:

Enhanced CNS depression

from several drugs

Case 4:

68 y/o W/F

Hx: vertigo, COPD, anemia.

Doc: No hx of depression

Last seen Dec 22 at 02:00 AM

Found unresponsive in bed at 10:00 AM

PCP said he would sign the DC listing AMI as COD, to be

transported to FH

Staff found empty bottle for hydrocodone - Rx filled Dec

21 for 30 pills

Acid/neutral drug Screen

Acetaminophen - 16.58 mg/L

Alcohols (GC) – ND

ALKALINE DRUG SCREEN

0.16 mg/L Hydrocodone

0.44 mg/L Amitriptyline

0.21 mg/L Nortriptyline

0.05 mg/L Promethazine

0.82 mg/L Tramadol

+ Diphenhydramine

+ Meclizine

+ dihydrocodeine

+ Desalkylflurazepam

Case 4: Toxicology Results

Femoral Blood (GC; GC/MS)

Toxicology Results

Flurazepam (Dalmane)

A benzodiazopine - relief of insomnia

Anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant

Variable half-life (40-250h)

Meclizine

Antihistamine,

antiemetic

Short-term treatment

of insomnia

So, What Happened?

Cause of Death: Mixed Drug

Intoxication

Manner of Death: Accidental

Mechanism:

Enhanced CNS depression

from several sedative hypnotic

drugs, including promethazine

Promethazine

Antiemetic, antihistamine and CNS depressant

May be combined with codeine or diphenhydramine

Metabolized by CYP2D6

Has strong anticholinergic and sedative/hypnotic effects

Therapeutic range - 0.011 - 0.023 mg/L Side effects: dizziness, fatigue, breathing, confusion,

sedation

Adverse effects begin at 0.048 mg/L

Recreational use – “purple drank” or “sizzurp”

Summary

Even properly prescribed medications may lead to

fatal consequences because of:

Miscommunication between doc-patient = drugs

Combined/additive actions on CNS depression –

without any one drug > fatal levels

Patient use of illicit drugs & drugs borrowed from friends

QUESTIONS?