The Expert Witness in Forensic Pharmacology and Toxicology

The Expert Witness in Forensic Pharmacology /

Toxicology

Professor N. J. BirchAcademic Consultancy Services Ltd


Evidence


Different lenses allow the investigation of different aspects of the evidence

Using this analogy we can see that we obtain different information from a handheld lens, from a dissecting lens and from the different forms of microscopy (e.g. transmitted light, polarised light, fluorescence, electron beam, EXAFS )

Each scientific specialism has its own “lenses” and this is equally true in Forensic Toxicology and Pharmacology. The “lenses” in this case are those of the relevant basic science, toxicology and pharmacology, PLUS extra skills based on forensic training and experience

Academic Consultancy Services Ltd

Forensic Pharmacology

• Basic tenet of pharmacology:– that there is always an ordered relationship

between the concentration of a drug acting in the body and the magnitude of its effect

– There are always TWO sets of considerations:

–Pharmacodynamics–Pharmacokinetics


Pharmacological issues in criminal cases• Those in which the drug is the main issue

• Illicit drugs, possession or dealing

• Those in which drug effects are related to the offence

• Driving offences:

• Behaviour alleged to be modified by presence of drug• Intent, memory, ability to comprehend, ability to perform


• Behaviour triggered by drug:• Aggression, Confusion, Amnesia, Consent, Unconsciousness

• Alcohol by definition, Other drugs by implication



Pharmacodynamics= response of the body to the presence of a drug

• The actions of a drug at a receptor or receptors

response is proportional to drug concentration at receptor


Drug effects and toxicity


Useful dose range Increasing toxicity

Ineffective

Drugtarget blood concentration

range


Phenytoin marginal overdose

Drug response may be influenced by:


naturally occurring substances present at receptor e.g. neurotransmitters, hormones

other drugs or xenobiotics present at receptor factors affecting number, structure or function of

receptors• disease, exercise, abnormal environment, starvation,

obesity dehydration, age, sex, previous drug or dietary history

genetic variability



Pharmacokinetics movement of drug to and from the locality of the receptor

ADME controls the concentration of drug present at the receptor at any precise time

–EXCRETION

–METABOLISM

–DISTRIBUTION

ABSORPTION


Drug distribution & kinetics• For many drugs :

– Blood concentration of drug (at equilibrium) is reasonably representative of whole body

– Volume of distribution is the volume apparently occupied by the drug at the same concentration as in blood.• characteristic of each drug

– Volume of distribution x blood concn. • = body load of drug • = dose administered – loss (metabolic & excretion)



Drug distribution & kinetics

concentration vs time

exponential

Blood Lorazepam vs Time Approximation from urine analysis: minimum blood concentration compatible with

urinary detection limit of 1mg / litre.

t0.5 = 14.0 hr, Vd= 1.3 l/kg, Body weight 44.5 kg, Clearance = 1.1ml/min/kg*

-2

-1

0

1

2

3

4

5

6

-36 -24 -12 0 12 24 36 48 60 72

Time before (-) or after (+) urine sample (hours)

Pro

ject

ed B

lood

Lor

azep

am (

Cte

m)

(mg/

l)C(Lorazepam)

log C(Lorazepam)

* = pharmacokinetic data from Hardman et al (1995)

log10 concentration vs time

linear


• characteristic range of values for each drug–long-acting drugs have long half-life

Copyright 2009 N.J.Birch Academic Consultancy Services Ltd

HALF LIFE Dose at time zero = 16

t0.5= 1 hours. Residual dose vs time

0

5

10

15

0.00 1.00 2.00 3.00 4.00 5.00

Time after dose (hours)

Re

sid

ua

l do

se

= t½

Half life is the time taken for the blood concentration to decline to one-half of its present value

Fluoxetine pharmacokineticsSingle dose. Half life = 72 hours

0

1

2

3

4

5

6

7

0 2 4 6 8 10 12 14 16 18 20

Days

Bloo

d flu

oxet

ine

conc

entra

tion

(arb

itary

uni

ts)

Multiple dosesFluoxetine:

Pharmacokinetic curve, 20mg / dayOnce daily dosing (Half-life = 72Hr)

0

5

10

15

20

25

30

35

0 2 4 6 8 10 12 14 16 18 20 22

days

Blo

od

co

ncen

trati

on

(a

rbit

rary

u

nit

s)

• Equilibrium occurs between four and five Half- Lives after first dose

Effect of single 60mg dose after equilibration with 20mg once daily dose

0

5

10

15

20

25

30

35

40

45

days

blo

od

co

nce

ntr

atio

n

srb

itra

ry u

nit

s

Fluoxetine(20mg/day): effect of discontinuation for three days followed by a single 3 x dose (60mg)

0

5

10

15

20

25

30

35

16 19 22 25 28 31

days

Blo

od fl

uoxe

tine

conc

entr

atio

n (a

rbitr

ary

units

)


Fluoxetine pharmacokineticsFluoxetine Comparison of

pharmacokinetics of 20mg and 60mg daily doses

0102030405060708090

1000 3 6 9

12 15 18 21 24 27 30 33 36 39 42 45

days

bloo

d co

ncen

trat

ion

arbi

trar

y un

its

Drug doses• Three variables:

–Dose of drug(= weight of drug administered)

–Concentration in body fluids

–Volume of body fluid in which it is diluted

• If we can measure any TWO of these we can calculate the third


Volume of distribution

Total water =

8.7 l 33.6 l 42 l

Weight =

14.5 kg (3yr) 56kg (20yr) 70 kg (20yr)

Total body water is approximately 60% of lean body mass


Total Body Water• The part of the body which is NOT hard

tissues, cell membranes/structures or fat– Approximately 60% of LEAN BODY MASS

• Depends on sex, age, height, weight– Fat content is sex dependant – Fat content generally increases with age

• WATSON(1988) formula for MEN:TBW = 2.45 + (0.11 x Height) + (0.34 x Weight) - (0.095 x Age)

– Data determined from 700 subjects aged from 17 to 86 years


Psychotropic drugs and crime• Drugs may be used in the performance of criminal acts:

e.g. murder, abduction

• Drugs may be themselves the main issue of the crime: e.g. drink driving, drug dealing

• Drugs may precipitate the criminal act: e.g. psychiatric patient who commits theft whilst confused or drug interaction leading to uncharacteristic disinhibition

• Drugs may cause failure of memory: false but sincere accusations: e.g. consent in cases of rape

• Drugs may trigger aggression, violence, sexual activitye.g. issues of intent and consent

BUT


CasesBenzo

Benzo + Alc Alcohol

A/D + AlcA/Depress

0

50

100

150

200

250

300

350

Sexual/Rape

Violent

Non-Violent

Total

NJB Criminal cases 1997 - 2008


a/da/d + alc

alcoholbenzo+alc

benzo

0

10

20

30

40

50

60

70

80

violent

non-violent

sex & rape

Percentage of each class of crime associ-ated with drug alone or in combination


Alcohol

Methanol = methyl alcohol = wood spirit (in methylated spirits)Ethanol = ethyl alcohol = beverages, surgical spirit (mild antiseptic) Propanol= propyl alcohol = industrial cleaning agent (e.g. printing)Butanol= butyl alcohol = industrial solvent


1 unit = 10 ml abs alcohol;

= 3 or 4 times pub measures

Beer 4%Wine 12%Spirits 37.5%


= 8 grams EtOH

Ethanol content of some domestic & medicinal products

% alcohol

Window cleaning products 10

Paint stripper 25

Hair tonics 25 – 65

Liquid hand washing detergents 1 - 10

Cough / cold medicines 3 - 25

Homeopathic / herbal medicines Variable but significant

Mouthwashes 14 - 27

Colognes & perfumes 40 - 60


Alcohol pharmacokinetics

•Distributed in Total Body Water (TBW)•Concentration in TBW depends on dose •Rate of metabolism is effectively constant (except below 20 mg %)

•Rate of excretion in urine, breath and sweat is relatively insignificant but proportional to blood alcohol

Absorption of alcohol in the gastrointestinal tract of man

Comparison of the time course of blood alcohol concentration following approximately 60 grams of alcohol (6 single measures of whisky, USA) taken with and without food. Based on data from Widmark (1981) 1

Widmark EMP. Principles and applications of medicolegal alcohol determination. Davis, California, USA: Biomedical Publications,

1981;


Volume of distribution

Total water(litres) =

8.7 33.6 42

Weight =

14.5 kg (3yr) 56kg (20yr) 70 kg (20yr)

Total body water is approximately 60% of lean body mass


Alcohol metabolism• Alcohol metabolism occurs at approximately constant rate

– the rate is related to body size– the rate is increased by previous exposure to alcohol

• Two means of calculating– Rate of reduction of blood alcohol (used by Forensic Science

Laboratory)

Low = 10 “Average” = 18 High = 25

mg alcohol / 100 ml blood / hour– Chronic alcoholics can reach or even exceed 30 mg % / hr

– Rate of removal of alcohol from body• 120 mg alcohol/ kg body weight /hour = 8.5 gm /hr (70 kg man) approx

10ml /hrCopyright 2012 N.J.Birch

-30 -25 -20 -15 -10 -5 00

100

200

300

400

500

600

700

800

Backtracking blood alcohol from sampleRates of metabolism:

Low = 10, Average = 18, High = 25 , Alcoholic = 30 (mg alcohol / 100 ml blood / hr)

Time (hr)

Blo

od

alc

oh

ol

(mg

/ 1

00

ml

blo

od

)


Alcohol in Breath & Urine

• Indirect measures• Blood alcohol is what is relevant to

behaviour and impairment of driving• Legal Limit for driving (UK)

– Blood 80 mg / 100 ml BLOOD– Breath 35 micrograms (g) / 100 ml BREATH– Urine 107 mg / 100 ml URINE


Alcohol


Early pharmacological

observations

• Macbeth Act 2 Scene 3• Enter MACDUFF and LENNOX.

• Macduff. Was it so late, friend, ere you went to bed, that you do lie so late?

• Porter. Faith, sir, we were carousing till the second cock: and drink, sir, is a great provoker of three things.

• Macduff. What three things does drink especially provoke?

• Porter. Marry, sir, nose-painting, sleep, and urine. Lechery, sir, it provokes and it unprovokes; it provokes the desire, but it takes away the performance:


Effects of alcohol variable

Depends on:

• Body size, body fat, sex, age • Rate of metabolism• Previous alcohol intake

history• Presence of other drugsCopyright 2012 N.J.Birch

Blood alcohol concentration

mg /100 ml blood

Stage of alcoholic influence Clinical signs / symptoms

10 - 50 subclinical Behaviour nearly normal by ordinary observationSlight changes detectable by special tests

20 - 120 euphoria Mild euphoria, sociability, talkativeness.Increased self-confidence; decreased inhibitionsDiminution of attention, judgment, controlBeginning sensory and motor impairmentSlowed information processing

90 – 250 excitement Emotional instability; loss of critical judgmentImpairment of perception, memory and comprehensionDecreased sensory response; increased reaction timeReduced visual acuity, peripheral vision, glare recoverySensorimotor incoordination; impaired balance

180 - 300 confusion Disorientation, mental confusion; dizzinessExaggerated emotional states (fear, rage, sorrow etc)Disturbances of vision (diplopia etc) and of perception of colour, form, motion, dimensionsIncreased pain threshold Increased muscular incoordination; staggering gait; slurred speechApathy, lethargy


250 - 400 stupor General inertia; approaching loss of motor functionsMarkedly decreased response to stimuliMarked muscle incoordination; inability to stand / walk;Vomiting; incontinence of urine/faecesImpaired consciousness; sleep or stupor

350 - 500 coma Complete unconsciousness: coma ; anaesthesiaDepressed or abolished reflexesSubnormal temperatureIncontinence of urine and faecesImpairment of circulation and respiration Possible death

450 + death Death from respiratory arrest

Blood alcohol concentration

mg /100ml blood

Stage of alcoholic influence Clinical signs / symptoms



Alcohol is a depressant drug: it inhibits a range of processes including those which INHIBIT antisocial behaviour. These processes are learned through childhood to provide a basis for normal social living.Alcohol is therefore DISINHIBITORY


Removal of successive layers of inhibitions leading to exposure of basic and instinctual behaviours

Loss of social controls, disinhibition


a/da/d + alc

alcoholbenzo+alc

benzo

0

10

20

30

40

50

60

70

80

violent

non-violent

sex & rape

Percentage of each class of crime associ-ated with drug alone or in combination


Disinhibition


Removal of successive layers of inhibitions leading to exposure of basic and instinctual behaviours

Loss of social controls, disinhibition


DisinhibitionLechery, sir, it provokes and it unprovokes; it provokes the desire, but it takes away the performance:


The Great ProvokerLecherySexual behaviour in both female and male affected by alcohol (and other

sedating drugs)

Main effect is DISINHIBITION. Alcohol inhibits the inhibitory controls of socially and sexually acceptable behaviour learned during childhood.

ProvokesSexually explicit, provocative or “inappropriate”, uncharacteristic?, disinhibited behaviour. Potentially more violent, loss of coordination, emotional extremes, increased pain threshold, anterograde amnesia

UnprovokesSexual performance in both male and female is compromised. Penile / vaginal pressures, lack of secretions, delayed or inhibited ejaculation. Sedative effects. Vomiting, dizziness.


Benzodiazepines•Diazepam (Valium®)•Temazepam• Nitrazepam (Mogadon®)• Flunitrazepam (Rohypnol®)• Midazolam• (zopiclone)

“Minor tranquilizers”


CasesBenzo

Benzo + Alc Alcohol

A/D + AlcA/Depress

0

50

100

150

200

250

300

350

Sexual/Rape

Violent

Non-Violent

Total

NJB Criminal cases 1997 - 2008


Benzodiazepines:• Act on Ascending Reticular Formation

(ARF) of the midbrain• ARF controls level of sensory input

– ↑= greater level of awareness (e.g. anxiety)

– ↓ = diminished level of awareness (e.g sedation)

• Also effects on memory mechanisms


MemoryAlcohol & drug induced

MEMORY BLACKOUTS


Drugs and Memory• Memory has four main divisions

– Acquisition– Working memory– Consolidation– Recall


Failure leads to ANTEROGRADE amnesia

Failure leads to RETROGRADE amnesia

Sensory Register< 2 sec

Short Term Memorysecs - hours

limited capacity

Long Term Memoryhours - decades

'unlimited' capacity

Decay of information

Not saved

Not rehearsed

RECALL

Drugs & Alcohol

Trauma

Fading recollection

MoodDistractions

AttentivenessVigilance

RehearsalConscious or Unconscious

Rehearsal


Benzodiazepine induced anterograde amnesia

• 22 yr old man, breaks up with girlfriend & attempts suicide• Parks car in entrance to farm & takes 20 + diazepam• Recovers several hours later, starts car, drives down road

erratically, misjudges next sharp bend and hits tree• Rescued by passing policemen and explains that he did not

deliberately drive into tree though knew he had taken O/D previously

• Ambulance to A & E• After a little wait becomes aggressive and denies that he has

been in car crash but remembers O/D• Had to be taken to scrap yard to see written off car before

convinced


Diazepam overdose

Partial Recovery, Sets off in car

Collision with tree

A& E department Aggression, Anterograde amnesia

Anterograde amnesia

4 hours 5 mins 2 hours

Dia

zep

amMemory of overdose & suicide intent consolidated when Valium concentration low

Short term

memory

Memory of RTA not retained long-term

Memory of O/D & intent in long-term memory

Anterograde amnesia

Can still access the memory

Diazepam inhibits consolidation of

short-term memory


Anterograde amnesia• Short term memory active at time but NO

LONG TERM MEMORY retained• Resulting absence of memory trace in long-term

historical record• May lead to CONFABULATION• Information consolidated from trusted internal /

external sources:– e.g. first account of friends or police, rationalisation

using existing prejudices, dreams and hallucinations.


Pharmacological issues in rape cases

Did it happen?

Did she consent?

Was she able to consent?

Could he reasonably believe

that she did consent?

sleepconsciousness

memory dreams

previous behaviour

Prejudices & previous experiences

External sources of

information

Drugs &

alcohol

confabulation

Anterograde amnesia


• ALCOHOL• Anaesthetics:

– Ketamine, gamma hydroxybutyrate

• Benzodiazepines: – Diazepam, temazepam, flunitrazepam

• Antidepressants– Amitriptyline, Dothiepin, Trimipramine, Trazodone

• Antipsychotics– Chlorpromazine, Thioridazine

• Antihistamines– Diphenhydramine, Brompheniramine, Chlorpheniramine

Drug Facilitated Sexual Assault (DFSA) _ DATE RAPE


Aggression• Paradoxical, disinhibitory effects of

benzodiazepines

• Similar effects seen with alcohol

• Combination of benzodiazepines and alcohol exceptionally dangerous


Paradoxical effects of Benzodiazepines

• Identified in British National Formulary and other prescribing guides

• Potential not usually recognised by General Practitioners or General Psychiatrists

• Violence often very extreme and apparently entirely unprovoked

• Particularly exacerbated by presence of alcohol


alcoholbenzo+alc

benzo

0

10

20

30

40

50

60

70

80

violent

non-violent

sex & rape

% of each class of crime involving alco-hol and benzo-diazepines alone and in combination


• If both benzodiazepines and alcohol are present you should assume that aggression and inexplicable violence may be more pronounced than might be expected following a relatively low level of provocation


SleepMarry, sir, nose-painting, sleep, and urine.


Hypnogram of a typical night’s sleep



ParasomniasWhat you perceive is not necessarily a true

record of what is happening

Confusional Arousal



Murder & Manslaughter


Post mortem redistribution of drugs

• Post mortem drug analyses should always be interpreted with caution.

• Major redistribution of drugs may occur• Blood in cadaver is not the same as living

blood• Believed to have been source of

miscarriages of justice• Main value is in establishing presence or

absence of drugs and whether large or small quantity present.


Urine & Blood alcohol in samples taken at post mortem

Subject to other observations: • If (corrected) urine alcohol is higher than blood alcohol:

DEATH occurred after peak of blood alcohol (ELIMINATION PHASE)

• If blood alcohol is higher than (corrected) urine alcohol:

DEATH occurred in ABSORPTIVE PHASE (i.e. within 30 -90 minutes of last alcohol)



Lawyers, including Judges, are not usually scientists though some are!

It is usually important to simplify your evidence without losing the fundamental truth

Similarly, juries may or may not have scientists or medical people in the group and it is a good tactic to find some analogy to explain your evidence or to use something as an example which is likely to be common knowledge.

Do not underestimate the ability of barristers to find any fundamental flaw in your evidence whether or not it is really significant in determining the truth or not. Once an error has been exposed it is likely to be highlighted repeatedly as a means of undermining everything else.

• Science becomes dangerous only when it imagines that it has reached its goal

George Bernard Shaw• It is the business of science to be wrong

Robert Oppenheimer


The Expert Witness in Forensic Pharmacology and Toxicology

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