cpd lecture forensic pharmacology

Forensic Pharmacology:the relevance of medicines and drugs to some criminal cases

Professor Nicholas J. Birch Academic Consultancy Services Ltd

How can the pharmacologist help the legal team to maximize the value of the evidence?

Professor Nicholas J.Birch Academic Consultancy Services Ltd

Forensic Pharmacology

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

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

Effects of alcohol on behaviour

Forensic Pharmacology

– There are always TWO sets of considerations:


–Pharmacodynamics

–Pharmacokinetics


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

• The actions of a drug at a receptor or receptors

response proportional to drug concentration at receptor

Drug effects and toxicity


Useful dose range Increasing toxicity

Ineffective

Phenytoin target blood concentration

range

Drug response may be influenced by:


naturally occurring substances present at receptore.g. neurotransmitters, hormones

other drugs or xenobiotics present at receptorfactors affecting number, structure or function of receptors

•disease, exercise, abnormal environment, starvation, obesity dehydration, age, sex, previous drug or dietary history

genetic variability


Drug Dosage Regimen

• Objective: To prescribe a dose, the size and timing of which will provide the maximal THERAPEUTIC effect at the minimal cost in ADVERSE effects

•Assumes: Orderly relationship between Dose Rate and both Therapeutic and Toxic effects•Boundaries: Ineffective¦ Effective ¦ Toxic

Phenytoin dosage


Size does matter• Dose depends on

– Body size

– Age dependent factors

– Gender dependent factors

– Current physiological state

Volume of distribution

Total water =

8.7 l 33.6 l 42 l

Weight =

14.5 kg (3yr) 56kg 70 kg

Total body water is approximately 60% of lean body mass


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

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


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

Multiple dosesFluoxetine pharmacokinetics

Single 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

Blo

od

flu

ox

eti

ne

c

on

ce

ntr

ati

on

(a

rbit

ary

un

its

)

Fluoxetine: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 c

once

ntra

tion

(arb

itrar

y u

nits

)

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

Phenytoin marginal overdose

Fluoxetine pharmacokinetics

Pharmacokinetic curve, Once daily dosing (Half-life = 72Hr)

0

5

10

15

20

25

30

35

days

Blo

od

co

ncen

tratio

n

(arb

itra

ry u

nits)

Effects of additional dose?

Effect of triple dose after equilibration to single dose (Once daily dosing, half life = 72hr)

0

5

10

15

20

25

30

35

40

45

days

Blo

od

co

nce

ntr

atio

nar

bit

rary

un

its


Drug kineticsMurder + Attempted Murder in which it was alleged that the victims had been drugged prior to lethal assault with machete

Blood Temazepam vs Time (Victim A)

(based on t0.5 = 11.0 hr)

-2

-1

0

1

2

3

4

5

6

-36 -24 -12 0 12 24 36 48

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

Estd. B

lood T

emaze

pam (C

tem) (mg

/l)

Ctem

log Ctem

Total Body Temazepam (mg) Victim A

based on one blood determination (KAH2)

0

80

0 12 24 3629th Sept Time 30th Sept

Total

Body

Tema

zepam

(mg)

Blood sampleRecalcd to give

body load

Alleged time of dose

Blood sample


Drug interactions• Drugs may interact:

– Pharmacodynamically• affect each other’s response at the same receptors

• block or modify biochemical action of receptor

– Pharmacokinetically• alter rate of absorption or distribution

• prevent access to receptors

• alter each other’s metabolism or excretion


Drug interactions• Pharmacokinetic interaction between

Prozac and diazepam (Valium)– these drugs are both metabolised in the liver by

a single enzyme, cytochrome P450-cyp2D6.– presence of Prozac will cause the rate of

removal of Valium to be decreased and vice versa

• Valium effects will be prolonged

• Prozac effects will be prolonged

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

Psychopharmacology• Drugs affecting the mind are the most

widely prescribed of all drugs

•10 % of the population will be treated for serious psychiatric disease at some stage in their life

•About 50 % of all GP’s consultations have a psychiatric component

Common psychotropic drugs

• Hypnotics: sleeping tablets

• Anti-anxiety drugs (anxiolytics)

• Antidepressants

• Antipsychotics

• Major tranquilizers

Other drugs which may also have psychiatric effects• Alcohol• Anaesthetics• Antihistamines• Calcium channel blockers• Anticonvulsants• Drugs leading to dependence:

– analgesics, stimulants, hallucinogens, solvents

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, drug interaction leading to uncharacteristic disinhibition


Forensic Pharmacology How can a pharmacologist assist the legal team?

• Pharmacologist can:– interpret drug actions

–evaluate potential interactions between drugs

–evaluate the likely interplay between drugs and related disease processes

–confirm other evidence by providing collateral data

–make estimates of the timescale of events based on the properties of drugs involved

cpd lecture forensic pharmacology

Health & Medicine

drug concentration

septprofessor nicholas

receptorprofessor nicholas

residual dose vs time

drug effects

drug response

halflifeprofessor nicholas

daysingle dose