cpd lecture forensic pharmacology
DESCRIPTION
A CPD lecture given to a Barristers’ Chambers in London outlining the possible assistance which a pharmacologist / toxicologist may be able to give in legal casesTRANSCRIPT
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:
Professor Nicholas J.Birch Academic Consultancy Services Ltd
–Pharmacodynamics
–Pharmacokinetics
Professor Nicholas J.Birch Academic Consultancy Services Ltd
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
Professor Nicholas J.Birch Academic Consultancy Services Ltd
Useful dose range Increasing toxicity
Ineffective
Phenytoin target blood concentration
range
Drug response may be influenced by:
Professor Nicholas J.Birch Academic Consultancy Services Ltd
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
Professor Nicholas J.Birch Academic Consultancy Services Ltd
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
Professor Nicholas J.Birch Academic Consultancy Services Ltd
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
Professor Nicholas J.Birch Academic Consultancy Services Ltd
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
Professor Nicholas J.Birch Academic Consultancy Services Ltd
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
Professor Nicholas 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
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
Professor Nicholas J.Birch Academic Consultancy Services Ltd
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
Professor Nicholas J.Birch Academic Consultancy Services Ltd
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
Professor Nicholas J.Birch Academic Consultancy Services Ltd
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
Professor Nicholas J.Birch Academic Consultancy Services Ltd
•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
Professor Nicholas J.Birch Academic Consultancy Services Ltd
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