Download Ei dian otsikkoa

GENERATION AND USE OF POSTMORTEM TOXICOLOGY DATA
EAPCCT International Congress
Athens, 2 May 2007
Erkki Vuori, professor
Department of Forensic Medicine
University of Helsinki
FORENSIC TOXICOLOGY
 ”The study and practice of the application of
toxicology to the purposes of law”
 The task is to produce valid toxicological information
for the administration of justice and to improve the
legal protection of individuals and society.
 As to the analysis of human samples, there are two
key questions:

Has the person under investigation been exposed
foreign substances

Has s/he been under the influence of alcohol, drugs or
other xenobiotics.
FORENSIC TOXICOLOGY 2
 Investigation of living persons

Driving under the influence of alcohol or drugs
 Clinical forensic toxicology
- Victims and offenders of assault
- Drug-facilitated crime
- Drug-running
- Child welfare
- Drunkenness in the workplace
 Drug testing programs
- Workplace
- Schools
- Armed forces
- Correctional facilities
- Treatment of drug-dependent persons
 Post-mortem toxicology
POST-MORTEM TOXICOLOGY
 Analytical results of a post-mortem investigation are
utilized to determine the cause and manner of death.
 Poisoning can be the:
Underlying cause of death (WHO Ic ”initiated the train of
morbid events leading directly to death”)
 Immediate cause of death (WHO Ia ”condition with the
symptoms of which the deceased died”)
 Contributing cause of death (WHO II)

 Traditionally, the results of a single forensic case are
used for the sake of the deceased in question only.
 Over time, cases accumulate to form a greater whole,
which can provide information that goes far beyond
the original purpose of the routine casework.
EPIDEMIOLOGICAL STUDIES,
REQUIREMENTS
 The results should be derived annually from a known
population or area.
 The analytical practices of the laboratory should be
known and should remain stable over years.
Scope and sensitivity of drug screening (“cut offs”)
 Interpretation of the analytical results
 If several laboratories are involved in an area the
detection limits and analytical principles should be
compatible and known

 The laboratory should have an information
management system
 In prospective studies, the questions to be studied
can be set out beforehand, while in retrospective
studies they must fit with the existing data.
FINLAND YEAR 2004, STATISTICS
 Inhabitants
5.23 millions
 Number of deaths
47,757
 Number of forensic autopsies
11,371 (23.8%)
 Number of clinical autopsies
3,952 (8.3%)
 Number of toxicogical analyses
6,109 (12.8%)
FINLAND IS AN IDEAL COUNTRY FOR POSTMORTEM TOXICOLOGICAL INVESTIGATIONS
 High autopsy rate
 Extensive use of post-mortem toxicological services
 All post-mortem toxicology is centralized to one
laboratory by law
 The screening methods are comprehensive and have
been accredited since 1997
 The laboratory gets as feedback a copy of the death
certificate from all cases investigated
 The laboratory has an information management
system with demographic data
 The National Agency for Medicines publishes
statistics annually on the consumption of medicines
TYPICAL FEATURES OF FATAL DRUG
POISONINGS
 Frequently several drugs are present
 Frequently alcohol has been taken simultaneously
 Frequently the victim has committed suicide
 Drugs of abuse are common
 Victims include young people also
THE MOST IMPORTANT FINDING
 A combination of several drugs is typically found in
the same subject.
 If all findings are included in the classification, the
number of possible fatal combinations is too high.
 The forensic pathologist always has a possibility to
choose the most important finding.
 If not stated, the drug which has the greatest ratio of
found concentration in relation to its therapeutic
concentration is taken as the basis of the
classification

The method used is a crude mathematical procedure
 However, this yields reasonable results from year to
year and a similar ranking of the most dangerous drugs
THE ATC CLASSIFICATION SYSTEM
 Classifies drugs according to anatomical, therapeutic
and chemical properties
 Gives every drug an individual code comprised of
letters and numbers
 The first letter indicates the therapeutic system
C = cardiovascular system, N = nervous system
 The next numbers and letters specify the group and
finally the specific drug
N05A = antipsychotics, N05AA = phenothiazine with aliphatic side
chain, N05AA01= chlorpromazine
 Gives also defined daily doses (DDD)
 Gives also the consumption of drugs as the DDD per
1000 inhabitants per day, calculated from the number
of wholesale sales to pharmacies
FATAL POISONINGS ACCORDING TO THE
MOST IMPORTANT FINDING IN 2003-2005
2003 2004 2005
C
Cardiac glycosides
Beta blocking agents
Other
N
Antiepileptics
Antipsychotics
Anxiolytics
Barbiturates
Antidepressants
Hypnotics and sedatives
Opioids
Other analgesics
5
23
12
4
36
4
9
28
5
10
77
15
0
107
37
132
4
4
70
15
0
151
29
135
5
13
86
14
1
123
49
126
8
Other drugs
36
37
39
All
458
490
501
THE MOST COMMON DRUGS IN FATAL
POISONINGS IN FINLAND 2003-2005
Amitriptyline
Codeine
Levomepromazine
Buprenorphine
Zopiclone
Doxepin
Tramadol
Propranolol
Alprazolam
Dextropropoxyphene
Insulin
Temazepam
Chlorprothixene
Quetiapine
Venlafaxine
Citalopram
Digoxin
Mirtazapine
Oxycodone
Metformin
Olanzapine
2003
2004
2005
37
47
29
33
15
21
21
12
10
14
8
17
12
2
9
11
5
9
7
8
6
48
44
32
35
16
25
21
15
11
15
8
10
8
3
14
13
4
14
11
3
5
46
45
38
32
30
22
21
14
13
12
12
12
11
11
11
10
9
9
9
7
7
ESTIMATION OF FATAL TOXICITY
 Different methods have been used to relate the deaths
by poisoning to the consumption of drugs since 1974
 The ”fatal toxicity index” by Cassidy and Henry (1987) is
defined as the ratio of the number of deaths divided
by the number of prescriptions (in millions) or by the
number of standard quantity units prescribed or by
the weight of drug prescribed.
 The ”fatality rate” by Farmer and Pinder (1989) is the
number of deaths divided by the estimated number of
prescriptions (in millions)
 The ”fatality ratio” by Vuori et al. (1989) is defined as
fatalities divided by DDD per 1000 inhabitants per day
ESTIMATION OF FATAL TOXICITY, CONT.
 Fatal poisonings depend on the intrinsic toxicity and
availability of drugs.
 By controlling drug availability, it is possible to
compare intrinsic toxicity.
 In general, different estimations give a similar ranking
of drugs in fatal poisonings, whether calculated
against the number of prescriptions or the sales of
drugs.
 Limitations

If the number of prescriptions is used, over-the-counter
drugs cannot be included.
 Indices cannot be calculated for drugs of abuse that are
also available on the streets
THE MOST DANGEROUS CATEGORY OF
DRUGS IN FINLAND IN 2004
ATC Group of drugs
code
C01A
N03A
N05A
N06A
Sales Deaths Fatality
ratio
Cardiac glycosides 6.59
4
Antiepileptics
11.5
4
Antipsychotics
16.7
70
Antidepressants
56.7 151
0.61
0.35
4.19
2.66
THE MOST DANGEROUS DRUG IN FINLAND
IN 2004
Drug
Sales Deaths Fatality
ratio
Propranolol
Metoprolol
Bisoprolol
1.91 15
18.6 10
20.2
7
7.85
0.54
0.35
Alprazolam
Temazepam
Oxazepam
7.73
19.0
7.77
11
10
3
1.42
0.53
0.39
Trimipramine
Doxepin
Amitriptyline
0.31
1.05
3.80
10
25
48
32.3
23.8
12.6
Melperone
0.17
Levomepromazine 0.80
Clorprothixene
0.69
8
32
8
47.1
40.0
11.6
THE FATALITY INDEX OF SOME HYPNOTICS
AND SEDATIVES IN 2002-2005
Zopiclone, deaths
Zopiclone, sales
Zopiclone, fatality ratio
Zolpidem, deaths
Zolpidem, sales
Zolpidem, fatality ratio
Temazepam, deaths
Temazepam, sales
Temazepam, fatality ratio
Oxazepam, deaths
Oxazepam, sales
Oxazepam, fatality ratio
DDD
2002
2003
2004
2005
7.5 mg
38
26.4
1.44
15
27.8
0.54
16
27.1
0.59
30
26.9
1.12
10 mg
2
4.59
0.44
2
5.28
0.38
3
5.78
0.52
4
6.11
0.65
20 mg
11
18.7
0.59
17
19.3
0.88
10
19.0
0.53
12
18.5
0.65
50 mg
2
7.85
0.25
1
7.84
0.13
2
7.77
0.26
1
7.69
0.13
CASE: PROMAZINE
1998 1999 2000 2001 2002 2003 2004
Promazine, deaths
38
45
61
43
20
8
1
Promazine, sales
0.37 0.39 0.38 0.34 0.28 0.05 Promazine, fatality ratio (FR) 103 115 160 126 71.4 Levomepromazine, deaths
Levomepromazine, sales
Levomepromazine, FR
40
60
35
43
34
29
32
0.96 1.00 0.93 0.90 0.85 0.84 0.80
41.7 60.0 37.6 47.8 40.0 34.5 40.0
Olanzapine, deaths
Olanzapine, sales
Olanzapine, FR
-
1
4
5
6
5
1.12 1.61 2.22 2.73 3.29 3.83
0.62 1.80 1.83 1.82 1.31
CASE: ANTIDEPRESSANTS IN 2003-2005
Cumulative Cumulative Fatality Risk
ratio
ratio
sales
deats
68
Doxepin
19
Trimipramine
131
Amitriptyline
3
Trazodone
6
Clomipramine
34
Venlafaxine
7
Moclobemide
32
Mirtazapine
19
Paroxetine
3
Fluvoxamine
10
Sertraline
34
Citalopram
4
Fluoxetine
3.10
0.92
11.4
0.42
0.87
10.8
2.29
16.8
10.6
1.74
13.7
56.7
17.7
21.9
20.7
11.5
7.14
6.90
3.14
3.06
1.91
1.79
1.72
0.73
0.60
0.23
95
90
50
31
30
14
13
8
8
7
3
3
1
CASE: ANTIDEPRESSANTS IN 2003-2005
Risk A death per
ratio patient years
Doxepin
Trimipramine
Amitriptyline
Trazodone
Clomipramine
Venlafaxine
Moclobemide
Mirtazapine
Paroxetine
Fluvoxamine
Sertraline
Citalopram
Fluoxetine
95
90
50
31
30
14
13
8
8
7
3
3
1
237
256
452
728
754
1,657
1,718
2,721
2,889
3,016
7,248
8,697
23,600
ANTIDEPRESSANTS: WHY DO THEY BEHAVE
DIFFERENTLY?
 Not because of poor analytics
 The unit DDD per 1000 inhabitants per day is
calculated based on the sales from pharmacies
 Some antidepressants are prescribed for other
indications than depression
 Prescription habits: Are the drugs selected according
to severity of depression or to different types of
patients?
 The intrinsic toxicity of the drugs varies.
ALCOHOL – DRUG INTERACTIONS,
STATISTICAL EVALUATION
 Alcohol is a frequent finding in post-mortem
toxicology. In Finland, about 50% of forensic cases
have a BAC >0.5 o/oo
 Alcohol has a non-specific membrane effect and
shares a specific effect with many drugs via the
GABA receptor
 Propoxyphene, amitriptyline and barbiturates are
known to be more toxic when used together with
alcohol
 We conducted a study of behavior of ten common
drugs together with alcohol and compared the BAC in
these cases against pure fatal alcohol poisonings
(Koski et al. 2003)
ALCOHOL – DRUG INTERACTIONS
FTIs vs. deviations of median BAC in drug-alcohol
poisonings from that found in pure alcohol poisonings
the bars represent
the 95% CIs for the
difference in BAC
SUMMARY
 Today, forensic toxicology is not restricted only to
revealing homicides by poisoning, but provides to the
society information that is otherwise difficult or
impossible to obtain.
 Exploits the results of ”natural experiments” for the
benefit of living human beings.
 The results can be used to

evaluate drug safety
 reveal differences in the intrinsic toxicity of drugs and
thereby to rank the drugs
 reveal the abuse potential of therapeutic drugs
 follow prescription practices
 study drug/alcohol or drug/drug interactions on a
statistical basis