Antidepressants

Drug overdose is the second most common method of suicide in the U.S. after shooting. For many years, the drug of choice was one of the barbiturates. This has changed dramatically in the past 20 years such that deaths caused by barbiturates are now relatively uncommon. The most common family of drugs used in suicides now are the antidepressants, specifically, the tricyclics. There are now three generations of tricyclic antidepressants. The first included amitriptyline, nortriptyline, imipramine, desipramine, and dox-epin; the second, amoxapine, trazodone, bupropion and maprotiline and the third venlafaxine, nefazodone and mirtazapine. The mechanism of death from an overdose of a tricyclic antidepressant is cardiac. Overdoses of tricyclic antidepressants produce intraventricular conduction abnormalities, tachycardia, a widening of the QRS complex, and arrhythmias that range from premature ventricular contractions to ventricular fibrillation. The CNS effects of the tricyclics are confusion, hallucinations, lethargy, and agitation that progress to seizures or coma. There is allegedly an increased incidence of seizures in epileptics taking the tricyclics. They can also cause hyperpyr-exia. The therapeutic, toxic, and overdose concentrations of the first two generations of these drugs are listed in Table 23.2.

A number of individuals have contended that there is significant postmortem redistribution of the tricyclic antidepressants and that concentrations of these drugs in postmortem blood do not accurately reflect their perimortem concentration. Apple and Bandt contend that only liver levels of the tricyclic antidepressants should be used for diagnosis of overdoses.l The authors of this book agree that the tricyclic antidepressants are highly tissue bound and that there is postmortem tissue release that may give rise to elevated blood levels. However, we believe that, in only rare instances, would there be sufficient release of the drug postmortem so as to even suggest that a case was a fatal overdose when it was not, if one uses the levels in Table 23.2. Even in the paper by Apple and Bandt, in the nine cases of fatal overdoses of tricyclics, the concentration of the tricyclic and its major metabolite in the

Drug name

Dose in milligrams

Therapeutic or Normal level mg/L*

Toxic mg/L

Fatal mg/L

Half- life in hours

Acetaminophen

Acetone

Alprazolam

(Xanax)

Aminophylline

Amitriptyline

Nortriptyline

(Elavil, Endep) Amobarbital

Amoxapine

(Asendin)

Amphetamine

Arsenic

324 1000 1800 normal controlled diabetes fasting/keto-acidosis 1.0 1.5-6/day 170 IV 500 oral

50 oral 150/day

120 oral 600 oral

50 300/day 5-15 oral 30 oral 160 IV 0.025-0.033 mg/kg/day (average dietary intake)

100-700

0.025-0.055

6-27

15-40 dose dependent 8

7-34

Brom-

8

0.015 (3)

>0.05

0.2

15-22

pheniramine

0.005 (24)

Bupropion

32-55

0.06-0.125 (3)

?

?

4-24

100

0.140 (3)

Butabarbital

600

7.6-16.9 (.5)

>10

30-88

>30

Butalbital

100

2.1 (2)

?

13-26

35-88

1.5 (24)

Caffeine

120

2-4 (1)

>40

79-344

2.3-12

300

6-9 (1)

500

14 (0.5)

Carbamazepine

420

6.5 (3.2)

35-70

18-65

(Tegretol)

4-8 (optimal)

Therapeutic or

Dose in

Normal level

Toxic

Fatal

Half- life in

Drug name

milligrams

mg/L*

mg/L

mg/L

hours

Carbon

urban

1-2% CoHb

15-25%

>50%

4-5 (without

monoxide

non-smoker

O2 therapy)

smoker

5-6% CoHb

Carisoprodol

350

2.1 (1)

>30

39-110

0.9-2.4

(Soma)

700

3.5 (0.8)

Chloral hydrate

1000 oral

2-12 (1)

50?

100-640

4 min chloral

(Noctec)

6.5-8 (2)

hydrate;

3-6.3 (6)

6-10 h tri-

chloroethanol

Chlordiazepoxide

30

1.6 (4)

9-60

>20

6-27

(Librium)

55/d

2.3

Chloroform

500 oral

1-5 (1)

10-194

1.5

anesthesia

20-232

Chloroquine

50/day

0.022

>0.6

3-16

3-14 days

300/d

0.176

Chlor-

4 IV

0.01

>0.5

>1.0

12-43

pheniramine

12 oral

0.017 (2)

0.010 (12)

0.004 (24)

Chlorpromazine

25 oral

0.001 (2.8)

>0.5

3-35

18-30

(Thorazine)

150 oral

0.018 (3)

600 mg/d

0.02-0.08

2400 mg/d

1.1

Chlorpropamide

250

28.5 (3)

300-750

?

25-42

(Diabinese)

500-1000/d

102-363

Clonazepam

2

0.017 (1-4)

>0.1

?

19-60

6/d

0.029-0.075

Clorazepate

15

0.16 (2)

?

?

2

(Tranxene)

50/d

1.21-2.64

Cocaine

17-48 oral

0.011-0.149(.4-2)

?

0.9-21

0.7-1.5

2mg/Kg

0.161 (1)

intranasal

2 mg/Kg oral

0.210 (1)

32 IV

0.308 (5 min)

50 smoked

0.203 (5 min)

Codeine

15

0.03 (2)

0.5

1-8.8

1.9-3.9

60

0.134 (1)

Cyanide

non-smoker

0.004

0.01-4.36

1.1-53

0.7-2.1

smoker

0.006

(ingestion)

fire victim

0.17-2.2

1-15

(inhalation)

Desipramine

82mg/70Kg/d

0.021-0.064

1.0

3-15

12-54

Therapeutic or

Dose in

Normal level

Toxic

Fatal

Half- life in

Drug name

milligrams

mg/L*

mg/L

mg/L

hours

Diazepam

10

0.148 (1)

>5

5-19

21-37

30/d

1.03

Dicumarol

150

17 (10)

22-192

?

21 (average)

Digoxin

0.25 oral

0.001 (1)

2.1-9

15 ng/ml

30-45

0.5 oral

0.0014 (2)

ng/ml

0.75 IV

0.013 (10 min)

Digitoxin

0.05-0.3/d

3-39 ng/ml

?

>320 ng/ml

Di

50

0.083 (3)

>1

8-31

3-14

phenhydramine

100

0.112 (2)

0.014 (24)

Doxepin

75

0.024 (2)

>0.14

0.7-29

8-25

(Sinequan,

113/d

0.005-0.115

Adapin)

Doxylamine

25 mg

0.07-0.14 (4)

?

0.7-12

10

Ephedrine

19.4

0.081 (3.9)

?

3.5-21

5-7.5

24

0.10 (1)

Ethchlorvynol

200

1.2 (1)

>50

14-400

19-32

(Placidyl)

500

6.5 (1)

Ether

workers

18

>90

600-3750

?

sub-anesthesia

100-500

anesthesia

500-1500

Ethylene glycol

?

any

300-4300

3-5

amount

Fentanyl

2^g/Kg IV

0.011

0.02

0.003-0.03

3-12

0.001 (1)

Fluoride

normal

0.01

?

2.6-56

2-9

1.5-10

0.06-0.4 (0.5)

Fluoxetine

40

0.015-0.055(6-8)

1.3-6.8

1-3 days

(Prozac)

20-60/d

0.025-0.473

(7-14 days

for

metabolites)

Flurazepam

15

<0.002 (0.5)

?

0.5-4

1-3

30

0.0021 (1)

Fluvoxamine

50

0.008-0.028 (4.8)

>0.115

3.4-11

8-28

(Luvox)

100

0.021-0.06 (4.5)

Haloperidol

20-200/d

0.006-0.245

0.01

1-1.9

14-41

Halothane

surgical

80-260

?

33-650

43 (from fat)

anesthesia

Hydrocodone

5

0.011 (1.5)

?

0.13-7

3.4-8.8

10

0.024 (1.5)

Hydrogen sulfide

normal

<0.05

any

0.9-3.8

?

amount

Hydromorphone

4

0.018-0.027(.8-1.5)

0.02

0.02-1.2

1.5-3.8

Therapeutic or

Dose in

Normal level

Toxic

Fatal

Half- life in

Drug name

milligrams

mg/L*

mg/L

mg/L

hours

Hydroxyzine

100

0.078 (4)

?

4.2-39

13-27

Ibuprofen

200

26 (1.5)

0.9-2.5

(Motrin, Advil)

400 800

17-36 (1-1.3) 49 (1)

>80

Imipramine (I)

75

0.037 I (4)

6-20

Desipramine( D)

150/d

0.008-0.105 I 0.15-.24 I&D (optimal)

>0.5

2.8-7 (I)

Insulin

normal fasting normal, non-

fasting insulin treated

27 |J.U/ml (range 7-37) 10-440 |J.U/ml (free insulin)

67-17,020 (total insulin)

?

>700 (free)

3.5-4.3

Iron

normal serum normal whole blood

0.27-2.93 380-560

2.76-25.5

18.8-50

?

Isoniazid

5/kg oral 450

1.2-4.8 (1) 0.2-2.7 (4)

>20

43-168

0.6-6.7

Isopropanol

0.04 g/dL

0.1-0.33 g/dL

2.5-3

Ketamine

2.5/kg

1.0 (12 min) 0.5 (0.5)

?

7-27

3-4

Lead

normal industrial society normal taxi drivers

0.07-0.22 0.16-0.49

0.20 (children)

1.11-3.5

Up to 7 years

Lidocaine

500 oral 1/Kg IV

0.6-1.1 (1-2) 0.96 (.25) 0.4 (1)

>8

6-33

0.7-1.8

Lithium

1500

1.66 mmol/L (1)

>2

0.3-4.6

17-58

(as carbonate)

0.5-1.3 mmol/L optimum

mmol/L

mmol/L

Lorazepam

10/d

0.018 (2) 0.009 (12) 0.140-0.24

0.3

?

9-16

Maprotiline

150 150/d

0.091 (8) 0.168-0.718

0.2370.317 (seizures)

1.3-13

36-105 continued

Therapeutic or

Dose in

Normal level

Toxic

Fatal

Half- life in

Drug name

milligrams

mg/L*

mg/L

mg/L

hours

Meperidine

100 IM

0.17 (1.3)

?

8-20

2-5

50 IV

0.31 (1)

oral

0.52 (12 min)

1-8 IV

Meprobamate

400

7.7(2)

>60

35-300

6-17

800

12-19 (2)

1600

8.6-27 (2)

Mercury

fish eaters

0.006-0.2

0.2

0.8-22

24 days

"acceptable"

0.02

(inorganic

mercury)

Methadone

15

0.075 (4)

0.1

0.4-1.8

15-55

100-200/d

0.83 (4)

0.46 (24)

d-Metha-

0.125/kg

0.02 (3.6)

>0.1

2.0

12-34

mphetamine

10

0.03 (1)

12.5

0.02 (2.5)

0.01 (24)

Methanol

normal

<1.5

?

>400

2-24

chronic

bourbon

27

consumption

Methaqualone

250

1-4 (2)

2-12

5-42

20-60

1.1 (5)

600

7.0 (1)

Metoclopromide

10

0.054 (0.9)

>2.0

?

3-6

Mexiletine

300

0.4 (4)

>2.0

21-45

8-17

400

0.9-1.6 (2-4)

750/day

0.9-1.4

0.75-2 (optimal

therapeutic level)

Mirtazapine

20

0.032 (1.7)

>0.2

?

20-40

(Remeron)

20/day

0.007-0.046

Morphine

0.125/kg IV

0.44 (0.5 min)

0.2

0.2-2.3

1.3-6.7

0.02 (2)

0.125/kg IM

0.07 (10 min)

Nefazodone

200

0.39 (1.3)

?

?

1-4

(Serzone)

400/day

2.0

Nicotine

non-smokers

0-0.006

?

11-63

24-84 min

smokers

0.012-0.054

Nitrous oxide

surgical

170-220 ml/L

?

46-180

? (min)

anesthesia

ml/L

Nortriptyline

75/d

0.01-0.275

1.0

1-26

15-90

(Pamelor)

150-250/d

0.171-0.375

Dose in milligrams

Therapeutic or Normal level mg/L*

Toxic mg/L

Fatal mg/L

Half- life in hours

Oxycodone

Paraldehyde

Paroxetine

Pentobarbital Phenacetin Phencyclidine Phenmetrazine

Phenobarbital

Phenol

Phentermine

Phenylbutazone

Phenytoin (Dilantin)

Primidone

Procainamide

Promethazine

Propoxyphene

Propranolol Propylhexedrine

4.88

10 ml IM

20 30 100 250

30 30/d 600

normal 0.375/kg 200 400 100 300-400/d

250 500 1000 1000 1000 IM 1000 IV 30

130 (as H Cl) 800-1600/d for narcotic withdrawal 80 160/d

0.009-.037 (1) 0.016 (2) 0.009 (4) 0.005 (8) 77 (1.2) 62 (2.3) 0.011 0.062 (5.2) 1.2-3.1 (.5-2) 0.09-0.22 (1-2) 0.007-0.24 0.13 (2) 0.06 (12) 0.7 8.1 18 (4.5) 10-30 optimal 0.10 0.09 (4) 16 (3) 60 (max conc) 1.6-2.8 (2.4) 7.8-17.5 (10-20 optimal) 4.9 (4) 6.7 11-15 4.5 (1) 5.9 (.5) 16 (10 min) 0.011 (2) 0.005 (12) 0.008-0.023 (3) 0.003-0.004 (12) 0.23 (2) 0.13-1.07

>100

115-480

55-114

80-260

1-17

3-10

7-37

2-6 days

8-60

6-22

9-16

8-24

continued

Therapeutic or

Dose in

Normal level

Toxic

Fatal

Half- life in

Drug name

milligrams

mg/L*

mg/L

mg/L

hours

Quinidine

600

3.2 (2.25)

>8

45

5-12

2-5 (optimal)

Quinine

650

2.8 (2)

>10

6-24

3-15

1.9 (8)

Salicylamide

1000

3-32 (1)

?

27 (?)

26-35 min

0-22 (3)

0-15 (5)

Salicylate

3000-5000/d

>500

61-7320

13-20 min

(acetylsalicylic

for arthritis

acid)

1000

31-114 (2)

3-20 hours

3000/d

44-330

for salicylic

acid

Secobarbital

3.3/kg

2.0 (3)

5-12

5-52

22-29

1.3 (20)

600

3.4-5.3 (0.5)

2.7 (18)

Sertraline

50

0.0095 (6-8)

0.6-3

24-26

100

0.016 (6-8)

Strychnine

?

0.5-61

10-11

A9-Tetrahydro-

10 mg = 1

0.005 (2)

?

None

20-57 hours,

cannabinol

cigarette

infrequent

8.8

0.046-0.188

user;

3-13 days,

frequent user

Thallium

normal

0-0.08

1-8

0.5-11

2-4 days

Theophylline

500

1.4(1)

>20

63-250

3-11

4.5 (2)

7.7 (4)

470 (syrup)

9 (1.5)

5-15 optimal range

Thioridazine

100

0.24 (1.7)

>2.4

0.3-18

26-36

400/d

0.64

Toluene

workers

0.4-1.2

0.3-30

10-79

72

(sniffers)

Trazodone

100

1.1 (2)

?

15-23

4-7

(Desyrel)

150

2.1 (2-4)

Triazolam

0.25

0.003 (1)

0.01-0.22

1.8-3.9

(Halcion)

Trichloroethane

Exposure to

7-10 (1)

1.5-720

53

955 ppm

Trichloro-

Exposure to

1.0 (6)

?

3-110

30-38

ethylene

100 ppm

(average

27)

Therapeutic or

Dose in

Normal level

Toxic

Fatal

Half- life in

Drug name

milligrams

mg/L*

mg/L

mg/L

hours

Valproic acid

400

32-42 (1.5-3)

?

720-1969

8-12

1400-2520/d

81-106

50-100 optimal

range

Venlafaxine

50

0.071 (2.2)

6

6.6-89

3-7

150/day

0.194

*Numbers in parentheses are hours post dose

*Numbers in parentheses are hours post dose blood ranged from 2.4 to 11.1 mg/L. In contrast, in the deaths from other causes in individuals taking therapeutic doses of tricyclic antidepressants, the range was 0.16 to 0.30 mg/L. Most of the aforementioned discussion is academic, because the authors recommend that blood for toxicologic analyses be obtained from either the femoral or subclavian vessels.

The newest group of antidepressants are the selective serotonin reuptake inhibitors (SSRI).29 These include fluoxetine, paroxetine, fluvoxamine and sertraline. Fluoxetine (Prozac) is the best known of the group. Fluoxetine is metabolized to norfluoxetine, which is an active metabolite. The SSRI are significantly less toxic than the tricyclics in that they do not have the car-diotoxic component. They still can cause death, however. Most deaths encountered seem to involve an SSRI and one or more other drugs. Deaths from these drugs alone are uncommon.

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