13.03.

2016

TOXICOLOGIE
CLINICA

Toate substantele sunt

toxice, nu exista nici
una care sa nu fie
toxica.
Numai doza diferentiaza
un toxic de un remediu

Paracelsus
1493-1541

13.03.2016

EVOLUTIA TOXICOLOGIEI: INTERRELATIILE SI

APLICATIILE SALE
BIOLOGIE
ZOOLOGIE
BIOCHIMIE
GENETICA
FIZIOLOGIE

CHIMIE
BOTANICA
FARMACOLOGIE

TOXICOLOGIE
OCUPATIONALA
LEGALA
TOXICOLOGIE
INHALATORIE

MEDIULUI

VETERINARA
CLINICA

PIROTOXICOLOGIE

TOXICOLOGIE
GENETICA

TOXICOLOGIE
BIOCHIMICA

FITOTOXICOLOGIE

TOXICOLOGIE
ACVATICA

EPIDEMIOLOGIA INTOXICATIILOR ACUTE

1986: 4.8 MILIOANE INTOXICATII
( ASOCIATIA AMERICANA A CENTRELOR CONTRA INTOXICATIILOR)
22% EVALUATI IN CENTRE DE INTOXICATI SAU URGENTA

~ 1% DECESE
80% CALE ORALA
COMPUSI UZUAL IMPLICATI
ALCOOL ETILIC
DIAZEPAM
MORFINICE
ASPIRINA
FENCICLIDINA
MARIJUANA
AMITRIPTILINA
FENOBARBITAL
HIDANTOINE
HIPNOTICE
AMFETAMINE
NEUROLEPTICE
DETERGENTI
SOLVENTI
INSECTICIDE
PLANTE

DISTRIBUTIE
SEX
M
F
VARSTA
67
12 29
30 39
> 40

ACC.
40
22

SUICID
28
42

NEC

47

53

40
42
19

27
24
46

32
34
34

31
36

13.03.2016

Zurich Toxicology Information Center, 2000

Adults

Children

Total

Agent groups/Severity of
poisoning

Mi

Mo

Mi

Mo

Drugs

264

1126

424

161

11

263

263

58

15

2586 (69.9 %)

Household products

28

123

20

83

89

359 (9.1%)

Technical and industrial products

20

169

46

10

24

26

301 (7.7%)

Recreational and abused drugs

72

83

50

16

19

256 (6.6%)

Plants

27

17

25

15

95 (2.4%)

Mushrooms

17

26

60 (1.5%)

Products used in agriculture and

horticulture

19

21

68 (1.7%)

Toilet articles and cosmetics

19

17

10

51 (1.3%)

Poisonous animals

15

36 (0.9%)

Food and beverages

17 (0.4%)

Veterinary drugs

8 (0.2%)

Other and unknown agents

50

11

21

89 (2.3%)

Total

350

1642

650

242

15

457

463

80

26

3926 (100%)

Severity of poisoning: N=no symptoms, Mi=minor, Mo=moderate, S=severe, F=fatal

INTOXICATII ACUTE INTERNATE IN SECTIA DE TOXICOLOGIE CLINICA INTRE ANII

2000-2004
INTOXICATII
VARSTA (ani)/
ETIOLOGIE

1520

2130

3140

4150

5160

6170

7180

8190

TOTAL

1520

2130

3140

4150

5160

6170

7180

8190

TOTAL

TOTAL
GENE
RAL

POLIMEDICAMENTOASE

270

324

239

220

124

81

51

18

1327

91

218

110

79

29

12

15

555

1882

BENZODIAZEPINE

82

116

83

37

31

20

20

398

39

54

25

26

11

171

569

BARBITURICE

113

154

89

63

28

10

12

478

22

79

23

27

165

643

ALCOOL ETILIC

33

44

31

33

20

11

177

109

103

151

145

88

38

14

650

827

ALCOOL+MEDICAMENTE

34

53

47

61

22

230

23

95

84

71

28

11

319

549

NEUROLEPTICE

13

15

10

12

61

16

39

100

TUBERCULOSTATICE

14

14

28

ANTIDEPRESIVE

26

32

22

30

15

131

12

11

46

177

MONOXID DE CARBON

39

77

44

50

36

31

28

17

322

49

57

57

45

37

25

19

296

618

ETILENGLICOL

14

12

48

62

CIUPERCI

14

29

26

25

12

14

124

10

22

24

17

11

95

219

COF

22

47

39

50

18

15

10

203

19

46

55

52

35

19

11

238

441

METANOL

13

16

OPIACEE

40

57

12

119

127

209

28

371

490

SDR. INTRERUPERE

20

33

61

70

155

20

261

322

SOLVENTI

18

10

14

64

13

34

27

27

19

10

137

201

COROZIVE / CAUSTICE

26

10

20

46

ANTICONVULSIVANTE

23

18

14

73

21

12

13

57

130

ANXIOLITICE

112

108

64

45

16

11

360

21

48

10

13

103

463

BETA-BLOCANTE

13

BLOCANTE DE CALCIU

14

18

22

PARACETAMOL

METALE

DIVERSE

116

144

100

131

101

99

109

16

816

30

94

73

92

100

76

71

16

552

1368

NEPRECIZATE

36

39

23

17

136

14

36

20

14

99

235

DECESE

14

12

16

11

67

11

15

14

13

18

13

94

161

FEMEI

BARBATI

13.03.2016

CAUSE DISTRIBUTION OF ICU HOSPITALIZED

POISENED PATIENTS

OTHER CAUSES
BARBITURATES
POLIDRUGS
ETHILICS

WOMEN
MEN

ANTIDEPRESIVES
NEUROLEPTICS
UNDETERMINATED
BENZODIAZEPINES
0

50

100

150

200

250

300

350

STATISTICS - 1995
Total Patients: 5 627
Hospitalisation
60%

Refuse
hospitalsation
40%

Hospitalized: 3 357

Drug
Intoxications
57%

Internal
Medicine
70%

2 357 Patients

Non-Drug
Intoxications
43%

Total STI: 1 000Women

Patients
54%

Non-Drug
Intoxications
19%

Men
46%
Drug
Intoxications
81%

13.03.2016

PATIENTS HOSPITALIZED IN ICU

Men
35%

TOTAL HOSPITALIZED
PATIENTIS IN ICU 1000

Women
65%

Death
7%

70 PATIENTS DIED
Survive
93%

DRUG INTOXICATION
Polidrug
Barbiturates
Benzodiazepines
Neuroleptics
Triciclic antidepresive
Izoniazide
Anticonvulsivantes
Unexplained Substances
0

20

Total

40

60

Women

80

Men

100

120

140

160

180

200

Death

13.03.2016

NON-DRUG INTOXICATION
140
120
100

Women

80

Men

60
40
20
0

Ethanol+Drugs or Nondrugs

Ethanol

Detergents

Aniline

Insecticides

Mushrooms

OPC

Methanol

Solvents

CO

Ethilenglicol

Burns (acids)

Burns (bases)

Average annual percent distribution of type of poisoning-related emergency

department visits by urgency and hospital admission: US, 1993 1996
(Source: CDC/NCHS, NHAMCS, 1993 - 1996)

80

75

70
60
50

45 47

40
22

30
20

17
6

10
0

Urgent
Poisoning

Admitted
Illness

Nonpoisoning injury

13.03.2016

Number and % of Poisoning Related ED Visits by the 10 Leading Principal Diagnoses for
Poisoning Related Injuries, Averaged over a
4-Year Period: US, 1993-1996
ICD-9CM
Code

Poisoning
Related ED
Visits in
1000s

95%
CI

%
PoisoningRelated ED
visits

Poisoning by other and unspecified drugs and

medicinal substances

977

200

169,232

20,7

18.1,
23.3

Poisoning by analgesic, antipyretics and

antirheumatics

965

79

53,105

8.2

5.6,
10.8

Poisoning by psyhotrops agents

969

52

37,67

5.4

3.9, 6.9

Toxic effect of other gases, fumes or vapors

987

42

27,57

4.4

2.9, 5.9

Toxic effect of other substances, chiefly

nonmedical as to source

989

39

27,51

4.1

2.8, 5.4

Toxic effect of carbon monoxide

986

34

19,49

3.6

2.1, 5.1

Neurotic disorders

300

31

17,44

3.2

1.8, 4.6

Certain adverse effects not elsewhere

classified

955

30

16,44

3.1

1.7, 4.5

Depressive disorder, not elsewhere classified

311

24

13,35

2.5

1.4, 3.6

Nondependent abuse of drugs

305

24

13,35

2.5

1.4, 3.6

Principal Diagnosis

95%
CI

The Poisoning Pyramid

(Source: CDC/NCHS, NVSS, 1995; NHDS, 1995; NHAMCS, 1993 1996; and TESS, 1995)

13

59

147

Death
Hospitalizations

Emergency
department visits

Poison exposures

13.03.2016

The prevalence of drug addicts (overdose and

withdrawal syndrome) between 1989-2008

13%
12%
14%

8%

8%

12%
6.70%

4%

10%

5%

3%

4%

4%

2% 2% 2% 2% 2% 2%

8%
2.70%

0% 1%1%

6%
4%
2%
0%

19 89

19 90

19 91

19 92

19 93

19 94

19 95

19 96

19 97

19 98

19 99

20 00

20 01

20 02

20 03

20 04

20 05

20 06

20 07

20 08

PARAMETRII CANTITATIVI AI TOXICITATII

DL 50 (EXPERIMENTAL)

mg/kg
mM/kg
mg/m2

DML (DOZA MINIMA LETALA OM)

CLORURA MERCURICA
METANOL
NICOTINA
PARALDEHIDA
PARATION
FENOLI
FOSFOR (galben)
STRICNINA
TALIU
FORMALDEHIDA

0.5 g
70 ml
50 mg
100 ml
25 mg
10 ml
0.1 g
50 mg
0.8 g
30 ml

ARSENIC

100 mg

ACONITINA
BARBITURICE
ACID BORIC
CAMFOR
CLORALHIDRAT
CLORAT DE K
FLUORURA DE K

10 mg
15g
12 g
2g
7g
8g
1g

Cl 50
CLt 50
CONCENTRATIA ATMOSFERICA EXPUNERI PROFESIONALE
ppm SAU g/m3

Mortalitate (%)

13.03.2016

Doza (mg/kg)

Doza medie letal pentru diverse substante

Compusul
ETANOL

Masa moleculara
(g/mol)

DL 50 (mM/kg)

10000

46

0.2173
0.068
0.0098

Specia

Dl50 (mg/kg,
parenteral)

SOARECE

CLORURA DE SODIU

SOARECE

4000

58.443

SULFAT FEROS

SOBOLAN

1500

151.908

MORFINA SULFAT

SOBOLAN

900

285.34

0.0031

FENOBARBITAL
SULFAT

SOBOLAN

150

232.235

0.00064

DDT

SOBOLAN

100

354.49

0.00028

PICROTOXINA

SOBOLAN

602.583

0.0000082

STRICNINA SULFAT

SOBOLAN

334.41

0.0000059

NICOTINA

SOBOLAN

162.26

0.0000061

d-TUBOCURARINA

SOBOLAN

0.5

624.765

0.0000008

HEMICOLINIUM-3

SOBOLAN

0.2

414.538

0.0000004

TETRODOTOXIN

SOBOLAN

0.1

319.27

0.0000003

COBAI

0.001

84.07

SOBOLAN

0.00001

149322.7

DIOXINA
TOXINA BOTULINICA

13.03.2016

CLASIFICAREA SUBSTANTELOR TOXICE CONFORM

TOXICITATII RELATIVE
CATEGORIA
SUPERTOXICE
EXTREM DE TOXICE
FOARTE TOXICE
MODERAT TOXICE
CU TOXICITATE REDUSA
PRACTIC NETOXICE

DL50
5 mg/kg sau <
5 50 mg/kg
50 500 mg/kg
0.5 5 g/kg
5 15 g/kg
> 15 g/kg

ENDOBIOTICE
METABOLISM
XENOBIOTICE

PREDICTIA CONSECINTELOR METABOLICE

DETERMINAREA POTENTIALULUI TOXIC
METABOLISM DETERMINANTA A TOXICITATII
DETOXIFIEREA
ECHILIBRU FRAGIL PLURIFACTORIAL
BIOACTIVAREA

CITOTOXICITATE
CARCINOGENEZA

10

13.03.2016

METABOLIZAREA XENOBIOTICELOR DE CATRE FLORA

INTESTINALA

HIDROLIZA

GLUCURONIZI
GLICOZIZI
SULFAMATI CICLAMAT
AMIDE METOTREXAT
ESTERI ACETILDIGOXINA
NITRATI PENTAERITR. TETRANITRAT

DEHIDROXILARE
DECARBOXILARE
DEAMINARE
DEHIDROGENARE
DEHALOGENARE

REDUCERE

AMINOACIZI
AMINOACIZI
COLESTEROL, ACIZI BILIARI
DDT

GRUPARE NITRO
LEGATURI DUBLE
ALDEHIDE
ALCOOLI

ACID P-NITROBENZOIC
ACIZI GRASI NESATURATI
BENZALDEHIDE
ALCOOLI BEZILICI

ALTE REACTII

FORMARE NITROZAMINE DIMETILNITROZAMINA

AROMATIZAREA
ACID CHINIC
ACETILAREA
HISTAMINA
ESTERIFICAREA
ACID GALIC

METABOLIZAREA XENOBIOTICELOR
REACTII FAZA I
OXIDAREA

MONOOXIGENAZE (P450)
XANTINOXIDAZE
PEROXIDAZE
AMINOXIDAZE
MAO
DIOXIGENAZE

HIDROLIZA
HIDROLIZA ESTERILOR
CARBOXILESTERAZE
AMIDAZE

REDUCEREA

MONOOXIGENAZE (P450)
CETOREDUCTAZE
GLUTATIONPEROXIDAZE
EPOXIDHIDROLAZE
SOD

11

13.03.2016

REACTII FAZA II

GLUCURONILTRANSFERAZA

SULFOTRANSFERAZA

GLUTATION S-TRANSFERAZA (GLUTATION - CONJUGAREA)

TIOLTRANSFERAZA

METILTRANSFERAZA

(METILAREA)

N-ACETILTRANSFERAZA

(ACETILAREA)

SULFTRANSFERAZA

(GLUCURONIDAREA)
(SULFOCONJUGAREA)

(RODANAZA)

ENTITATI TOXICE CONSECUTIVE METABOLIZARI

UNOR COMPUSI
EPOXIZI
RADICALI LIBERI

COMPUSI N-HIDROXILATI
NITROZAMINE
AFLATOXINA B1
BENZEN, BROMBENZEN

EPOXIZI

FUROSEMID
OLEFINE
BIFENILI POLICLORURATI SI POLIBROMATI
TRICLORETILENA
CLORURA DE VINIL

RADICALI LIBERI

COMPUSI N-HIDROXILATI

TETRACLORURA DE CARBON
HALOTAN
BROMTRICLORMETAN
PARAQUAT
UNELE ALIMENTE
RADIATII IONIZANTE
INFLAMATIE
PROCESE PATOGENICE
PARACETAMOL
URETAN
AMINE

NITROZAMINE
(tub digestiv)

NITRITI

12

13.03.2016

Compusi bioactivi
(modificat dupa Frank Lu, 1991)
Mecanismul toxicitatii

Consecinte organo-functionale

Acetaminofen
(Paracetamol)

Compusul initial

Derivat N-hidroxi

Metabolit toxic

Legatura covalenta

Necroza hepatica

2-Acetilaminofluoren

N-acetoxi-AAF
AAF N-sulfat

Legatura covalenta

Cancer

Aflatoxin B1

Aflatoxin-2,3-epoxid

Legatura covalenta

Cancer hepatic

Alil formiat

Acroleina

Legatura covalenta

Necroza hepatica

Alilizopropil acetamida

Epoxid

Necunoscut

Distructie citocrom P450

Porfirie

Amigdalina

Mandelonitril
(flora intestinala)

Formare de cianura

Hipoxie citotoxica

Benzen

Benzen epoxid

Legatura covalenta

Depresie maduva hematopetica

Brombenzen

Brombenzen

Legatura covalenta

Necroza hepatica, renala,

bronsiolara

Tetraclorura de carbon

Radical liber
triclormetan

Legatura covalenta,
peroxidarea lipidelor

Necroza hepatica,
Cancer hepatic

Alchilnitrosamine
carciogene

Alfa-hidroxilare

Alchilare

Cancer hepatic

Coloranti amino
carciogeni

Derivati N-hidroxi

Legatura covalenta

Cancer hepatic

Compusi bioactivi
(modificat dupa Frank Lu, 1991)
Mecanismul toxicitatii

Consecinte organo-functionale

Hidrocarburi policiclice
carciogene

Compusul initial

Epoxizi in diverse
organe

Metabolit toxic

Legatura covalenta

Cancer, citotoxicitate

Cloroform

Fosgen

Legatura covalenta

Necroza hepatica, renala

Cicasin

Metilazometanol

Alchilare

Cancer, necroza hepatica

Ciclamat

Ciclohexilamina

Necunoscut

Cancer de vezica

Etanol

Acetaldehida in
diverse organe

Complex

Diferite

Fluoracetat

Fluorocitrat

Inhibitie enzimatica

Toxicitate generala

Furosemid

Epoxid

Legatura covalenta

Necroza hepatica, renala

Halotan

Radical liber

Legatura covalenta

Necroza hepatica

Amine aromatice
hemolizante

Metaboliti N-hidroxi

Necunoscut

Hemoliza

Izoniazida

Acetihidrazina

Legatura covalenta

Necroza hepatica

Meclizina

Noroclorciclizina

Necunoscut

Teratogeneza

13

13.03.2016

Compusi bioactivi
(modificat dupa Frank Lu, 1991)
Mecanismul toxicitatii

Consecinte organo-functionale

Metanol

Compusul initial

Formaldehida

Metabolit toxic

Complex

Toxicitate retiniana si generala

Compusi nitro si amine

aromatice
methemoglobinizante

Metaboliti N-hidroxi

Oxidare, reducere
ciclica

Methemoglobinemie

Metoxifluran

Fluor anorganic

Inhibitie enzimatica

Insuficienta renala

Naftilamina

N-hidroxi naftilamina

Legatura covalenta

Cancer vezical

Nitriti si amine
secundare si tertiare

Nitrosamine

Alchilare

Cancer hepatic, pulmonar

Olefine

Epoxizi

Legatura covalenta

Cancer de piele

Paration

Paraoxon

Legatura covalenta cu
colinesterazele

Paralizie neuromusculara,
insuficienta respiratorie

Analogi baze purinice si

pirimidinice

Mononucleotide,
nucleotizi trifosfat

Sinteza letala,
incorporare letala

Citotoxicitate

Alcaloizi pirolizidinici

Derivati pirolitici

Necunoscut

Necroza hepatica si canceroasa

Talidomida

Acid ftalil L-glutamic

Necunoscut

Teratogeneza

Uretan

N-hidroxil uretan

Alchilare

Cancer, citotoxicitate

FARMACOCINETICA TOXOCINETICA
PARAMETRU

FARMACOCINETICA

TOXOCINETICA

DOZA

CUNOSCUTA
REDUSA

NECUNOSCUTA
FOARTE MARE

EFECT

TERAPEUTIC

TOXIC

STEADY STATE

UZUAL

NU

DATE CLINICE
COROBORANTE

FRECVENT

INCOMPLETE

CONCENTRATIE-EFECTE

DA

INCOMPLETE

14

13.03.2016

TOXICE, RECEPTORI SI CONSECINTA INTERACTIUNII LOR

RECEPTOR TOXODINAMIC

TOXIC

MECANISM

COLINESTERAZE

COMPUSI ORGANOFOSFORICI

BLOCAREA CENTRULUI
ESTERAZIC

CITOCROMOXIDAZA

CIANURI

BLOCAREA TRANSPORTULUI DE
ELECTRONI IN LANTUL
RESPIRATOR

GRUPARI TIOLICE
ENZIMATICE

METALE GRELE

INACTIVAREA GRUPARILOR
TIOLICE

HEMOGLOBINA

MONOXID DE
CARBON, NITRITI,
NITRATI

FORMAREA:
CARBOXIHEMOGLOBINEI
METHEMOGLOBINEI

ACIZI NUCLEICI

ALCHILANTE
RADIOMIMETICE

BLOCAREA SINTEZEI ACIZILOR

NUCLEICI

LIPIDE STRUCTURALE

TETRACLORURA DE
RADICALI LIBERI
CARBON
PEROXIDARE
BROMTRICLORMETAN

RECEPTOR NICOTINIC

NICOTINA
CURARIZANTE

STIMULARE DIRECTA
BLOCARE, PARALIZIE

RECEPTOR MUSCARINIC

MUSCARINA
(AMANITA MUSCARIA)

STIMULARE INTENSA, SINDROM

MUSCARINIC

15