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

EVOLUTIA TOXICOLOGIEI:

INTERRELATIILE SI APLICATIILE SALE

BIOLOGIE
CHIMIE
ZOOLOGIE
BIOCHIMIE
BOTANICA
GENETICA
FIZIOLOGIE
FARMACOLOGIE

TOXICOLOGIE
OCUPATIONALA
LEGALA
TOXICOLOGIE
TOXICOLOGIE

MEDIULUI

VETERINARA
CLINICA

PIROTOXICOLOGIE
INHALATORIE
BIOCHIMICA

TOXICOLOGIE
GENETICA

FITOTOXICOLOGIE

TOXICOLOGIE

EPIDEMIOLOGIA INTOXICATIILOR ACUTE

1986:

4.8 MILIOANE INTOXICATII

( ASOCIATIA AMERICANA A CENTRELOR CONTRA INTOXICATIILOR)
22% EVALUATI
~ 1%
80%

IN CENTRE

DE

INTOXICATI

SAU

DECESE
CALE ORALA

COMPUSI UZUAL IMPLICATI

IMPLICATI
ALCOOL ETILIC
DIAZEPAM
31
MORFINICE
36
ASPIRINA
FENCICLIDINA
MARIJUANA
AMITRIPTILINA
FENOBARBITAL
32
HIDANTOINE
34
HIPNOTICE
34
AMFETAMINE
NEUROLEPTICE
DETERGENTI

URGENTA

DISTRIBUTIE
SEX

ACC.

SUICID

NEC

40

28

22

42

VARSTA
67

47

53

12 29

40

27

30 39

42

24

> 40

19

46

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

FEMEI

BARBATI

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

CAUSE DISTRIBUTION OF ICU

HOSPITALIZED POISENED PATIENTS

STATISTICS - 1995
Total Patients: 5 627

Hospitalized: 3 357
Interna
l
Medicin
e 70%

2 357
Patients

Total STI: 1 000

Patients

PATIENTS HOSPITALIZED
IN ICU
TOTAL HOSPITALIZED
PATIENTIS IN ICU
1000
70 PATIENTS DIED

DRUG INTOXICATION

NON-DRUG
INTOXICATION

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)

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

Poisoning by other and unspecified

drugs and medicinal substances

977

200

169,2
32

20,7

18.1,
23.3

Poisoning by analgesic, antipyretics

and antirheumatics

965

79

53,10
5

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

Principal Diagnosis

95%
CI

%
PoisoningRelated ED
visits

95%
CI

The Poisoning Pyramid

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

Death

13

Hospitalizatio
ns

59

Emergency
department
visits

14
7

Poison
exposures

The prevalence of drug addicts (overdose

and withdrawal syndrome) between 19892008
13%
12%
8%

14%

8%

12%
6.70%

4%
3%
0% 1%1%

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

10%

5%
4%

4%

8%
2.70%

6%
4%
2%
0%

PARAMETRII CANTITATIVI AI TOXICITATII

DL 50 (EXPERIMENTAL)
mM/kg
mg/m2

mg/kg

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

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

ARSENIC

100 mg

ACONITINA
10 mg
BARBITURICE
15g
ACID BORIC
12 g
CAMFOR
2g
CLORALHIDRAT
7g
CLORAT DE K
8g
FLUORURA DE K
1g

PROFESIONALE

Doza (mg/kg)

Mortalitate (%)

Doza medie letal pentru

diverse substante
Specia

Dl50
(mg/kg,
parenteral)

Masa
moleculara
(g/mol)

DL 50 (mM/kg)

ETANOL

SOARECE

10000

46

0.2173

CLORURA DE
SODIU

SOARECE

4000

58.443

0.068

SULFAT FEROS

SOBOLAN

1500

151.908

0.0098

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

SOBOLAN

0.00001

Compusul

DIOXINA
TOXINA
BOTULINICA

84.07
149322.7

CLASIFICAREA SUBSTANTELOR
TOXICE CONFORM TOXICITATII
RELATIVE
CATEGORIA
SUPERTOXICE
sau <
EXTREM DE TOXICE
mg/kg
FOARTE TOXICE
mg/kg
MODERAT TOXICE
CU TOXICITATE REDUSA
PRACTIC NETOXICE

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

ENDOBIOTICE
METABOLIS
M

XENOBIOTIC
E

PREDICTIA CONSECINTELOR
METABOLICE
DETERMINAREA POTENTIALULUI TOXIC
METABOLISM DETERMINANTA A TOXICITATII
DETOXIFIERE
A
BIOACTIVAREA

ECHILIBRU FRAGIL
PLURIFACTORIAL
CITOTOXICITATE
CARCINOGENEZA

METABOLIZAREA XENOBIOTICELOR
DE CATRE FLORA INTESTINALA

HIDROLIZA

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

DEHIDROXILARE
DECARBOXILARE
DEAMINARE
DEHIDROGENARE
DEHALOGENARE

REDUCERE

GRUPARE NITRO
LEGATURI DUBLE
ALDEHIDE
ALCOOLI

AMINOACIZI
AMINOACIZI
COLESTEROL, ACIZI BILIARI
DDT
ACID P-NITROBENZOIC
ACIZI GRASI NESATURATI
BENZALDEHIDE
ALCOOLI BEZILICI

ALTE REACTII

FORMARE NITROZAMINE
AROMATIZAREA
ACETILAREA
ESTERIFICAREA

DIMETILNITROZAMINA
ACID CHINIC
HISTAMINA
ACID GALIC

METABOLIZAREA XENOBIOTICELOR
REACTII FAZA I
OXIDAREA
MONOOXIGENAZE (P450)
XANTINOXIDAZE
PEROXIDAZE
AMINOXIDAZE
MAO
DIOXIGENAZE

REDUCEREA

MONOOXIGENAZE (P450)
CETOREDUCTAZE
GLUTATIONPEROXIDAZE
EPOXIDHIDROLAZE
SOD

HIDROLIZA

HIDROLIZA ESTERILOR
CARBOXILESTERAZE
AMIDAZE

REACTII FAZA II

GLUCURONILTRANSFERAZA

SULFOTRANSFERAZA

GLUTATION S-TRANSFERAZA

TIOLTRANSFERAZA

METILTRANSFERAZA

N-ACETILTRANSFERAZA

SULFTRANSFERAZA

(GLUCURONIDAREA)
(SULFOCONJUGAREA)
(GLUTATION - CONJUGAREA)

(METILAREA)
(ACETILAREA)
(RODANAZA)

ENTITATI TOXICE CONSECUTIVE

METABOLIZARI UNOR COMPUSI

EPOXIZI
RADICALI LIBERI

COMPUSI N-HIDROXILATI
NITROZAMINE

EPOXIZI

RADICALI LIBERI

AFLATOXINA B1
BENZEN, BROMBENZEN
FUROSEMID
OLEFINE
BIFENILI POLICLORURATI SI POLIBROMATI
TRICLORETILENA
CLORURA DE VINIL
TETRACLORURA DE CARBON
HALOTAN
BROMTRICLORMETAN
PARAQUAT
UNELE ALIMENTE
RADIATII IONIZANTE
INFLAMATIE
PROCESE PATOGENICE
PARACETAMOL

COMPUSI N-HIDROXILATI

URETAN
AMINE

NITROZAMINE
(tub digestiv)

NITRITI

Compusi bioactivi
(modificat dupa Frank Lu, 1991)
Compusul initial

Metabolit toxic

Mecanismul
toxicitatii

Consecinte organofunctionale

Acetaminofen
(Paracetamol)

Derivat N-hidroxi

Legatura
covalenta

Necroza hepatica

2-Acetilaminofluoren

N-acetoxi-AAF
AAF N-sulfat

Legatura
covalenta

Cancer

Aflatoxin B1

Aflatoxin-2,3epoxid

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

Compusi bioactivi
(modificat dupa Frank Lu, 1991)
Compusul initial

Metabolit toxic

Mecanismul
toxicitatii

Consecinte organofunctionale

Hidrocarburi
policiclice
carciogene

Epoxizi in diverse
organe

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 Nhidroxi

Necunoscut

Hemoliza

Izoniazida

Acetihidrazina

Legatura
covalenta

Necroza hepatica

Meclizina

Noroclorciclizina

Necunoscut

Teratogeneza

Compusi bioactivi
(modificat dupa Frank Lu, 1991)
Compusul initial

Metabolit toxic

Mecanismul
toxicitatii

Consecinte organofunctionale

Metanol

Formaldehida

Complex

Toxicitate retiniana si
generala

Compusi nitro si
amine aromatice
methemoglobinizant
e

Metaboliti Nhidroxi

Oxidare, reducere
ciclica

Methemoglobinemie

Metoxifluran

Fluor anorganic

Inhibitie
enzimatica

Insuficienta renala

Naftilamina

N-hidroxi
naftilamina

Legatura
covalenta

Cancer vezical

Nitriti si amine
Nitrosamine
secundare si tertiare

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

FARMACOCINETICA TOXOCINETICA
PARAMETRU

FARMACOCINETIC
A

TOXOCINETICA

DOZA

CUNOSCUTA
REDUSA

NECUNOSCUTA
FOARTE MARE

EFECT

TERAPEUTIC

TOXIC

STEADY STATE

UZUAL

NU

DATE CLINICE
COROBORANTE

FRECVENT

INCOMPLETE

CONCENTRATIE-EFECTE

DA

INCOMPLETE

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
CARBON
BROMTRICLORMETA
N

RADICALI LIBERI
PEROXIDARE

RECEPTOR NICOTINIC

NICOTINA
CURARIZANTE

STIMULARE DIRECTA
BLOCARE, PARALIZIE

RECEPTOR MUSCARINIC

MUSCARINA

STIMULARE INTENSA,