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 MEDIULUI CLINICA VETERINARA

TOXICOLOGIE INHALATORIE
TOXICOLOGIE GENETICA

PIROTOXICOLOGIE

TOXICOLOGIE BIOCHIMICA
TOXICOLOGIE ACVATICA

FITOTOXICOLOGIE

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 DISTRIBUTIE

ALCOOL ETILIC DIAZEPAM MORFINICE ASPIRINA FENCICLIDINA MARIJUANA AMITRIPTILINA FENOBARBITAL HIDANTOINE HIPNOTICE AMFETAMINE NEUROLEPTICE DETERGENTI SOLVENTI INSECTICIDE

SEX M F
VARSTA 67 12 29 30 39 > 40

ACC. 40 22
47 40 42 19

SUICID 28 42
53 27 24 46

NEC 31 36
_ 32 34 34

Zurich Toxicology Information Center, 2000

Adults
Agent groups/Severity of poisoning Drugs Household products Technical and industrial products Recreational and abused drugs Plants Mushrooms Products used in agriculture and horticulture Toilet articles and cosmetics Poisonous animals Food and beverages Veterinary drugs Other and unknown agents Total
N 264 28 20 9 8 3 6 2 1 2 3 4 350 Mi 1126 123 169 72 27 17 19 19 15 4 1 50 1642 Mo 424 20 46 83 17 26 9 3 4 3 4 11 650 S 161 4 10 50 4 6 4 1 2 242 F 11 2 1 1 15 N 263 83 24 16 25 4 21 17 2 1 1 457

Children
Mi 263 89 26 19 15 1 6 10 7 6 21 463 Mo 58 6 3 4 3 3 3 80 S 15 6 1 2 2 26 F 1 1

Total

2586 (69.9 %) 359 (9.1%) 301 (7.7%) 256 (6.6%) 95 (2.4%) 60 (1.5%) 68 (1.7%) 51 (1.3%) 36 (0.9%) 17 (0.4%) 8 (0.2%) 89 (2.3%) 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 POLIMEDICAMENTOASE BENZODIAZEPINE BARBITURICE ALCOOL ETILIC ALCOOL+MEDICAMENTE NEUROLEPTICE TUBERCULOSTATICE ANTIDEPRESIVE MONOXID DE CARBON

FEMEI
1520 270 82 113 33 34 13 4 26 39 2130 324 116 154 44 53 15 3 32 77 3140 239 83 89 31 47 10 3 22 44 4150 220 37 63 33 61 6 3 30 50 5160 124 31 28 20 22 12 0 15 36 6170 81 20 10 11 9 5 1 5 31 7180 51 20 12 5 4 0 0 2 28 8190 18 9 9 0 0 0 0 1 17 TOTAL 1520 91 39 22 109 23 7 2 5 49 2130 218 54 79 103 95 16 8 12 57 3140 110 25 23 151 84 7 3 11 57 4150 79 26 27 145 71 3 1 9 45

BARBATI
5160 29 11 8 88 28 6 0 6 37 6170 12 9 1 38 11 0 0 0 25 7180 15 4 5 14 5 0 0 3 19 8190 1 3 0 2 2 0 0 0 7 TOTAL

TOTAL GENE RAL

1327 398 478 177 230 61 14 131 322

555 171 165 650 319 39 14 46 296

1882 569 643 827 549 100 28 177 618

ETILENGLICOL
CIUPERCI COF METANOL OPIACEE SDR. INTRERUPERE SOLVENTI

3
14 22 1 40 20 5

2
29 47 0 57 33 18

0
26 39 0 12 5 10

2
25 50 1 6 2 14

2
12 18 1 1 1 7

1
14 15 0 2 0 4

4
4 10 0 1 0 3

0
0 2 0 0 0 3

14
124 203 3 119 61 64

3
10 19 1 127 70 13

5
22 46 1 209 155 34

8
24 55 5 28 20 27

12
17 52 4 5 6 27

8
11 35 1 1 6 19

8
9 19 1 1 4 10

4
2 11 0 0 0 3

0
0 1 0 0 0 4

48
95 238 13 371 261 137

62
219 441 16 490 322 201

COROZIVE / CAUSTICE
ANTICONVULSIVANTE ANXIOLITICE BETA-BLOCANTE BLOCANTE DE CALCIU PARACETAMOL METALE DIVERSE NEPRECIZATE DECESE

4
23 112 2 1 2 1 116 36 7

7
18 108 1 2 1 0 144 39 4

6
14 64 1 1 0 0 100 23 2

4
8 45 1 4 O 0 131 17 14

3
6 16 1 2 O 0 101 7 1

2
0 11 1 4 O 0 99 3 12

0
2 3 0 0 O 0 109 8 16

0
2 1 0 0 O 0 16 3 11

26
73 360 7 14 3 1 816 136 67

0
8 21 1 3 0 2 30 14 2

5
21 48 1 2 1 0 94 36 11

3
12 10 1 4 0 0 73 20 15

1
13 13 3 0 0 0 92 14 14

10
2 7 0 6 0 0 100 6 13

0
0 4 0 3 0 0 76 5 18

1
1 0 0 0 0 0 71 4 13

0
0 0 0 0 0 0 16 0 8

20
57 103 6 18 1 2 552 99 94

46
130 463 13 22 4 3 1368 235 161

CAUSE DISTRIBUTION OF ICU HOSPITALIZED POISENED PATIENTS

OTHER CAUSES BARBITURATES POLIDRUGS ETHILICS ANTIDEPRESIVES NEUROLEPTICS UNDETERMINATED BENZODIAZEPINES 0 50 100 150 200 250 300 350

WOMEN MEN

STATISTICS - 1995
Total Patients: 5 627
Hospitalisation 60%

Refuse hospitalsation 40%

Non-Drug Intoxications 43%

Hospitalized: 3 357
Internal Medicine 70%

Drug Intoxications 57%

Total STI: 1 000 Patients Women

54%
Non-Drug Intoxications 19%

2 357 Patients
Drug Intoxications

Men 46%

PATIENTS HOSPITALIZED IN ICU

TOTAL HOSPITALIZED PATIENTIS IN ICU 1000
Men 35% Women 65%

Death 7%

70 PATIENTS DIED

Survive 93%

DRUG INTOXICATION
Polidrug Barbiturates Benzodiazepines Neuroleptics Triciclic antidepresive Izoniazide Anticonvulsivantes Unexplained Substances
0 20 40 60 80 100 120 140 160 180 200

Total

Women

Men

Death

NON-DRUG INTOXICATION

Ethanol+Drugs or Nondrugs Ethanol Detergents Aniline Mushrooms

Men

Insecticides OPC Methanol Solvents CO Ethilenglicol Burns (acids) Burns (bases)

140

120

100

80

Women
60 40

20

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 70 60 50 40 30 20 10 0

75

45 47 22

17 6

Urgent Poisoning Illness

Admitted Nonpoisoning injury

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
Principal Diagnosis ICD-9CM Code
977 965

Poisoning Related ED Visits in 1000s

200 79

95% CI
169,232 53,105

% PoisoningRelated ED visits
20,7 8.2

95% CI
18.1, 23.3 5.6, 10.8

Poisoning by other and unspecified drugs and medicinal substances Poisoning by analgesic, antipyretics and antirheumatics

Poisoning by psyhotrops agents

Toxic effect of other gases, fumes or vapors Toxic effect of other substances, chiefly nonmedical as to source Toxic effect of carbon monoxide Neurotic disorders Certain adverse effects not elsewhere classified Depressive disorder, not elsewhere classified Nondependent abuse of drugs

969
987 989 986 300 955 311 305

52
42 39 34 31 30 24 24

37,67
27,57 27,51 19,49 17,44 16,44 13,35 13,35

5.4
4.4 4.1 3.6 3.2 3.1 2.5 2.5

3.9, 6.9
2.9, 5.9 2.8, 5.4 2.1, 5.1 1.8, 4.6 1.7, 4.5 1.4, 3.6 1.4, 3.6

The Poisoning Pyramid

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

Death
Hospitalizations

13

59

Emergency department visits Poison exposures

147

The prevalence of drug addicts (overdose and withdrawal syndrome) between 1989-2008

13% 12% 8% 14%

8%
6.70%

12%
5%

4% 3% 2% 2% 2% 2% 2% 2% 0% 1%1%

10%
4%

4%
2.70%

8% 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
0.5 g 70 ml 50 mg 100 ml 25 mg 10 ml 0.1 g 50 mg 0.8 g 30 ml ARSENIC ACONITINA BARBITURICE ACID BORIC CAMFOR CLORALHIDRAT CLORAT DE K FLUORURA DE K 100 mg 10 mg 15g 12 g 2g 7g 8g 1g

DML (DOZA MINIMA LETALA OM) CLORURA MERCURICA METANOL NICOTINA PARALDEHIDA PARATION FENOLI FOSFOR (galben) STRICNINA TALIU FORMALDEHIDA

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

Mortalitate (%)

Doza (mg/kg)

Doza medie letal pentru diverse substante

Compusul
ETANOL CLORURA DE SODIU SULFAT FEROS MORFINA SULFAT FENOBARBITAL SULFAT

Specia
SOARECE SOARECE SOBOLAN SOBOLAN SOBOLAN

Dl50 (mg/kg, parenteral)

10000 4000 1500 900 150

Masa moleculara (g/mol)

46 58.443 151.908 285.34 232.235 354.49

DL 50 (mM/kg)
0.2173 0.068 0.0098 0.0031 0.00064 0.00028

DDT
PICROTOXINA STRICNINA SULFAT NICOTINA d-TUBOCURARINA HEMICOLINIUM-3 TETRODOTOXIN DIOXINA TOXINA BOTULINICA

SOBOLAN
SOBOLAN SOBOLAN SOBOLAN SOBOLAN SOBOLAN SOBOLAN COBAI SOBOLAN

100
5 2 1 0.5 0.2 0.1 0.001 0.00001

602.583
334.41 162.26 624.765 414.538 319.27 84.07 149322.7

0.0000082
0.0000059 0.0000061 0.0000008 0.0000004 0.0000003

CLASIFICAREA SUBSTANTELOR TOXICE CONFORM TOXICITATII RELATIVE

CATEGORIA DL50

SUPERTOXICE EXTREM DE TOXICE FOARTE TOXICE MODERAT TOXICE CU TOXICITATE REDUSA PRACTIC NETOXICE

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

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 BENZILICI

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

HIDROLIZA
HIDROLIZA ESTERILOR CARBOXILESTERAZE AMIDAZE

REDUCEREA
MONOOXIGENAZE (P450) CETOREDUCTAZE GLUTATIONPEROXIDAZE EPOXIDHIDROLAZE SOD

REACTII FAZA II
GLUCURONILTRANSFERAZA (GLUCURONIDAREA)

SULFOTRANSFERAZA

(SULFOCONJUGAREA)

GLUTATION S-TRANSFERAZA (GLUTATION - CONJUGAREA) TIOLTRANSFERAZA METILTRANSFERAZA N-ACETILTRANSFERAZA (METILAREA) (ACETILAREA)

SULFTRANSFERAZA

(RODANAZA)

EPOXIZI RADICALI LIBERI

ENTITATI TOXICE CONSECUTIVE METABOLIZARI UNOR COMPUSI

COMPUSI N-HIDROXILATI NITROZAMINE AFLATOXINA B1 BENZEN, BROMBENZEN FUROSEMID OLEFINE BIFENILI POLICLORURATI SI POLIBROMATI TRICLORETILENA CLORURA DE VINIL

EPOXIZI

RADICALI LIBERI

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

COMPUSI N-HIDROXILATI NITROZAMINE (tub digestiv)

PARACETAMOL URETAN
AMINE NITRITI

Compusi bioactivi (modificat dupa Frank Lu, 1991)

Compusul initial Acetaminofen (Paracetamol) 2-Acetilaminofluoren Aflatoxin B1 Alil formiat Alilizopropil acetamida Amigdalina Benzen Brombenzen Tetraclorura de carbon Alchilnitrosamine carcinogene Coloranti amino carcinogeni Metabolit toxic Derivat N-hidroxi N-acetoxi-AAF AAF N-sulfat Aflatoxin-2,3-epoxid Acroleina Epoxid Mandelonitril (flora intestinala) Benzen epoxid Brombenzen Radical liber triclormetan Alfa-hidroxilare Derivati N-hidroxi Mecanismul toxicitatii Legatura covalenta Legatura covalenta Legatura covalenta Legatura covalenta Necunoscut Formare de cianura Legatura covalenta Legatura covalenta Legatura covalenta, peroxidarea lipidelor Alchilare Legatura covalenta Consecinte organo-functionale Necroza hepatica Cancer Cancer hepatic Necroza hepatica Distructie citocrom P450 Porfirie Hipoxie citotoxica Depresie maduva hematopetica Necroza hepatica, renala, bronsiolara Necroza hepatica, Cancer hepatic Cancer hepatic Cancer hepatic

Compusi bioactivi (modificat dupa Frank Lu, 1991)

Compusul initial Hidrocarburi policiclice carcinogene Cloroform Cicasin Ciclamat Etanol Fluoracetat Furosemid Halotan Amine aromatice hemolizante Izoniazida Metabolit toxic Epoxizi in diverse organe Fosgen Metilazometanol Ciclohexilamina Acetaldehida in diverse organe Fluorocitrat Epoxid Radical liber Metaboliti N-hidroxi Acetihidrazina Mecanismul toxicitatii Legatura covalenta Legatura covalenta Alchilare Necunoscut Complex Inhibitie enzimatica Legatura covalenta Legatura covalenta Necunoscut Legatura covalenta Consecinte organo-functionale Cancer, citotoxicitate Necroza hepatica, renala Cancer, necroza hepatica Cancer de vezica Diferite Toxicitate generala Necroza hepatica, renala Necroza hepatica Hemoliza Necroza hepatica

Meclizina

Noroclorciclizina

Necunoscut

Teratogeneza

Compusi bioactivi (modificat dupa Frank Lu, 1991)

Compusul initial Metanol Compusi nitro si amine aromatice methemoglobinizante Metoxifluran Naftilamina Nitriti si amine secundare si tertiare Olefine Paration Analogi baze purinice si pirimidinice Alcaloizi pirolizidinici Talidomida Metabolit toxic Formaldehida Metaboliti N-hidroxi Mecanismul toxicitatii Complex Oxidare, reducere ciclica Inhibitie enzimatica Legatura covalenta Alchilare Legatura covalenta Legatura covalenta cu colinesterazele Sinteza letala, incorporare letala Necunoscut Necunoscut Consecinte organo-functionale Toxicitate retiniana si generala Methemoglobinemie

Fluor anorganic N-hidroxi naftilamina Nitrosamine Epoxizi Paraoxon Mononucleotide, nucleotizi trifosfat Derivati pirolitici Acid ftalil L-glutamic

Insuficienta renala Cancer vezical Cancer hepatic, pulmonar Cancer de piele Paralizie neuromusculara, insuficienta respiratorie Citotoxicitate Necroza hepatica si canceroasa Teratogeneza

Uretan

N-hidroxil uretan

Alchilare

Cancer, citotoxicitate

FARMACOCINETICA TOXOCINETICA
PARAMETRU
DOZA EFECT STEADY STATE DATE CLINICE COROBORANTE CONCENTRATIE-EFECTE

FARMACOCINETICA
CUNOSCUTA REDUSA TERAPEUTIC UZUAL FRECVENT DA

TOXOCINETICA
NECUNOSCUTA FOARTE MARE TOXIC NU INCOMPLETE INCOMPLETE

TOXICE, RECEPTORI SI CONSECINTA INTERACTIUNII LOR

RECEPTOR TOXODINAMIC COLINESTERAZE CITOCROMOXIDAZA TOXIC COMPUSI ORGANOFOSFORICI CIANURI MECANISM BLOCAREA CENTRULUI ESTERAZIC BLOCAREA TRANSPORTULUI DE ELECTRONI IN LANTUL RESPIRATOR

GRUPARI TIOLICE ENZIMATICE

HEMOGLOBINA

METALE GRELE
MONOXID DE CARBON, NITRITI, NITRATI ALCHILANTE RADIOMIMETICE

INACTIVAREA GRUPARILOR TIOLICE

FORMAREA: CARBOXIHEMOGLOBINEI METHEMOGLOBINEI BLOCAREA SINTEZEI ACIZILOR NUCLEICI

ACIZI NUCLEICI

LIPIDE STRUCTURALE

TETRACLORURA DE RADICALI LIBERI CARBON PEROXIDARE BROMTRICLORMETAN

NICOTINA CURARIZANTE MUSCARINA (AMANITA MUSCARIA) STIMULARE DIRECTA BLOCARE, PARALIZIE STIMULARE INTENSA, SINDROM MUSCARINIC

RECEPTOR NICOTINIC RECEPTOR MUSCARINIC