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

INTERRELATIILE SI APLICATIILE SALE

BIOLOGIE CHIMIE ZOOLOGIE BIOCHIMIE BOTANICA GENETICA FIZIOLOGIE FARMACOLOGIE

EVOLUTIA TOXICOLOGIEI:

TOXICOLOGIE
OCUPATIONALA LEGALA TOXICOLOGIE TOXICOLOGIE MEDIULUI VETERINARA CLINICA

PIROTOXICOLOGIE INHALATORIE BIOCHIMICA FITOTOXICOLOGIE TOXICOLOGIE

TOXICOLOGIE GENETICA

EPIDEMIOLOGIA INTOXICATIILOR ACUTE

1986: 4.8 MILIOANE INTOXICATII ( ASOCIATIA AMERICANA A CENTRELOR CONTRA INTOXICATIILOR) 22% EVALUATI ~ 1% 80% DECESE CALE ORALA
DISTRIBUTIE SEX M F VARSTA 67 12 29 30 39 > 40 ACC. 40 22 SUICID 28 42 NEC

IN CENTRE

DE

INTOXICATI

SAU

URGENTA

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

47 40 42 19

53 27 24 46

Zurich Toxicology Information Center, 2000

Adults
Agent groups/Severity of poisoning N 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
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

FEMEI
15-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90 TOTAL 15-20 21-30 31-40 41-50

BARBATI
51-60 61-70 71-80 81-90 TOTAL

TOTAL GENERAL

POLIMEDICAMENTOASE BENZODIAZEPINE BARBITURICE ALCOOL ETILIC ALCOOL+MEDICAMENTE NEUROLEPTICE TUBERCULOSTATICE ANTIDEPRESIVE MONOXID DE CARBON ETILENGLICOL CIUPERCI COF METANOL OPIACEE SDR. INTRERUPERE SOLVENTI COROZIVE / CAUSTICE ANTICONVULSIVANTE ANXIOLITICE BETA-BLOCANTE BLOCANTE DE CALCIU PARACETAMOL METALE DIVERSE NEPRECIZATE

270 82 113 33 34 13 4 26 39 3 14 22 1 40 20 5 4 23 112 2 1 2 1 116 36

324 116 154 44 53 15 3 32 77 2 29 47 0 57 33 18 7 18 108 1 2 1 0 144 39

239 83 89 31 47 10 3 22 44 0 26 39 0 12 5 10 6 14 64 1 1 0 0 100 23

220 37 63 33 61 6 3 30 50 2 25 50 1 6 2 14 4 8 45 1 4 O 0 131 17

124 31 28 20 22 12 0 15 36 2 12 18 1 1 1 7 3 6 16 1 2 O 0 101 7

81 20 10 11 9 5 1 5 31 1 14 15 0 2 0 4 2 0 11 1 4 O 0 99 3

51 20 12 5 4 0 0 2 28 4 4 10 0 1 0 3 0 2 3 0 0 O 0 109 8

18 9 9 0 0 0 0 1 17 0 0 2 0 0 0 3 0 2 1 0 0 O 0 16 3

1327 398 478 177 230 61 14 131 322 14 124 203 3 119 61 64 26 73 360 7 14 3 1 816 136

91 39 22 109 23 7 2 5 49 3 10 19 1 127 70 13 0 8 21 1 3 0 2 30 14

218 54 79 103 95 16 8 12 57 5 22 46 1 209 155 34 5 21 48 1 2 1 0 94 36

110 25 23 151 84 7 3 11 57 8 24 55 5 28 20 27 3 12 10 1 4 0 0 73 20

79 26 27 145 71 3 1 9 45 12 17 52 4 5 6 27 1 13 13 3 0 0 0 92 14

29 11 8 88 28 6 0 6 37 8 11 35 1 1 6 19 10 2 7 0 6 0 0 100 6

12 9 1 38 11 0 0 0 25 8 9 19 1 1 4 10 0 0 4 0 3 0 0 76 5

15 4 5 14 5 0 0 3 19 4 2 11 0 0 0 3 1 1 0 0 0 0 0 71 4

1 3 0 2 2 0 0 0 7 0 0 1 0 0 0 4 0 0 0 0 0 0 0 16 0

555 171 165 650 319 39 14 46 296 48 95 238 13 371 261 137 20 57 103 6 18 1 2 552 99

1882 569 643 827 549 100 28 177 618 62 219 441 16 490 322 201 46 130 463 13 22 4 3 1368 235

CAUSE DISTRIBUTION OF ICU CAUSE DISTRIBUTION OF ICU HOSPITALIZED POISENED PATIENTS HOSPITALIZED POISENED PATIENTS
OTHE CAUS S R E B ARB ITURATE S P OLIDRUGS E THILICS ANTIDE RE IVE P S S NE UROLE TICS P UNDE RMINATE TE D B NZ E ODIAZE INE P S 0 5 0 10 0 10 5 20 0 20 5 30 0 30 5

W OMEN MEN

STATISTICS - 1995
Total Patients: 5 627
Hospitalisation 60%

Refuse hospitalsation 40 %

Non-Drug Intoxications 43%

Hospitalized: 3 357
Interna l Medicin e 70%

Drug Intoxications 57%

Total STI: 1 000 Patients

W mn o e 5% 4
Non-Drug Intoxications 19%

2 357 Patients
Drug Intoxications 81%

Me n 4% 6

PATIENTS HOSPITALIZED IN ICU

Men 35%

TOTAL HOSPITALIZED PATIENTIS IN ICU 1000

Death 7%

Women 65%

70 PATIENTS DIED

Survive 93%

DRUG INTOXICATION
Polidrug Ba rbitura s te Be nzodia pine ze s Ne urole ptics Tricic a ide sive lic nt pre Izonia zide Anticonvulsiva e nt s Une xpla d Substa s ine nce
0 2 0 4 0 6 0 8 0 10 0 10 2 10 4 10 6 10 8 20 0

Tota l

Wo e mn

Me n

De th a

Et nol+ ha Drugs or Nondrugs

NON-DRUG INTOXICATION

Et nol ha De e t rge s nt Aniline Mushroom s

Mn e

Inse icide ct s OPC Me ha t nol

W mn o e

Solve s nt CO Et hile nglicol Burns (a cids) Burns (ba s) se

8 0

6 0

4 0

10 4

10 2

10 0

2 0

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-9-CM Poisoning 95% CI % Poisoning- 95% CI
Code Related ED Visits in 1000s
200 79 52 42 39 34 31 30 24

Related ED visits
20,7 8.2 5.4 4.4 4.1 3.6 3.2 3.1 2.5

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

977 965 969 987 989 986 300 955 311

169,232 53,105 37,67 27,57 27,51 19,49 17,44 16,44 13,35

18.1, 23.3 5.6, 10.8 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

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

The Poisoning Pyramid

Death Hospitalizatio ns Emergency department visits Poison exposures

13

59

14 7

The prevalence of drug addicts (overdose and withdrawal syndrome) between 19892008

13% 12% 8%

14

8%
6.70% 5%

12

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

4%
2.70%

4%

10

8%

6%

4%

2%
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

0%

PARAMETRII CANTITATIVI AI TOXICITATII

DL 50 (EXPERIMENTAL) mM/kg mg/m2
CLORURA MERCURICA METANOL NICOTINA PARALDEHIDA PARATION FENOLI FOSFOR (galben) STRICNINA TALIU FORMALDEHIDA

mg/kg

DML (DOZA MINIMA LETALA OM) 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 10 mg BARBITURICE 15g ACID BORIC 12 g CAMFOR 2g CLORALHIDRAT 7g CLORAT DE K 8g FLUORURA DE K 1g

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

Mortalitate (%)

Doza (mg/kg)

Compusul

Doza medie letal pentru diverse substante Masa DL 50 (mM/kg)

Specia Dl50 (mg/kg, parenteral)
10000 4000 1500 900 150 100 5 2 1 0.5 0.2 0.1 0.001 0.00001

moleculara (g/mol)
46 58.443 151.908 285.34

ETANOL CLORURA DE SODIU SULFAT FEROS MORFINA SULFAT FENOBARBITAL SULFAT DDT PICROTOXINA STRICNINA SULFAT NICOTINA d-TUBOCURARINA HEMICOLINIUM-3 TETRODOTOXIN DIOXINA TOXINA BOTULINICA

SOARECE SOARECE SOBOLAN SOBOLAN SOBOLAN SOBOLAN SOBOLAN SOBOLAN SOBOLAN SOBOLAN SOBOLAN SOBOLAN COBAI SOBOLAN

0.2173 0.068 0.0098 0.0031 0.00064 0.00028 0.0000082 0.0000059 0.0000061 0.0000008 0.0000004 0.0000003

232.235 354.49 602.583 334.41 162.26 624.765 414.538 319.27 84.07 149322.7

CLASIFICAREA SUBSTANTELOR TOXICE CONFORM TOXICITATII RELATIVE

CATEGORIA CATEGORIA SUPERTOXICE SUPERTOXICE < < EXTREM DE TOXICE EXTREM DE TOXICE FOARTE TOXICE FOARTE TOXICE mg/kg mg/kg MODERAT TOXICE MODERAT TOXICE CU TOXICITATE REDUSA CU TOXICITATE REDUSA PRACTIC NETOXICE PRACTIC NETOXICE DL50 DL50 5 mg/kg sau 5 mg/kg sau 5 50 mg/kg 5 50 mg/kg 50 500 50 500 0.5 5 g/kg 0.5 5 g/kg 5 15 g/kg 5 15 g/kg > 15 g/kg > 15 g/kg

ENDOBIOTICE METABOLIS M XENOBIOTIC E

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

ECHILIBRU FRAGIL PLURIFACTORIAL CITOTOXICITATE CARCINOGENEZA

METABOLIZAREA XENOBIOTICELOR METABOLIZAREA XENOBIOTICELOR DE CATRE FLORA INTESTINALA DE CATRE FLORA INTESTINALA

HIDROLIZA HIDROLIZA

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

DEHIDROXILARE DEHIDROXILARE DECARBOXILARE DECARBOXILARE DEAMINARE DEAMINARE DEHIDROGENARE DEHIDROGENARE DEHALOGENARE DEHALOGENARE REDUCERE REDUCERE
GRUPARE NITRO GRUPARE NITRO LEGATURI DUBLE LEGATURI DUBLE ALDEHIDE ALDEHIDE ALCOOLI ALCOOLI FORMARE NITROZAMINE FORMARE NITROZAMINE AROMATIZAREA AROMATIZAREA ACETILAREA ACETILAREA ESTERIFICAREA ESTERIFICAREA

AMINOACIZI AMINOACIZI AMINOACIZI AMINOACIZI COLESTEROL, ACIZI BILIARI COLESTEROL, ACIZI BILIARI DDT DDT
ACID P-NITROBENZOIC ACID P-NITROBENZOIC ACIZI GRASI NESATURATI ACIZI GRASI NESATURATI BENZALDEHIDE BENZALDEHIDE ALCOOLI BEZILICI ALCOOLI BEZILICI DIMETILNITROZAMINA DIMETILNITROZAMINA ACID CHINIC ACID CHINIC HISTAMINA HISTAMINA ACID GALIC ACID GALIC

ALTE REACTII ALTE REACTII

METABOLIZAREA XENOBIOTICELOR METABOLIZAREA XENOBIOTICELOR REACTII FAZA I REACTII FAZA I

OXIDAREA OXIDAREA

HIDROLIZA

MONOOXIGENAZE (P450) MONOOXIGENAZE (P450) XANTINOXIDAZE XANTINOXIDAZE PEROXIDAZE PEROXIDAZE AMINOXIDAZE AMINOXIDAZE MAO MAO DIOXIGENAZE DIOXIGENAZE
REDUCEREA

HIDROLIZA ESTERILOR CARBOXILESTERAZE AMIDAZE

MONOOXIGENAZE (P450) CETOREDUCTAZE GLUTATIONPEROXIDAZE EPOXIDHIDROLAZE SOD

REACTII FAZA II REACTII FAZA II

GLUCURONILTRANSFERAZA GLUCURONILTRANSFERAZA SULFOTRANSFERAZA SULFOTRANSFERAZA GLUTATION S-TRANSFERAZA GLUTATION S-TRANSFERAZA CONJUGAREA) CONJUGAREA) TIOLTRANSFERAZA TIOLTRANSFERAZA METILTRANSFERAZA METILTRANSFERAZA N-ACETILTRANSFERAZA N-ACETILTRANSFERAZA SULFTRANSFERAZA SULFTRANSFERAZA

(GLUCURONIDAREA) (GLUCURONIDAREA) (SULFOCONJUGAREA) (SULFOCONJUGAREA) (GLUTATION (GLUTATION -

(METILAREA) (METILAREA) (ACETILAREA) (ACETILAREA) (RODANAZA) (RODANAZA)

EPOXIZI RADICALI LIBERI

ENTITATI TOXICE CONSECUTIVE METABOLIZARI UNOR COMPUSI

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 URETAN AMINE

COMPUSI N-HIDROXILATI NITROZAMINE

EPOXIZI

RADICALI LIBERI

COMPUSI N-HIDROXILATI NITROZAMINE (tub digestiv)

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 Metabolit toxic Derivat N-hidroxi N-acetoxi-AAF AAF N-sulfat Mecanismul toxicitatii Consecinte organofunctionale Legatura covalenta Necroza hepatica Legatura covalenta Cancer

Aflatoxin-2,3-epoxidLegatura covalenta Cancer hepatic Acroleina Epoxid Mandelonitril (flora intestinala) Benzen epoxid Brombenzen Radical liber triclormetan Legatura covalenta Necroza hepatica Necunoscut Distructie citocrom P450 Porfirie

Formare de cianura Hipoxie citotoxica Legatura covalenta Depresie maduva hematopetica Legatura covalenta Necroza hepatica, renala, bronsiolara Legatura covalenta, Necroza hepatica, peroxidarea Cancer hepatic lipidelor

Compusi bioactivi (modificat dupa Frank Lu, 1991)

Compusul initial Metabolit toxic Mecanismul toxicitatii Consecinte organofunctionale Hidrocarburi Epoxizi in diverse policiclice carciogene organe Cloroform Cicasin Ciclamat Etanol Fluoracetat Furosemid Halotan Amine aromatice hemolizante Izoniazida Meclizina Fosgen Metilazometanol Ciclohexilamina Acetaldehida in diverse organe Fluorocitrat Epoxid Radical liber Legatura covalenta Cancer, citotoxicitate

Legatura covalenta Necroza hepatica, renala Alchilare Necunoscut Complex Cancer, necroza hepatica Cancer de vezica Diferite

Inhibitie enzimatica Toxicitate generala Legatura covalenta Necroza hepatica, renala Legatura covalenta Necroza hepatica Hemoliza

Metaboliti N-hidroxi Necunoscut Acetihidrazina Noroclorciclizina

Legatura covalenta Necroza hepatica Necunoscut Teratogeneza

Compusul initial Metanol

Compusi bioactivi (modificat dupa Frank Lu, 1991)

Metabolit toxic Mecanismul toxicitatii Formaldehida Complex

Consecinte organofunctionale

Toxicitate retiniana si generala Methemoglobinemie

Compusi nitro si Metaboliti N-hidroxi Oxidare, reducere amine aromatice ciclica methemoglobinizante Metoxifluran Naftilamina Nitriti si amine secundare si tertiare Olefine Paration Fluor anorganic N-hidroxi naftilamina Nitrosamine Epoxizi Paraoxon

Inhibitie enzimatica Insuficienta renala Legatura covalenta Cancer vezical Alchilare Cancer hepatic, pulmonar

Legatura covalenta Cancer de piele Legatura covalenta Paralizie neuromusculara, cu colinesterazele insuficienta respiratorie Sinteza letala, incorporare letala Necunoscut Citotoxicitate

Analogi baze purinice Mononucleotide, si pirimidinice nucleotizi trifosfat Alcaloizi pirolizidinici Derivati pirolitici

Necroza hepatica si canceroasa

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

FARMACOCINETICA TOXOCINETICA
CUNOSCUTA REDUSA TERAPEUTIC UZUAL FRECVENT DA 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 INACTIVAREA GRUPARILOR TIOLICE FORMAREA: CARBOXIHEMOGLOBINEI METHEMOGLOBINEI BLOCAREA SINTEZEI ACIZILOR NUCLEICI

GRUPARI TIOLICE ENZIMATICE HEMOGLOBINA

METALE GRELE MONOXID DE CARBON, NITRITI, NITRATI ALCHILANTE RADIOMIMETICE

ACIZI NUCLEICI LIPIDE STRUCTURALE

TETRACLORURA DE RADICALI LIBERI CARBON PEROXIDARE BROMTRICLORMETAN NICOTINA CURARIZANTE MUSCARINA STIMULARE DIRECTA BLOCARE, PARALIZIE STIMULARE INTENSA, SINDROM

RECEPTOR NICOTINIC RECEPTOR MUSCARINIC