curs nr 1

TOXICOLOGIE TOXICOLOGIE CLINICA CLINICA

Toate substantele suntToate substantele sunt

toxice, nu exista nici toxice, nu exista nici

una care sa nu fie una care sa nu fie

toxica. toxica.

Numai doza Numai doza diferentiaza un toxic de diferentiaza un toxic de un remediuun remediu

ParacelsusParacelsus

1493-15411493-1541

EVOLUTIA TOXICOLOGIEI:EVOLUTIA TOXICOLOGIEI: INTERRELATIILE SI APLICATIILE SALEINTERRELATIILE SI APLICATIILE SALE

BIOLOGIEBIOLOGIE CHIMIECHIMIEZOOLOGIEZOOLOGIE BIOCHIMIE BIOCHIMIE BOTANICA BOTANICA GENETICA GENETICA FIZIOLOGIE FIZIOLOGIE

FARMACOLOGIE FARMACOLOGIE

TOXICOLOGIETOXICOLOGIE

OCUPATIONALAOCUPATIONALA MEDIULUI MEDIULUI VETERINARA VETERINARA LEGALALEGALA CLINICA CLINICA

TOXICOLOGIE PIROTOXICOLOGIE TOXICOLOGIE PIROTOXICOLOGIE TOXICOLOGIE INHALATORIE TOXICOLOGIE INHALATORIE BIOCHIMICA BIOCHIMICA TOXICOLOGIE FITOTOXICOLOGIE TOXICOLOGIE TOXICOLOGIE FITOTOXICOLOGIE TOXICOLOGIE GENETICA GENETICA

ACVATICAACVATICA

EPIDEMIOLOGIA INTOXICATIILOR ACUTEEPIDEMIOLOGIA INTOXICATIILOR ACUTE1986: 4.8 MILIOANE INTOXICATII 1986: 4.8 MILIOANE INTOXICATII ( ASOCIATIA AMERICANA A CENTRELOR CONTRA INTOXICATIILOR)( ASOCIATIA AMERICANA A CENTRELOR CONTRA INTOXICATIILOR)

22% EVALUATI IN CENTRE DE INTOXICATI SAU URGENTA22% EVALUATI IN CENTRE DE INTOXICATI SAU URGENTA

~ 1% DECESE~ 1% DECESE

80% CALE ORALA80% CALE ORALA

COMPUSI UZUALCOMPUSI UZUAL I IMPLICATIMPLICATI DISTRIBUTIEDISTRIBUTIE

ALCOOL ETILIC SEX ACC. SUICID NEC ALCOOL ETILIC SEX ACC. SUICID NEC

DIAZEPAM M 40 28 DIAZEPAM M 40 28 31 31

MORFINICE F 22 42 MORFINICE F 22 42 36 36

ASPIRINAASPIRINAFENCICLIDINA VARSTAFENCICLIDINA VARSTAMARIJUANA 6 – 7 47 53 MARIJUANA 6 – 7 47 53

_ _ AMITRIPTILINAAMITRIPTILINAFENOBARBITAL 12 – 29 40 27 FENOBARBITAL 12 – 29 40 27

32 32 HIDANTOINE 30 – 39 42 24 HIDANTOINE 30 – 39 42 24

34 34 HIPNOTICE > 40 19 46 HIPNOTICE > 40 19 46

34 34 AMFETAMINEAMFETAMINENEUROLEPTICENEUROLEPTICEDETERGENTIDETERGENTISOLVENTISOLVENTIINSECTICIDEINSECTICIDEPLANTEPLANTE

Zurich Toxicology Information Center, 2000Zurich Toxicology Information Center, 2000

AdultsAdults ChildrenChildren TotalTotal

Agent groups/Severity of Agent groups/Severity of poisoningpoisoning

NN MiMi MoMo SS FF NN MiMi MoMo SS FF

DrugsDrugs 264264 1’1261’126 424424 161161 1111 263263 263263 5858 1515 11 2’586 (69.9 %)2’586 (69.9 %)

Household productsHousehold products 2828 123123 2020 44 -- 8383 8989 66 66 -- 359 (9.1%)359 (9.1%)

Technical and industrial productsTechnical and industrial products 2020 169169 4646 1010 22 2424 2626 33 11 -- 301 (7.7%)301 (7.7%)

Recreational and abused drugsRecreational and abused drugs 99 7272 8383 5050 11 1616 1919 44 22 -- 256 (6.6%)256 (6.6%)

PlantsPlants 88 2727 1717 -- -- 2525 1515 33 -- -- 95 (2.4%)95 (2.4%)

MushroomsMushrooms 33 1717 2626 44 -- 44 11 33 22 -- 60 (1.5%)60 (1.5%)

Products used in agriculture and Products used in agriculture and horticulturehorticulture

66 1919 99 66 11 2121 66 -- -- -- 68 (1.7%)68 (1.7%)

Toilet articles and cosmeticsToilet articles and cosmetics 22 1919 33 -- -- 1717 1010 -- -- -- 51 (1.3%)51 (1.3%)

Poisonous animalsPoisonous animals 11 1515 44 44 -- 22 77 33 -- -- 36 (0.9%)36 (0.9%)

Food and beveragesFood and beverages 22 44 33 11 -- 11 66 -- -- -- 17 (0.4%)17 (0.4%)

Veterinary drugsVeterinary drugs 33 11 44 -- -- -- -- -- -- -- 8 (0.2%)8 (0.2%)

Other and unknown agentsOther and unknown agents 44 5050 1111 22 -- 11 2121 -- -- -- 89 (2.3%)89 (2.3%)

TotalTotal 350350 1’6421’642 650650 242242 1515 457457 463463 8080 2626 11 3’926 (100%)3’926 (100%)

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

INTOXICATII ACUTE INTERNATE IN SECTIA DE INTOXICATII ACUTE INTERNATE IN SECTIA DE TOXICOLOGIE CLINICA INTRE ANII 2000-2004TOXICOLOGIE CLINICA INTRE ANII 2000-2004

INTOXICATIIINTOXICATII

VARSTA (ani)/VARSTA (ani)/

ETIOLOGIEETIOLOGIE

FEMEIFEMEI BARBATIBARBATI TOTAL TOTAL GENEGENERALRAL15-15-

202021-21-3030

31-31-4040

41-41-5050

51-51-6060

61-61-7070

71-71-8080

81-81-9090

TOTALTOTAL 15-15-2020

21-21-3030

31-31-4040

41-41-5050

51-51-6060

61-61-7070

71-71-8080

81-81-9090

TOTALTOTAL

POLIMEDICAMENTOASEPOLIMEDICAMENTOASE 270270 324324 239239 220220 124124 8181 5151 1818 13271327 9191 218218 110110 7979 2929 1212 1515 11 555555 18821882

BENZODIAZEPINEBENZODIAZEPINE 8282 116116 8383 3737 3131 2020 2020 99 398398 3939 5454 2525 2626 1111 99 44 33 171171 569569

BARBITURICEBARBITURICE 113113 154154 8989 6363 2828 1010 1212 99 478478 2222 7979 2323 2727 88 11 55 00 165165 643643

ALCOOL ETILICALCOOL ETILIC 3333 4444 3131 3333 2020 1111 55 00 177177 109109 103103 151151 145145 8888 3838 1414 22 650650 827827

ALCOOL+MEDICAMENTEALCOOL+MEDICAMENTE 3434 5353 4747 6161 2222 99 44 00 230230 2323 9595 8484 7171 2828 1111 55 22 319319 549549

NEUROLEPTICENEUROLEPTICE 1313 1515 1010 66 1212 55 00 00 6161 77 1616 77 33 66 00 00 00 3939 100100

TUBERCULOSTATICETUBERCULOSTATICE 44 33 33 33 00 11 00 00 1414 22 88 33 11 00 00 00 00 1414 2828

ANTIDEPRESIVEANTIDEPRESIVE 2626 3232 2222 3030 1515 55 22 11 131131 55 1212 1111 99 66 00 33 00 4646 177177

MONOXID DE CARBONMONOXID DE CARBON 3939 7777 4444 5050 3636 3131 2828 1717 322322 4949 5757 5757 4545 3737 2525 1919 77 296296 618618

ETILENGLICOLETILENGLICOL 33 22 00 22 22 11 44 00 1414 33 55 88 1212 88 88 44 00 4848 6262

CIUPERCICIUPERCI 1414 2929 2626 2525 1212 1414 44 00 124124 1010 2222 2424 1717 1111 99 22 00 9595 219219

COFCOF 2222 4747 3939 5050 1818 1515 1010 22 203203 1919 4646 5555 5252 3535 1919 1111 11 238238 441441

METANOLMETANOL 11 00 00 11 11 00 00 00 33 11 11 55 44 11 11 00 00 1313 1616

OPIACEEOPIACEE 4040 5757 1212 66 11 22 11 00 119119 127127 209209 2828 55 11 11 00 00 371371 490490

SDR. INTRERUPERESDR. INTRERUPERE 2020 3333 55 22 11 00 00 00 6161 7070 155155 2020 66 66 44 00 00 261261 322322

SOLVENTISOLVENTI 55 1818 1010 1414 77 44 33 33 6464 1313 3434 2727 2727 1919 1010 33 44 137137 201201

COROZIVE / CAUSTICECOROZIVE / CAUSTICE 44 77 66 44 33 22 00 00 2626 00 55 33 11 1010 00 11 00 2020 4646

ANTICONVULSIVANTEANTICONVULSIVANTE 2323 1818 1414 88 66 00 22 22 7373 88 2121 1212 1313 22 00 11 00 5757 130130

ANXIOLITICEANXIOLITICE 112112 108108 6464 4545 1616 1111 33 11 360360 2121 4848 1010 1313 77 44 00 00 103103 463463

BETA-BLOCANTEBETA-BLOCANTE 22 11 11 11 11 11 00 00 77 11 11 11 33 00 00 00 00 66 1313

BLOCANTE DE CALCIUBLOCANTE DE CALCIU 11 22 11 44 22 44 00 00 1414 33 22 44 00 66 33 00 00 1818 2222

PARACETAMOLPARACETAMOL 22 11 00 OO OO OO OO OO 33 00 11 00 00 00 00 00 00 11 44

METALEMETALE 11 00 00 00 00 00 00 00 11 22 00 00 00 00 00 00 00 22 33

DIVERSEDIVERSE 116116 144144 100100 131131 101101 9999 109109 1616 816816 3030 9494 7373 9292 100100 7676 7171 1616 552552 13681368

NEPRECIZATENEPRECIZATE 3636 3939 2323 1717 77 33 88 33 136136 1414 3636 2020 1414 66 55 44 00 9999 235235

DECESEDECESE 77 44 22 1414 11 1212 1616 1111 6767 22 1111 1515 1414 1313 1818 1313 88 9494 161161

CAUSE DISTRIBUTION OF ICU CAUSE DISTRIBUTION OF ICU HOSPITALIZED POISENED PATIENTSHOSPITALIZED POISENED PATIENTS

CAUSE DISTRIBUTION OF ICU CAUSE DISTRIBUTION OF ICU HOSPITALIZED POISENED PATIENTSHOSPITALIZED POISENED PATIENTS

0 50 100 150 200 250 300 350

BENZODIAZEPINES

UNDETERMINATED

NEUROLEPTICS

ANTIDEPRESIVES

ETHILICS

POLIDRUGS

BARBITURATES

OTHER CAUSES

WOMENMEN

STATISTICS - 1995STATISTICS - 1995STATISTICS - 1995STATISTICS - 1995

Hospitalisation60%

Refuse hospitalsation40%

Non-Drug Intoxications

43%

Drug Intoxications

57%

Total Patients: 5 627

Total STI: 1 000 Patients

Hospitalized: 3 357

Internal

Medicine 70%

Drug Intoxications

81%

Non-Drug Intoxications

19%2 357 Patients

Women54%

Men46%

PATIENTS HOSPITALIZED PATIENTS HOSPITALIZED IN ICUIN ICU

PATIENTS HOSPITALIZED PATIENTS HOSPITALIZED IN ICUIN ICU

Death7%

Survive93%

Men35%

Women65%

TOTAL HOSPITALIZED PATIENTIS IN ICU 1000

70 PATIENTS DIED

DRUG INTOXICATIONDRUG INTOXICATION

0 20 40 60 80 100 120 140 160 180 200

Unexplained Substances

Anticonvulsivantes

Izoniazide

Triciclic antidepresive

Neuroleptics

Benzodiazepines

Barbiturates

Polidrug

Total Women Men Death

NON-DRUG NON-DRUG INTOXICATIONINTOXICATION

0

20

40

60

80

100

120

140

Burn

s (bases)

Burn

s (acids)

Eth

ilenglicol

CO Solven

ts

Meth

anol

OPC

Insecticid

es

Mush

rooms

Anilin

e

Detergen

ts

Eth

anol

Eth

anol+

Dru

gs or Non

dru

gs

Women Men

Average annual percent distribution of type of poisoning-related Average annual percent distribution of type of poisoning-related emergency department visits by urgency and hospital admission: emergency department visits by urgency and hospital admission:

US, 1993 – 1996US, 1993 – 1996(Source: CDC/NCHS, NHAMCS, 1993 - 1996)(Source: CDC/NCHS, NHAMCS, 1993 - 1996)

75

45 47

2217

6

0

10

20

30

40

50

60

70

80

Urgent Admitted

Poisoning Illness Nonpoisoning injury

Number and % of Poisoning – Related ED Visits by the 10 Number and % of Poisoning – Related ED Visits by the 10

Leading Principal Diagnoses for Poisoning Related Injuries, Leading Principal Diagnoses for Poisoning Related Injuries, Averaged over a Averaged over a

4-Year Period: US, 1993-19964-Year Period: US, 1993-1996

Principal DiagnosisPrincipal DiagnosisICD-9-ICD-9-

CM CM CodeCode

Poisoning Poisoning Related ED Related ED

Visits in Visits in 1000’s1000’s

95% 95% CICI

% % Poisoning-Poisoning-Related ED Related ED

visitsvisits

95% 95% CICI

Poisoning by other and unspecified Poisoning by other and unspecified drugs and medicinal substancesdrugs and medicinal substances

977977 200200 169,2169,23232

20,720,7 18.1, 18.1, 23.323.3

Poisoning by analgesic, antipyretics Poisoning by analgesic, antipyretics and antirheumaticsand antirheumatics

965965 7979 53,1053,1055

8.28.2 5.6, 5.6, 10.810.8

Poisoning by psyhotrops agentsPoisoning by psyhotrops agents 969969 5252 37,6737,67 5.45.4 3.9, 3.9, 6.96.9

Toxic effect of other gases, fumes or Toxic effect of other gases, fumes or vaporsvapors

987987 4242 27,5727,57 4.44.4 2.9, 2.9, 5.95.9

Toxic effect of other substances, Toxic effect of other substances, chiefly nonmedical as to sourcechiefly nonmedical as to source

989989 3939 27,5127,51 4.14.1 2.8, 2.8, 5.45.4

Toxic effect of carbon monoxideToxic effect of carbon monoxide 986986 3434 19,4919,49 3.63.6 2.1, 2.1, 5.15.1

Neurotic disordersNeurotic disorders 300300 3131 17,4417,44 3.23.2 1.8, 1.8, 4.64.6

Certain adverse effects not Certain adverse effects not elsewhere classifiedelsewhere classified

955955 3030 16,4416,44 3.13.1 1.7, 1.7, 4.54.5

Depressive disorder, not elsewhere Depressive disorder, not elsewhere classifiedclassified

311311 2424 13,3513,35 2.52.5 1.4, 1.4, 3.63.6

Nondependent abuse of drugsNondependent abuse of drugs 305305 2424 13,3513,35 2.52.5 1.4, 1.4, 3.63.6

The Poisoning PyramidThe Poisoning Pyramid(Source: CDC/NCHS, NVSS, 1995; NHDS, 1995; NHAMCS, 1993 – 1996; and TESS, 1995)(Source: CDC/NCHS, NVSS, 1995; NHDS, 1995; NHAMCS, 1993 – 1996; and TESS, 1995)

1

13

59

147

Death

Hospitalizations

Emergency department visits

Poison exposures

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

20082008

6.70%

4%

2.70%

5%

4%

8%

12%13%

8%

4%

3%2%2%2%2%2%2%

1%1%0%

0%

2%

4%

6%

8%

10%

12%

14%

1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

PARAMETRII CANTITATIVI AI TOXICITATIIPARAMETRII CANTITATIVI AI TOXICITATIIDL 50 (EXPERIMENTAL) mg/kgDL 50 (EXPERIMENTAL) mg/kg

mM/kgmM/kgmg/mmg/m22

DML (DOZA MINIMA LETALA OM)DML (DOZA MINIMA LETALA OM)

CLORURA MERCURICA 0.5 g ARSENIC 100 mgCLORURA MERCURICA 0.5 g ARSENIC 100 mgMETANOL 70 ml METANOL 70 ml NICOTINA 50 mg ACONITINA 10 mgNICOTINA 50 mg ACONITINA 10 mgPARALDEHIDA 100 ml BARBITURICE 1 – 5 gPARALDEHIDA 100 ml BARBITURICE 1 – 5 gPARATION 25 mg ACID BORIC 12 gPARATION 25 mg ACID BORIC 12 gFENOLI 10 ml CAMFOR 2 gFENOLI 10 ml CAMFOR 2 gFOSFOR (galben) 0.1 g CLORALHIDRAT 7 gFOSFOR (galben) 0.1 g CLORALHIDRAT 7 gSTRICNINA 50 mg CLORAT DE K 8 gSTRICNINA 50 mg CLORAT DE K 8 gTALIU 0.8 g FLUORURA DE K 1 gTALIU 0.8 g FLUORURA DE K 1 gFORMALDEHIDA 30 mlFORMALDEHIDA 30 ml

Cl 50Cl 50CLt 50CLt 50CONCENTRATIA ATMOSFERICA – EXPUNERI PROFESIONALECONCENTRATIA ATMOSFERICA – EXPUNERI PROFESIONALE

ppm ppm SAUSAU g/m3 g/m3

Doza (mg/kg)

Mort

alit

ate

(%

)

Doza medie letalã pentru Doza medie letalã pentru diverse substantediverse substante

Compusul Compusul Specia Specia Dl50 Dl50 (mg/kg, (mg/kg,

parenteral) parenteral) ETANOLETANOL SOARECE SOARECE 10000 10000

CLORURA DE CLORURA DE SODIUSODIU

SOARECE SOARECE 4000 4000

SULFAT FEROSSULFAT FEROS SOBOLAN SOBOLAN 1500 1500

MORFINA SULFATMORFINA SULFAT SOBOLAN SOBOLAN 900 900

FENOBARBITAL FENOBARBITAL SULFATSULFAT

SOBOLAN SOBOLAN 150 150

DDTDDT SOBOLAN SOBOLAN 100100

PICROTOXINAPICROTOXINA SOBOLAN SOBOLAN 55

STRICNINA SULFATSTRICNINA SULFAT SOBOLAN SOBOLAN 22

NICOTINANICOTINA SOBOLAN SOBOLAN 11

d-TUBOCURARINAd-TUBOCURARINA SOBOLAN SOBOLAN 0.50.5

HEMICOLINIUM-3HEMICOLINIUM-3 SOBOLAN SOBOLAN 0.20.2

TETRODOTOXINTETRODOTOXIN SOBOLAN SOBOLAN 0.10.1

DIOXINADIOXINA COBAI COBAI 0.001 0.001

TOXINA TOXINA BOTULINICABOTULINICA

SOBOLAN SOBOLAN 0.00001 0.00001

Masa Masa moleculara moleculara

(g/mol)(g/mol)

DL 50 (mM/kg)DL 50 (mM/kg)

4646 0.21730.2173

58.443 58.443 0.068 0.068

151.908 151.908 0.0098 0.0098

285.34 285.34 0.0031 0.0031

232.235 232.235 0.00064 0.00064

354.49 354.49 0.00028 0.00028

602.583 602.583 0.0000082 0.0000082

334.41 334.41 0.0000059 0.0000059

162.26 162.26 0.0000061 0.0000061

624.765 624.765 0.0000008 0.0000008

414.538 414.538 0.0000004 0.0000004

319.27 319.27 0.0000003 0.0000003

84.07 84.07

149322.7 149322.7

CLASIFICAREA SUBSTANTELOR CLASIFICAREA SUBSTANTELOR TOXICE CONFORM TOXICITATII TOXICE CONFORM TOXICITATII

RELATIVERELATIVE

CATEGORIACATEGORIA DL50DL50

▪ ▪ SUPERTOXICE 5 mg/kg SUPERTOXICE 5 mg/kg sau <sau <

▪ ▪ EXTREM DE TOXICE 5 – 50 EXTREM DE TOXICE 5 – 50 mg/kgmg/kg

▪ ▪ FOARTE TOXICE 50 – 500 FOARTE TOXICE 50 – 500 mg/kgmg/kg

▪ ▪ MODERAT TOXICE 0.5 – 5 MODERAT TOXICE 0.5 – 5 g/kgg/kg

▪ ▪ CU TOXICITATE REDUSA 5 – 15 g/kgCU TOXICITATE REDUSA 5 – 15 g/kg

▪ ▪ PRACTIC NETOXICE > 15 g/kgPRACTIC NETOXICE > 15 g/kg

CATEGORIACATEGORIA DL50DL50

▪ ▪ SUPERTOXICE 5 mg/kg SUPERTOXICE 5 mg/kg sau <sau <

▪ ▪ EXTREM DE TOXICE 5 – 50 EXTREM DE TOXICE 5 – 50 mg/kgmg/kg

▪ ▪ FOARTE TOXICE 50 – 500 FOARTE TOXICE 50 – 500 mg/kgmg/kg

▪ ▪ MODERAT TOXICE 0.5 – 5 MODERAT TOXICE 0.5 – 5 g/kgg/kg

▪ ▪ CU TOXICITATE REDUSA 5 – 15 g/kgCU TOXICITATE REDUSA 5 – 15 g/kg

▪ ▪ PRACTIC NETOXICE > 15 g/kgPRACTIC NETOXICE > 15 g/kg

METABOLISMMETABOLISM

ENDOBIOTICEENDOBIOTICE

XENOBIOTICEXENOBIOTICE

•PREDICTIA CONSECINTELOR METABOLICE•PREDICTIA CONSECINTELOR METABOLICE•DETERMINAREA POTENTIALULUI TOXIC•DETERMINAREA POTENTIALULUI TOXIC

METABOLISM – DETERMINANTA A TOXICITATIIMETABOLISM – DETERMINANTA A TOXICITATII

ECHILIBRU FRAGIL PLURIFACTORIALECHILIBRU FRAGIL PLURIFACTORIAL

DETOXIFIEREADETOXIFIEREA

BIOACTIVAREABIOACTIVAREA

CITOTOXICITATECITOTOXICITATE

CARCINOGENEZACARCINOGENEZA

METABOLIZAREA XENOBIOTICELOR METABOLIZAREA XENOBIOTICELOR DE CATRE FLORA INTESTINALADE CATRE FLORA INTESTINALA

METABOLIZAREA XENOBIOTICELOR METABOLIZAREA XENOBIOTICELOR DE CATRE FLORA INTESTINALADE CATRE FLORA INTESTINALA

• HIDROLIZAHIDROLIZA• GLUCURONIZIGLUCURONIZI• GLICOZIZIGLICOZIZI• SULFAMATI – CICLAMATSULFAMATI – CICLAMAT• AMIDE – METOTREXATAMIDE – METOTREXAT• ESTERI – ACETILDIGOXINAESTERI – ACETILDIGOXINA• NITRATI – PENTAERITR. TETRANITRATNITRATI – PENTAERITR. TETRANITRAT

• DEHIDROXILAREDEHIDROXILARE• DECARBOXILARE DECARBOXILARE AMINOACIZIAMINOACIZI• DEAMINARE DEAMINARE AMINOACIZIAMINOACIZI• DEHIDROGENAREDEHIDROGENARE COLESTEROL, ACIZI BILIARICOLESTEROL, ACIZI BILIARI• DEHALOGENARE DEHALOGENARE DDTDDT

• REDUCEREREDUCERE• GRUPARE NITROGRUPARE NITRO ACID P-NITROBENZOICACID P-NITROBENZOIC• LEGATURI DUBLELEGATURI DUBLE ACIZI GRASI NESATURATIACIZI GRASI NESATURATI• ALDEHIDEALDEHIDE BENZALDEHIDEBENZALDEHIDE• ALCOOLIALCOOLI ALCOOLI BEZILICIALCOOLI BEZILICI

• ALTE REACTIIALTE REACTII• FORMARE NITROZAMINEFORMARE NITROZAMINE DIMETILNITROZAMINADIMETILNITROZAMINA• AROMATIZAREAAROMATIZAREA ACID CHINICACID CHINIC• ACETILAREAACETILAREA HISTAMINAHISTAMINA• ESTERIFICAREAESTERIFICAREA ACID GALICACID GALIC

• HIDROLIZAHIDROLIZA• GLUCURONIZIGLUCURONIZI• GLICOZIZIGLICOZIZI• SULFAMATI – CICLAMATSULFAMATI – CICLAMAT• AMIDE – METOTREXATAMIDE – METOTREXAT• ESTERI – ACETILDIGOXINAESTERI – ACETILDIGOXINA• NITRATI – PENTAERITR. TETRANITRATNITRATI – PENTAERITR. TETRANITRAT

• DEHIDROXILAREDEHIDROXILARE• DECARBOXILARE DECARBOXILARE AMINOACIZIAMINOACIZI• DEAMINARE DEAMINARE AMINOACIZIAMINOACIZI• DEHIDROGENAREDEHIDROGENARE COLESTEROL, ACIZI BILIARICOLESTEROL, ACIZI BILIARI• DEHALOGENARE DEHALOGENARE DDTDDT

• REDUCEREREDUCERE• GRUPARE NITROGRUPARE NITRO ACID P-NITROBENZOICACID P-NITROBENZOIC• LEGATURI DUBLELEGATURI DUBLE ACIZI GRASI NESATURATIACIZI GRASI NESATURATI• ALDEHIDEALDEHIDE BENZALDEHIDEBENZALDEHIDE• ALCOOLIALCOOLI ALCOOLI BEZILICIALCOOLI BEZILICI

• ALTE REACTIIALTE REACTII• FORMARE NITROZAMINEFORMARE NITROZAMINE DIMETILNITROZAMINADIMETILNITROZAMINA• AROMATIZAREAAROMATIZAREA ACID CHINICACID CHINIC• ACETILAREAACETILAREA HISTAMINAHISTAMINA• ESTERIFICAREAESTERIFICAREA ACID GALICACID GALIC

METABOLIZAREA XENOBIOTICELORMETABOLIZAREA XENOBIOTICELORREACTII FAZA IREACTII FAZA I

METABOLIZAREA XENOBIOTICELORMETABOLIZAREA XENOBIOTICELORREACTII FAZA IREACTII FAZA I

OXIDAREAOXIDAREA• MONOOXIGENAZE (P450)MONOOXIGENAZE (P450)• XANTINOXIDAZEXANTINOXIDAZE• PEROXIDAZEPEROXIDAZE• AMINOXIDAZEAMINOXIDAZE• MAOMAO• DIOXIGENAZEDIOXIGENAZE

OXIDAREAOXIDAREA• MONOOXIGENAZE (P450)MONOOXIGENAZE (P450)• XANTINOXIDAZEXANTINOXIDAZE• PEROXIDAZEPEROXIDAZE• AMINOXIDAZEAMINOXIDAZE• MAOMAO• DIOXIGENAZEDIOXIGENAZE

REDUCEREAREDUCEREA• MONOOXIGENAZE (P450)MONOOXIGENAZE (P450)• CETOREDUCTAZECETOREDUCTAZE• GLUTATIONPEROXIDAZEGLUTATIONPEROXIDAZE• EPOXIDHIDROLAZEEPOXIDHIDROLAZE• SODSOD

REDUCEREAREDUCEREA• MONOOXIGENAZE (P450)MONOOXIGENAZE (P450)• CETOREDUCTAZECETOREDUCTAZE• GLUTATIONPEROXIDAZEGLUTATIONPEROXIDAZE• EPOXIDHIDROLAZEEPOXIDHIDROLAZE• SODSOD

HIDROLIZAHIDROLIZA• HIDROLIZA ESTERILORHIDROLIZA ESTERILOR• CARBOXILESTERAZECARBOXILESTERAZE• AMIDAZEAMIDAZE

HIDROLIZAHIDROLIZA• HIDROLIZA ESTERILORHIDROLIZA ESTERILOR• CARBOXILESTERAZECARBOXILESTERAZE• AMIDAZEAMIDAZE

REACTII FAZA IIREACTII FAZA IIREACTII FAZA IIREACTII FAZA II

• GLUCURONILTRANSFERAZA (GLUCURONIDAREA)GLUCURONILTRANSFERAZA (GLUCURONIDAREA)

• SULFOTRANSFERAZA (SULFOCONJUGAREA)SULFOTRANSFERAZA (SULFOCONJUGAREA)

• GLUTATION S-TRANSFERAZA (GLUTATION - GLUTATION S-TRANSFERAZA (GLUTATION - CONJUGAREA)CONJUGAREA)

• TIOLTRANSFERAZATIOLTRANSFERAZA

• METILTRANSFERAZA (METILAREA)METILTRANSFERAZA (METILAREA)

• N-ACETILTRANSFERAZA (ACETILAREA)N-ACETILTRANSFERAZA (ACETILAREA)

• SULFTRANSFERAZA (RODANAZA)SULFTRANSFERAZA (RODANAZA)

• GLUCURONILTRANSFERAZA (GLUCURONIDAREA)GLUCURONILTRANSFERAZA (GLUCURONIDAREA)

• SULFOTRANSFERAZA (SULFOCONJUGAREA)SULFOTRANSFERAZA (SULFOCONJUGAREA)

• GLUTATION S-TRANSFERAZA (GLUTATION - GLUTATION S-TRANSFERAZA (GLUTATION - CONJUGAREA)CONJUGAREA)

• TIOLTRANSFERAZATIOLTRANSFERAZA

• METILTRANSFERAZA (METILAREA)METILTRANSFERAZA (METILAREA)

• N-ACETILTRANSFERAZA (ACETILAREA)N-ACETILTRANSFERAZA (ACETILAREA)

• SULFTRANSFERAZA (RODANAZA)SULFTRANSFERAZA (RODANAZA)

ENTITATI TOXICE CONSECUTIVE ENTITATI TOXICE CONSECUTIVE METABOLIZARI UNOR COMPUSIMETABOLIZARI UNOR COMPUSI

▪ ▪ EPOXIZI ▪ COMPUSI N-HIDROXILATIEPOXIZI ▪ COMPUSI N-HIDROXILATI▪ ▪ RADICALI LIBERI ▪ NITROZAMINERADICALI LIBERI ▪ NITROZAMINE

AFLATOXINA B1AFLATOXINA B1 BENZEN, BROMBENZENBENZEN, BROMBENZEN

EPOXIZI EPOXIZI FUROSEMID FUROSEMID OLEFINEOLEFINE BIFENILI POLICLORURATI SI POLIBROMATIBIFENILI POLICLORURATI SI POLIBROMATI TRICLORETILENATRICLORETILENA CLORURA DE VINILCLORURA DE VINIL

TETRACLORURA DE CARBONTETRACLORURA DE CARBON RADICALI LIBERI RADICALI LIBERI HALOTAN HALOTAN

BROMTRICLORMETANBROMTRICLORMETAN PARAQUATPARAQUAT UNELE ALIMENTEUNELE ALIMENTE RADIATII IONIZANTERADIATII IONIZANTE INFLAMATIEINFLAMATIE PROCESE PATOGENICEPROCESE PATOGENICE

PARACETAMOLPARACETAMOLCOMPUSI N-HIDROXILATICOMPUSI N-HIDROXILATI URETAN URETAN

AMINEAMINENITROZAMINENITROZAMINE(tub digestiv)(tub digestiv) NITRITI NITRITI

Compusi bioactiviCompusi bioactivi(modificat dupa Frank Lu, 1991)(modificat dupa Frank Lu, 1991)

Compusul initialCompusul initial Metabolit toxicMetabolit toxic Mecanismul Mecanismul toxicitatiitoxicitatii

Consecinte organo-Consecinte organo-functionalefunctionale

AcetaminofenAcetaminofen

(Paracetamol)(Paracetamol)Derivat N-hidroxiDerivat N-hidroxi Legatura Legatura

covalentacovalentaNecroza hepaticaNecroza hepatica

2-Acetilaminofluoren2-Acetilaminofluoren N-acetoxi-AAFN-acetoxi-AAF

AAF N-sulfatAAF N-sulfatLegatura Legatura covalentacovalenta

CancerCancer

Aflatoxin B1Aflatoxin B1 Aflatoxin-2,3-Aflatoxin-2,3-epoxidepoxid

Legatura Legatura covalentacovalenta

Cancer hepaticCancer hepatic

Alil formiatAlil formiat AcroleinaAcroleina Legatura Legatura covalentacovalenta

Necroza hepaticaNecroza hepatica

Alilizopropil Alilizopropil acetamidaacetamida

Epoxid Epoxid NecunoscutNecunoscut Distructie citocrom P450Distructie citocrom P450

PorfiriePorfirie

AmigdalinaAmigdalina MandelonitrilMandelonitril

(flora intestinala)(flora intestinala)Formare de Formare de cianuracianura

Hipoxie citotoxicaHipoxie citotoxica

BenzenBenzen Benzen epoxidBenzen epoxid Legatura Legatura covalentacovalenta

Depresie maduva Depresie maduva hematopeticahematopetica

BrombenzenBrombenzen BrombenzenBrombenzen Legatura Legatura covalentacovalenta

Necroza hepatica, Necroza hepatica, renala, bronsiolararenala, bronsiolara

Tetraclorura de Tetraclorura de carboncarbon

Radical liber Radical liber triclormetantriclormetan

Legatura Legatura covalenta, covalenta, peroxidarea peroxidarea lipidelorlipidelor

Necroza hepatica, Necroza hepatica,


Alchilnitrosamine Alchilnitrosamine carciogenecarciogene

Alfa-hidroxilareAlfa-hidroxilare AlchilareAlchilare Cancer hepaticCancer hepatic

Coloranti amino Coloranti amino carciogenicarciogeni

Derivati N-hidroxiDerivati N-hidroxi Legatura Legatura covalentacovalenta





Hidrocarburi Hidrocarburi policiclice policiclice carciogenecarciogene

Epoxizi in diverse Epoxizi in diverse organeorgane


Cancer, citotoxicitateCancer, citotoxicitate

CloroformCloroform FosgenFosgen Legatura Legatura covalentacovalenta

Necroza hepatica, renalaNecroza hepatica, renala

CicasinCicasin MetilazometanolMetilazometanol AlchilareAlchilare Cancer, necroza hepaticaCancer, necroza hepatica

CiclamatCiclamat CiclohexilaminaCiclohexilamina NecunoscutNecunoscut Cancer de vezicaCancer de vezica

EtanolEtanol Acetaldehida in Acetaldehida in diverse organediverse organe

ComplexComplex DiferiteDiferite

FluoracetatFluoracetat FluorocitratFluorocitrat Inhibitie Inhibitie enzimaticaenzimatica

Toxicitate generalaToxicitate generala

FurosemidFurosemid EpoxidEpoxid Legatura Legatura covalentacovalenta

Necroza hepatica, renalaNecroza hepatica, renala

HalotanHalotan Radical liberRadical liber Legatura Legatura covalentacovalenta


Amine aromatice Amine aromatice hemolizantehemolizante

Metaboliti N-Metaboliti N-hidroxihidroxi

NecunoscutNecunoscut HemolizaHemoliza

IzoniazidaIzoniazida AcetihidrazinaAcetihidrazina Legatura Legatura covalentacovalenta


MeclizinaMeclizina NoroclorciclizinaNoroclorciclizina NecunoscutNecunoscut TeratogenezaTeratogeneza




MetanolMetanol FormaldehidaFormaldehida ComplexComplex Toxicitate retiniana si Toxicitate retiniana si generalagenerala

Compusi nitro si Compusi nitro si amine aromatice amine aromatice methemoglobinizantmethemoglobinizantee

Metaboliti N-Metaboliti N-hidroxihidroxi

Oxidare, reducere Oxidare, reducere ciclicaciclica

MethemoglobinemieMethemoglobinemie

MetoxifluranMetoxifluran Fluor anorganicFluor anorganic Inhibitie Inhibitie enzimatica enzimatica

Insuficienta renalaInsuficienta renala

NaftilaminaNaftilamina N-hidroxi N-hidroxi naftilamina naftilamina


Cancer vezicalCancer vezical

Nitriti si amine Nitriti si amine secundare si tertiaresecundare si tertiare

NitrosamineNitrosamine AlchilareAlchilare Cancer hepatic, Cancer hepatic, pulmonarpulmonar

OlefineOlefine EpoxiziEpoxizi Legatura Legatura covalenta covalenta

Cancer de pieleCancer de piele

ParationParation ParaoxonParaoxon Legatura Legatura covalenta cu covalenta cu colinesterazelecolinesterazele

Paralizie Paralizie neuromusculara, neuromusculara, insuficienta respiratorieinsuficienta respiratorie

Analogi baze Analogi baze purinice si purinice si pirimidinicepirimidinice

Mononucleotide, Mononucleotide, nucleotizi trifosfatnucleotizi trifosfat

Sinteza letala, Sinteza letala, incorporare letalaincorporare letala

CitotoxicitateCitotoxicitate

Alcaloizi Alcaloizi pirolizidinicipirolizidinici

Derivati piroliticiDerivati pirolitici NecunoscutNecunoscut Necroza hepatica si Necroza hepatica si canceroasacanceroasa

TalidomidaTalidomida Acid ftalil L-Acid ftalil L-glutamic glutamic

NecunoscutNecunoscut TeratogenezaTeratogeneza

UretanUretan N-hidroxil uretanN-hidroxil uretan AlchilareAlchilare Cancer, citotoxicitateCancer, citotoxicitate

FARMACOCINETICA – TOXOCINETICAFARMACOCINETICA – TOXOCINETICA

PARAMETRUPARAMETRU FARMACOCINETICFARMACOCINETICAA

TOXOCINETICATOXOCINETICA

DOZA DOZA CUNOSCUTA CUNOSCUTA

REDUSA REDUSA NECUNOSCUTA NECUNOSCUTA FOARTE MARE FOARTE MARE

EFECT EFECT TERAPEUTIC TERAPEUTIC TOXIC TOXIC

STEADY STATE STEADY STATE UZUAL UZUAL NU NU

DATE CLINICE DATE CLINICE COROBORANTE COROBORANTE

FRECVENT FRECVENT INCOMPLETE INCOMPLETE

CONCENTRATIE-EFECTE CONCENTRATIE-EFECTE DA DA INCOMPLETE INCOMPLETE

TOXICE, RECEPTORI SI CONSECINTA TOXICE, RECEPTORI SI CONSECINTA INTERACTIUNII LORINTERACTIUNII LOR

RECEPTOR RECEPTOR TOXODINAMIC TOXODINAMIC

TOXIC TOXIC MECANISM MECANISM

COLINESTERAZECOLINESTERAZE COMPUSI ORGANO-COMPUSI ORGANO-FOSFORICIFOSFORICI

BLOCAREA CENTRULUI BLOCAREA CENTRULUI ESTERAZICESTERAZIC

CITOCROMOXIDAZACITOCROMOXIDAZA CIANURICIANURI BLOCAREA TRANSPORTULUI BLOCAREA TRANSPORTULUI DE ELECTRONI IN LANTUL DE ELECTRONI IN LANTUL RESPIRATORRESPIRATOR

GRUPARI TIOLICE GRUPARI TIOLICE ENZIMATICEENZIMATICE

METALE GRELEMETALE GRELE INACTIVAREA GRUPARILOR INACTIVAREA GRUPARILOR TIOLICETIOLICE

HEMOGLOBINAHEMOGLOBINA MONOXID DE MONOXID DE CARBON, NITRITI, CARBON, NITRITI, NITRATINITRATI

FORMAREA: FORMAREA: CARBOXIHEMOGLOBINEI CARBOXIHEMOGLOBINEI METHEMOGLOBINEIMETHEMOGLOBINEI

ACIZI NUCLEICIACIZI NUCLEICI ALCHILANTE ALCHILANTE RADIOMIMETICERADIOMIMETICE

BLOCAREA SINTEZEI ACIZILOR BLOCAREA SINTEZEI ACIZILOR NUCLEICINUCLEICI

LIPIDE STRUCTURALELIPIDE STRUCTURALE TETRACLORURA DE TETRACLORURA DE CARBONCARBON BROMTRICLORMETABROMTRICLORMETANN

RADICALI LIBERI RADICALI LIBERI

PEROXIDAREPEROXIDARE

RECEPTOR NICOTINICRECEPTOR NICOTINIC NICOTINA NICOTINA

CURARIZANTECURARIZANTE STIMULARE DIRECTASTIMULARE DIRECTA

BLOCARE, PARALIZIEBLOCARE, PARALIZIE

RECEPTOR MUSCARINICRECEPTOR MUSCARINIC MUSCARINAMUSCARINA

(AMANITA (AMANITA MUSCARIA)MUSCARIA)

STIMULARE INTENSA,STIMULARE INTENSA, SINDROM MUSCARINICSINDROM MUSCARINIC

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