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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,
Cancer hepaticCancer hepatic
Alchilnitrosamine Alchilnitrosamine carciogenecarciogene
Alfa-hidroxilareAlfa-hidroxilare AlchilareAlchilare Cancer hepaticCancer hepatic
Coloranti amino Coloranti amino carciogenicarciogeni
Derivati N-hidroxiDerivati N-hidroxi Legatura Legatura covalentacovalenta
Cancer hepaticCancer hepatic
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
Hidrocarburi Hidrocarburi policiclice policiclice carciogenecarciogene
Epoxizi in diverse Epoxizi in diverse organeorgane
Legatura Legatura covalentacovalenta
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
Necroza hepaticaNecroza hepatica
Amine aromatice Amine aromatice hemolizantehemolizante
Metaboliti N-Metaboliti N-hidroxihidroxi
NecunoscutNecunoscut HemolizaHemoliza
IzoniazidaIzoniazida AcetihidrazinaAcetihidrazina Legatura Legatura covalentacovalenta
Necroza hepaticaNecroza hepatica
MeclizinaMeclizina NoroclorciclizinaNoroclorciclizina NecunoscutNecunoscut TeratogenezaTeratogeneza
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
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
Legatura Legatura covalentacovalenta
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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