M. Balíková: The Fate of Poison 1
TOXICOLOGYTOXICOLOGY
I. The fate of poison in organismI. The fate of poison in organism
M. BalíkováM. Balíková
M. Balíková: The Fate of Poison 2
What is the poisonWhat is the poisonThe substance which after the resorption into The substance which after the resorption into the blood stream can induce the harmful effects the blood stream can induce the harmful effects to the organism to the organism Toxic effectsToxic effects::
contemporarycontemporary with permanent damage to organswith permanent damage to organs fatal fatal
Mutual action between poison and organism:Mutual action between poison and organism:
PHARMACODYNAMICS PHARMACODYNAMICS (What does the poison (What does the poison to the organism?)to the organism?)
PHARMACOKINETICSPHARMACOKINETICS (What does the organism (What does the organism to the poison?)to the poison?)
M. Balíková: The Fate of Poison 3
The fate of poison in The fate of poison in organismorganism
ApplicationApplication mode and mode and bioavailability,metabolismbioavailability,metabolism
Inhalation-Sniffing-Injection-Ingestion-Dermal ResorptionResorption into blood stream into blood stream Distribution into tissuesDistribution into tissues BiotransformationBiotransformation into metabolites into metabolites Elimination waysElimination ways::
a) Urine – polar compoundsa) Urine – polar compoundsb) Feaces – lipophilic compoundsb) Feaces – lipophilic compoundsc) Lungs – gases, volatiles c) Lungs – gases, volatiles d) Hair – deposits of basic compounds above alld) Hair – deposits of basic compounds above alle) Saliva – hydrophilic/lipophilice) Saliva – hydrophilic/lipophilicf) Sweat – hydrophilic/lipophilicf) Sweat – hydrophilic/lipophilic
M. Balíková: The Fate of Poison 5
The individual variation in The individual variation in pharmacokinetics and pharmacokinetics and
pharmacodynamicspharmacodynamics
Genetics (e. g. variation among races)Genetics (e. g. variation among races) SexSex AgeAge Actual health stateActual health state Life style, toleranceLife style, tolerance The mode of application, drug mixturesThe mode of application, drug mixtures
a) Variation in effects (receptors)a) Variation in effects (receptors)
b) Variation in metabolism b) Variation in metabolism (enzymes)(enzymes)
M. Balíková: The Fate of Poison 6
Biotransformation:Biotransformation:
Modification of the chemical Modification of the chemical structure of parent compound in structure of parent compound in organism, catalysed by enzymesorganism, catalysed by enzymes
Metabolites with different potencyMetabolites with different potency
Most of enzymes bound in hepatocytesMost of enzymes bound in hepatocytes
The liver and the first pass metabolismThe liver and the first pass metabolism
Lipophilic compounds – extensive Lipophilic compounds – extensive metabolism metabolism
Polar metabolites – excreted by urinePolar metabolites – excreted by urine
M. Balíková: The Fate of Poison 7
Biotransformation:
1st phase1st phaseOxidation Oxidation
(P450 (P450 system)system)
ReductionReductionHydrolysisHydrolysis
2nd phase-2nd phase-conjugationconjugation
Sulphuric acidSulphuric acidGlucuronic ac.Glucuronic ac.GlycineGlycineCysteineCysteineGlutathioneGlutathione
M. Balíková: The Fate of Poison 21
CONJUGATION CONJUGATION with GLYCINEwith GLYCINE
Biotransformation of Biotransformation of SalicylatesSalicylates
M. Balíková: The Fate of Poison 23
cccc111111AAAAABiotransformation of heroin, Biotransformation of heroin, codeinecodeine
M. Balíková: The Fate of Poison 25
Biotransformation of Biotransformation of methamphetaminemethamphetamine
M. Balíková: The Fate of Poison 27
Nonspecific metabolites of some Nonspecific metabolites of some benzodiazepinesbenzodiazepines
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Specific metabolites of Specific metabolites of flunitrazepamflunitrazepam
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Metabolism of paracetamolMetabolism of paracetamolAcetaminophenAcetaminophen(COLDREX, KORYLAN, PANADOL)(COLDREX, KORYLAN, PANADOL)
Risk of hepatotoxicity Risk of hepatotoxicity Hepatoprotection Hepatoprotection Antidotum N-Acetylcystein Antidotum N-Acetylcystein
M. Balíková: The Fate of Poison 30
Why to care about Why to care about biotransformationbiotransformation
Development of a toxicological Development of a toxicological methodmethod
Interpretation of toxicological Interpretation of toxicological findingsfindings
Understanding of drug effectsUnderstanding of drug effectsCorrect and effective therapy, Correct and effective therapy,
reduction of adverse drug reduction of adverse drug effectseffects
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