M. Balíková: The Fate of Poison1 TOXICOLOGY I. The fate of poison in organism M. Balíková

M. Balíková: The Fate of Poison2 What is the poison The substance which after the resorption into the blood stream can induce the harmful effects to the organism Toxic effects:  contemporary  with permanent damage to organs  fatal Mutual action between poison and organism: PHARMACODYNAMICS (What does the poison to the organism?) PHARMACOKINETICS (What does the organism to the poison?)

M. Balíková: The Fate of Poison3 The fate of poison in organism Application mode and bioavailability,metabolism  Application mode and bioavailability,metabolism Inhalation-Sniffing-Injection-Ingestion-Dermal Resorption into blood stream  Resorption into blood stream  Distribution into tissues  Biotransformation into metabolites  Elimination ways: a) Urine – polar compounds b) Feaces – lipophilic compounds c) Lungs – gases, volatiles d) Hair – deposits of basic compounds above all e) Saliva – hydrophilic/lipophilic f) Sweat – hydrophilic/lipophilic

M. Balíková: The Fate of Poison4 OVERVIEW

5 The individual variation in pharmacokinetics and pharmacodynamics  Genetics (e. g. variation among races)  Sex  Age  Actual health state  Life style, tolerance  The mode of application, drug mixtures a) Variation in effects (receptors) b) Variation in metabolism (enzymes)

M. Balíková: The Fate of Poison6 Biotransformation: Modification of the chemical structure of parent compound in organism, catalysed by enzymes  Metabolites with different potency  Most of enzymes bound in hepatocytes  The liver and the first pass metabolism  Lipophilic compounds – extensive metabolism  Polar metabolites – excreted by urine

M. Balíková: The Fate of Poison7 Biotransformation: 1st phase  Oxidation (P450 system)  Reduction  Hydrolysis 2nd phase- conjugation  Sulphuric acid  Glucuronic ac.  Glycine  Cysteine  Glutathione

M. Balíková: The Fate of Poison8 Oxidation of alcohols

M. Balíková: The Fate of Poison9 Oxidation of unsaturated bonds

M. Balíková: The Fate of Poison10 O-Dealkylation

M. Balíková: The Fate of Poison11 N-Dealkylation

M. Balíková: The Fate of Poison12 N-Oxidation

M. Balíková: The Fate of Poison13 S-Oxidation

M. Balíková: The Fate of Poison14 Oxidative desulphuration

M. Balíková: The Fate of Poison15 Oxidative deamination

M. Balíková: The Fate of Poison16 Reduction of aldehydes, ketones

M. Balíková: The Fate of Poison17 Reduction of nitrogroups

M. Balíková: The Fate of Poison18 Hydrolysis of esters

M. Balíková: The Fate of Poison19 Hydrolysis of amides

M. Balíková: The Fate of Poison20 Hydrolysis of benzodiazepines

M. Balíková: The Fate of Poison21 CONJUGATION with GLYCINE Biotransformation of Salicylates

M. Balíková: The Fate of Poison22 CONJUGATION of MORPHINE

M. Balíková: The Fate of Poison23 cccc111111AAAAA Biotransformation of heroin, codeine

M. Balíková: The Fate of Poison24 Biotransformation of cocaine

M. Balíková: The Fate of Poison25 Biotransformation of methamphetamine

M. Balíková: The Fate of Poison26 Biotransformation of 9-THC

M. Balíková: The Fate of Poison27 Nonspecific metabolites of some benzodiazepines

M. Balíková: The Fate of Poison28 Specific metabolites of flunitrazepam

M. Balíková: The Fate of Poison29 Metabolism of paracetamol Acetaminophen (COLDREX, KORYLAN, PANADOL) Risk of hepatotoxicity Hepatoprotection Antidotum N-Acetylcystein

M. Balíková: The Fate of Poison30 Why to care about biotransformation  Development of a toxicological method  Interpretation of toxicological findings  Understanding of drug effects  Correct and effective therapy, reduction of adverse drug effects