TOXICOLOGY I. The fate of poison in organism

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TOXICOLOGY I. The fate of poison in organism
M. Balíková
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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?)

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The fate of poison in organism

• Application mode and bioavailability,metabolism
• Inhalation-Sniffing-Injection-Ingestion-Dermal
  
• 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

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OVERVIEW
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The individual variation in pharmacokinetics and
pharmacodynamics
a) Variation in effects (receptors) b) Variation
in metabolism (enzymes)

• Genetics (e. g. variation among races)
• Sex
• Age
• Actual health state
• Life style, tolerance
• The mode of application, drug mixtures

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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

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Biotransformation

• 2nd phase-conjugation
• Sulphuric acid
• Glucuronic ac.
• Glycine
• Cysteine
• Glutathione

• 1st phase
• Oxidation (P450 system)
• Reduction
• Hydrolysis

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Oxidation of alcohols
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Oxidation of unsaturated bonds
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O-Dealkylation
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N-Dealkylation
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N-Oxidation
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S-Oxidation
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Oxidative desulphuration
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Oxidative deamination
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Reduction of aldehydes, ketones
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Reduction of nitrogroups
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Hydrolysis of esters
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Hydrolysis of amides
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Hydrolysis of benzodiazepines
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Biotransformation of Salicylates
CONJUGATION with GLYCINE

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CONJUGATION of MORPHINE
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Biotransformation of heroin, codeine
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Biotransformation of cocaine
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Biotransformation of methamphetamine
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Biotransformation of 9-THC
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Nonspecific metabolites of some benzodiazepines
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Specific metabolites of flunitrazepam
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Metabolism of paracetamol

• Acetaminophen
• (COLDREX, KORYLAN, PANADOL)
• Risk of hepatotoxicity Hepatoprotection
  Antidotum N-Acetylcystein

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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