MedChem Exam II

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Anonymous
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9645
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MedChem Exam II
Updated:
2010-03-08 16:51:50
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Chapter 4
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Metabolism of drugs and xenobiotics
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  1. Xenobiotics
    • exogenous substance modified in the body and excreted
    • 90% excreted in urine
    • Metabolism divided into Phase I and Phase II
  2. Phase I reactions
    • Functionalize chemical for excretion by increasing water solubility
    • Oxidative Reactions
    • Reductive Reactions
    • Hydrolytic Reactions
  3. Phase II Reactions
    • Couple the chemical with another moiety to facilitate excretion
    • Conjugation reactions
  4. Sites of transformation reactions
    • Liver
    • Intestines
    • Kidney, lungs, brain and skin
  5. Cytochrome P-450 Reactions
    • Oxidation
    • Heme protein w/ Fe3+ Center
    • Mixed Function Oxygenases
    • Monooxygenases
  6. Stoichiometric Cytochrome P-450 Reaction
    RH + NADPH + O2 --> ROH + NADP+ +H2O
  7. Committed Step of Cytochrome P-450 Reactions
    Binding substrate
  8. Resting State of CP450 Heme
    Fe3+
  9. Aromatic Oxidation
    • Arene Oxide intermediate to give arenol
    • Attack is usually para to group
    • Electron deficient rings not succeptable
  10. 4 fates of Arene Oxide Intermediate
    • 1. Arenol
    • 2. Trans-Dihydrodiols through epoxide hydratase
    • 3. Glutathione Adducts through Glutathione S-Transferase
    • 4. Binding to macromolecules such as DNA
  11. Olefinic Oxidation
    • Break double bonds by addking 2 -OHs
    • Epoxide Hydratase
  12. Epoxide Intermediate that can inhibit p450 enzymes
    Secobarbital
  13. Benzylic oxidation
    CH3 off aromatic ring oxidized to corresponding alcohol
  14. Allylic oxidation
    Carbon next to C=C oxidized
  15. alpha-carbonyl oxidation
    oxidation next to C=O
  16. Aliphatic oxidation
    • Omega oxidation
    • Omega -1 oxidation
  17. Omega Oxidation
    End CH3 oxidized to CH2OH
  18. Omega -1 Oxidation
    • Oxidation on the carbon next to the end of the chain
    • R-CH2-CH3 -> R-CHOH-CH3
  19. Heteroatom Oxidation
    • Can occur alpha to heteroatom (O) or on N or S
    • Dealkylation
  20. Secondary and Primary Amines may undergo
    • dealkylation
    • deamination
    • N-oxidation
  21. Primary Amines
    • Oxidation on N
    • 2 Steps
    • Forms Hydroxylamine
    • Nitroso
    • Nitro
  22. Secondary Amines
    • 2 steps
    • Hydroxylamine formed
    • -OH added on Nitrogen
    • Nitrone formed
  23. Tertiary Amine
    • 1 step possible
    • Amine Oxide formed
  24. Aromatic Amines
    Hydroxylamine -> Nitroso
  25. N-oxidaton toxicity
    Nitrenium Ion can form adducts with DNA, RNA and Protein
  26. Alpha hydroxylation of ethers
    Alcohol and aldehyde or ketone
  27. Carbon-Sulfur System
    Oxidation Alpha to the sulfer atom resulting in dealkylation
  28. Oxidation of Alcohols and Aldehydes
    • via dehydrogenase
    • Zn2+ Center
  29. Primary Alcohols
    • oxidized to aldehyde then carboxylic acid
    • Use NAD+/NADH or NADP+/NADPH
  30. Secondary Alcohols
    alcohol form favored
  31. Reductions of aldehydes
    yeilds carboxyl group
  32. Reduction of Secondary Ketones
    Secondary alcohol
  33. Hydrolysis reactions
    • enzymes in all tissues and blood
    • Esters (prodrug) hydrolyzed (activated)
  34. Phase II Reactions
    • Make molecules more hydrophilic by attaching H2O soluble groups.
    • Detoxification and elimination of toxic compounds.
  35. Glucuronic acid conjugation
    • most common conjugation pathway
    • Pathway not well developed in children
  36. Sulfate conjugation
    • phenols
    • alcohols
    • aromatic amines
    • N-hydroxy compounds
  37. Activated form of Suflate
    Phosphoadenosine phosphosulfate
  38. Amino Acid Conjugation
    • Aromatic and arylalkyl acids
    • Requires activation of carboxyl group on target molecule
  39. Activated drug for amino acid conjugation
    Acyl-CoA Intermediate
  40. Glutathione (GSH)
    • Gamma-Glu-cys-gly
    • reaction driven by Glutathione S-Transferase
  41. Molecules which can deplete glutathione pools
    Nitrates
  42. Acetylation
    • Does not increase solubility
    • Metabolic route for primary amines
    • Acetyl-CoA is the acetyl donor
  43. Acetylation of sulfonamides
    • decreases solubility
    • may damage kidney
  44. Fast acetylation
    • no theraputic response
    • toxicity
  45. Methylation
    • Minor reaction
    • Requires activation by S-Adenosylmethionine
    • Does not increase solubility
    • Initiated by mehtyltransferases
    • 3 high energy phosphates used
    • Occurs mostly on aromatic oxygens
  46. Factors Affecting Drug Metabolism
    • metabolic rates
    • age
    • species
    • Smoking
  47. Enzyme Induction
    • exposure to a drug or other chemical will induce the biosynthesis of an enzyme.
    • May lead to resistance and interactions.
  48. Phenobarbital
    Induces glururonyl trasferase activity
  49. P450 inducers
    • Phenobarb inducers 450nm
    • PAH inducers 448 nm

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