Med Chem Exam 1 Part 1

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crmozingo
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130859
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Med Chem Exam 1 Part 1
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2012-01-27 10:59:55
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Med Chem Exam 1 Part 1
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  1. Methylxanthines
    • Caffeine
    • -AKA: trimethylxanthine, morning thunder
    • -Can be superimposed on Theophylline (Theo-Dur)
    • -not effective in treating ADHD
    • -Prototype for 1A2 (inducible)

    • - FDA: “Narrow Therapeutic Index (NTI) drug (TI<2) and implications for generic
    • substitutions*! (or highly variable PK (within-subject AUC or Cmax>30%)
    • -FDA does not use this for bioequivalence; some STATES consider variable PK for classification of NTI and might have stricter classifications than the FDA, pharmacies must comply with the strictest law for
    • that state
  2. CYP1A2
    • -inducible
    • -probe/marker for caffeine or theophylline
    • -M/R measures caffein to paraxanthine ratio
    • -minor metabolites include theophylline and uric acid
    • -substrate for R-warfarin
    • -combination of multiple drugs metabolized by 1A2 increases the plasma concentration of both drugs (decreased metabolic clearance)
    • -induced by cigarettes, charcoal foods, heterocyclic amines, cabbage, phenobarb, phenytoin, rifampin
    • -monomorphic
    • -ontogeny: expressed in adults not in fetus
  3. CYP1A1
    • -extrahepatic
    • -biotoxification of polycyclic armontic hydrocarbons
    • -2010 Gulf of Mexico shrimp "smell test"
    • -monomorphic
    • -preclinical data cannot always predict human effect (rat is 80% similar to humans)
  4. Polycyclic aromatic hydrocarbon (PAH)
    • -forms a covalent bond with DNA through epoxide intermediate
    • -Gulf of Mexico shrimp 2010: "smell test" GC-MS for crude oil PAH levels
  5. Caffeine PD
    • 1. adenosine antagonist
    • 2. inhibits phosphodiesterase (prevents cAMP--- AMP)
    • 3. blocks GABA activation of glutamtergic Cl- channel preventing hyperpolarization and promoting excitatory glutamatergic neurotransmission
  6. Antiobesity agents (stimulants)
    -phenylethylamine pharmacophore

    • Examples:
    • amphetamine
    • phentermine
    • bupropion-naltexone
    • sibutramine
  7. Antiobestity (non-stimulant)
    Orlistat

    • -suicide inhibitor
    • -beta lactone transesterfied
    • -acetylated lipase binds to the critical active site so TGs cannot be absorbed
  8. Benzodiazepines
    -seven membered ring with 2 N and a benzene ring

    • Indications:
    • anxiolytics
    • hypntics
    • adjuncts to treat convulsant disorders
    • skeletal muscle relaxants
  9. Chlordiazepoxide
    • -first benzodiazepine
    • -low potency
    • -accumulation (long half life) PD does not equal PK
  10. Diazepam
    • -benzodiazepine
    • -anxiolytic
    • -metabolized to oxazepam contains a glucoronide
    • -UGT2B15 - important in the clearance if xenobiotics and drug metabolism
  11. clorazepate
    • -not technically a prodrug because it is not metabolized by an enzyme but by acid catalyzed decarboxylation
    • -metabolized to nordazepam (metabolite of chlordiazepoxide and diazepam) (European form of diazepam)
  12. Oxazepam
    • -benzodiazepine
    • -marker for UGT2B15
  13. Lorazepam
    • -benzodiazepine
    • -chlorine attached to oxazepam
    • -chlorine that increases potency
    • -PGx: inducbile and polymorphic
  14. Alprazolam
    • -benzodiazepine
    • -prototype triazolo derivative
    • -potent (has a chlorine)
  15. Triazolam
    -benzodiazepine
  16. Flurazepam
    • -benzodiazepine
    • -aliphatic amine (protonated, basic)
    • -ammonium is what passes through the body
    • -renal clearance
    • -half life of a hypnotic
  17. Midazolam
    • -benzodiazepine
    • -adjunct for anesthesia
    • -CYP3A4 substrate/probe
  18. CYP3A4
    • -CYP3A4 is in the gut unlike the other CYPs
    • -inducible
    • -not polymorphic
    • -enteric and hepatic first pass
    • -as you move down the small intestines 3x less (proximal to distal gradient)
    • -sex dimorphism: women express more than men
    • -food inhibitors: grapefruite juice (inhibits OAT) which binds tightly to 3A4
    • -CYP3A7 largely silenced as infants transition to CYP3A4 - CYP3A4 increases with age
  19. Nifedipine
    -additional 3A4 marker
  20. Cortisol
    • -noninvasive 3A4 expression marker
    • -based on metaboism of an endobiotic and not a radioisotope
    • -erythromycin C14 breath test
  21. Beta-Carboline
    • -pro convulsant
    • -not a drug but an BNZ anxiogenic endobiotic
    • -Tryptophan + EtOH can be superimposed
  22. Flumazenil
    • -BNZ antagonist
    • -reverses BZN anesthesia, BZN OD
    • -proconvulsant anxiogenic compound
  23. Zolpidem and Zaleplon
    • -GABA agonists
    • -hypnotics
    • -potent GABA-A-alpha omega 1 agonist
  24. Eszopiclone
    • -GABA agonist
    • -S enantiomer --- developed through racemic switch
    • -metabolized by 3A4 and 2E1
  25. GABA and BZN omega receptors
    • -BNZ indirectly acts on GABA-A ionotropic receptors
    • -GABA is synthesized by decarboxylation of glutamate
  26. GABA-A ionotropic receptor complex
    • -BZN facilitate GABA binding and function moving chlorine into the cytosol
    • -opposite effect of caffeine
    • *GABA is inhibitory
    • -BZN binds allosterically
  27. GABA-B
    -metabotropic
  28. Buspirone
    • -depressant
    • -serotonergic partial agonist
    • -anxiolytic
    • -not GABA-ergic
  29. Ramelteon
    • -hypnotic
    • -oxygen isostere of melatonin
    • -melatonin agoinst (mimics melatonin)
    • -circadian rhythm
  30. Fospropofol
    • -prodrug of propofol
    • -used for the induction of anesthesia
  31. Propofol
    • -"milk of anesthesia"
    • -induces anesthesia but DO NOT USE off label as hypnotic
  32. Ethanol
    • -absorbed duodenum
    • -metabolized by ADH
    • -DDI with aspirin increases bioavailability of EtOH
    • -ethanol + ADH = Acetaldehyde (flush) + ALDH = Acetate (vinegar)
  33. Methanol
    • -"wood" alcohol
    • -POISON
    • -methanol + ADH = formaldehyde + ALHD = Formic acid
    • -Tx: give EtOH because it is a better ADH substrate
  34. CYP2E1
    • -inducible
    • -interindividual differences in expression
    • -substrates are small molecules, volatile anesthetics
    • -limited evidence of polymorphism
  35. Chlorzoxazone
    • -probe/marker substrate for CYP2E1
    • -muscle relaxant
    • *Metabolic ratio is usually D/M but in this case it is M/D
  36. Acetominophen
    • -Phase II metabolism - conjugation and glutathion S- transferases
    • -ring oxidation by 2E1 increases with alcohol induction (toxic)
    • -Tx: N-acetylcysteine
  37. Glutathione S-Transferase (GST)
    • -bonds glutathione
    • -yields mercapturic acid
  38. Common pharmacophore of anticonvulsants
    N-C(=O)(X)

    X = N, O, C
  39. Barbituates
    • -used as a second line BZN
    • -acidity allows water-soluble salts which cause a low TI
  40. Phenobarbitol
    • -prototypic GENERAL enzyme inducer
    • -barbituate
  41. Pentobarbital
    • -used for lethal injection
    • -exit Marilyn Monroe
  42. Metholbarbital and Primidone
    • -barbituates
    • -prodrugs
    • -Metholbarbital is N-methylated to phenobarbitol
    • -Primidone is C-oxidized to phenobarbitol
    • -metabolized by 2Cs
  43. CYP2C9
    • -inducible
    • -polymorphic
    • -EM is wild type *1
    • -PM requires lower dose
  44. S-Warfarin
    • -metabolized by 2C9
    • -eutomer and substrate
    • -FDA recommends 2C9 genotyping (not ID on Amplichip)
  45. CYP2C19
    • -inducible
    • -polymorphism (EM, IM, PM)
  46. Mephenytoin
    • -anticonvulsant
    • -synthesized from hydantoin
    • -CYP2C19 is a marker for prototyping
    • -no longer available
  47. Phenytoin and Fosphenytoin sodium
    • -anticonvulsant
    • -synthesized from hydantoin
    • -metabolized by 2C9 and 2C19
    • -over proportionality (nonlinear PK)
    • -Fosphenytoin is the prodrug; reacts with water to form phenytoin
  48. Carbamazepine and Oxacarbazepine
    • -anticonvulsant
    • -biotoxification to epoxide
    • -oxacarbazepine overcomes biotoxification because of the ketone instead of the epoxide
  49. Valproic Acid
    • -anticonvulsant
    • -UGT based DDI
    • -increase GABA; decrease in succinic acid
    • -increases anabolism (synthesis); decrease catabolism (break down)
    • -activating glutamate decarboxylase and inhibiting GABA transaminase
  50. Lamotrigine
    • anticonvulsant
    • inhibits sodium channel
    • as seen in local anesthetics, decreasing action potential
  51. Gabapentin
    • anticonvulsant
    • calcium channel blocker
  52. Tiagabine
    • anticonvulsant
    • GABA uptake inhibitor
  53. Topiramate
    • anticonvulsant
    • sodium channel blocker
    • potentiates GABA
    • glutamate antagonist
  54. Levetiracetem
    • anticonvulsant
    • MOA unknown
  55. Clonsazepam
    • anticonvulsant
    • benzodiazepine MOA
    • metabolized by 3A4 - nitro group to amine
  56. Strychnine
    • -convulsant/analeptic
    • -glycine antagonist

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