PHRD5935 Pharm/Tox Lecture 11 - Liver Toxicity

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  1. 5 major fcns of the liver
    • 1) nutrient homeostasis
    • 2) filtration of particulates
    • 3) protein synthesis
    • 4) biotransformation/detox
    • 5) formation of bile & biliary excretion
  2. 4 major types of cells in the liver
    • 1) hepatocytes
    • 2) Kupfer cells
    • 3) hepatic stellate cells (lipocytes)
    • 4) NK cells
  3. 6 mechanisms of liver injury
    • 1) membrane disruption
    • 2) disruption of actin filaments in canaliculus
    • 3) CYP disruption in ER generating ROS
    • 4) inflammation by cytokines
    • 5) apoptosis by casp activation
    • 6) inhibition of beta-oxidation & respiration (dysfcnal mitochondria)
  4. 2 types of drug-induced liver toxicity
    • 1) predictable (pharmacological)
    • 2) idiosyncratic
  5. predictable dose effects of APAP, cyclophosphamide, or methotrexate
    inc dose: hepatocyte necrosis
  6. predicatable dose effects of cocaine, phencyclidine, or niacin
    inc dose: ischemic necrosis
  7. predictable dose effects of oral contraceptives
    cumulative dose: hepatic adenomas
  8. mechanism of EtOH-APAP syndrome
    consumption of EtOH results in more CYP2E1 present due to slower degradation. after removal of EtOH, too much APAP is metabolized at once, resulting in a buildup of NAPQI -> toxicity
  9. how APAP can cause irreversible inhibition of fatty acid oxidation
    CYP2E1-mediated metabolic activation & oxidative stress suppresses PPARImage Upload 1-regulated pathways
  10. P450 enzymes involved in APAP metabolism
    • CYP2E1 (major)
    • CYP1A2
    • CYP3A
  11. classic example of idiosyncratic rxn
    isoniazid (dependent on genetic polymorphism)
  12. what hepatic clearance of drugs depends on
    activity of transport proteins on the hepatocyte canalicular membrane
  13. decrease in the volume of bile formed or impaired secretion of specific solutes into bile
  14. drugs associated w/ cholestasis (5)
    • 1) chlorpromazine
    • 2) sulfonamides
    • 3) sulfonylureas
    • 4) erythromycin
    • 5) captopril
  15. also known as cholangiodestructive cholestasis; results in inc serum levels of enzymes localized in the bile duct
    bile duct damage
  16. liver disease that involves damage to the bile canaliculi & bile ducts

    long-term estrogen therapy has been indicated in this disease
    cholestatic jaundice
  17. treatment with this drug was assoc'd w/ a huge incidence of cholestatic jaundice
    Image Upload 2-tocopherol acetate (IV form of vit E)
  18. liver-specific inflammatory rxn caused by hypersensitivity to a particular drug
    allergic hepatitis
  19. drugs assoc'd w/ allergic hepatitis (3)
    • phenytoin
    • erythromycin
    • sulfonamides (trimethoprim, sulfamethoxazole)
  20. indolent liver damage that closely resemble autoimmune chronic hepatitis (difficult to ID)
    drug-induced chronic hepatitis
  21. drugs that cause drug-induced chronic hepatitis (7)
    • methyldopa
    • APAP
    • ASA (in high doses)
    • nitrofurantoin
    • trazodone
    • ketoconazole
    • halothane
  22. increase of hepatic lipid content by more than 5% (often reversible)
    steatosis (fatty liver)
  23. characterized by an abnormal accumulation of small cytoplasmic lipid droplets in hepatocytes
    microvesicular steatosis
  24. MOA of ASA in Reye's Syndrome
    damage to mitochondria leads to depletion of acetyl-CoA & carnitine -> FA accumulation, impaired gluconeogenesis -> hypoglycemia -> advanced steatonecrosis
  25. end stage of chronic liver injury in which extensive amts of fibrous tissue, esp collagen fibers, are deposited in response to direct injury/inflammation
  26. drugs assoc'd w/ cirrhosis
    • methotrexate
    • vit A
    • methyldopa
    • alcohol
  27. benign tumor that itself causes no sx but may rupture vessels leading to bleeding in the IP cavity
Card Set
PHRD5935 Pharm/Tox Lecture 11 - Liver Toxicity
Liver Toxicity
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