PHRD 5985 Pharmacotherapy Lecture 6 - Alcoholic Liver Diseases

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PHRD 5985 Pharmacotherapy Lecture 6 - Alcoholic Liver Diseases
2014-02-18 05:53:27

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  1. #1 cause of alcoholic liver disease
    chronic alcohol consumption
  2. most common hepatic manifestation
    steatosis (fatty liver)
  3. fat accumulates in liver due to ethanol's interference with normal cellular metabolism
  4. fat accumulation within hepatocytes leads to lysis and hepatocellular necrosis & inflammation
    steatohepatitis (alcoholic hepatitis)
  5. - acetaldehyde stimulates synthesis of collagen w/in parenchyma of liver
    - fibrous tissue is deposited around terminal hepatic venules and hepatocytes to cause obstruction of flow
    chronic liver disease/cirrhosis
  6. mainstay of therapy for all stages of alcoholic liver disease
    abstinence from alcohol
  7. causes fibrosis in chronic liver disease
    synthesis of collagen
  8. types of ALD that are assoc'd with a possible genetic predisposition, and develop in only ~10-20% of alcoholics (2)
    • steatohepatitis
    • cirrhosis
  9. risk factors for ALD (5)
    • 1) amt of alcohol ingested (LT >30g/day)
    • 2) drinking outside of meals/binging
    • 3) type of alcohol (spirits)
    • 4) women > men, AA & Hisp > Cauc
    • 5) presence of HepC
  10. ratio of AST/ALT suggestive of alcohol abuse
  11. albumin lab result in ALD

    (diminished hepatic synthesis of proteins, sequestration, malnutrition)
  12. PT or INR lab results in ALD

    (decreased hepatic production of coagulation factors)
  13. bilirubin lab results in ALD

    (decreased liver excretory capacity)
  14. 3 medical conditions present in ALD
    • 1) hyponatremia (inc ADH activity)
    • 2) anemia (folate deficiency, typically megalycytic anemia)
    • 3) thrombocytopenia (dec hepatic TPO prod)
  15. clinical manifestations of ALD (10)
    • 1) jaundice
    • 2) spider angioma
    • 3) splenomegaly
    • 4) caput medusae
    • 5) white nails
    • 6) finger clubbing
    • 7) gynecomastia
    • 8) hypogonadism
    • 9) asterixis ("liver flap")
    • 10) anorexia, weight loss, fatigue, muscle wasting
  16. small dilated blood vessels near the surface of the skin w/ radiating capillary branches
    spider angioma, palmer erythema
  17. indicative clinical manifestation of hepatic encephalopathy
    asterixis (liver flap)
  18. distended/engorged paraumbilical veins radiating from the umbilicus across the abdomen to join systemic veins
    caput medusae
  19. low risk MDF score
  20. low risk MELD score
  21. DF score for contraindication to prednisolone
  22. first-line treatment of high risk AH
  23. when to use pentoxifylline
    in high-risk AH, when there are steroid contraindications or signs of early renal failure
  24. prednisolone dosing for AH
    • 40mg PO QD for 4 weeks
    • taper off in 2 weeks
  25. pentoxifylline (PTX) treatment of AH
    400mg PO TID x 4weeks
  26. MOA of PTX
    PDE inhibitor that decreases TNF production
  27. Child-Pugh A score
    <7 points
  28. Child-Pugh B score
    7-9 points
  29. Child-Pugh C score
    10-15 points
  30. MELD score for pts considered candidates for transplanation
  31. Compensated Cirrhosis (2)
    • 1) Child-Pugh A
    • 2) median survival ~9years
  32. Decompensated Cirrhosis (3)
    • 1) any: jaundice, encephalopathy, variceal hemmorhage, ascites
    • 2) Child-Pugh B or C
    • 3) 60% 5yr survival if abstain from EtOH vs 30%
  33. spectrum of neuropsychiatric sx due to liver disease (mainly a dx of exclusion)
    hepatic encephalopathy
  34. recurrent encephalopathy
    2 episodes w/in 1 year
  35. Mechanism for HE development
    accumulation of gut-derived nitrogenous substances (mainly ammonia) that enter the CNS & cause alterations in neurotransmission
  36. what ammonia is normally converted to in the liver
  37. how GI bleed can be a precipitating factor in increased nitrogen load
    increased ammonia production through breakdown of Hb in gut
  38. how metabolic/electrolyte disturbances (alkalosis, hypokalemia) can be precipitating factors in increased nitrogen load
    NH4+ -> NH3 conversion facilitation
  39. primary aim of HE therapy
    reduction of blood ammonia levels
  40. possible drug therapies for HE (3)
    • 1) lactulose
    • 2) rifaximin
    • 3) lactulose + rifaximin

    (RARELY: neomycin or metronidazole)
  41. MOAs of lactulose in HE treatment (2)
    • 1) degraded by colonic bacteria to acetic acid & lactic acid -> decrease colonic pH -> promotion of NH3 to NH4+ (ammonium ion)
    • 2) acts as osmotic laxative
  42. acute dosing of lactulose for HE tx
    30-45mL PO q1-2hrs until stool, then 15-30mL q8-12hr to maintain 2-3 soft stools/day
  43. MOA of rifaximin for HE tx
    "non-absorbable" abx that eliminates urease-producing bacteria in colon which convert protein to ammonia
  44. acute dosing of rifaximin for HE tx
    400mg PO TID or 550mg PO BID

  45. 1st-line tx for episodic HE and prevention of recurrent HE
  46. extremely dilated sub-mucosal veins in the lower third of the esophagus
    esophageal varices
  47. mechanism for development of esophageal varices
    fibrosis -> portal hypertension -> inc collateral blood flow/backup into left gastric vein (innervates lower esophagus) -> varices
  48. when to screen for varices
    any pt w/ a dx of cirrhosis
  49. primary prevention of variceal hemorrhage
    non-selective -blockers 

    (propranolol, nadolol, carvediol)
  50. MOA for non-selective -blockers w/ respect to variceal hemorrhage
    • reduce portal flow & pressure by...
    • 1) inhibiting 2-adrenergic Rs -> vasoconstriction of splanchnic capillaries/arterioles
    • 2) inhibiting 1-adrenergic Rs -> dec cardiac output
  51. 1st line option in med-large varices or pts that can't take non-selective beta-blockers
    endoscopic variceal ligation
  52. endoscopic variceal ligation (EVL)
    placement of rubber bands around the varices (q1-2weeks) until obliteration
  53. tx for acute variceal hemorrhage (3)
    • 1) supportive fluids, blood transfusion
    • 2) prophylaxis w/ antibiotics for 7 days
    • 3) drug tx & endoscopic variceal ligation/sclerotherapy
  54. main drug used to treat variceal bleed
    ocreotide (IV)
  55. ocreotide MOA
    • decrease portal pressure & collateral flow by...
    • 1) inhibited release of vasodilatory GI peptides (eg: glucagon)
    • 2) local vasoconstrictor effects in splanchnic vasculature
  56. pathologic accumulation of free fluid w/in the peritoneal cavity
  57. most common complication of portal hypertension
  58. SAAG value that confirms ascites due to portal HTN
    1.1 g/dL

    (SAAG = serum-ascites albumin gradient = [albumin] in serum - [albumin] in ascitic fluid)
  59. #1 activation of the renin-angiotensin aldosterone system
  60. causes of moment of fluid out of vasculature into peritoneal cavity (3)
    • 1) dec plasma oncotic P (low albumin)
    • 2) inc capillary permeability
    • 3) inc plasma hydrostatic P (Na/H2O retention)
  61. new-onset ascites drug treatment
    • 1st line diuretic tx:
    • spironolactone + furosemide (100:40)
  62. spironolactone MOA
    acts by inhibiting aldosterone's effects on the distal tubule/cortical collecting duct, reducing Na+ & H2O retention
  63. furosemide MOA
    acts on ascending limb of Henle to reduce Na+ & H2O retention
  64. when spironolactone should be used alone
    only in the management of mild ascites
  65. when should furosemide be used alone for ascites management?
  66. goal in random spot urine test during tx of ascites
    urinary Na > urinary K
  67. therapeutic treatment used to relieve abdominal pain or respiratory difficulties when tense ascites is present
    paracentesis (abdominal fluid tap)
  68. when paracentesis is appropriate (3)
    • 1) when tense ascites is present
    • 2) diuretic-resistant (refractory) ascites
    • 3) to diagnose spontaneous bacterial peritonitis (SBP)
  69. infection in the peritoneal cavity in pt w/ ascites
    spontaneous bacterial peritonitis (SBP)
  70. tx of SBP
    PO or IV abx for 5days, then consider LT PO abx prophylaxis
  71. complication of cirrhosis due to thiamine (Vit. B1) deficiency
    Wernicke-Korsakoff Syndrome
  72. how to treat Wernicke-Korsakoff Syndrome
    • high dose IV thiamine for 3-5days
    • (100mg PO QD for prevention)
  73. progression of Wernicke-Korsakoff Syndrome
    Wernicke Encephalopathy (WE) -> continued thiamine deficiency -> Korsakoff Dementia (KD)
  74. bleeding from an esophageal varice into the esophagus, or bleeding of collateral varices into the stomach
    variceal hemorrhage