GI Lect III

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Accelipse
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210297
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GI Lect III
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2013-03-30 02:29:25
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Pharmacology II Rutgers
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For Rutgers P2 students studying for the 2nd pharmacology II exam
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  1. Ulcerative colitis
    • Location: Mucosal inflammation starting at the distal rectum and extends into colon
    • Symptoms: bloody diarrhea, rectal urgency, feeling of incomplete defecation, weight loss
  2. Crohn's Disease
    • Location: Transmural inflammation of any part of GIT but often near ileocecal valve (often discontinuous) Can lead to fibrosis, strictures, or fistula formation
    • Symptoms: Watery diarrhea (sometimes blood), RLQ abdominal pain, low grade fever, malabsorption, weight loss
  3. Pathophysiology for Ulcerative Colitis & Crohn's Disease
    • Antigen exposure: Impairment of epithelial barrier allows access of bacterial antigens to APCs (dendritic cells)
    • T cell activation: APCs present antigen and secrete cytokines = TH1 differentiation (CD) or TH2 differentiation (UC)
    • Inflammation: IFNγ and TNFα activate macrophages; Recruit leukocytes (Integrin adhesion)
  4. Tx Ulcerative Colitis & Crohn's Disease
    • Aminosalicylates: Sulfasalazine and mesalamine
    • Corticosteroids
    • Immunosuppresants: Azathiopurine and mercaptopurine
    • Biologics: Infliximab, adalimumab, certolizumab, natalizumab
  5. Aminosalicylates: Examples, MoA, Location, Tx
    • Sulfasalazine, mesalamine, olsalazine, balsalazide
    • MoA: 5-aminosalicylate (5-ASA) is responsible for anti-inflammation; Inhibit IL-1, TNFα, lipoxygenases, NFκB and scavenge free radicals
    • Location: Act at varying sites in the GIT; 5-ASA routes = Rowasa (suppository), Canasa (enema), Asacol (delayed release), Pentasa (pH coating)
    • UC: Mild-to-moderate disease has 60-80% response rate
    • CD: Modest benefit, not great for maintaining remission
  6. Aminosalicylates: PK, ADEs
    • PK: Sulfasalazine is metabolized to 5-ASA and sulfapyridine
    • Sulfapyridine portion: highly lipid soluble, hepatic metabolism (acetylation, hydroxylation, glucuronidation)
    • Acetylation phenotype of patient determines side effects (rapid acetylators have fewer ADEs)
    • ADEs: related to sulfa moiety = headache, nausea, fatigue, rash, fever, Stevens-Johnson syndrome, hepatitis, hemolytic anemia; Inhibits folate absorption (need supplementation)
    • 5-ASA may cause interstitial nephritis (rare)
    • Newer forms = less frequent/severe, i.e. diarrhea
  7. Corticosteroids
    • Tx: acute attacks in moderate to severe disease
    • Responsiveness varies: 40% responsive, 30-40% partial response or become glucocorticoid dependent, and 15-20% don't respond.
    • ADEs: hyperglycemia, hypertension, hypothyroidism, osteoporosis, insulin resistance
    • Dosing: PO prednisolone, budesonide; Rectal cortifoam; IV hydrocortisone, methylprenisolone (sever)
  8. Immunosuppressants
    • Tx: steroid resistant or dependent IBD
    • 6-mercaptopurine & azathiopurine: impair purine biosynth and inhibit cell proliferation; beware polymorphisms in thiopurine methyltransferase; ADEs: pancreatitis, arthralgia, bone marrow suppression
    • Methotrexate (Tx Crohn's only): Inhibit dihydrofolate reductase which blocks DNA synthesis and causes cell death; IM or SC
  9. Biologics: TNFα Inhibitors
    • Tx Crohn's
    • Infliximab: Chimeric mAb against TNFα (IV)
    • Adalimumab: Human mAb against TNFα (SC)
    • Certolizumab pegol: Humanized pegylated Fab fragment against TNFα (SC)
  10. Biologics: A4 Integrin Inhibitor
    Natalizumab: Inhibits leukocyte adhesion and migration by targeting α4 integrin
  11. What is Short Bowel Syndrome?
    • Poor absorption of nutrients due to small intestine removal
    • Some causes: Necrotizing enterocolitis, congenital defects, meconium ileus (CF patients), Crohn’s disease, trauma
    • Main symptom is diarrhea
    • Intestinal adaptation begins 24-48 h post-surgery and continues up to 2 y
  12. Tx Short Bowel Syndrome
    • NonRx: Eat small meals, supplements, antidiarrheals, enteral/parenteral nutrition in severe cases
    • Somatropin (Zorbitive) – recombinant growth hormone to stimulate bowel adaptation
    • Glutamine (Nutrestore) – amino acid that contributes to intestinal structure
    • Teduglutide (Gattex) – analog of glucagon-like peptide 2 (SC) for patients on parenteral nutrition (ADEs:intestinal cancer, pancreas/gall bladder/biliary tract disease)
  13. Ursodeoxycholic acid (Ursodiol, Actigall)
    • Dried extract from Himalayan bear bile (Only 1 to 3% of human bile supply)
    • Increases bile formation
    • Solubilize cholesterol monohydrate stones (30-50% efficacy)
    • Counter the effects of the hydrophobic bile acids on cell membranes
    • Decrease biliary lipid secretion
    • Reduce cholesterol content of bile
  14. Cholestyramine (Questran), Colestipol (Colestid)
    • Bile Acid Sequesterants
    • MoA: bind bile acids and prevents reabsorption by acting as an anion exchange resin
    • Tx: bile-salt induced diarrhea; C.diff GI infxn; pruritis associated with biliary obstruction (i.e. primary biliary cirrhosis)
    • ADEs: constipation
  15. What is/causes cirrhosis?
    • Progressive destruction of liver cells and replacement with scar tissue (fibrosis)
    • 1. Increase portal vein pressure and decrease plasma oncotic pressure ⇨ varices (dilated submucosal veins, rupture risk) and ascites (fluid in abdomen)
    • 2. Increase ammonia levels ⇨ encephalopathy (reduced mental status)
    • 3. Reduce ability to fight infection ⇨ bacterial peritonitis
    • Major causes: chronic alcohol, chronic viral hepatitis, nonalcoholic steatohepatitis
  16. Portal Hypertension & Varices
    • Prevention: Non-selective Beta blockers Propanolol and nadolol decrease portal blood pressure
    • Treatment of active variceal bleeding: Vasopressin (Pitressin) and Terlipressin (Varipres) act as vasopressor and ADH; Octreotide (Sandostatin) is synthetic somatostatin analog that causes splanchnic vasoconstriction by blocking vasodilatory peptides
  17. Tx Cirrhosis
    • Bacterial peritonitis: E. coli (g-) and Klebsiella (g+)
    • - 3rd generation cephalosporin (cefotaxime), fluoroquinolones (norfloxacin, ciprofloxacin) and trimethoprim-sulfamethoxazole)

    • Ascites: salt restriction, diuretics
    • - Spironolactone (K+-sparing diuretic) and furosemide (loop diuretic)

    • Encephalopathy: protein restriction, reduce ammonia
    • - Lactulose (Cephulac) decreases GI pH, osmotic laxative
    • -Neomycin (Mycifradin) and Rifaximin (Xifaxan) = aminoglycosides that target ammonia-producing gut bacteria
  18. Acute Pancreatitis
    • Symptoms: Severe, persistent epigastric pain, N/V, abdominal tenderness
    • Pathophysiology: “Autodigestion” Associated with gallstones, alcohol, viruses, trauma, drugs (Estrogens, metronidazole, ACEI, tetracycline, valproic acid, corticosteroids, 6-mercaptopurine, thiazide diuretics, azathioprine)
    • Supportive treatment: pain management, nutrition, IV antibiotics against gram negative bacteria
  19. Chronic Pancreatitis
    • Symptoms: Abdominal pain, steatorrhea, malabsorption, diabetes
    • Pathophysiology: Inflammation with fibrosis and calcification; Associated with alcohol (1° cause), hyperlipidemia, pancreatic cancer; Increased release of cholecystokinin (CCK) = cause pain due to continuous stimulation of enzyme output and increased intraductal pressure
    • Treatment: pain management, reduce fat consumption, pancreatic enzyme supplements to prevent malabsorption
  20. Pancrease, Pancreacarb, Zenpep, Viokace, Ultrase, Creon
    • Pancreatic Enzyme Supplements
    • Enteric-coated, delayed release to activate in duodenum
    • Often derived from porcine pancreas (avoid if allergy)
    • Take with meals and snacks
    • ADEs: N/V/D/C, bloating
  21. Lactose Intolerance
    • Pathology: Deficiency in digestive enzyme lactose galactosidases
    • Symptoms: Diarrhea, abdominal cramping, pain, flatulence, and malabsorption
    • Tx: Enzyme replacements are over the counter and can be added to meals. They are bacterial or yeast-derived β-galactosidases, with varying efficacy (LACTAID, LACTRASE, DAIRYEASE, others)
    • Because of the essential requirements to maintain protein, calcium, and vitamin D intake, these must be supplemented if dairy products are limited.
  22. Children's Celiac Disease
    • Symptoms: Fatigue, bloating, constipation, abdominal pain, chronic diarrhea, irritability, vomiting
    • Signs: Muscle wasting, weight loss, short stature, delayed puberty, osteopenia, hepatitis, dental anomalies, anemia
    • Cause: Genetic predisposition (HLA-DQ2 and HLA-DQ8) and exposure to gluten
  23. Adult's Celiac Disease
    • Symptoms: Abdominal pain, chronic diarrhea, abdominal distension
    • Signs: Weight loss, infertility, dermatitis herpetiformis, hepatitis, anemia, alopecia, malignancy, seizures, osteopenia, arthritis
    • Cause: Genetic predisposition (HLA-DQ2 and HLA-DQ8) and exposure to gluten
  24. Tx Celiac Disease
    • Treatments: Dietary changes (avoid gluten), vitamin and mineral supplements (calcium and vitamin D)
    • May consider immunomodulators (corticosteroids, azathioprine, cyclosporine, tacrolimus, infliximab, alemtuzumab) for refractory cases
  25. Gluten-full foods
    Wheat, barley, rye, bran, graham flour, spelt, wheat germ, oats

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