Disorders of Integrated GI Function Pharmacology

  1. Nausea is due to decresaed gastric motility, increased intestinal tone
  2. In retching, glottis is closed
  3. Vomiting (Emesis) - deep breath, larynx raised to open esophageal sphincter, soft palate raised to close nares, diaphragm contacts down, abdominal muscles contact
  4. Emesis controlled by CNS - Medullary with afferent peripheral input - Chemoreceptor Trigger Zone (CTZ) projects to EC, in area postrema
  5. Afferent input to EC includes five sources - CTZ, VI tract, non-GI visceral input, forebrain input, vestibular system
  6. Peripheral treatment of nausea and vomiting includes treating inflammation, toxins, CTX and other drugs
  7. 5-HT3 Antagonists
    • Receptors present on visceral afferents in CTZ and EC
    • "-setron" family
    • Great for chemotherapy induced nausea and vomiting (CINV) - interfere with vagal afferents
    • Less effective for motion sickness and psychological emesis
    • Liver metabolism is extensive, good toxicity profile
    • Prolonged QT, esp. with dolasetron
  8. NK1 antagonists
    • Substance P and Tachykinin receptor antagonists
    • Suffix "-pitant" - Substance P it antagonizes
    • Great for delayed CINV
    • Long DOA, better for second phase of CINV, anxiolytic and antidepressant efficacy
    • Decreased appetite, dizziness reported
  9. Phenothiazines antagonize dopamine receptors primarily in the CTZ
    • Sedating with antihistamine properties
    • Suffix "-azine", e.g. Promethazine
    • Butyrophenones included Doperidol - prolonged QT at high doses
    • Particularly effective against post-operative nausea and vomiting
    • Adverse effects - Extrapyramidal effects, Prolonged QT, torsades with droperidol
  10. Substituted Benzamides included Metoclopramide and trimethobenzamide, both dopamine receptor antagonists that can cause tardive dyskinesia and should only be used short-term
  11. Scopolamine is a muscarinic antagonist that is very effective against motion sickness - transdermal patch localizes effects
  12. H1 antihistamines like diphenhydramine and dimenhydrinate are efficacious against motion sickness, but anticholinergic effects can be an issue
  13. Benzodiazepines are effective against anxiety-related emsis - particular importance in chemotherapy - but sedation is a risk, and short acting compounds like Lorazepam should be preferred
  14. Cannabinoids are effective against all forms of nausea and vomiting - derivatives approved in the US include Dronabinol and Nabilone for CINV and AIDS-related chachexia
  15. Treatment of IBD
    • Aminosalicylates - contain 5-aminosalicyclic acid - anti-inflammatory with localized effects and low systemic exposure
    • Aminosalicylates can cause renal toxicity, allergic reactions
    • Azo compounds - suffix "-salazine" - are prodrugs that release 5-ASA and produce systemtic effects
    • Mesalamine formulations deliver 5-ASA to targeted portions of the GI: Pentasa - entire GI; Asacol - ileum and colon; Roawasa - enema formulation targets colon; Canasa - suppository formulation
    • Glucocorticoids are anti-inflammatory and reduce gene expression of pro-inflammatory products
      • Prednisone, Dexamethasone, Hydrocortisone, etc.
      • Intermediate half-life
      • Widespread side effects, including Cushing's-type effects, adrenal insufficiency, infection, CNS effects, electrolyte imbalancing
    • Antimetabolites
      • Purine analogs - Asathioprene and 6-Mercaptopurine
      • Inhibit DNA synthesis and proliferation of inflammatory mediators
      • DHFR-inhibitor Methotrexate inhibits DNA synthesis but is contraindicated in pregnancy
      • Low dose compared to chemotherapeutic use but can still cause myelosupression, hepatotoxicity, etc.
      • Allopurinol reduces metabolism of purines
    • Anti-TNF-alpha
      • Antibodies that target T-cell activation, which is implicated in IBD
      • Infliximab, Adalimumab, etc.
      • Cause immunosuppression, infusion reaction, etc.
    • Anti-alpha4-integrin
      • Natalizumab
      • Monthly IV treatment
      • Addressin is elevated in Crohn's and an integrin agonist - anti-integrin antibody disrupts
      • Can cause viral progressive multifocal leukoencephalopathy (PML) when used with immunosuppresants