Disorders of Integrated GI Function Pharmacology
- Nausea is due to decresaed gastric motility, increased intestinal tone
- In retching, glottis is closed
- Vomiting (Emesis) - deep breath, larynx raised to open esophageal sphincter,
soft palate raised to close nares, diaphragm contacts down, abdominal muscles contact
- Emesis controlled by CNS - Medullary with afferent peripheral input - Chemoreceptor Trigger Zone (CTZ) projects to EC, in area postrema
- Afferent input to EC includes five sources - CTZ, VI tract, non-GI visceral input, forebrain input, vestibular system
- Peripheral treatment of nausea and vomiting includes treating inflammation, toxins, CTX and other drugs
- 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
- 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
- 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
- Substituted Benzamides included Metoclopramide and trimethobenzamide, both dopamine receptor antagonists that can cause tardive dyskinesia and should only be used short-term
- Scopolamine is a muscarinic antagonist that is very effective against motion sickness - transdermal patch localizes effects
- H1 antihistamines like diphenhydramine and dimenhydrinate are efficacious against motion sickness, but anticholinergic effects can be an issue
- 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
- 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
- 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