GI Flashcards

Question

What is the most commonly used agent in combination anti-emetic therap?

Answer 1

Dexamethasone (a glucocorticoid steroid) is the most commonly used agent in combination anti-emetic therapy

Answer 2

- ginger can prove mildly effective against nausea from motion sickness, morning sickness, and after surgery - Antiemetic action attributed to the shogaols and gingerols, thought to stimulate the flow of saliva, bile and gastric secretions - Constituents in ginger believed to interact with 5HT-3 receptors, and partially responsible for antiemetic activity

Answer 3

Water The treatment approach for diarrhea & constipation remains largely empirical

Answer 4

Mild constipation should initially be treated with diet and behavior changes: adopting a fiber rich diet, increase fluid intake, increase physical activity, and develop bowel habits that take advantage of natural physiological rhythms Slower bulk-forming and surfactant laxatives represent the common first ‘pharmacotherapy’ intervention When using stimulant laxatives (promote water accumulation of water in the intestines, as well as stimulate intestinal motility), they should be administered at the least-effective dosage for the shortest period of time, to prevent developing a laxative dependence for normal bowel function and to prevent a diarrheal-like response If conventional laxatives prove ineffective, prokinetic agents may be employed

Answer 5

A sudden onset of diarrhea is usually a benign, self-limited, illness requiring no treatment In severe cases dehydration and electrolyte imbalances are the principal risks, particularly in infants and frail elderly patients Oral rehydration therapy is a cornerstone treatment of patients with significant diarrhea. Sodium and chloride absorption is linked to glucose uptake by the enterocyte; this is followed by the movement of water in the same direction FINALLY of those don't work: - Bulk forming agent = Metamucil (psyllium seed husks) - Clay = Kaopectate (kaolin), which bind water avidly - Bismuth compounds, most commonly Pepto-Bismol (bismuth subsalicylate) Has anti-secretory, anti-inflammatory and antimicrobial effects. Generally safe, but will blacken the stool, and side effects may include tinnitus and constipation - Opioids can act as antidiarrheal agents - Loperamide (Imodium and Imodium-AD) is 40-50 times more potent than morphine, as an antidiarrheal agent, and has a limited ability to enter the CNS. It is orally active and generally safe, but side effects may include abdominal pain, constipation, dizziness, nausea

Answer 6

Antacids (Histamine) H2-receptor antagonists - Cimetidine Proton pump inhibitors - Omeprazole

Answer 7

Gastric acid secretion is under: - neuronal (acetylcholine) - paracrine (histamine) - endocrine (gastrin) control *All three impact the activity of the H+, K+-ATPase (proton pump) responsible for gastric acid release *Gastrin from antral G cells binds to cholecystokinin B receptors (CCKBR or CCK2) in parietal cells and ECL cells (the latter stimulates the release of histamine) Gastrin’s mechanism is both direct and indirect

Answer 8

Histamine comes from ECL cells and it binds H2 receptors in parietal cells, stimulating gastric acid secretion of proton pumps

Answer 9

- Neutralize secreted acid; do not alter acid secretion - Most clinically useful preparations are combinations of aluminum or magnesium hydroxide (Liquids are more effective than tablets) - Primary mechanism is neutralizing the released acid to raise pH and thereby inactivate pepsin * Aluminum hydroxide can cause constipation * Magnesium hydroxide has laxative properties

Answer 10

"-dine" - Pepcid AC® (Famotidine), Pepcid Complete® (Famotidine + CaCO3 + Mg(OH)2), Zantac® (Ranitidine), Tagamet® (Cimetidine) - Safe competitive inhibitors of the H2-receptor - Available OTC - Highly effective in healing duodenal ulcers and treating uncomplicated GERD - greatest effect of H2 blockers is on basal acid release; less effective on stimulated release

Answer 11

- Omeprazole is the prototypical PPI; all others are clinically comparable - PPIs are prodrugs that are activated to a highly reactive species in an acid environment - Inhibition occurs by the covalent and irreversible binding of the reactive PPI metabolite to the pump protein - Indicated for short-term treatment and prevention of several acid-related disorders - Longer term use, however, has been increasingly associated with adverse outcomes of varying significance * interactions w/ Clopidogrel * Individuals on PPIs had significantly increased risk of incident dementia compared with those not receiving PPIs (statistical association)

Answer 12

Stage 1 (sporadic symptoms, less than 2-3 per wk) -- lifestyle changes, antacid, & maybe H2 antagonist Anything more than stage 1 = PPI

Answer 13

A functional disorder, marked by chronic or recurrent GI symptoms, which are not explained by obvious organic (anatomical or biochemical) abnormalities IBS-C (constipation) IBS-D (diarrhea) IBS-M (mixed constipation & diarrhea) - Lower abdominal pain is the central defining feature

Answer 14

Reduced plasma serotonin levels may be correlated with IBS-Constipation Increased serotonin release may play a role in IBS-Diarrhea

Answer 15

Alosetron (Lotronex) for IBS-D - 5-HT3 receptor antagonist for women with severe diarrhea-predominant IBS (IBS-D) who have failed to respond to conventional treatment for IBS - Reduces motility and intestinal sensitivity to distension *withdrawn from the market in November, 2000, because of serious, life-threatening, gastrointestinal side effects (ischemic colitis).

Answer 16

Tegasarod is a 5-HT4 agonist intended for short-term treatment of women with IBS-C, or chronic constipation. - Relieves pain, bloating and constipation. Can induce mild to severe diarrhea, which is dose-dependent. There may also be increased risk of ischemic colitis * higher chance of heart attack, stroke, and unstable angina (compared to placebo)

Answer 17

Adverse effects of the early 5‑HT4 agonists are thought to be related their relative lack of selectivity and resultant actions on other targets hERG potassium channels dopamine receptors 5‑HT1 and 5‑HT2 receptors

Answer 18

Uses: - IBS-C (adult women) - Chronic idiopathic constipation (CIC in adults) - Opioid-induced constipation (OIC in adults w/chronic non-cancer pain) Mechanism: - Activates ClC-2 chloride channel in epithelial cells lining the intestinal tract. [Cl-] in the intestinal lumen increases; as chloride moves into the intestinal lumen, Na+ ions and fluids passively follow

Answer 19

Mechanism: - Guanylate cyclase-C (GC-C) agonist (First in class) - Increases [cGMP]; increases [Cl-] in intestinal lumen; as chloride moves into the intestinal lumen, increase in intestinal fluid and faster transit - Metabolized within the GI tract to its principal, active metabolite by loss of the terminal Tyr

Answer 20

- A mixed opioid receptor agonist that reduces bowel contractions - μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist that acts locally in the enteric nervous system

Answer 21

- IBD is a spectrum of chronic idiopathic inflammatory intestinal conditions. - Etiology is unknown, but genetic, environmental and intestinal microbial factors are reported to play a role - Symptoms include diarrhea, abdominal pain, bleeding, anemia, weight loss IBD conventionally divided into two major subtypes: - Ulcerative colitis (UC): lining of the large intestine (colon) and rectum are inflamed - Crohn’s disease (CD): can affect the small and large intestine as well as other organs in the digestive tract; commonly involves all layers of the intestinal wall (transmural inflammation of any part of the the GI tract)

Answer 22

no unique abnormality identified, pharmacological therapies seek to to dampen generalized inflammatory response - Mild to moderate disease is treated with sulfasalazine/mesalamine and steroids - Steroid refractory or intolerant patients are treated with methotrexate or cyclosporine for short-term efficacy and azathiopurine/6-mercaptopurine for long-term therapy - Newer therapies (‘biologics’) target immunologic mediators and are changing therapeutic strategies

Answer 23

- Used to treat mild to moderately active UC with lower doses useful in remission. - Major action is anti-inflammatory * More effective in UC than CD - Not given to patients with sulfa drug or salicylate allergies. * prodrug cleaved by gut bacteria (diazo linkage cleaved... azo linkage in sulfasalazine prevents absorption in the stomach or small intestine) * Mesalamine (5-aminosalicylic acid, or 5-ASA) is primary active metabolite in the gut. Sulfapyridine is the more toxic metabolite * mesalamine couldn't be given orally w/o azo linkage, the bulk of it would be absorbed in the upper GI tract. Second generation 5-ASA compounds were designed as prodrugs with an azo linkage, or were coated to control site of absorption

Answer 24

Budesonide approved for treatment of mild-to-moderately active CD and UC Prednisone and prednisolone used for moderate-to-severe CD and UC Steroids are potentially toxic; withdrawal must be tapered

Answer 25

Azathioprine and 6-mercaptopurine (‘Mercaptopurine’ or 6MP) are the most commonly used immunosuppressive agents to treat moderate to severe IBD and to maintain remission Azathioprine is the prodrug and can be used interchangeably with its metabolite mercaptopurine, to treat moderate to severe disease and to maintain remission The major limitation of these drugs is that they take several weeks to produce effects in ulcerative colitis and Crohn’s disease. However, they reduce the requirement for steroids to maintain patients in remission Major side effects are bone marrow depression, leukopenia, teratogenesis

Answer 26

alternative immunosuppressant used for IBD Effective for CD Originally used for cancer treatment, through inhibition of dihydrofolate reductase, DNA synthesis blocked, resulting in cell death Subsequently recognized to have beneficial effect in autoimmune disease (rheumatoid arthritis, psoriasis). Anti-inflammatory mechanism not fully understood Reserved for patients with CD that is steroid-resistant or steroid-dependent, although treatment has largely been replaced by biological therapies

Answer 27

Murine antibodies - short half-life* - potential issues concerning the generation of human anti-mouse antibodies leading to allergic-like reactions or immunogenicity Chimeric antibodies - fusion of mouse variable with human constant domains 25-33% mouse and 67-75% human amino acid sequences relatively favorable safety profile and half-life, while retaining the specificity (e.g., high target or antigen affinity) of murine antibodies Humanized antibodies - contain 5−10% mouse and 90−95% human amino acid sequences - exhibited a lower challenge to the human immune system - CDRs within variable regions of heavy and light chains grafted or interspersed by murine antigen into the human immunoglobulin. “Fully human” antibodies 100% human amino acid sequence

Answer 28

Protein-based therapies (e.g. antibodies, receptor antagonists) are becoming the main strategy for treating refractory CD and UC - high level of efficacy in patients unresponsive to conventional therapies - Potentially dangerous in individuals with chronic infections, cancers, or immune deficiencies - Possible induction of neutralizing antibodies (“antidrug antibody” or ADA), with loss of response to drug

Answer 29

TNF-α is a potent proinflammatory cytokine that plays a key role in orchestrating the inflammatory process in multiple autoimmune diseases IBD is characterized by a dysregulated mucosal immune response toward the commensal enteric flora in genetically susceptible individuals This immune dysregulation results in an overproduction of TNF-α by monocytes, macrophages, and T cells mAbs targeting TNF-α (infliximab, adalimumab, and certolizumab) induce the formation of regulatory macrophages with immunosuppressive properties This population of macrophages inhibits proliferation of activated T cells and produces anti-inflammatory cytokines

Answer 30

bind to TNF and prevent the molecule from interacting with its two receptors, TNFRI and TNFRII, thereby stopping signaling events. These large inhibitor molecules prevent binding of either sTNF or proTNF to their membrane receptor targets

Answer 31

Infliximab (Remicade) - mouse/human IgG Ab Adalimumab - Human IgG Ab (Humira) Certolizumab pegol - Humanized Fab fragment linked to 2 PEG molecules (Cimzia)

Answer 32

Integrins are cell adhesion molecules essential for the regulation of cell growth and function cell surface receptors, comprising non-covalently linked α- and β-subunits - Natalizumab, a humanized mAb specific for α4, found to be effective in the treatment of MS, then for Crohn’s disease FDA approved for MS in 2004, then withdrawn when several patients developed fatal viral infection PML Targets both α4β1 and α4β7 integrins Reintroduced in 2006 with a black-box warning - Vedolizumab, humanized mAb specific for α4β7, shown effective in CD Modulates gut but not brain lymphocyte trafficking Received FDA approval in 2014 for moderate-to-severe UC and CD