GI drugs Flashcards
What is acid-peptic disease?
Disease of upper digestive tract caused by acid and pepsin - ex. gastroesophageal reflux, erosions, ulcers - due to gastric acid, decreased mucosal resistance to acid, H. pylori infection, Drugs (NSAIDs, warfarin and corticosteroids), stress, life style, gastrinoma
What is Zollinger-Ellison syndrome?
Hypersecretion of gastric acid and pepsin most commonly due to gastrinoma - it is associated with severe acid-peptic ulcerations and diarrhea
What is a gastrinoma?
Tumor that produces large amounts of gastrin - this is associated with hypersecretion of gastric acid and pepsin leading to ulcerations
What is carcinoid syndrome?
Neoplasm of the GI tract or bronchi that secretes serotonin and other peptides - symptoms include skin flushing, facial skin lesions, diarrhea, difficulty breathing, rapid heartbeat
What are the categories of drugs used to treat acid peptic disease?
- Antacids - neutralize gastric acid
- H2 receptor blockers and proton pump inhibitors - reduce gastric acid secretion
- antimicrobial treatment - to eradicate H. pylori infection
- mucosal protective agents - help to augment mucosal surface defense
What are antacids and the most commonly used antacids?
Gastric antacids - weak bases that react with gastric HCl to form salt and water in order to increase gastric pH. The purpose of antacids are to provide quick relief of symptoms. Antacids may also affect drug absorption.
Common antacids:
- Magnesium hydroxide
- Aluminum hydroxide
- Calcium carbonate
What are the adverse effects of magnesium hydroxide?
Produces Mg salt, which is not absorbed very well leading to diarrhea
What are the adverse effects of aluminum hydroxide?
Reacts with HCl to form aluminum chloride which is insoluble leading to constipation. There is also hypophosphatemia.
What are the adverse effects of Calcium carbonate?
Hypercalcemia, nephrolithiasis, constipation
How do antacids affect drug absorption?
- decrease oral absorption of tetracyclines via milk (Ca2+), antacids (Ca2+ or Mg2+), or iron preparations (via chelation)
- increase oral absorption of weak bases (ex. quinidine)
- decrease oral absorption of weak acids (ex. warfarin)
What is the regulation of gastric acid secretion?
- Acetylcholine - binds M3 leading to elevation of Ca2+ to activate protein kinase
- Histamine - Gs activation increasing adenylate cyclase
- Gastrin - elevate Ca2+ to activate protein kinase
* All three of these terminate in the activation of the H+/K+ ATPase pathway
What are the different H2 receptor blockers used to decrease gastric acid secretion?
- Cimetidine
- Ranitidine
- Famotidine
- Nizatidine
* Ranitidine, Famotidine, Nizatidine - longer acting and more potent than the 1st generation Cimetidine
What is the role of H2 receptor blockers in the decrease of gastric acid secretion?
H2 blockers reduce almost 90% of basal gastric acid secretions. They do not have any effect on gastric emptying fine. H2 blockers are reversible receptor blockers therefore are usually give more than once a day.
Not only do they decrease amt of gastric acid secretion they are shown to be effective in promoting the healing of duodenal, gastric ulcers and relieving GERD. If monotherapy of H2 antagonist is used and then terminated, peptic ulcer recurrence is common.
H2 blockers may also be used preoperatively in the prevention of aspiration pneumonia (regurgitation of acid).
May be used to treat acute stress ulcers which are common in trauma and high risk patients in ICU. In this case, the H2 blocker is given via IV and not orally. It can also be used as a prophylaxis for pts in ICU.
What are the adverse effects of H2 blockers?
Cimetidine has anti-androgenic effects leading to gynecomastia, elevated prolactin levels, decreased libido, confusion in elderly and may cross BBB or placenta. Ranitidine, Famotidine, Nizatidine do not produce these same effects that cimetidine does. The newer drugs also DO NOT inhibit mixed-function oxygenase systems in the liver (CYP450 enzymes). The most common side effects are nausea, headache, and dizziness due to their entrance in to the CNS.
Cimetidine and ranitidine can decrease renal excretion of creatinine.
Cimetidine is a strong inhibitor of cytochrome P450 slowing metabolism of drugs such as warfarin, procainamide, phenytoin, benzos, theophylline, imipramine and quinidine.
What is the mechanism of proton pump inhibitors to control gastric acid secretion? Give examples of specific PPIs.
PPIs are consumed (IV or PO) as a prodrug that is converted to its active form in the parietal cells. Once in its active form it reacts with a cysteine residue of the H+/K+ ATPase forming a stable covalent bond leading to IRREVERSIBLE inactivation of the enzyme. Because it creates a reversible bond, the drug only needs to be given once a day (nearly 100% of the gastric acid secretion is inhibited with a single daily dose).
PPIs are used to treat…
- GERD, duodenal and gastric ulcers, MEN-1 or zollinger-Ellison syndrme
- heals ulcers in combination with Abx for H. pylori
- Treats NSAID induced ulcers by supporting platelet aggregation and maintaining clot integrity needed in hemorrhagic ulcers
Omeprazole (first generation) Esomeprazole Lansoprazole Rabeprazole Pantoprazole
What are the side effects of PPIs?
- nausea or diarrhea (but usually well tolerated)
- long term administration of omeprazole in animals has been linked to gastric carcinoid tumors (but this is not seen in humans)
- Omeprazole is a CYP450 inhibitor thereby inhibiting metabolism of Warfarin, clopidogrel, phenytoin, diazepam and cyclosporine
- small increase in respiratory and GI infections with long term use
- few cases have shown pancreatitis, hepatotoxicity, and interstitial-nephritis
- Prolonged use of PPIs and H2 blockers decrease bioavailability of vitamin B12, digoxin and ketoconazole b/c acid is required for their absorption
How do you diagnose an H. pylori infection?
- endoscopic biopsy of ulcer margin
- serologic tests
- urea breath tests
What are the first line antibiotics used to treat H. pylori?
ANTIMICROBIALS Macrolides - Clarithromycin B-lactams - Amoxicillin Antiprotozoals - Metronidazole Broad-spectrum antibiotics - Tetracycline
Treatment regimens…
PPI+Clarithromycin+amoxicillin = 10-14 days
PPI+Clarithromycin+metronidazole = 10-14 days
Bismuth subsalicylate+metronidazole+tetracycline+Ranitidine or PPI = 10-14 days
What is the role of macrolides (ex. Clarithromycin) in the treatment of H. pylori?
Clarithromycin is a bacteriostatic antimicrobial that binds to the 23S rRNA of the 50S bacterial ribosomal subunit thereby inhibiting protein synthesis by preventing translocation. Clarithromycin is given orally or via IV and resistance can be acheieved via methylation of the 23S rRNA-binding site preventing binding of the drug.
Clarithromycin is used to treat…. H. pyloria, atypical pneumonia, community-acquired pneumonia, pertussis, corynebacteria, and chlamydial infections
AE - binds motilin receptors, GI upset, prolonged QT intervals (causing arrhythmias), hepatitis, rash, eosinophilia
*It also increases serum concentration of theophyllin and oral anticoagulants as it inhibits CYP450 inhibition
What is the role of B-lactams (ex. Amoxicillin) in the treatment of H. pylori?
Amoxicillin is a bacteriocidal antimicrobial that binds transpeptidase (penicillin-binding proteins [PBP]) thereby preventing cross-linking of peptidoglycans in the cell wall. It also activates autolytic enzymes. Amoxicillin is administered orally or via IV and resistance can be achieved when B-lactamase cleaves the B-lactam ring on the drug.
Amoxicillin is effective against H pylori we well as gram positive and some gram negative bacteria.
AE - rash, hypersensitivity reactions, pseudomembrane colitis
What is the role of Antiprotozoals (ex. Metronidazole) in the treatment of H. pylori?
Metronidazole inhibits the electron transport system thereby producing toxic metabolites in the bacterial cell that damages DNA. Metronidazole is administered orally or via IV.
Metronidazole is active against H. pylori, anaerobes (C. difficile, bacteriodes), antiprotozoal
AE - severe flushing, tachycardia, hypotension with alcohol, metallic taste, headache, disulfiram reaction
What is the role of Broad-spectrum antibiotics (ex. Tetracycline) in the treatment of H. pylori?
Tetracycline is an antibiotic that binds to the 30S ribosomal subunit and prevents attachment of aminoacyl-tRNA. It is administered orally or via IV and resistance may be caused by reduced uptake or enhanced efflux out of the bacterial cells by plasmid-encoded transport pumps.
Tetracycline is effective against H. pylori, Chlamydia, Rickettsia, M pneumonia, Borrelia burgdorferi, and acne tx (at low dose).
AE - Gi upset, discoloration of teeth, inhibition of bone growth in children, superinfection, photosensitivity.
*do not use during pregnancy
What is the role of mucosal protective agents?
Sucralfate, Bismuth subsalicylate, Misoprostol
Sucralfate - sulfated disaccharide used in peptic ulcer disease. The drug undergoes polymerization and selective binding to necrotic tissue where it acts as a barrier to acid. [it may also stimulate endogenous prostaglandin synthesis]. Sucralfate requires an acidic pH to be activated therefore should not be administered with H2 blockers, PPIs or other antiacids.
Bismuth Subsalicylate - selectively binds to ulcer creating coat and protects it from acid and pepsin. It has some antimicrobial effect on H. pylori when used with metronidazole and Tetracycline.
Misoprostol - PGE1 analogue that decreases acid secretion, stimulates mucin and bicarb production (and causes uterine contractions). It is approved to prevent gastric ulcers induced by NSAIDs, but because of its adverse effects, it is less effective than PPIs or H2 blockers in acute cases. It is given orally and lasts for minutes.
What are the adverse effects of Misoprostol (PGE1)?
Diarrhea, uterine cramping, abortifacient, exacerbation of inflammatory bowel disease (IBD)
What is GERD?
Gastroesophageal reflux disease - the LES normally acts as barrier b/t stomach and esophagus. With GERD there is abnormal relaxation of the LES allowing for the release of stomach acid into the esophagus. GERD is associated with increased BMI (obesity), ZES and drugs.
Non-pharmacological treatment of GERD - small meals, weight loss, avoid bed time acid rich drinks, elevate head of the bed 6-8 inches and lifestyle modifications (stop smoking and consuming alcohol)
Pharmacological treatments of GERD - Antacids, PPIs +/- H2 blockers
