SE: constipation (Al), diarrhea (Mg) (used together to counterbalance), Al and Mg are metals that can accumulate in the renal (avoid in kidney diseases). Alka-Seltzer contains >1g Na (high sodium content should be avoided in high BP).
DDI: Separate with quinolones and tetracyclines due to chelation (2-hrs before, 4-hrs after), itra/ketoconazole (needs acid environment to work), Ca carbonate and iron (reduced absorption from increased pH).
MOA: Binds reversibly to the H2 receptor on parietal cells in the stomach.
Second-line for an NSAID-induced ulcer.
May increase risk of GI infection/pneumonia (stomach’s acidic environment is an important body defense mechanism, less acid = more bacteria surviving), worsen renal function, CNS (HA, confusion, dizziness due to blocking histamine receptors).
Cimetidine has lots of side effects: CNS effect (common to lipophilic agents), gynecomastia (due to androgen blocking, also more common with lipophilic agents), blood dyscrasias, increase LFT (makes sense to have CYP interactions), arthralgia.
DDI: Cimetidine is a potent 3A4 inhibitor, and thus has more interactions compared to other H2RAs.
SE: increase risk of C. diff & pneumonia (less acid may lead to more bacteria surviving), osteoporosis/fracture (ensure sufficient Ca supplement), ↑ INR (risk of bleeding).
Recommend Ca citrate (instead of carbonate) as a calcium supplement for better absorption.
Effervescent and ODT contain phenylalanine, do not use in PKU.
Available as OTC now: Prilosec, Nexium, Prevacid, Zegerid.
DDI: Omeprazole/esomeprazole are 2C19 inhibitors that prevent the conversion of clopidogrel to its active form (less effective antiplatelet treatment); CYP2C19 breaks down cilostazol and citalopram; Caution use in drugs prefer acidic environment: azoles (itra/ketoconazole), Ca carbonate, iron (absorption would be better).
Metoclopramide (Reglan)
MOA: Dopamine receptor antagonist (both peripheral and central), 5-HT4 receptor agonist (migraine treatment “triptans” are 5HT-1 agonists with vasoconstrictive effects) and a direct stimulant of gastric smooth muscle with prokinetic and antiemetic effects, thus facilitate gastric emptying (may also reduce LES sphincter pressure, food content is less likely to move back to the esophagus).
It is the only FDA-approved medication for gastroparesis (stomach paralysis).
SE: movement disorders (EPS & Parkinson-like symptoms, common to antipsychotics), CNS (dizziness, somnolence, fatigue, depression).
CI: GI obstruction/movement disorders (more stimulation would be futile), history of seizure.
10mg QID 30 mins before meals and HS; Decrease dose 50% if CrCl < 40.
Peptic ulcer disease (PUD)
Background
Mucosal erosion within the GI tract, compared to GERD, this condition seems more austere.
Causes: H. pylori (responsible for most peptic ulcers), chronic use of NSAIDs or ASA, or from hypersecretory states (e.g: Zollinger-Ellison syndrome: increased gastric acid).
The primary symptom is epigastric pain.
H. pylori Treatment
Triple therapy: PPI + 2 antibiotics (clarithromycin 500mg, amoxicillin 1000 mg) BID x 14 days
If PCN or macrolide allergy: replace with metronidazole.
Quadruple therapy: PPI BID + (bismuth + metronidazole + tetracycline = Pylera) QID x 10-14 days
Who’d want to use quadruple drugs instead of triple drugs? Choose if a patient used a macrolide or metronidazole in the past or recent failure with triple therapy.
Notice that PPI dosing frequency is at most BID, which does not follow the schedule of the other 3 drugs.
Avoid alcohol (CI with metronidazole), pregnancy & children (TCN), salicylate allergy (bismuth subsalicylate).
Sequential therapy: PPI +Amoxil x 5 days followed by PPI + clarithromycin + tinidazole x 5 days.
NSAIDS-induced ulcer
High dose induces GI ulcers (risk factor: >65 y/o, use of steroid, anticoagulant, previous ulcer). Caution use of NSAID in CV (vasoconstriction of renal tubules leads to edema and increased BP, ↑CV risk) or renal disease (decreased renal blood flow).
1st line: PPI.
2nd line: H2RA or misoprostol.
Misoprostol (Cytotec, + diclofenac = Arthrotec)
MOA: prostaglandin analog, replaces protective prostaglandins that have been removed by NSAIDs. Not first line in NSAID-induced ulcer.
SE: diarrhea, abdominal pain (if its primary action site is in the GI, then it’s going to cause GI side effects) This is also used in abortive therapy, which explains its abdominal side effects.
Start 100mcg after diner, not first line in NSAID-induced ulcer.
Sucralfate (Carafate)
MOA: a complex of aluminum hydroxide and sucrose. It dissociates in the acid environment and binds to the ulcer base. This creates a protective barrier to pepsin and bile and inhibits the diffusion of gastric acid.
SE: constipation (aluminum complex), avoid in renal disease (heavy metal accumulation).
1 g tab QID before meals and HS.
Not the first line in NSAID-induced ulcer.
vonoprazan (Voquezna)
New MOA: the first potassium-competitive acid blocker (PCAB) approved for erosive esophagitis.
A “fancy PPI” blocks both active and resting proton pumps (PPIs only block active ones), hence why vonoprazan starts working within hours, and can be taken with or without food. (Vs. days for PPIs to kick in and prior to a meal).
better at healing more severe esophagitis.
Continue to recommend PPIs as the mainstay and reinforce lifestyle modifications (smoking cessation, etc).
Co-packaged with amoxicillin (Voquezna Dual Pak), or amoxicillin + clarithromycin (Triple Pak) to treat H. pylori.
Quiz
A patient using NSAIDs chronically and develops a bleeding ulcer. Which of the following medications would be MOST appropriate to treat his condition?
Magnesium hydroxide
Bismuth subsalicylate
Calcium carbonate
Metoclopramide
Misoprostol
A patient takes warfarin for chronic atrial fibrillation develops GERD. Which of the following medications would most likely interact with warfarin and increase patient’ s risk for bleeding?
Cimetidine
Magnesium hydroxide
Misoprostol
Omeprazole
Misoprostol
Which of the following reasons could explain why the plasma levels of ketoconazole are decreased in patients taking pantoprazole?
Pantoprazole induces the CYP450 enzymes that metabolize ketoconazole.
Ketoconazole requires an acidic environment for its oral absorption.
Pantoprazole binds acidic drugs in the GI tract.
Pantoprazole has prokinetic effects, which decrease GI transit time.
Which of the following medications needs to be dose-adjusted in patients with renal impairment? (Select ALL that apply.)
Infliximab
Budesonide
Esomeprazole
Metoclopramide
Ranitidine
Which of the following is a contraindication for the use of metoclopramide?
Hyperkalemia
Myasthenia gravis
Porphyria
Seizure disorder
Sulfa allergy
E. The first-line therapy for an NSAID-induced ulcer is a PPI. However, PPIs is not among the answer choices. Second-line therapies are either misoprostol or an H2RA. Misoprostol is a prostaglandin E1 analog that acts to replace protective prostaglandins that have been stripped away by NSAIDs.
A. Cimetidine is a strong CYP3A4 inhibitor, a moderate inhibitor of CYP1A2, and a weak inhibitor of CYP2C9. (R)-warfarin is a substrate of CYP3A4 and CYP1A2, (S)-warfarin is a substrate of CYP2C9. Therefore, cimetidine may inhibit the metabolism of both the (S)- and (R)-enantiomers of warfarin, which could lead to an increased risk of bleeding. All other choices do not inhibit the CYP450 system.
B. The absorption of ketoconazole is pH-dependent, of which requires an acidic environment to be adequately absorbed; the bioavailability of this drug decreases as gastric pH increases. By increasing gastric pH, pantoprazole may reduce the absorption of ketoconazole, which would lead to decreased plasma concentrations. Pantoprazole is not an inducer of the CYP450; metoclopramide has prokinetic effects in the GI tract.
DE. Both metoclopramide and ranitidine are primarily excreted in the urine as unchanged drug. Therefore, the doses of these drugs need to be adjusted in patients with renal impairment. This suggests hydrophilic property of the drug. All H2RAs needs to be adjusted in renal impairment. None of the PPIs needs to be dose adjusted in renal impairment. Also, neither Infliximab nor budesonide needs to be dose-adjusted.
D. Seizure disorder is a contraindication for the use of metoclopramide. Although B. Myasthenia gravis (weak muscle tone) seem like a correct answer, but metoclopramide is an antipsychotic, and it is contraindicated in movement disorder, and seizure is listed as one of the contraindications.
