Omeprazole

Proton Pump Inhibitor (PPI) Substituted Benzimidazole Anti-secretory agent Therapeutic Category: Antiulcer Agent

Omeprazole is a prodrug that accumulates in the acidic environment of parietal cell canaliculi where it is activated to a sulfenamide derivative. The active form covalently binds to cysteine residues (Cys813 and Cys822) on the luminal surface of gastric H+/K+ ATPase (proton pump), irreversibly inhibiting the final step of gastric acid secretion. This inhibition blocks both basal and stimulated acid secretion, with effects lasting 24-72 hours until new proton pumps are synthesized. Full acid suppression typically requires 3-4 days of continuous dosing.

Absorption: Rapidly absorbed after oral administration (bioavailability 30-40%). Delayed-release formulations require intact enteric coating to prevent degradation in stomach acid. Absorption is decreased with food intake. Distribution: Volume of distribution: 0.3 L/kg. 95% protein-bound, primarily to albumin. Concentrates in parietal cells due to acidic environment activation. Metabolism: Extensively metabolized in liver by CYP2C19 (major) and CYP3A4 (minor). CYP2C19 genetic polymorphisms significantly affect metabolism (poor vs. extensive metabolizers). Major metabolites: omeprazole sulfone and hydroxy-omeprazole. Excretion: Primarily renal (77%) as inactive metabolites, with some fecal excretion. Less than 1% excreted unchanged. Half-life: Approximately 0.5-1 hour (plasma), but pharmacological effect lasts 24+ hours due to irreversible proton pump binding.

• Dose-dependent inhibition of gastric acid secretion • Increases gastric pH to >4 for 14-21 hours/day with standard dosing • Reduces pepsin activity by preventing acid activation • Increases serum gastrin levels (2-4 fold) through feedback mechanisms • May impair absorption of vitamin B12, calcium, iron, and magnesium with chronic use

• Treatment of active duodenal ulcer • Treatment of active benign gastric ulcer • Gastroesophageal reflux disease (GERD): - Healing of erosive esophagitis - Maintenance therapy for healed esophagitis - Symptomatic GERD without esophageal lesions • Treatment of NSAID-associated gastric ulcers • Pathological hypersecretory conditions (Zollinger-Ellison syndrome) • Part of combination therapy for Helicobacter pylori eradication (with antibiotics)

Absolute: • Hypersensitivity to omeprazole or substituted benzimidazoles • Concomitant use with rilpivirine-containing products Relative: • Osteoporosis or risk factors for bone fracture • History of Clostridium difficile-associated diarrhea • Acute interstitial nephritis with previous PPI use • Severe hepatic impairment • Concurrent use with CYP2C19 inhibitors (e.g., fluvoxamine) • Chronic kidney disease (stage 3b-5)

Duodenal Ulcer: 20 mg once daily for 4-8 weeks Gastric Ulcer: 40 mg once daily for 4-8 weeks GERD: - Healing: 20 mg daily for 4-8 weeks - Maintenance: 20 mg daily Erosive Esophagitis: 20 mg daily for 4-8 weeks Zollinger-Ellison Syndrome: Initial 60 mg daily, adjust based on acid output (max 120 mg TID) H. pylori Eradication: 20 mg BID for 10-14 days (with clarithromycin + amoxicillin or metronidazole) Administration: Take before meals (preferably morning), swallow whole. For patients with difficulty swallowing, capsules can be opened and contents mixed with applesauce. Avoid crushing or chewing enteric-coated granules.

Pediatric: • GERD (1-16 years): 10-20 mg daily based on weight • <1 year: Not established Geriatric: No dose adjustment required but consider increased fracture risk with long-term use Renal impairment: No dose adjustment needed Hepatic impairment: • Mild-moderate: Max 20 mg/day • Severe: Avoid use or max 10 mg/day

Common (>10%): • Headache (7-10%) • Abdominal pain (5-10%) • Diarrhea (4-10%) • Nausea (3-10%) • Flatulence (3-10%) Serious (<1%): • Acute interstitial nephritis • Clostridium difficile-associated diarrhea • Hypomagnesemia (with prolonged use) • Vitamin B12 deficiency (long-term) • Bone fracture (long-term) • Cutaneous lupus erythematosus • Severe hepatic reactions

• Clopidogrel: Reduced antiplatelet effect due to CYP2C19 inhibition • Methotrexate: Increased methotrexate levels (reduced renal clearance) • CYP2C19 substrates (diazepam, phenytoin): Increased drug exposure • CYP3A4 substrates (clarithromycin): Possible mutual inhibition • Atazanavir: Significantly reduced absorption (requires acidic environment) • Tacrolimus: Increased tacrolimus exposure • St. John's Wort: Reduced omeprazole efficacy • Warfarin: Potential increased INR (monitor coagulation parameters)

• Black Box Warning: Long-term use (≥3 years) may cause low magnesium levels • Increased risk of bone fractures with long-term/high-dose therapy • Hypomagnesemia (monitor after prolonged use) • Vitamin B12 deficiency with long-term use (>3 years) • Acute interstitial nephritis (discontinue if occurs) • Cutaneous and systemic lupus erythematosus exacerbation • Fundic gland polyps (risk increases with long-term use) • Cyanocobalamin (B12) malabsorption • Increased risk of Clostridium difficile infection

Pregnancy: FDA Category C • Animal studies show fetal toxicity at high doses • Use only if potential benefit justifies potential risk • Not recommended for routine heartburn in pregnancy Lactation: • Excreted in human milk (0.004-0.3% maternal dose) • Consider risk-benefit (AAP states compatible with breastfeeding) • Monitor infants for gastrointestinal effects

• Magnesium levels (with prolonged therapy) • Renal function (BUN, creatinine) • Vitamin B12 status in long-term users (>3 years) • Bone density in patients at risk for osteoporosis • Liver function tests (in hepatic impairment) • Symptom relief and healing (endoscopy if indicated) • CBC if H. pylori therapy includes clarithromycin • INR monitoring with concurrent warfarin use

• Take 30-60 minutes before breakfast • Swallow delayed-release capsules whole • Report severe diarrhea, abdominal cramps, or bloody stools • Long-term use may increase fracture risk - maintain calcium/vitamin D • Notify provider if taking warfarin, clopidogrel, or antifungal medications • Complete full antibiotic course for H. pylori treatment • Do not exceed 14 days of OTC use without medical consultation • Report new joint pain or rash (possible lupus-like reactions)

• Store at 20-25°C (68-77°F) • Protect from light and moisture • Keep in original blister packaging until use • Reconstituted suspension stable for 30 minutes • Stability after opening capsule: 30 minutes in applesauce, 6 hours in water • Do not freeze

• More effective when taken before the first meal of the day • Poor CYP2C19 metabolizers may require lower doses • Consider therapeutic drug monitoring in refractory cases • Tapering may reduce rebound acid hypersecretion • Consider calcium citrate supplementation in chronic users • Screen for H. pylori before long-term maintenance therapy • Avoid bedtime dosing (minimal nocturnal acid suppression) • PPI responsiveness predicts GERD diagnosis better than pH testing

• UpToDate: Omeprazole drug information (2023 update) • Micromedex DrugDex Evaluation: Omeprazole (2023) • FDA Prescribing Information: Prilosec (2022) • Katz PO, et al. ACG Clinical Guideline for GERD (Am J Gastroenterol 2022) • Shin JM, et al. Pharmacology of proton pump inhibitors. Curr Gastroenterol Rep. 2013 • Chey WD, et al. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection (2017)