Omeprazole

Omeprazole is a substituted benzimidazole proton pump inhibitor (PPI) that irreversibly blocks the gastric H+/K+ ATPase, the final common step of acid secretion. It is a racemic mixture of R and S isomers and suppresses both basal and meal-stimulated acid output for longer than its short plasma half-life suggests.

Classification. Proton pump inhibitor; gastric antisecretory agent.

Mechanism. A weak base prodrug that concentrates in the acidic secretory canaliculus, converts to an active sulphenamide and binds cysteine residues on the pump covalently. Only actively secreting pumps are inhibited, so dosing 30 to 60 minutes before the first meal gives the greatest effect.

Pharmacodynamics. Maximal acid suppression is reached after 3 to 5 days of daily dosing as successive pump populations are inactivated. Acid secretion returns over 3 to 5 days after stopping as new pumps are synthesised.

Pharmacokinetics. Acid labile, so given as gastro-resistant pellets or tablets. Oral bioavailability is about 35% after a single dose, rising to about 60% with repeated dosing. Protein binding is about 95% and half-life 0.5 to 1 hour.

Metabolism. Hepatic, mainly CYP2C19 with a CYP3A4 contribution; metabolites are excreted chiefly in urine. Omeprazole inhibits CYP2C19. Poor metabolisers have several-fold higher exposure; rapid metabolisers have lower eradication rates for Helicobacter pylori.

Adult oral doses unless stated. Use the lowest effective dose for the shortest necessary duration and set a review date at the start.

Gastro-oesophageal reflux disease (GORD) with erosive oesophagitis.

• Healing: 20 mg once daily for 4 weeks, continued for a further 4 weeks if not healed.

• Severe or refractory oesophagitis: 40 mg once daily for 8 weeks.

• Maintenance after healing: 10 to 20 mg once daily, stepping down to the lowest dose that controls symptoms.

Nonerosive reflux and dyspepsia. 10 to 20 mg once daily for 4 weeks; thereafter 10 to 20 mg on demand.

Peptic ulcer disease.

• Duodenal ulcer: 20 mg once daily for 4 weeks; 40 mg once daily if severe or refractory.

• Gastric ulcer: 20 mg once daily for 8 weeks; 40 mg once daily if severe or refractory.

• Confirm gastric ulcer healing endoscopically at 6 to 8 weeks and biopsy where malignancy has not been excluded.

NSAID-associated ulcer. Healing 20 mg once daily for 4 to 8 weeks. Prophylaxis 20 mg once daily for as long as the NSAID continues in those at raised gastrointestinal risk (age over 65, previous ulcer, concurrent anticoagulant, antiplatelet or corticosteroid).

Helicobacter pylori eradication. Omeprazole 20 mg twice daily (40 mg twice daily is often used to improve eradication) for 14 days, combined with one of:

• Amoxicillin 1 g twice daily plus clarithromycin 500 mg twice daily.

• Penicillin allergy: clarithromycin 500 mg twice daily plus metronidazole 400 to 500 mg twice daily.

• Bismuth quadruple therapy, preferred where clarithromycin resistance is high or after a failed first attempt: bismuth subsalicylate 524 mg four times daily, tetracycline 500 mg four times daily and metronidazole 400 to 500 mg three times daily.

Clarithromycin resistance is reported to be high in several East African settings, so bismuth quadruple therapy or a 14-day course is advised where local susceptibility data are lacking.

Zollinger-Ellison syndrome. Start 60 mg once daily and titrate to suppress basal acid output; usual range 20 to 120 mg daily. Give doses over 80 mg daily in two divided doses. Doses up to 120 mg three times daily have been used.

Prevention of acid aspiration. 40 mg the evening before surgery and 40 mg 2 to 6 hours before induction.

Upper gastrointestinal bleeding from peptic ulcer after endoscopic haemostasis (high-risk stigmata). 80 mg IV bolus, then 8 mg/hour continuous infusion for 72 hours. Intermittent 40 mg IV twice daily is an accepted alternative. Then oral omeprazole 40 mg twice daily to day 14, then 40 mg once daily to complete 6 to 8 weeks.

Paediatric dosing (GORD and peptic ulcer).

• Body weight 10 to 19 kg: 10 mg once daily, increased to 20 mg once daily if needed.

• Body weight 20 kg and over: 20 mg once daily, increased to 40 mg once daily if needed.

• Infants and children under 10 kg: about 1 mg/kg once daily, adjusted to response.

• Usual course 4 to 8 weeks, then review.

Contraindications. Hypersensitivity to any PPI; coadministration with rilpivirine. Avoid with atazanavir and nelfinavir.

Before starting. Alarm features need endoscopy before acid suppression masks them: new dyspepsia over age 55, weight loss, dysphagia, gastrointestinal bleeding, iron deficiency anaemia, persistent vomiting or an epigastric mass.

Common adverse effects. Headache, diarrhoea, nausea, abdominal pain, flatulence and constipation.

Serious adverse effects.

• Hypomagnesaemia, usually after over 3 months and often after a year, with secondary hypocalcaemia and hypokalaemia; risk rises with diuretics and digoxin.

• Clostridioides difficile infection and other enteric infections.

• Acute interstitial nephritis, which may present late with unexplained rising creatinine.

• Vitamin B12 deficiency with use over 2 to 3 years.

• Hip, wrist and vertebral fracture with high-dose or prolonged use.

• Subacute cutaneous lupus erythematosus; microscopic colitis; fundic gland polyps.

• Rebound acid hypersecretion after abrupt withdrawal of prolonged therapy.

Major interactions.

• Clopidogrel: omeprazole reduces formation of the active metabolite. Avoid the combination; pantoprazole is the preferred PPI.

• Methotrexate at high dose: reduced clearance and toxicity; withhold omeprazole around high-dose methotrexate.

• Raised levels of diazepam, phenytoin, cilostazol, citalopram and tacrolimus; monitor phenytoin levels, tacrolimus levels and INR with warfarin.

• Reduced absorption of drugs needing gastric acid: ketoconazole, itraconazole capsules, atazanavir, rilpivirine, erlotinib, dasatinib, oral iron and mycophenolate mofetil.

• Rifampicin and St John's wort reduce omeprazole exposure.

Special groups.

• Pregnancy: large cohort data show no consistent rise in malformation; acceptable when acid suppression is needed after lifestyle measures and antacids fail.

• Breastfeeding: small amounts enter milk and are destroyed by infant gastric acid; compatible.

• Children: weight-based dosing; reassess the indication regularly because infant reflux is usually self-limiting.

• Older adults: no dose change, but greater risk of C. difficile, fracture, hypomagnesaemia and B12 deficiency; review need at every medication review.

• Kidney impairment: no dose adjustment; not removed by dialysis.

• Liver impairment: 10 to 20 mg daily is usually sufficient; avoid exceeding 20 mg daily.

• Ancestry: CYP2C19 poor metaboliser frequency is higher in East Asian populations; no routine adjustment, but consider 10 mg daily with liver disease in this group.

Formulations. Gastro-resistant capsules 10 mg, 20 mg and 40 mg; dispersible gastro-resistant tablets; oral suspension; powder for IV injection or infusion 40 mg.

Oral administration. Take 30 to 60 minutes before breakfast; a second daily dose goes before the evening meal. Swallow whole. Capsules may be opened and pellets mixed with acidic juice, yoghurt or apple purée and swallowed without chewing.

Enteral tubes. Disperse dispersible tablets in water, or use oral suspension. Do not crush pellets, which blocks tubes and destroys the enteric coating.

IV administration.

• Injection: reconstitute 40 mg with the supplied solvent and give over at least 2.5 minutes, not faster than 4 mL/min.

• Intermittent infusion: dilute 40 mg in 100 mL sodium chloride 0.9% or glucose 5% and give over 20 to 30 minutes.

• Use within 12 hours in sodium chloride 0.9% and within 6 hours in glucose 5%.

• Give through a dedicated line or flush before and after.

Baseline. No routine tests. Check magnesium before long-term use with digoxin, loop or thiazide diuretics.

Monitoring.

• Review symptom response and continued need at 4 to 8 weeks, then at least annually.

• Magnesium periodically on long-term therapy in those at risk.

• Vitamin B12 with prolonged use if anaemia or neuropathy develops.

• Renal function if unexplained creatinine rise.

• Stop omeprazole 2 weeks before a urea breath test or stool antigen test for H. pylori.

• Stop at least 5 days before chromogranin A testing, because PPI-induced rises in chromogranin A cause false positives.

Therapeutic drug monitoring. Not applicable.

Stopping. After long-term use, step down to the lowest dose, then on-demand use, or halve the dose for 2 to 4 weeks before stopping, to limit rebound. Antacids cover rebound symptoms. Stop immediately if acute interstitial nephritis, C. difficile infection or cutaneous lupus is suspected.

Referral and escalation. Urgent endoscopy for alarm features or failure of 8 weeks of twice daily therapy. Refer refractory reflux for pH impedance study. Suspected Zollinger-Ellison syndrome needs a fasting gastrin level off PPI only under specialist supervision, because abrupt withdrawal risks ulcer complications.