Why is my patient not doing well on omeprazole?

A 45 year old lady, an executive in a bank, has been seeing you for painful stiff knees. She has some pain in the base of her thumbs and in her neck. You diagnose osteoarthritis, start her workup for the disease and prescribe diclofenac sodium for pain. She is normotensive, is not diabetic and has a BMI of 29. She is a bank executive, has a sedentary job and is very tense and has an anxiety prone personality. She also mentions that she gets pain in the upper chest radiating to the jaws lasting for 40 minutes to an hour especially after eating a rich meal. If she overeats at dinner she gets this pain after going to sleep and it wakes her up. She denies any heartburn or exertional chest pain. She has a family history of ischemic heart disease and hypertension in both parents and an older sibling. Her resting ECG done in your office is unremarkable. You decide to add omeprazole 40 mg once daily to her prescription and schedule her for an ETT.

She rings you up two days later to say that with the pain medicine she now has heartburn and that the omeprazole is not helping her. You had not advised her when to take the medicines so she took the diclofenac sodium after breakfast and dinner and the omeprazole also after dinner.

How do you explain her current problems?

She probably has GERD which may present as pain rather than heartburn with characteristics resembling angina pectoris. she has an anxiety prone personality and panic attacks may also cause or make the pain worse. However cardiac ischemia must be excluded and an ETT and Thallium scan are probably the least invasive investigations advisable initially. She needs to have an upper GI endoscopy to see if she has erosive or non-erosive (gastroesophageal) reflux disease NERD. The NSAID prescribed has caused an increase in gastric acid secretion hence the heartburn. Why has the PPI not kicked in?

Proton pump inhibitors (PPIs) effectively block gastric acid secretion by irreversibly binding to and inhibiting the hydrogen-potassium ATPase pump (proton pump)that resides on the luminal surface of the parietal cell membrane. Since PPIs inhibit only activated enzyme present in the canalicular membrane, the reduction of gastric acid secretion after an initial dose will probably be suboptimal. That is why the medicine has not helped her as yet. As inactive enzyme is recruited into the secretory canaliculus, acid secretion will resume, albeit at a reduced level. After the second dose is given on the next day, more H-K-ATPase will have been recruited and subsequently inhibited, and after the third dose, additional recruitment and further acid inhibition will probably occur and so on. By the fifth day 66% of patients experience maximum acid secretion inhibition so warn the patient that the PPI will be effective in a week or so and give yourself a respite from the patient’s ire. Because the amount of H-K-ATPase present in the parietal cell is greatest after a prolonged fast, PPIs should be administered before the first meal of the day. Prescribe the PPI one hour before breakfast or just before the breaking of the fast in Ramadan. So ask the lady to change the timing of her omeprazole to before breakfast. Many patients feel that taking medicines on an empty stomach may be harmful so she may need a little explanatory talk. Change her NSAID to paracetamol or to one that does not activate acid secretion as rapidly as diclofenac.

Do all PPIs work equally well?

PPIs are similar in structure and mechanism of action, but PPIs differ in their pKa, bioavailability, peak plasma levels, and route of excretion. PPIs undergo an acid catalyzed conversion to a reactive species, the thiophilic sulfonamides, which are permanent cations. The rate of conversion varies among the compounds and is inversely proportional to the pKa of the benzimidazole (rabeprazole >omeprazoleesomeprazole, and lansoprazole >pantoprazole). The magnitude of these differences are small and their clinical relevance has not been established.

Differences in efficacy of the drug may also depend on whether the patient is a slow metabolizer ( homozygous for a CYP2C19 mutation ) when the drug will achieve its effect almost 100% or a rapid metabolizer when the effect may vary from 16 to 49%. How can you predict? Check the plasma levels of the drug, these will be low for rapid metabolizers. 

What will be the side effects of PPI administration for long periods of time i.e. two years or more in GERD? Which of these effects need to be monitored? What drug interaction can be expected?

PPIs are metabolized in the liver via the P450 cytochrome pathway: if this metabolic pathway becomes saturated, the isoenzyme can become a major target for interactions with many drugs, including: 

Warfarin: prothrombin time increased by 10 secs by omeprazole.

Diazepam: half life increased by 130% with simultaneous omeprazole administration but not other PPIs.

Clopidogrel: A 2015 meta-analysis of six observational studies demonstrated an increased hazard ratio (HR) for a one-year composite outcome of death, myocardial infarction, or stroke associated with pantoprazole (HR 1.38, 95% CI 1.12-1.70), lansoprazole (HR 1.29, 95% CI 1.09-1.52), and esomeprazole (HR 1.27, 95% CI 1.02-1.58), but not omeprazole (HR 1.16, 95% CI 0.93-1.44). PPIs elevate plasma asymmetric dimethylarginine (ADMA) levels; elevated plasma ADMA is associated with an increased risk for CVD.

Phenytoin: 1/2 life increased by omeprazole but not others.

HIV protease inhibitors – PPIs may decrease the absorption of certain HIV protease inhibitors. PPIs are contraindicated in patients being treated with rilpivatin. Atazanavir should not be used in patients who require a PPI dose equivalent to >20 mg omeprazole  daily.

Methotrexate – Coadministration of PPIs with high dose methotrexate appears to be correlated with delayed methotrexate elimination and potentially may lead to methotrexate toxicity if not monitored appropriately.

What other side effects should you anticipate in this lady?

Diarrhoea. PPI use has been associated with an increased risk of C. difficile infection, even in the absence of antibiotic use. Associations with other enteric infections, including salmonellosis and campylobacteriosis, have also been reported.

Microscopic colitis — PPI use has been associated with microscopic colitis, including lymphocytic and collagenous colitis. In a case-control study that included 95 cases of microscopic colitis, exposure to PPIs was significantly higher in patients with microscopic colitis as compared with controls (38 versus 13 percent, OR 4.5, 95% CI 2.0-9.5)

Malabsorption of minerals and vitamins

Magnesium malabsorption — PPIs can cause hypomagnesemia due to reduced intestinal absorption. Clinical manifestations of hypomagnesemia include neuromuscular excitability (eg, tremor, tetany, convulsions), weakness, and apathy. Severe PPI-induced hypomagnesemia has been associated with QT interval prolongation and torsades de pointes. Magnesium levels should be monitored before beginning treatment in patients who are likely to need PPIs for longer than a year. Six monthly or more frequent monitoring should be carried out in patients who have had an arrhythmia in the past and at least annually in other patients.

Vitamin B12. It would be a good idea to monitor obtain vitamin B12 levels yearly in patients on long-term PPIs. However, routinely monitoring vitamin B12 levels is controversial specially in patients who will take the medicine for shorter periods of time. Some clinicians administer B12 oraly as there is no interference with intestinal absorption.

Calcium and fracture risk — Although hypochlorhydria could theoretically reduce calcium absorption, the effect appears to be relevant only for the absorption of water insoluble calcium (eg, calcium carbonate) and can be overcome by ingestion of a slightly acidic meal. The absorption of water soluble calcium salts or calcium in dairy products are not impacted by PPI-induced hypochlorhydria. When calcium supplementation is necessary in patients taking PPIs, use calcium supplements that do not require acid for absorption, such as calcium citrate. PPI-induced hypochlorhydria can augment osteoclastic activity, thereby decreasing bone density.

Iron malabsorption. Gastric acid plays a role in the absorption of nonheme iron, and the use of PPIs has been associated with decreased iron absorption. However, in most cases the decreased absorption does not appear to be of clinical significance.

Hypergastrinemia. Induction of hypergastrinemia has been associated with gastric carcinoid tumors in rats, however, these observations are not generalizable to species with gastrin physiology more analogous to humans . While patients treated with omeprazole for up to 11 years have shown some enterochromaffin-like cell hyperplasia, no dysplasia or neoplastic changes have been observed. An increased risk of colon cancer due to hypergastrinemia has also not been established.

Atrophic gastritis — Patients on long-term PPI therapy have a propensity to develop chronic atrophic gastritis. However, the risk of atrophic gastritis is small and, in the rare patient who develops atrophic gastritis, the clinical consequences are uncertain.

Kidney disease — PPIs can cause acute interstitial nephritis which is not dose-dependent, and recurrence or exacerbation can occur with a second exposure to the same or a related drug.

Drug induced lupus. lesions of CLE-associated with PPI use are subacute and occur within weeks to years after continuous PPI therapy. PPI-associated SLE usually occurs days to years after initiating PPI treatment and typically presents with a rash. Most patients improve within 4 to 12 weeks of discontinuation of PPI therapy. 

Dementia — Although some studies have found a significant association between use of PPIs and incident dementia, others have not found an association between PPI use and cognitive function. So this lady is unlikely to lose her job on account of mental capacity.

Mortality; does it increase with PPIs? PPI users have an increase in risk of death as compared with individuals without any PPI use and individuals without any acid suppression use probably because currently first time users tend to be older and hence have other compounding factors.

I think that I have provided enough information to help you give this lady rational counselling on her condition, why you are doing certain tests and what side effects she may have if she takes the PPI for more than a year. What you need to figure out is is it necessary or even worthwhile to prescribe PPIs every time you prescribe an NSAID or aspirin for antiplatelet activity?

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I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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