Proton pump inhibitors (PPI’s)

 

PPIs inhibit gastric acid secretion by inactivating the hydrogen potassium ATPase molecules of the parietal cell. 

 

Parietal cell are maximally stimulated after a meal, and PPIs activated at that time have  optimal acid suppression.

Reduce the production of gastric acid through irreversible binding to the hydrogen/potassium ATPase enzyme found on gastric parietal cells.Most common adverse events associated with PPI’s are headache, diarrhea, abdominal pain and nausea.

They are highly effective for healing reflux esophagitis, but less effective for eliminating GERD symptoms, which persist in 30% of patients treated with PPIs.

Parietal cell are maximally stimulated after a meal, and PPIs activated at that time have  optimal acid suppression.

 

All PPIs should be taken 30 to 60 minutes before a meal for optimal pH control except for dexlansoprazole.

 

Dexlansoprazole employs dual delayed-release technology leading to sustained plasma drug concentrations, and can therefore be taken at any time of day. 

 

For patients with daytime symptoms, a PPI should be taken once daily in the morning for daytime symptoms.

For  nighttime symptoms, the dose should be taken in the evening.

 

For patients with daytime symptoms, a PPI should be taken once daily in the morning for daytime symptoms.

For  nighttime symptoms, the dose should be taken in the evening.

Only 58% of patients taking prescription PPIs for chronic heartburn report complete satisfaction, and PPI refractory GERD is the most common reason for GERD related referral to gastroenterology.

Five mechanisms underlie PPI refractory heartburn: abnormal acid reflux persists despite PPI therapy, reflux hypersensitivity, in which esophageal exposure to acid is normal but physiologic reflux episodes evoke heartburn, heartburn is caused by esophageal disorders other than GERD such as achalasia, heartburn could be caused by extraesophageal disorders such as heart disease, or heartburn is functional.

Approved for the treatment of erosive gastritis, gastroesophageal reflux, peptic ulcer disease, caused by Helicobacter pylori and Zollinger Ellison syndrome.

Long-term PPI use inducing gastric achlorhydria and hypergastrinemis may have an adverse effect on the absorption of calcium, iron, magnesium, vitamin B 12 and may predispose to infection.

Some studies suggest an increased incidence of community acquired pneumonia Clostridium difficile infection and chronic kidney disease.

Studies show no association between long-term PPI use and the following:

 

Myocardial infarction

 

Small intestinal bacterial overgrowth

 

Pneumonia

 

Gastrointestinal malignancies.

 

PPIs have been consistently shown to be superior at healing erosive esophagitis and relieving symptoms than histamine 2 receptor antagonists (H2RAs).

 

PPIs can maintain intragastric pH higher than 4 for 15 to 21 hours daily, compared with the 8 hours that H2RAs can achieve.

Help prevent NSAID gastric ulcers.

Can markedly decrease acid reflux.

Used to prevent GI bleeding in patients on antiplatelet therapy.

Mechanism of acid suppression is related to antagonism of the hydrogen potassium and adenosine triphosphate in gastric parietal cells.

113.4 million prescriptions/year, $13.9 billion in sales.

In 2014, approximately 170 million prescriptions for PPI’s were written, and this number does not include OTC PPIs.

When given at high dose and intravenously can maintain a neutral gastric pH.

Optimal acid suppression facilitates clot formation over bleeding arterial peptic ulcers.

Most common adverse events include headache, diarrhea, abdominal pain, and nausea.

Effective treatment erosive and ulcerative esophagitis, Barrett esophagus, Zollinger-ellison syndrome, GERD, ulcer disease, part of treatment for H. pylori eradication, and prevention of ulcers due to NSAIDs.

Widely prescribed for nosocomial upper gastrointestinal bleeding prophylaxis.

Agents of choice when NSAID therapy must be continued in the presence of ulcer disease and for large ulcers.

Are included among the regimens with the highest eradication rates in H. pylori.

Often utilized prophylactically with clopidogrel to reduce gastrointestinal bleeding risk.

May decrease effects of clopidogrel on platelet aggregation inhibition.

Between 25 and 70% of prescriptions for proton pump inhibitors have no appropriate indication(Forgacs I et al).

The duration of use of PPI’s frequently extends beyond recommended guidelines.

PPI use can lead to false negative test results when confirming H. pylori eradication.

Associated with increased risk of stomach cancer.

Observational studies link use to hip fracture, community acquired pneumonia, Closidium difficile infection, acute interstitial nephritis, and acute kidney injury.

In the prospective Atherosclerosis Risk in Community study 10,482 participants with normal baseline renal function followed for a median of 13.9 years: PPI users had a 50% greater risk of developing chronic kidney disease thannonusers which is an absolute increase10 year risk of 3.3%

Can lead to acute interstitial nephritis, typically within several months after use is initiated, but this is uncommon.

In the above study there was a 64% increased risk of acute kidney injury among PPI users.

Use may be associated with hypomagnesemia.

Up to 43% of patients have an increased risk of hypomagnesemia in patients on long term PPIs.

Observational studies show long-term use of PPIs are associated with an increased all-cause mortality, cardiovascular and renal diseases, dementia, infections, fractures, hypomagnesemia, and cancers.

In patients on long term PPIs magnesium should be monitored, and this is true particularly for those who are concomitantly using diuretics or have a malabsorption disorder.

Associated with small intestine bacterial overgrowth.

Decreased gastric acid production associated with PPI use can lead to small intestine bacterial overgrowth.

Proton pump inhibitors, one of the most commonly prescribed classes of drug.

A randomized trial found that for the most part, use of PPIs was safe and generally was not associated with the adverse events observed in other studies.

Among more than 17,000 participants, there was no statistically significant difference between patients who received the PPI pantoprazole (Protonix) for up to 3 years and the group that received placebo with respect to safety events.

The only exception was an increase in enteric infections among patients in the PPI group (1.4% vs 1.0%).

Observational studies have linked PPI use to uncommon but serious adverse events: osteoporosis-related fractures, Clostridium difficile infection, community-acquired pneumonia, cerebrovascular events, kidney disease, gastric cancer, and increased mortality.

A study of the use of high-dose PPIs and aspirin for patients with Barrett esophagus found that PPIs could reduce the rate of high-grade dysplasia and esophageal adenocarcinoma.

There was no significant difference in the composite outcome of myocardial infarction, stroke, or cardiovascular death with pantoprazole compared to placebo.

Hospitalization rates and all-cause mortality were also similar between pantoprazole and placebo cohorts.

There were no statistically significant differences in overall cancer rates.

Enteric infections occurred more frequently in patients taking pantoprazole, It was statistically significant but only marginally so.

C difficile infection was about twice as common among patients taking pantoprazole, but because there were only 13 events, the difference was not statistically significant.

The risk of small intestine bacterial overgrowth is 7.5 times greater among individuals using duodenal/jejunal aspirate for diagnosis of small intestinal bowel bacterial overgrowth.

Associated with community acquired pneumonia, Clostridia difficile infection hypomagnesemia, bone fractures, acute kidney injury, chronic kidney disease, and dementia.

Long-term PPI’s cause magnesium deficiency in approximately 20% of patients receiving them, and these effects occur in a dose dependent fashion.

Proton pump inhibitors may be associated with a greater risk of hip fractures and Clostridium difficile-associated diarrhoea.

Patients are frequently administered the drugs in intensive care as a protective measure against ulcers, but this use is also associated with a 30% increase in occurrence of pneumonia.

Long-term use of proton pump inhibitors in patients treated for Helicobacter pylori has been shown to dramatically increase the risk of gastric cancer.

Acute tubulointerstitial nephritis is a possible adverse reaction when using proton pump inhibitors.

There is a correlation between the increase in proton pump inhibitor use and the increase in hospital acquired C. Difficile infection incidence

Use is associated with 20-50% highest risk of chronic kidney disease (Lazarus B et al).

Adults who use PPI’s have a 16-21% increased chance of having myocardial infarction (Shah NH et al).

Studies suggest excess risk of death among PPI users; risk is also increased among those without gastrointestinal conditions and with prolonged duration of use.

In the Omeprazole Clopidogrel Aspirin Study patients undergoing coronary stent placement receiving clopidogrel and aspirin combined with omeprazole had a higher platelet reactivity index value at the end of a 7 day treatment period than did patients taking clopidogrel and aspirin with placebo (Gilard M).

Reduced action of clopidogrel mat be due to the competitive metabolic effects of PPIs on CYP2C19.

When utilized with clopidogrel after hospital discharge for acute coronary artery syndrome associated with increased risk of adverse outcomes compared to the use of clopidogrel alone.

Concomitant PPI medications with clopidogrel can be used for patients with a history of prior upper G.I. bleeding, advanced age, use of steroids, or nonsteroidal anti-inflammatory drugs, and infection with Helicobacter pylori.

Coadministration of low dose aspirin and a PPI for prevention of cardiovascular events results in fewer lifetime upper G.I. bleeding events (3.4% vs. 7.2%) and fewer recurrent myocardial infarctions (26 fewer events per 10,000 patients), and an additional 38 days of life for patient compared with aspirin alone (Saini SD et al).

Randomized controlled trials have shown that proton pump inhibitors reduce the rate of recurrent gastrointestinal bleeding in high risk patients receiving aspirin (Lai KC et al).

In the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) assessing the efficacy of concomitant clopidogrel and PPI’s in patients with coronary artery disease also receiving aspirin: there was a significant reduction in the risk of gastrointestinal clinical events, including upper gastrointestinal bleeding in patients receiving dual antiplatelet therapy and no significant increases in the risk of cardio vascular events occurred (Bhatt DL et al).

In a retrospective study evaluating clinical outcomes in patients using clopidogrel alone or with PPIs after myocardial infarction or coronary artery stent placement: patients who received clopidogrel and a proton pump inhibitor, had a significant higher risk of rehospitalization or myocardial infarction or coronary artery stent placement than did patients receivng clopidogrel alone (Sockl KM).

May be associated with hypomagnesemia.

Lansoprazole treatment in children with asthma associated with increased episodes of sore throats and bronchitis, and in a trial in infants when compared to placebo was associated with more lower respiratory tract infections (Orenstein SR et al).

The use of chronic proton pump Inhibitors does not improve symptom control in children with asthma, and may be associated with adverse effects.

PPI use associated with increased risk of community acquired pneumonia in adults and children: related to decreased host defense against bacterial colonization imparted by low gastric acidity.

PPIs

Potential complications of long-term PPI therapy include: pneumonia, dementia, myocardial infarction, chronic kidney disease, fracture, enteric infections, small bowel bacterial overgrowth, C. difficile associated infection,  and micro nutrient deficiency anemia.

Eradication of H. pylori and long-term treatment with proton pump inhibitors are effective in the prevention of aspirin induced GI lesions and symptoms in patients with aspirin induced erosions or peptic ulcers.

In a randomized, double-blind, controlled study comparing the efficacy of famotidine with pantoprazole in the prevention of recurrent dyspeptic or complicated ulcer/erosions. In patients taking low-dose aspirin: the prevalence of significant dyspepsia or peptic alteration was significantly higher in the famotidine group compared with the pantoprozole group (20% vs. 0%)(Ng FH).

The above the study demonstrates that famotidine is inferior to proton pump inhibitor therapy in preventing aspirin related peptic ulcer/erosions in the upper G.I. tract.

Overprescribed between 53-69% of PPI presciptions.

Associated with incresed rate of rate of spine, lower arm and total fractures demonstrated in the Women’s Health Study (Gray SL et al).

Long-term use may reduce calcium malabsorption and increase hip fracture risk (Insogna KL, YangYX et al).

Suspected decreased absorption of calcium results in decreased bone mineral density.

Long term use have potential adverse effects including: risk of fractures, pneumonia, Clostridium difficile diarrhea, hypomagnesemia, vitamin B12 deficiency, chronic kidney disease, bacterial gastroenteritis, bacterial overgrowth in the small intestine, chronic kidney disease, bone fracture, dementia, and myocardial infarction.

Proton pump inhibitors can interfere with vitamin B12 absorption from food by slowing the release of gastric acid into the stomach.

Epidemiological studies suggest that PPI use is associated with increased osteoporotic fracture risk.

Meta-analyses indicate PPI use associated with 33% increased risk for fracture at any site.

Yu et al sound PP I use was not associated with increased hip fracture risk in patients without fracture risk factors.

PPI’s associated with 20-50% increased risk of chronic kidney disease, the same was not found for the use of histamine2 receptor antagonists.

In a prospective analysis of 161,806 postmenopausal women age 50-79 years without history of hip fracture, part of the Women’s Health Initiative (WHI) Observational Study and Clinical Trials with a mean follow-up of 7.8 years: use of PPI’s was not associated with hip fractures but was modestly associated with spine, forearm, wrist, and total fractures (Gray SL et al).

Use associated with increases in the risk of Clostridium difficile infections reflects importance of gastric acid in protecting against infection with this agent.

Patients with continuous PPI use have elevated risk of CDI recurrence and that cessation of unnecessary PPI should be considered at the time of CDI (McDonald EG et al).

May increase risk of community acquired pneumonia and nosocomial pneumonia.

Proton pump inhibitors are associated with greater risk of G.I. bleeding, pneumonia, and C. difficile infections then H2RAs in mechanically ventilated patients (MacLaren R et al.).

Proton pump inhibitors slightly, but significantly decrease the risk of important gastrointestinal bleeding and have a decent chance of slightly decreasing mortality, in less severely ill patients with mechanical ventilation.

Certain proton pump inhibitors do not decrease, and may slightly increase mortality in severely ill patients.

Use of PPIs during the first trimester of pregnancy is not associated with significant increase of major birth defects (Pasternak B, Hviid A).

PPIs Appear Largely Safe in Multiyear Trial: A randomized trial found that for the most part, use of PPIs was safe and generally was not associated with the adverse events observed in other studies.

Among more than 17,000 participants, there was no statistically significant difference between patients who received the PPI pantoprazole (Protonix) for up to 3 years and the group that received placebo with respect to safety events.

The only exception was an increase in enteric infections among patients in the PPI group (1.4% vs 1.0%).

Observational studies have linked PPI use to uncommon but serious adverse events: osteoporosis-related fractures, Clostridium difficile infection, community-acquired pneumonia, cerebrovascular events, kidney disease, gastric cancer, and increased mortality.

A study of the use of high-dose PPIs and aspirin for patients with Barrett esophagus found that PPIs could reduce the rate of high-grade dysplasia and esophageal adenocarcinoma.

There was no significant difference in the composite outcome of myocardial infarction, stroke, or cardiovascular death with pantoprazole compared to placebo.

Hospitalization rates and all-cause mortality were also similar between pantoprazole and placebo cohorts.

There were no statistically significant differences in overall cancer rates.

Enteric infections occurred more frequently in patients taking pantoprazole, It was statistically significant but only marginally so.

C difficile infection was about twice as common among patients taking pantoprazole, but because there were only 13 events, the difference was not statistically significant.

Concomitant use of PPIs with colorectal cancer treated with fluoropyrimidine based chemotherapy may be related to alterations in the gut microbiome altered immune milieu  within the tumor and interactions through transporters impairing survival.