- Proton pump inhibitors
- What are Proton Pump Inhibitors used for?
- What are the differences between Proton Pump Inhibitors?
- Are Proton Pump Inhibitors safe?
- What are the side effects of Proton Pump Inhibitors?
- What Are Proton Pump Inhibitors (PPIs)?
- Warnings and Precautions
- Common Side Effects
- Drug Interactions
- PPIs and Antacids: How to Avoid Interactions
- Is It Safe to Take PPIs? A Gastroenterologist Explains the Risks
- How do you take proton-pump inhibitors (PPIs)?
- Treating Heartburn and Gastro-Esophageal Reflux (GERD): Using Proton-Pump Inhibitors (PPI) carefully
Proton pump inhibitors
PPIs reduce the production of acid by the stomach. They work by irreversibly blocking an enzyme called H+/K+ ATPase which controls acid production. This enzyme is also known as the proton pump and is found in the parietal cells of the stomach wall.
What are Proton Pump Inhibitors used for?
PPIs treat conditions that are caused by either an overproduction of stomach acid or exacerbated by stomach acid. Taking a PPI once a day inhibits around 70% of proton pumps, so a small amount of acid is still available for food digestion.
PPIs may be used for the treatment of:
- Acid reflux, also called gastroesophageal reflux disease (GERD)
- Conditions characterized by an overproduction of stomach acid (such as Zollinger-Ellison syndrome)
- Duodenal or stomach ulcers including those caused by NSAIDs
- In combination with certain antibiotics for the eradication of Helicobacter pylori, a bacteria associated with duodenal ulcer recurrence
- Erosive esophagitis, and to maintain healing of erosive esophagitis.
What are the differences between Proton Pump Inhibitors?
All PPIs work in the same way, by inhibiting the proton pump. However, there are differences in their propensity for drug interactions, and in the way they bind to the proton pump. This can affect how long they last for.
All the PPIs available in the U.S. are metabolized in the liver by certain liver enzymes (mainly CYP2C19 and 3A4). There is a lot of individual variation in the way these liver enzymes work, and experts have identified three categories of people; extensive metabolizers (homEM), poor metabolizers (PM), and people that sit somewhere in between (hetM).
Approximately 3% of Caucasians and 15-20% of Asians are PM. PM take longer to excrete the drug and therefore their response to PPIs is increased several fold. For example, the pH of gastric acid is around 6 in PM after PPIs compared to around 3-4 in extensive metabolizers (where 1 is the most acidic pH). Metabolism is also affected in people of an older age and in those with liver disease. Esomeprazole is the only PPI that is well tolerated by people with liver disease. The extent somebody is able to metabolize a PPI can also affect their risk of drug interactions.
|Generic name||Brand name examples|
Are Proton Pump Inhibitors safe?
When taken at the recommended dosage for the recommended duration of time, PPIs are considered safe. However, they have been associated with several serious adverse effects including:
- Acute interstitial nephritis (a type of kidney failure): May occur at any point during PPI treatment
- Clostridium difficile-associated diarrhea: This is a particularly severe and persistent type of diarrhea
- An increased risk for osteoporosis-related fractures of the hip, wrist, or spine: The risk is higher in people who received high-dose therapy (typically multiple daily doses), and with PPI treatment that lasts longer than one year
- Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE)
- An inhibition of the effect of clopidogrel, a medicine used to reduce the ability of platelets to clot in people with heart disease.
In addition, there is a risk that the use of PPIs may mask the symptoms of gastric cancer. All patients with a suboptimal response to PPIs or whose symptoms recur following PPI withdrawal should have additional diagnostic testing, and an endoscopy should be considered in older people before treatment initiation.
Patients should only take PPIs as directed by their doctor or according to the instructions on the packet if bought over the counter.
What are the side effects of Proton Pump Inhibitors?
PPIs are generally well tolerated. The more common side effects reported with their use include:
- A headache
- Gastrointestinal effects (such as abdominal pain, constipation, diarrhea, flatulence, nausea, or vomiting)
- Magnesium or vitamin B12 deficiency (usually only with long-term administration)
- Tongue discoloration or taste disturbances.
For a complete list of side effects, please refer to the individual drug monographs.
What Are Proton Pump Inhibitors (PPIs)?
These drugs treat heartburn by limiting acid production in the stomach.
Proton pump inhibitors, or PPIs, are a class of drugs used to help relieve heartburn caused by acid reflux and stomach ulcers.
Decreasing stomach acid can help ulcers heal or prevent them from forming.
Many people with heartburn experience discomfort because a special valve that’s meant to keep stomach acid and food particles from flowing back up into the esophagus (food pipe) doesn’t close completely.
As a result, the acid produced by your stomach irritates the lining of the food pipe, causing symptoms like heartburn, irritation, chest pain, and coughing.
PPIs work by preventing acid pumps (proton pumps) in the stomach from releasing hydrochloric acid, so that even if the valve above the stomach doesn’t close properly, less acid flows into your food pipe and irritates its lining.
Less acid also means a decreased likelihood of an ulcer.
Proton pump inhibitors include the following drugs:
- Aciphex (rabeprazole)
- Omeprazole, found in Prilosec, Prilosec OTC, and Zegerid (in combination with sodium bicarbonate)
- Nexium (esomeprazole)
- Protonix (pantoprazole)
- Dexilant (deslansoprazole)
- Prevacid (lansoprazole)
Warnings and Precautions
Many people fail to follow drug label instructions and take PPIs at the onset of symptoms, which may occur after finishing a meal. Taking them in this manner is usually ineffective.
This is because if you take a PPI at the start of a meal or after eating, by the time it starts working, your stomach has already released most of its acid.
For best results, take a PPI 30 minutes before you eat a heavy meal, or on an empty stomach at the time of the day when you’ve noticed you have the most discomfort.
This gives the medication enough time to shut down the acid pumps that cause your heartburn.
Don’t take PPIs if you’re allergic to the active or inactive ingredients found in the medication.
Also, ask your doctor about whether PPIs are right for you if you:
- Have been using PPIs for a year or more already
- Are taking high doses of PPIs
- Have liver problems
- Have low magnesium levels in your blood
- Are over age 50
Common Side Effects
You may experience some of the following side effects when taking a PPI:
- Nausea, stomach pain, or gas
- Low vitamin B12 levels (with long-term use of drug)
Less common but more concerning side effects include:
- Increased risk of bone fracture in patients with osteoporosis
- Increased risk of the bowel infection Clostridium difficile (C. diff)
- Increased risk of heart attack
Don’t take PPIs if you’re taking:
- Viracept (nelfinavir)
- Drugs that contain rilpivirine, like Complera and Edurant
Also, ask your doctor about PPIs if you’re already taking certain blood thinners like Plavix (clopidogrel) or Brilinta (ticagrelor).
Dosages may need to be adjusted when you take PPIs along with:
- Antifungal agents, such as ketoconazole
- Dizepam (valium)
- Warfarin (Coumadin)
- Phenytoin (Dilantin)
PPIs and Antacids: How to Avoid Interactions
Lois Obert, DNP, and Jonathan Obert, MD Monday February 01, 2016 The introduction of proton pump inhibitors (PPIs) in the late 1980s dramatically changed the treatment and outcome of gastroesophageal reflux disease. Commonly prescribed PPIs include omeprazole (Prilosec), lansoprazole (Prevacid), pantoprazole (Protonix), rabeprazole (Aciphex), dexlansoprazole (Dexilant), and esomeprazole (Nexium). Because billions of dollars are spent on PPIs each year in the United States, it is important for retail clinicians to know how to use them correctly.
PPIs are appropriate for most stomach acid–related pathologies. The onset of action of PPIs is much longer than the 1-hour onset of H2-receptor antagonists, such as famotidine (Pepcid).1,2 On the other hand, neither PPIs nor H2 blockers work as quickly as antacids such as Rolaids or Tums. There are certain situations and reasons for taking each category of these medications, and each has different contraindications and interactions, as well.
Potential Interactions with Oral Medications
Omeprazole and other PPIs inhibit the CYP2C19 enzyme, which is a pathway for many medications. One medication metabolized into its active form through this pathway is clopidogrel (Plavix), a very commonly used antiplatelet agent.3 The FDA issued a strong warning against using omeprazole and esomeprazole with clopidogrel because of the potentially decreased effectiveness for clopidogrel. A different PPI with weaker CYP2C19 inhibition, such as pantoprazole, should be used instead.3,4 Other medications metabolized by the CYP2C19 enzyme pathway include diazepam, warfarin, citalopram, and phenytoin—all of which show increased serum levels with concomitant use of PPIs.
PPIs have the potential to interact with a wide variety of medications due to alteration of the pH of the stomach, which can potentially change absorption, activation, and binding of medications. Multiple HIV medications such as nelfinavir (Aricept) and rilpivirine (Edurant) require acid for proper absorption, so they are not absorbed in therapeutic doses when given with PPIs.5,6 For the same reason, some hepatitis C medications require that lower-dose or no PPIs be given during therapy.7 Conversely, PPIs will increase digoxin (Lanoxin) levels in the blood because of increased absorption, potentially leading to digoxin toxicity.8
Debate about whether PPIs alter absorption of vitamins and minerals has been ongoing for many years. Longterm treatment with a PPI decreases absorption of vitamin B12 and iron, potentially leading to anemia, neurologic dysfunction, and other long-term complications.9 Absorption of calcium and magnesium is also altered, and a systematic review of some studies has shown that long-term use of PPIs leads to increased risk for hip fracture in the elderly; however, the same systematic review of further studies failed to show correlation between osteoporosis and PPIs.9 Nevertheless, dual-energy x-ray absorptiometry scans are now being considered by some providers for patients who are on chronic PPI therapy.
Potential Effects on Gastrointestinal Health
PPIs not only affect oral medications in a variety of ways, they also alter gut flora by increasing the pH of the stomach, allowing ingested bacteria to survive the usual harsh acid environment. Results of many studies have shown a correlation between the use of PPIs and increased incidence of nosocomial and community-acquired pneumonia, as well as Clostridium difficile infection, especially when PPIs are co-administered with antibiotics.10-12 Results from a recent study linked PPI use with small bowel intestinal overgrowth, which can lead to bloating, diarrhea, or abdominal discomfort.13
Antacids are not without drug interactions. Not only do they change the pH of the stomach transiently, they also add different multivalent ions to which medications can bind. Fluoroquinolones and tetracycline are well known to bind to these ions, forming insoluble chelate complexes that inhibit their absorption. Bisphosphonates are also known to bind via a similar mechanism, inhibiting their absorption, as well. One option is to space antacids 4 hours apart from medications that can be altered, given that the stomach normally clears antacids in this time frame.14
PPIs and antacids are not benign. Multiple drug interactions and adverse effects need to be considered when prescribing these medications (Table). Retail clinicians should have a careful plan to manage patients on PPIs and antacids, and patients should be monitored at every clinic visit to determine whether the medication should be continued. PPIs and antacids truly are wonderful medications when used correctly.
Lois Obert is a nurse practitioner with a doctorate in nursing practice from the University of Alabama. She works as a market educator in retail health for Take Care Health Systems. Her nurse practitioner background is primarily in education, leadership, and curriculum development.
Jonathan Obert is a gastroenterologist, hepatologist, and nutrition fellow at the University of Louisville Department of Medicine in Louisville, Kentucky.
- Drepper, M, Spahr, L, Frossard, JL. Clopidogrel and proton pump inhibitors-where do we stand in 2012? World J Gastroenterol. 2012 May 14;18(18):2161-71.doi: 10.3748/wjg.v18.i18.2161.
- http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm225843.htm. FDA website to show actual FDA warning for clopedigril and omeprazole.
- Vinay K, Abul A,Nelson F, Robbins and Cotran Pathologic Basis of Disease.7th ed. Elsevier Inc. 810-875, 2005.
- Abe Y, Inamori M, Togawa J, et al. The comparative effects of single intravenous doses of omeprazole and famotidine on intragastric pH. J Gastroenterol. 2004 Jan;39(1):21-5.
- Lida H, Inamori M, Akimoto K, et al. Early effects of intravenous administrations of lansoprazole and famotidine on intragastric pH. Hepatogastroenterology. 2009 Mar-Apr;56(90): 551-4.
- Putcharoen O, Kerr S, Ruxrungtham K. An update on clinical utility of rilpivirine in the management of HIV infection in treatment-naïve patients.HIV AIDS (Auckl). 2013 Sept 16;5:231-41.doi:10.2147/HIV.S25712.
- Lewis J, Stott K, Monnery D, et al. Managing potential drug-drug interactions between gastric acid-reducing agents and antiretroviral therapy: experience from a large HIV-positive cohort. Int J STD AIDS. 2015 Feb. 25. pii:0956462415574632.
- Diana G, Gregory H. Ledipasvir/Sofosbuvir (Harvoni): Improving options for hepatitis C virus infection. P T. 2015 Apr; 40(4): 256-259.
- Oosterhuis B, Jonkman J, Anderson T, et al. Minor effect of multiple dose omeprazole on the pharmacokinetics of digoxin after a single oral dose. Br J Clin Pharmacol. 1991 Nov; 32(5): 569-572. PMCID:PMC1368632.
- Tetsuhide I, Robert J. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep. 2010 Dec; 12(6): 448-457. doi: 10.1007/s11894-010-0141-0 PMCID: PMC2974811 NIHMSID: NIHMS239233.
- Emmae N, Ramsay, Nicole L, et al. Proton pump inhibitors and the risk of pneumonia: a comparison of cohort and self-controlled case series designs. BMC Med Res Methodol. 2013; 13:82. Published online 2013 Jun 24. doi: 10.1186/1471-2288-13-82.
- Roughead E, Ramsay E, Pratt N, Ryan P, Gilbert A. Proton-pump inhibitors and the risk of antibiotic use and hospitalization for pneumonia. Med J Aust. 2009 Feb 2;190(3):114-6.
- Jimenez A, Drees M, Loveridge-Lenza B, et al. TI exposure to gastric acid-suppression therapy is associated with health care-and community-associated clostridium difficile infection in children. J Pediatr Gastroenterol Nutr. 2015 Aug;61(2):208-11.
- Fujiwara Y, Watanabe T, Muraki M, et al. Association between chronic use of proton pump inhibitors and small-intestinal bacterial overgrowth assessed using lactulose hydrogen breath tests. Hepatogastroenterology. 2015 Mar-Apr;62(138):268-72.
- Ogawa R, Echizen H. Clinically significant drug interactions with antacids: an update. Drugs. 2011 Oct 1;71(14):1839-64. Published online 2013 Jun 24. doi: 10.1186/1471-2288-13-82.
Proton pump inhibitors (PPIs) are a group of drugs used primarily to inhibit gastric acid secretion. They have largely replaced H2 blockers such as ranitidine in the management of conditions caused by excessive gastroesophageal acidity (e.g., dyspepsia, GERD, Barrett’s esophagus, peptic ulcers). PPIs act by completely and irreversibly inhibiting the H+/K+ ATPase enzyme system (gastric proton pump) in the parietal cells of the stomach, resulting in decreased acid production and an increase in gastric pH. PPIs are available in oral and intravenous forms, of which the oral form is more commonly administered. Intravenous PPIs are reserved for management of severe disease, since they can cause irreversible visual disturbances in rare cases. Other side effects are predominantly gastrointestinal, including symptoms such as nausea and abdominal pain, and usually decrease during the course of treatment. Significant drug interactions occur especially with anticoagulants (warfarin, clopidogrel) and should be considered before prescribing PPIs.
Is It Safe to Take PPIs? A Gastroenterologist Explains the Risks
When PPIs are necessary
Some people might need to take PPIs over an extended period, possibly for life. For others, the picture is murkier.
Many PPI users started taking the drugs “as a diagnostic test,” Rubenstein says. But there can be a substantial placebo response for symptoms, and patients whose symptoms improved on PPIs should almost always have a trial of stopping them, or using a less potent acid-blocking medication, under a doctor’s supervision.
People taking PPIs for ulcer prophylaxis (with or without GERD symptoms) shouldn’t discontinue the medication without talking to a physician. A sudden stoppage could lead to an ulcer that bleeds or perforates, potentially causing further complications.
Meanwhile, those with only periodic or light heartburn can get by with a basic antacid instead.
Those with GERD might first be steered toward H2 blockers, which block histamine receptors that promote stomach acid production — and, according to Rubenstein, have a seemingly lower risk. But, he notes, they’re ineffective for about 40 percent of users.
Patients should also take steps to lessen GERD triggers: Lose weight, avoid smoking and alcohol, sleep at an incline and avoid commonly problematic foods such as citrus, coffee and tomato products, among other things.
In some cases, these efforts can bring relief without medication.
Medication do’s and don’ts
When taking prescription or over-the-counter therapies to treat GERD, consider these tips:
Take PPIs on an empty stomach and eat something 30 to 45 minutes later.
Take PPIs first thing in the morning unless told otherwise by your doctor. If you take it in the morning, do so as soon as you wake up (before you shower or brush your teeth).
If you are instructed to take a PPI twice daily, take the second dose before dinner, not at bedtime.
If you take your medication in the evening, keep a supply at work and take it before you leave for home. If you cook your dinner, take the PPI as soon as you start preparing the meal.
Take over-the-counter acid-reducing medications for longer than 14 days without talking to your doctor, especially if you get little to no relief from your symptoms.
Eat foods that can make your symptoms worse.
Ignore your symptoms, particularly trouble swallowing. These could indicate a more serious condition.
How do you take proton-pump inhibitors (PPIs)?
Academy of Nutrition and Dietetics: “It’s About Eating Right.”
AHRQ: “Treatment Options for GERD or Acid Reflux Disease: A Review of the Research for Adults.”
American Academy of Family Physicians: “Antidiarrheal Medicines: OTC Relief for Diarrhea.”
American Academy of Family Physicians: “Heartburn.”
American College of Gastroenterology: “Acid Reflux.”
American College of Gastroenterology: “Probiotics for the Treatment of Adult Gastrointestinal Disorders.”
American Family Physician: “Effective management of flatulence.”
American Gastroenterological Association: “Understanding Heartburn and Reflux Disease.”
American Society for Gastrointestinal Endoscopy: “Understanding Gastroesophageal Reflux Disease.”
American Society of Health-System Pharmacists: “Cimetidine.”
Brahm, N. , April 2011. The Consultant Pharmacist
Canadian Society of Intestinal Research: “Exercise helps pass gas.”
Children’s Hospital of Pittsburgh: “Organs: small and large intestine.”
Cleveland Clinic: “Constipation.”
Cleveland Clinic: “Diarrhea.”
Cleveland Clinic: “The Fiber Lifestyle.”
Cleveland Clinic: “Gas.”
Cleveland Clinic: “GERD.”
Cleveland Clinic: “GERD and Asthma.”
Cleveland Clinic: “Heartburn.”
Cleveland Clinic: “Heartburn Treatment.”
Cleveland Clinic: “Hemorrhoids.”
Cleveland Clinic: “Probiotics.”
FDA: “Possible Increased Risk of Bone Fractures with Certain Antacid Drugs.”
Harvard School of Public Health: “Fiber.”
Harvard Health: “Hemorrhoids and what to do about them.”
Hye-kyung J. , January 2010. Journal of Neurogastroenterol Motility
International Foundation for Functional Gastrointestinal Disorders: “Exercise & GI Symptoms.”
Katz, P. , 2013. American Journal of Gastroenterology
National Institutes of Health: “Gas in the Digestive Tract.”
National Institutes of Health: “Hemorrhoids.”
National Institutes of Health: “Symptoms and Causes of Constipation.”
National Institutes of Health: “Your digestive system and how it works.”
NHLBI: “What are the symptoms of a heart attack?”
NIDDK: “Gastroesophageal Reflux (GER) and Gastroesophageal Reflux Disease (GERD) in Adults.”
Thompson, W. International Foundation for Functional Gastrointestinal Disorders.
Treating Heartburn and Gastro-Esophageal Reflux (GERD): Using Proton-Pump Inhibitors (PPI) carefully
Heartburn is a feeling of burning pain in your lower chest, behind the breastbone. It comes from acid backing up from your stomach to your throat. You may have seen ads on American channels for heartburn drugs, such as pantoprazole (e.g., Tecta), omeprazole (e.g., Losec), esomeprazole (Nexium) or lansoprazole (Prevacid). These drugs are called PPIs (proton pump inhibitors). They keep the stomach from making too much acid.
In most cases, you don’t need a PPI for heartburn. You can get relief from a less powerful drug. And when you do need a PPI, you should take the lowest dose for as short a time as possible. Here’s why:
Do you need a PPI?
PPIs are powerful drugs. Studies suggest that more than half of the people who take PPIs probably do not need them. Simple heartburn can be relieved with antacids or other less powerful drugs.
- Do you have heartburn every now and then—after a big, spicy meal, for example? This kind of heartburn is uncomfortable, but it is not serious. You don’t need a PPI. You can usually get relief from an antacid, like Rolaids or Tums, or an H2 blocker, such as Pepcid AC or Zantac.
- Have you had heartburn more than twice a week for several weeks? Then you may have GERD (gastroesophageal reflux disease). This is when acid made in the stomach backs up into your throat. Over time, it damages the lining of your esophagus (the tube from your throat to your stomach). If your doctor thinks you have GERD, you may need a PPI.
PPIs have risks.
If you need a PPI, taking a low dose for less than a year is probably safe. But taking a PPI for a year or longer has been linked to:
- A higher risk of breaking a hip.
- Low levels of the mineral magnesium in your blood. This can cause shaking, muscle cramps, and irregular heartbeats.
- An intestinal infection called Clostridium difficile, which can lead to severe diarrhea, fever, and, in rare cases, death.
PPIs can change the way other drugs work.
PPIs interact with some common prescription drugs. For example, some PPIs can reduce the blood-thinning effect of the drug Plavix (generic clopidogrel). This can increase the risk of heart attack and even death.
When should you consider a PPI?
If you have GERD, you probably need a PPI. Talk to your doctor if:
- You have heartburn at least twice a week for several weeks.
- Food often comes back up into your throat.
- Your heartburn does not go away after you make the diet and lifestyle changes listed in the blue section below and you take antacids or H2 blockers.
If your doctor thinks you need a PPI:
- Ask to start with a low dose of generic PPI such as rabeprazole (Aciphex), Losec (10 or 20 mg) or Prevacid (15 or 30 mg).
- If the heartburn gets better after a few weeks, try to slowly stop using the PPI.
- Slowly lower your dose. Try taking it every other day. On the days you don’t take the PPI, take an antacid instead.
Ease heartburn without drugs:
Many people who have heartburn don’t need drugs at all. They can feel better by making changes in their diet and lifestyle. Try these things before you try drugs:
Watch what you eat. Try to figure out which foods and beverages give you heartburn. Then try to avoid them. Foods and drinks that may cause heartburn include:
- Fried foods
- Spicy foods
- Garlic and onions
- Oranges and other citrus fruits
- Chocolate and peppermint
- Coffee and other drinks with caffeine, such as Coke
- Foods with a lot of tomatoes, such as pizza, salsa, and red pasta sauce
Eat smaller meals and do not go to bed right after you eat. Do not overload your stomach. And avoid lying down for two hours after you eat.
Stop smoking. If you need a reason to stop smoking, heartburn may be it. Research shows that smoking raises your risk for heartburn and GERD.
Lose extra weight. It has been proven that losing just a few extra pounds can help lessen the effects of heartburn and GERD.
Loosen up. Don’t wear tight clothes or tight belts that press on your middle. The extra pressure can make heartburn worse.
Sleep with your head raised. Raise your upper body with pillows. Or raise the head of your bed about 15 to 20 cm (six to eight inches). Try putting wooden blocks under the top legs of the bed.