Long Term PPI Use and Associated Complications - September 2014 Jessica Farrell, Pharm.D Co-Director Steffens Scleroderma Center Assistant ...
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Long Term PPI Use and
Associated Complications
September 2014
Jessica Farrell, Pharm.D
Co-Director Steffens Scleroderma Center
Assistant Professor of Pharmacy Practice
Albany College of Pharmacy and Health Sciences
Do I take a Proton Pump Inhibitor (PPI)?
Currently, physicians are pre- irritation, heartburn and other ing them increasingly accessible
scribing proton pump inhibitors symptoms. PPIs work by inhibiting and commonly misused. For many
(PPIs) to treat patients for a variety the proton pump in parietal cells people, the use of a PPI, especially
of diseases or symptoms. PPIs are (the cells that create stomach acid). long term use, is not necessary and
commonly used to treat heartburn, As a result of this inhibition, the may promote unwanted side effects.
ulcers or gastroesophageal reflux amount of stomach acid produced For other patients, such as those
disease (GERD). GERD is a condi- is decreased. PPIs are available with Scleroderma, the utility of PPI
tion where stomach contents leak in both prescription and over the therapy vastly outweighs the side
back into the esophagus causing counter (OTC) formulations, mak- effect associated risks.
Available as Prescription Only Available Over the Counter
Brand Name Generic Name Brand Name Generic Name
Protonix® Pantoprazole Prilosec® Omeprazole
Nexium ®
Esomeprazole Zegerid® Omeprazole and
Vimovo ®
Esomeprazole and Naproxen Sodium Bicarbonate
Dexilant ®
Dexlansoprazole Prevacid® Lansoprazole
Aciphex® Rabeprazole
What is Long-Term Use? – Side effects less commonly seen from using these products, but
– PPIs have a variety of Food and include alopecia, upper respira to better educate individuals on
Drug Administration (FDA) tory tract infection, increased the safety and appropriate use
labeled indications, most of liver enzymes, abnormal vision of these medications.
which call for a short course and hypomagnesemia
of therapy. Self-treatment for (low magnesium levels).
Gastroesophageal Reflux Disease
(GERD) with over the counter What are Potential
(OTC) PPI therapy is only recom- Conditions PPIs
mended for 2 weeks. Conversely, can Effect?
when prescribed by a physician,
– Recently, PPIs have
PPIs may be utilized for long-
gained negative pub-
term use if the benefit outweighs
licity for the risks
the risk. Although there is no
associated with their
definitive answer as to what
long-term use. Through
qualifies as long-term therapy,
years of clinical experi-
multiple sources have identified 1
ence, drug studies and
year as the cut off between short
increased awareness to
and long-term therapy. For cer-
tain disease states, such as sclero- the possibility of side
derma, long term PPI therapy is effects, PPIs have been
recommended in order to avoid associated with effects
the complications associated with on: vitamin/mineral
gastric reflux. absorption, increased
risk of bone fractures,
Common Side Effects pneumonia, enteric
of PPLs infections, Clostridium
– Side effects most commonly difficileassociated diar-
associated with PPI use include rhea and the formation
headache, nausea, vomiting, of gastric polyps. The
diarrhea, dizziness, rash, anemia goal of disclosing these
and arthralgias; but are generally possible side effects is
well tolerated. not to deter patients
2
Decreased Absorption It is very important to
of Important Vitamins/ read product labels.
From this Citrical ® Supplement Foods
Minerals label it can be seen
that each serving (2 Serving Size: 2 tablets
– Calcium. PPIs affect the body’s
tablets) is only 500 mg Servings Per Container: (Net Qty Contents/Serving Size [# tablets])
ability to absorb calcium from of elemental calcium. Amount Per Serving % Daily Value
the diet, as well as from calcium Therefore to get the
Vitamin D 400 IU 100%
recommended daily
supplements. By lowering the amount of calcium, at Calcium (elemental) 500 mg 50%
stomach acid levels, the abil- least 4 tablets should Sodium 5 mg < 1%
be taken every day.
ity to digest the calcium and
adequately absorb it into the body vitamin B12 levels include ane- absence of gastric acid. The terms
is decreased. Once your blood cal- mia, fatigue, weakness, constipa- heme and non-heme, describe if
cium levels are low, the body will tion, loss of appetite and weight the iron is derived from hemo-
attempt to correct this imbalance loss.6 To prevent the development globin (the protein involved in
in the only way it can, by taking of these side effects, it is impor- oxygen transport). Heme iron is
it from the bones. The longer the tant to have B12 levels monitored found in animal foods that origi-
body is low on calcium, the more when on long term PPI therapy. nally contained hemoglobin, while
calcium will be removed from the • Low B12 levels may require non-heme iron comes from plant
bone. This chain of events can supplementation with oral foods. Patients undergoing long
lead to osteoporosis and bone frac- tablets, sublingual tablets or term suppression of gastric acid
tures. Studies have found a link fortified foods. If B12 levels do may be at risk for low iron levels
between long term PPI use and not normalize with oral supple- so it is important to have your
the risk of hip fractures. Studies mentation, vitamin B12 is iron levels monitored.1,3
also show a correlation between available as a monthly injection • According to studies, the
higher dosages, and longer that bypasses gastrointestinal absorption of iron bis-glycine is
duration of use towards overall absorption. not associated with decreased
increased fracture risk.1,2,3 – Iron is an important part of absorption with changes in
• Calcium Citrate is the best many proteins and enzymes that gastric pH.4 Iron-bisglycine is
option for calcium supplementa- maintain good health. In addi- available in products known as
tion for patients currently on a tion it is an essential component Ferrochels, and Hemagenics.
PPI. Calcium citrate does not of oxygen transport in the blood. Also, the possibility of iron
require an acidic environment to Iron digestion and absorption can by injection is available for
absorb the calcium in the diges- be affected by PPI usage. Like patients not able to tolerate oral
tive tract, while calcium carbon- other vitamins and minerals, iron supplementation. Always con-
ate does require stomach acid. (specifically non-heme iron, 66% sult with your doctor or phar-
– Vitamin B12 is necessary for of iron found in food), has mark- macist before starting a new
proper red blood cell formation, edly decreased absorption in the medication.
neurological function, and DNA
synthesis. It is also an essential
factor in metabolism of fats and
proteins. In order for the body to
absorb vitamin B12, gastric acid
is needed to release the B12 from
food. There is also an association
of decreased absorption in elderly
populations. Therefore, patients
utilizing long-term PPIs and/
or elderly populations will have
decreased absorption of B12 from
food sources.1,3,4 To reduce the
likelihood of low levels of B12, it
is recommended to take B12 sup-
plements or ingest B12 fortified
foods to counteract malabsorption.
Side effects associated with low
3– Magnesium is an important • To prevent bacteria from enter- stomach acid and thus increase
mineral in the body used to main- ing the lungs, prop the bed up the growth of bacteria. By making
tain normal muscle and nerve at night or sleep with multiple the stomach less acidic, PPIs may
function, and heart rhythm. In pillows to elevate the upper por- leave the door open for infections
addition, magnesium supports tion of your body. This will pre- that may not have taken hold
the immune system and improves vent both heartburn and gastric if the acid levels had been “nor-
bone stability. Although rare, acid from entering the lungs. mal.”2 Recently in February 2012,
PPIs have been linked with states Also, there are multiple ways the FDA added a special alert to
of hypomagnesemia (low magne- to prevent pneumonia including the drug monographs of PPIs to
sium levels), but the mechanism washing your hands before eat- include a possible increased risk
is unknown at this time. Theories ing and preparing foods, smok- of C. diff-associated diarrhea. It is
suggest that PPI-induced hypo- ing cessation, and being vac- reported that there is an estimat-
magnesemia is likely due to cinated. Always consult with ed 1.4 to 2.75 fold increased risk
gastrointestinal magnesium loss. your doctor or pharmacist about of developing C.diff-associated
Symptoms of hypomagnesemia the need for a vaccination. diarrhea. Risk factors and most
include fatigue, unsteadiness, par- reported cases include elderly
esthesia, tetany, cardiac arrhyth- Enteric Infections patients, chronic or underlying
mias, so it is important to monitor – Enteric infections are defined conditions, simultaneous use of
patients’ magnesium level with as an infection of the intestinal broad-spectrum antibiotics (amox-
prolonged use of PPIs.3 tract and present with diarrhea, icillin, ciprofloxacin, levofloxacin).7
• If you are experiencing low abdominal discomfort, nausea, • It is recommended to contact
magnesiumlevels, your physi- vomiting and anorexia. Patients your physician if patients expe-
cian may advise you to take a may be more susceptible to chol- rience persistent watery stools,
magnesium supplement in order era and species of Shigella and bloody diarrhea, abdominal
to counteract the magnesium Salmonella while under PPI ther- pain/tenderness, nausea, loss of
loss in the stomach. Always apy due to small bowel bacterial appetite, or fever while taking
consult with your doctor or overgrowth. This increased risk PPIs. It is also advised to use
pharmacist before starting a can be attributed to the gastric the lowest dose for the shortest
new medication. acid suppression due to PPI ther- duration.7
apy. Normally, gastric acid would
PPI Associated Pneumonia destroy the majority of ingested Gastric Polyps
– Pneumonia is a breathing condi- bacteria and prevent infection. – Gastric polyps are masses of
tion caused by a bacterial infec- Only a few cases of infections in cells that form on the inside
tion of the lung. It is an unpleas- patients taking PPIs have been lining of the stomach and are
ant condition that affects millions reported and a variety of case considered rare. Gastric polyps
of people each year and includes studies argue against this risk.1 are typically asymptomatic and
symptoms of cough, fever, shak- • Even with conflicting evidence very rarely progress to cancer-
ing chills and shortness of breath. there are still recommendations ous tissue. One risk factor for
Patients who use PPIs are at an to avoid such infections. Taking developing gastric polyps is the
increased risk for pneumonia extra care in making sure food long term use of PPIs; as there
and other upper respiratory tract is not spoiled or contaminated. has been an increased incidence
infections.1 PPI use can lead to Practicing not only proper of polyps in recent years due to
an increase in bacterial coloniza- hygiene, but proper kitchen increased usage of PPIs. This is
tion of the stomach due to a less hygiene (cleaning surfaces and because when parietal cells (acid
acidic environment. In addition, utensils after contact with raw producing cells) are suppressed
PPI use may be associated with meats). Avoiding sick or infected by PPIs, hyperplasia (increase in
pulmonary micro-aspiration and individuals and frequent hand the number of cells) can occur in a
lung colonization. In other words, washing are all ways to avoid time dependent manner. In other
during ventilation, materials from enteric infections. words, the body will create more
the gastrointestinal tract can cells because the previous cells
enter the lungs and be deposited. Growth of Gastric Bacteria are not producing acid. Majority
Therefore, patients using PPIs – Clostridium difficile (C.diff) can of polyps may not require treat-
have more bacterial colonization cause life-threatening cases of ment; treatment is usually indi-
leading to an increased risk of diarrhea and conditions like coli- cated only if polyps are cancer-
bacteria entering the respiratory tis and inflammation of the lining ous or larger than 1cm. Antral
tract. of the colon. PPIs can decrease the polyposis is often attributed to
4Helicobacter pylori (H. pylori)
infection, which has a decreased
incidence since the widespread
use of PPIs. However, it is not
guaranteed that antral polyposis
and H. pylori are seen together.
PPI usage has been associated
with a 4 fold increased risk of
developing benign gastric polyps.
Typically when PPIs are stopped
for a period of months, gastric
polyps will dissipate.5
Drug Interactions
– PPIs, like any other drug, can Are Other Antacids/Acid minimize these unwanted effects.
interact with other drug therapies Suppressants Safe? Your healthcare professionals
– Other over the counter prod- are aware of these conditions and
you may be taking. Although an
ucts work to lower the amount under their supervision, unde-
interaction may exist, it may still
of acid produced by the body to sired side effects can be avoided.
be safe for you to take the com-
fight GERD, heartburn, ulcers, If patients are indicated for the
bination together. Talk to your
etc. These antacid products long term use of PPIs, following
pharmacist about the risk of com-
include Tums, Maalox, Gaviscon, the above advice can help reduce
bining these therapies.
Mylanta, Pepto-Bismol and possible adverse effects associated
• PPIs may increase the effects
Rolaids. Another class of acid with this class of medication.
of: amphetamines (Adderall),
aripiprazole (Abilify), benzodiaz- suppressing drugs are Histamine Why am I taking a PPI
epines (Xanax, Valium, Ativan), H2-receptor antagonists (H2RA)
for the treatment of
carvedilol (Coreg), cilostazol which include Pepcid (famotidine),
Scleroderma?
(Pletal), citalopram (Celexa), Zantac (ranitidine), Tagamet
(cimetidine) and Axid (nizatidine). – In Scleroderma, esophageal dys-
escitalopram (Lexapro), cyclo-
In contrast to PPIs, antacids only function can lead to severe compli-
sporine (Neoral, SandIMMUNE),
temporarily neutralize stomach cations if not treated effectively.
dexmethylphenidate (Focalin),
acid and similarly H2RAs limit Normally, the lower esophageal
fluconazole (Diflucan), phe-
acid secretion to a lesser degree sphincter, or valve, acts as a gate
nytoin (Dilantin), methotrexate
than PPIs. Due to their lower between the stomach and esopha-
(Rheumatrex), pimozide (Orap),
degree of acid suppression or neu- gus which opens to allow food
raltegravir (Isentress), saqui-
tralizing, these drugs do not show to enter the stomach and then
navir (Invirase), tacrolimus
the same long term effects as PPIs closes promptly to prevent food
(Prograf), vitamin K antagonists
when considering osteoporosis, from coming back up. In systemic
(Coumadin, warfarin), voricon-
azole (VFEND). decreased mineral bioavailability scleroderma, the gate does not
• PPIs may decrease the effects of: or gastric polyps. close properly and the result is a
atazanavir (Reyataz), bisphos- backwash of acid and a burning
phonates (Fosamax, Boniva, What should I do? sensation (heartburn) as food and
Actonel), cefditoren (Spectracef), – Discuss with your doctor your acid return into the esophagus.
clopidogrel (Plavix), clozapine symptoms and overall need for The acid may also injure the lin-
(Clozaril), dabigatran (Pradaxa), a PPI instead of alternative ing of the lower portion of the
dasatinib (Sprycel), delavir- treatments with over the coun- esophagus, causing scarring and a
dine (Rescriptor), erlotinib ter antacids and acid suppres- narrowing (stricture) of the tube.
(Tarceva), gefitinib (Iressa), sants. Although there are issues The addition of PPI therapy can
indinavir (Crixivan), iron salts with long term use, PPIs are an decrease the risk of scarring and
(ferrous sulfate, ferrous gluco- effective and beneficial treat- stricture formation. The benefit
nate, ferrous fumarate, Iron), ment for a variety of indications. of using PPIs outweighs the risks
itraconazole (Sporanox), mesa- Patients and prescribers must associated with PPI use. In gen-
lamine (Asacol), mycophenolate always weigh the risk vs. benefit eral, the side effects associated
(CellCept), nelfinavir (Viracept), of medication use, as with all with long-term PPI therapy can
posaconazole (Noxafil), rilpi- medications. Increased awareness be prevented with proper monitor-
virine (Edurant), tipranavir of the possible side effects and ing by your provider.
(Aptivus), vismodegib (Erivedge). precautions is important to help
5References:
1. Thomson A, Sauve M, Kassam N, Kamitakahara. Safety of the long-term use of proton pump inhibitors. World J
Gastroenterol. 2010;16(19):2323-30.
2. Laria A, Zoli A, Gremese E, Ferraccioli GF. Proton pump inhibitors in rheumatic diseases: clinical practice, drug interac-
tions, bone fractures and risk of infections. Reumatismo. 2011;63(1):5-10.
3. Ito T, Jenson R. 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;12(6):448-57.
4. Jameson R Lam, Jennifer L Schneider, Douglas A Corley et al. Proton Pump Inhibitor and Histamine 2 Receptor Antagonist
Use and Vitamin B12 Deficiency. JAMA. 2013;310(22):2435-2442.
5. Garcia-Casal MN, Layrisse M. The effect of change in pH on the solubility of iron bis-glycinate chelate and other iron com-
pounds. Arch Latinoam Nutr. 2001;51(1 Suppl 1):35-6.
6. Alqutub AN, Masoodi I. A case of gastric polyposis in antral area of stomach following prolonged proton-pump therapy. Ger
Med Sci. 2010;2(8):pii Doc19.
7. Office of Dietary Supplements. National Institute of Health. Dietary supplement fact sheet: Vitamin B12. Reviewed 2011
June 24. [cited 2012 June 19] Available from: http://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/
8. U.S. Food and Drug Administration. Proton Pump Inhibitors (PPIs) – Drug Safety Communication: Clostridium Difficile-
Associated Diarrhea (CDAD) can be associated with stomach acid drugs. 2012 [cited 2012 June 19] Available from:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm290838.htm
Acknowledgements:
I’d like to thank Michael Sautter, PharmD. Candidate 2013 for his hard work on this project.
The Scleroderma Foundation’s mission is three-fold:
a To help patients and their families cope with scleroderma through mutual support programs,
peer counseling, physician referrals, and educational information.
a To promote public awareness and education through patient and health professional semi-
nars, literature, and publicity campaigns.
a To stimulate and support research to improve treatment and ultimately find the cause and
cure of scleroderma and related diseases.
300 Rosewood Drive, Suite 105
Danvers, MA 01923
Phone: 978-463-5843
Fax: 978-463-5809
Info Line: 800-722-HOPE (4673)
Email: sfinfo@scleroderma.org
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Text and logo © 2014, The Scleroderma Foundation, Inc.
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