Proton-pump inhibitor

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Proton-pump inhibitor
Drug class
Proton pump inhibitors structure.svg
General structure of a proton-pump inhibitor
Use Reduction of gastric acid production
Biological target Hydrogen potassium ATPase
ATC code A02BC
External links
MeSH D054328
AHFS/Drugs.com Drug Classes
WebMD medicinenet 

Proton-pump inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available. The group followed and has largely superseded another group of pharmaceuticals with similar effects, but a different mode of action, called H2-receptor antagonists. These drugs are among the most widely sold drugs in the world, and are generally considered effective.[1] The vast majority of these drugs are benzimidazole derivatives, but promising new research indicates the imidazopyridine derivatives may be a more effective means of treatment.[2] High dose or long-term use of PPIs carries a possible increased risk of bone fractures.[3]

Medical uses[edit]

These drugs are used in the treatment of many conditions, such as:

Specialty professional organizations recommend that people take the lowest effective dose possible to achieve the desired therapeutic result when using proton pump inhibitors to treat gastroesophageal reflux disease long-term.[5][6] In the United States, the Food and Drug Administration advises that no more than three 14-day treatment courses should be used in one year.[3]

The effectiveness of PPIs has not been demonstrated in every case, despite their widespread use for these conditions. For example, they do not change the length of Barrett's esophagus.[7] The most objective test to assess success of PPI therapy in patients with GERD is esophageal pH monitoring.

Adverse effects[edit]

PPIs (as well as other antacid preparations), by suppressing acid-mediated breakdown of proteins, lead to an elevated risk of one's developing food allergies. These undigested proteins then pass into the gastrointestinal tract, potentially leading to sensitization to a range of foods or drugs. It is unclear whether this risk occurs with only long-term use or with short-term use as well.[8][9][10][11][12][13]

Patients are also at risk of developing drug hypersensitivity[14][15]

Exposure to acid-suppressive drugs during pregnancy is associated with childhood asthma.[16]

Short-term[edit]

In general, proton pump inhibitors are well tolerated, and the incidence of short-term adverse effects is relatively low. The range and occurrence of adverse effects are similar for all of the PPIs, though they have been reported more frequently with omeprazole. This may be due to its longer availability and, hence, clinical experience. Common adverse effects include: headache (in 5.5% of users in clinical trials[17]), nausea, diarrhea, abdominal pain, fatigue, and dizziness.[18]

Because the body uses gastric acid to release vitamin B12 from food particles, decreased vitamin B12 absorption may occur with long-term use of PPIs, and may lead to vitamin B12 deficiency.[18][19] Prospective studies and reviews demonstrate reduced B12 levels that are within the normal range, suggesting that the risk of deficiency may be clinically insignificant[20][21][22][23] However, older patients are thought to be at risk of developing B12 deficiency with PPI usage.[24][25][26]

Infrequent adverse effects include rash, itch, flatulence, constipation, anxiety, and depression. In rare cases, PPI use may cause ‘idiosyncratic’ reactions, such as erythema multiforme, pancreatitis, Stevens–Johnson syndrome, thrombocytopenia and acute interstitial nephritis.[27][28][29][30][31] There was a reported case of hyperprolactinaemia as a rare adverse effect of PPI.[32][33]

Gastric acid suppression, using H2-receptor antagonists and PPIs, is associated with an increased risk of community-acquired pneumonia.[34] Acid suppression may result in insufficient elimination of pathogenic organisms. Therefore, patients at higher risk of pneumonia are suggested to be prescribed proton pump inhibitors only at lower doses and only when necessary.[35] A meta analysis found no increased risk of hospitalisation for community-acquired pneumonia with PPI usage[36]

On 8 February 2012, the US-FDA issued a safety announcement on PPIs, based on the review report from the Adverse Event Reporting System. This review report suggested an increased risk of Clostridium difficile-associated diarrhea with PPI use.[37] The safety announcement reported that PPIs have been shown to raise risk of Clostridium difficile infection by 1.7 times with once-daily use and 2.4 times with more-than-once-daily use.[38][39] The risk can be minimized by judicious short-term prescriptions.[40][41]

PPIs have been linked with increased skin aging.[42]

PPI's can cause transmucosal gastric leak. This can happen within days of first taking the drug.[43][44][45]

PPI use may be associated with occurrence of myopathies, including the serious reaction rhabdomyolysis.[46]

Long-term[edit]

In the specific but common case of the use of PPIs as long-term treatment for managing GERD, medical societies recommend that patients use the minimal effective dosage to achieve the goals of the therapy.[5][6][47]

Long-term use of PPIs has been less studied than short-term use. A 2006 study of 135,000 people 50 or older found that those taking high doses of PPIs for longer than one year were 2.6 times more likely to break a hip. Those taking smaller doses for 1 to 4 yr were 1.2 to 1.6 times more likely to break a hip, and the risk of a fracture increased with the length of time taking PPIs.[48][49][50] However, in 2010, data from the same source (the UK General Practice Research Database) were analysed a second time, and reported a different trend: Risk of fracture more than doubled immediately after initiation of medication, but dropped to slightly less than double baseline with prolonged use. This information was not taken into account in the 25 May 2010 FDA labeling change because it would not be published until a year later - May, 2011, and it was not even published online until the following month.[51] Furthermore, of the seven studies the FDA did make note of, all but the smallest study found marked increased risks of fractures.[52] Theories as to the cause of the increase are the possibility that the reduction of stomach acid reduces the amount of calcium dissolved in the stomach or that PPIs may interfere with the breakdown and rebuilding of bone by interfering with the acid production of osteoclasts.[53][54] The reduction of vitamin B12 may also increase bone fragility by raising homocysteine). Another theory is the effects of PPI on bone could be driven by in part by increased histamine release.[55] A recent study also suggested that PPIs significantly decreased the effect of clopidogrel on platelets, as tested by VASP phosphorylation. The clinical impact of these results must be assessed by further investigations, but a PPI treatment should not be added to the antiplatelet dual therapy without formal indication.[56]

PPIs may cause dependency by increasing gastric symptoms if they are discontinued.[57] In healthy volunteers given pantoprazole or placebo for four weeks and then followed for six additional weeks, one week after treatment was stopped, 44% of the pantoprazole recipients reported symptoms of dyspepsia, compared to 9% of the placebo recipients. By the third week, this difference between the two groups had disappeared.[58] Such "rebound hyperacidity" is thought to be mediated by gastrin hormone secretion, which occurred following the discontinuation of PPIs, and patients should expect symptoms of hyperacidity to worsen for a week or two after stopping these drugs.

The FDA is revising both the prescription and the over-the-counter (OTC) labels for PPIs to include the possible increased risk of fractures. This new information is based upon FDA review of several long-term studies that reported an increased risk of fractures of the hip, wrist, and spine with PPI use. Some studies found a greater risk for these fractures from higher doses of PPI or use for one year or more. Most studies evaluated individuals aged 50 or older and the increased risk of fractures was primarily in this group.

However, 12-week PPI therapy had no impact on calcium, vitamin D, or bone metabolism in healthy young males.[59]

Long-term PPI therapy also interferes with zinc absorption and zinc body stores. None of the PPI users, however, were found to be classically zinc-deficient.[60] Long term PPI therapy may cause anemia[61] Studies on patients with Zollinger-Ellison syndrome did not find that PPI therapy decreased body iron stores or caused iron deficiency[62][63] A dairy product fermented by lactobacilli and galactooligosaccharides improved zinc, iron, Calcium, and phosphorus retention in rats with hypochlorhydria induced by a proton pump inhibitor[64]

Three months of PPI therapy caused bacterial overgrowth in 35% of patient, compared to 10% on placebo.[65] Chronic PPI use may also impair leukocyte function by increasing basal cytosolic calcium concentrations in neutrophils and decreasing intracellular and extracellular reactive oxygen species impairing bactericidal activity.[66]

12 months of PPI therapy is linked with Fundic gland polyps[67] However, PPI treatment does not cause colon cancer[68]

A December 2010 report suggested a nearly four-fold increase in certain heart arrhythmias (focal atrial tachycardia and right ventricular outflow tract, RVOT tachycardia) in PPI users.[69] The potential mechanism was hypothesized to be related to changes in pH, potassium, and calcium level in selected cardiac cells. Though this has not been confirmed by additional study yet, it is suggested that patients with these focal arrhythmias who are taking PPIs should bring this to the attention of their physician.

In March 2011, the US Food and Drug Administration notified healthcare professionals and the public that PPI drugs may cause low serum magnesium levels (hypomagnesemia) if taken for prolonged periods of time - in most cases, longer than one year.[70] Most patients on long-term PPIs will not develop symptomatic hypomagnesemia unless accompanied by precipitating factors such as gastroenteritis, diuretics, and chronic comorbidities.[71]

Another rare potential adverse event of PPI administration is acute interstitial nephritis leading to chronic kidney disease and end-stage renal disease[72]

Omeprazole may increase the elimination of riluzole, a medication often prescribed for people with amyotrophic lateral sclerosis.[73]

Mechanism of action[edit]

The activation of PPIs
Micrograph of the gastric antrum showing G cell hyperplasia, a histomorphologic change seen with PPI use (H&E stain)

Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or, more commonly, the gastric proton pump) of the gastric parietal cells.[4] The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion.

Targeting the terminal step in acid production, as well as the irreversible nature of the inhibition, results in a class of drugs that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%. ("Irreversibility" refers to the effect on a single copy of the enzyme; the effect on the overall human digestive system is reversible, as the enzymes are naturally destroyed and replaced with new copies.)

The lack of the acid in the stomach will aid in the healing of duodenal ulcers, and reduces the pain from indigestion and heartburn, which can be exacerbated by stomach acid. The lack of stomach acid, also called hypochlorhydria, is the lack of sufficient hydrochloric acid, HCl, which is required for the digestion of proteins and the absorption of nutrients, in particular vitamin B12 and calcium.

The PPIs are given in an inactive form, which is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) with acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it.

Potassium-competitive acid blockers[edit]

Potassium-competitive inhibitors are experimental drugs that reversibly block the potassium-binding site of the proton pump. Soraprazan and revaprazan block H+ secretion much more quickly than classical PPIs (within a half-hour).[74] The development of soraprazan, however, was discontinued in 2007.[75]

Pharmacokinetics[edit]

The rate of omeprazole absorption is decreased by concomitant food intake. In addition, the absorption of lansoprazole and esomeprazole is decreased and delayed by food. It has been reported, however, that these pharmacokinetic effects have no significant impact on efficacy.[76][77]

The elimination half-life of PPIs ranges from 0.5 to 2.0 hr, but the effect of a single dose on acid secretion usually persists up to three days. This is because of accumulation of the drug in parietal cell canaliculi and the irreversible nature of proton pump inhibition.

Examples[edit]

Clinically used proton pump inhibitors:

  • Omeprazole (OTC; brand names: Gasec, Losec, Prilosec, Zegerid, ocid, Lomac, Omepral, Omez, Omepep, UlcerGard, GastroGard)
  • Lansoprazole (brand names: Prevacid, Zoton, Monolitum, Inhibitol, Levant, Lupizole)
  • Dexlansoprazole (brand name: Kapidex, Dexilant)
  • Esomeprazole (brand names: Nexium, Esotrex, esso)
  • Pantoprazole (brand names: Protonix, Somac, Pantoloc, Pantozol, Zurcal, Zentro, Pan, Controloc, Tecta)
  • Rabeprazole (brand names: AcipHex, Pariet, Erraz, Zechin, Rabecid, Nzole-D, Rabeloc, Razo. Dorafem: combination with domperidone[citation needed]).
  • Ilaprazole (not FDA approved as of October 2013; brand names: Noltec, Yili'an, Ilapro, Lupilla, Adiza)

History[edit]

See also[edit]

References[edit]

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