Proton pump inhibitors

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Proton pump inhibitors , even proton pump inhibitors (PPI), commonly referred to as "gastric resistance" are drugs that the formation of gastric acid by inhibition of H + / K + -ATPase - a so-called proton pump  - in the parietal cells (parietal cells) of the stomach suppress (so-called gastric acid blockers or acid blockers for short). They are indicated in human medicine for the relief of heartburn , for the treatment of reflux oesophagitis , gastric and duodenal ulcers and in the eradication therapy of infections with Helicobacter pylori . Another indication of some PPIs is Zollinger-Ellison syndrome .

Drugs of this class are omeprazole and its pure ( S ) - enantiomer esomeprazole , pantoprazole , lansoprazole and its pure (R) enantiomer Dexlansoprazol and rabeprazole . Proton pump inhibitors are given in the form of enteric capsules or tablets . Some of the substances are also available for intravenous use.

meaning

Proton pump inhibitors help to avoid many gastric surgeries: In the past, recurrent gastric or duodenal ulcers ( ulcera ventriculi or ulcera duodeni ) were the most common reasons for gastric resection , which is usually performed as a partial resection according to Billroth (" Billroth I " or " Billroth II ") has been. Since the 1990s, the rate of surgical ulcers in the western world has decreased dramatically due to the effectiveness and widespread use of PPIs. The widespread prophylactic use to prevent stress ulcers, even in patients without a particular risk, does not make sense, however.

Mode of action

All proton pump inhibitors developed to date are acid-sensitive and can only be absorbed in the small intestine. That is why they are available in gastro-resistant pharmaceutical forms and tablets cannot usually be divided.

They reach the secretory channels of the parietal cells of the stomach via the bloodstream . All substances are prodrugs that are only converted into the active form by the acid (protons) of the parietal cells at the site of action, which binds to the H + / K + -ATPase and irreversibly blocks its function as a proton pump . The blockage is dose-dependent and affects both the basal (at rest) and the stimulated gastric acid secretion. The reduction in acid production in the stomach and the resulting increase in the pH value of the gastric juice reduce the aggressiveness of the gastric juice and thus accelerate the healing of gastric wall injuries (such as mucosal erosions or ulcers ).

Despite their short plasma half-life of only 0.5 to 1.5 hours, proton pump inhibitors still work for around 1–3 days, because only after this time does the H + / K + -ATPase regenerate itself. However, they are subject to an activity-dependent effect (English use dependency ), so that it is best to take them about 1/2 hour before eating.

Proton pump inhibitors are completely metabolized by the cytochrome P450 system (CYP) . The majority of the metabolism takes place through the multiform (polymorphic) CYP2C19, a small part is metabolized by CYP3A4.

Adverse effects and restrictions on use

Side effects

With global sales of US $ 26.5 billion (2008), proton pump inhibitors are among the most commonly prescribed drugs worldwide and are considered to be relatively safe. The most common side effects are gastrointestinal in nature; In addition, tiredness, dizziness, headaches, sleep disorders, skin changes and altered liver values , especially at the beginning, can accompany the therapy. Serious side effects, u. a. Visual disturbances up to blindness, however, were only very rarely, especially with parenteral administration, z. B. by injection observed.

Interactions

In addition to proton pump inhibitors, platelet aggregation inhibitors are also among the most widely used drugs. In addition to interventional and surgical measures, the therapy of coronary artery disease is essentially based on drug-based inhibition of platelet aggregation using acetylsalicylic acid (ASA) and inhibitors of the P2Y12 receptor such as B. Clopidogrel . The positive benefits of these drugs are offset by gastrointestinal risks such as gastric and duodenal ulcers and possible bleeding complications. Proton pump inhibitors can reduce this and were recommended as concomitant medication for dual platelet inhibition with ASA and clopidogrel. After reports about possible interactions of clopidogrel with proton pump inhibitors, the relevant medical societies in Germany adopted a position paper in 2010 with recommendations on the use of proton pump inhibitors. The therapy recommendations take into account the individual risk for cardiovascular and gastrointestinal events. Proton pump inhibitors are suspected of weakening the protective effects of clopidogrel. The bioavailability of atazanavir and other HIV therapeutics is decreased during treatment with PPIs. The changed bioavailability of the tyrosine kinase inhibitors when the proton pump inhibitors are administered at the same time is also therapeutically problematic .

Special patient groups

In general, proton pump inhibitors are not suitable for use in children. In exceptional cases, some formulations of omeprazole are approved for the treatment of severe reflux esophagitis in children aged two years and over, if other therapeutic measures have proven ineffective. Treatment should be carried out by a pediatric specialist.

A therapy with proton pump inhibitors required during pregnancy or breastfeeding is possible with the best-studied omeprazole.

In patients with liver dysfunction, depending on the severity, dose adjustment and / or monitoring of liver enzymes and, if necessary, discontinuation of therapy should be considered.

Possible associated diseases

  • Food allergy: Proton pump inhibitors are suspected of promoting the development of food allergies (Jensen-Jarolim et al.).
  • Pneumonia : Herzig et al. estimate that up to 0.9 percent of all hospital-acquired pneumonia in the US can be attributed to PPIs, avoiding up to 33,000 deaths per year in the US alone.
  • Bone fractures : With high-dose PPI therapy, the risk of femoral neck fractures (“hip fractures”) doubles. Also for other fractures, e.g. B. on vertebral bodies, the risk increases.
  • Withdrawal phenomenon: Long-term use of these medications can cause the stomach to make too much acid after stopping the medication, even if it was healthy before treatment began.
  • Nephritis: Very rarely interstitial nephritis can occur with PPI therapy .
  • Intestinal inflammation: Enteritis due to Salmonella or Campylobacter occurs due to PPI according to Logan et al. up to three times more often and are explained by the loss of the natural acid barrier . Moreover, there is evidence of an emergence of a hypomagnesemia , and an iron and vitamin B12 - malabsorption is apparently more common.
  • Vitamin B12 deficiency: Lam et al. show that PPIs and other acid blockers (H2 blockers) could be connected to a vitamin B12 deficiency and its consequences ( anemia , neurological disorders, dementia ).
  • Chronic kidney disease: A study published in the United States in February 2016 with over 10,000 participants showed that the use of proton pump inhibitors was associated with an increased risk of chronic kidney disease.
  • Dementia : According to the Ärzteblatt in February 2016, very old members of a German health insurance company were more likely to develop dementia if they had previously been prescribed proton pump inhibitors. Two large studies from 2015 and 2016 also showed that proton pump inhibitors do indeed promote the development of dementia. In 2020, an animal experiment at the Karolinska Institute in Stockholm showed that the proton pump inhibitors do indeed influence the synthesis of the neurotransmitter acetylcholine . The authors of the study warn against taking the proton pump inhibitors unnecessarily for long periods of time. Since there is no therapy for dementia, all risk factors should be minimized, according to the researchers.

Medicines on the German market

INN Commercial preparation (s) Dosage form (s)
Omeprazole Antra MUPS , Gastracid and numerous generics enteric coated tablets / capsules of 10, 20 or 40 mg; infusion
Esomeprazole Nexium and various generics enteric coated tablets / capsules of 10, 20 or 40 mg; infusion
Pantoprazole Rifun , Pantozol , Pantoloc and numerous generics gastro-resistant tablets or capsules containing 20 or 40 mg; infusion
Lansoprazole Agopton , Lanzor and various generics gastro-resistant capsules with 15 or 30 mg
Dexlansoprazole Dexilant Modified-release capsules of 30 or 60 mg
Rabeprazole Pariet enteric coated tablets of 10 or 20 mg

Omeprazole, pantoprazole and esomeprazole are available without a prescription in Germany for the short-term treatment of heartburn and acid regurgitation in limited doses and pack sizes .

literature

  • Manfred Schubert-Zsilavecz, Holger Stark: Proton Pump Inhibitors . In: Pharmacy in our time . Volume 34, 2005, No. 3, pp. 194-199, ISSN  0048-3664
  • Holger Stark, Yvonne Syha, Laura Popescu, Manfred Schubert-Zsilavecz: New active ingredients for GERD treatment . In: Pharmacy in our time . Volume 34, 2005, No. 3, pp. 224-227, ISSN  0048-3664
  • P. Schweikert-Wehner: Proton pump inhibitors. How the bioavailability of other drugs changes. In: Deutsches Ärzteblatt. Volume 113, 2016, pp. 22-23.

Web links

Individual evidence

  1. ↑ Lansoprazole (C 16 H 14 F 3 N 3 O 2 S) differs from the structurally related omeprazole in that it has a trifluoroethoxy group in the molecule. A chiral center is on the sulfur atom of the sulfinyl group. Agopton - lansoprazole. Basic scientific brochure. Takeda Pharma, Aachen 1993.
  2. ↑ CP Farrell: Overuse of stress ulcer prophylaxis in the critical care setting and beyond . In: J Crit Care , June 2010, 25 (2), pp. 214-220.
  3. ↑ Klaus Aktories, Ulrich Förstermann, Franz Hofmann, Klaus Starke: General and special pharmacology and toxicology . 10th edition. Elsevier, Urban & Fischer, Munich / Jena 2009, ISBN 978-3-437-42522-6 .
  4. ↑ Björn Lemmer , Georges Fülgraff: Pharmacotherapy, clinical pharmacology: with 192 tables; [the textbook on the cross-sectional subject] . Springer, Heidelberg 2010, ISBN 978-3-642-10540-1 .
  5. ↑ W. Fischbach, H. Darius, M. Gross, H. Koop, I. Kruck, KU Petersen: Simultaneous use of platelet aggregation inhibitors and proton pump inhibitors (PPIs) , Kardiologe 2010, 4: 353–364 doi: 10.1007 / s12181-010- 0298-7
  6. ↑ PM Ho, TM Maddox, MS Li Wang et al .: Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome. In: JAMA. Volume 301, No. 9, March 4, 2009, pp. 937-944.
  7. ↑ P. Schweikert-Wehner: Proton Pump Inhibitors, How the bioavailability of other drugs changes . Ed .: Deutsches Ärzteblatt. No. 113 . ÄrzteVerlag, Berlin May 27, 2016, p. 22.23 .
  8. ↑ Omeprazole on www.embryotox.de
  9. ↑ Core Safety Profile Omeprazole (PDF) April 2013.
  10. ^ Susanne C. Diesner, Isabella Pali-Schöll, Erika Jensen-Jarolim, Eva Untersmayr: Mechanisms and risk factors for type 1 food allergies: the role of gastric digestion ; doi: 10.1007 / s10354-012-0154-4
  11. ↑ SJ Herzig et al .: Acid-suppressive medication use and the risk for hospital acquired pneumonia . In: J. Am. Med. Ass. , 301, 2009, pp. 2110-2128, PMID 19470989 .
  12. ↑ Risk of fracture from acid inhibitors . In: MMW update. Med. , 149, No. 3, 2007, p. 3.
  13. ↑ FDA Safety Announcement. Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. May 25, 2010.
  14. ↑ Kenneth EL McColl and Derek Gillen: Proton-Pump Inhibitor Therapy Induces Acid-Related Symptoms in Healthy Volunteers After Withdrawal of Therapy . In: Gastroenterology , 137, 2009, pp. 20-22
  15. ^ IJ Simpson, MR Marshall, H Pilmore et al .: Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases , Nephrology (Carlton). 2006 Oct; 11 (5): 381-385, PMID 17014549
  16. ^ IC Logan et al .: Gastric acud suppressants - too much of a good thing? In: Age and Aging , 39, 2010, pp. 410-411
  17. ↑ Jameson R. Lam, Jennifer L. Schneider, Wei Zhao, Douglas A. Corley: Proton Pump Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B Deficiency. In: JAMA. 310, 2013, p. 2435, doi: 10.1001 / jama.2013.280490 .
  18. ^ B Lazarus, Y Chen, FP Wilson et al .: Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease . In: JAMA Intern Med. , 2016, 176 (2), pp. 238–246, doi: 10.1001 / jamainternmed.2015.7193 .
  19. ↑ aerzteblatt.de
  20. ↑ Akter S, Hassan MR, Shahriar M, Akter N, Abbas MG, Bhuiyan MA (2015): Cognitive impact after short-term exposure to different proton pump inhibitors: assessment using CANTAB software. Alzheimers Res Ther. 2015 Dec 27; 7:79. doi: 10.1186 / s13195-015-0164-8 . [1] .
  21. ^ Gomm W, von Holt K, Thomé F, Broich K, Maier W, Fink A, Doblhammer G, Haenisch B (2016): Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis. In: JAMA Neurol. 2016 Apr; 73 (4): 410-6. doi: 10.1001 / jamaneurol.2015.4791 . [2]
  22. ↑ Rajnish Kumar, Amit Kumar, Agneta Nordberg, Bengt Långström and Taher Darreh-Shori (2020): Proton pump inhibitors act with unprecedented potencies as inhibitors of the acetylcholine biosynthesizing enzyme - A plausible missing link for their association with incidence of dementia . In: Alzheimer's & Dementia , online May 8, 2020, doi: 10.1002 / alz.12113
  23. ↑ https://news.ki.se/newly-discovered-mechanism-can-explain-increased-risk-of-dementia
  24. ↑ Manfred Schubert-Zsilavecz: Gastric acid blockers in wide use In: Pharmazeutische Zeitung , 32/2013.
  25. ↑ Verena Arzbach: News against heartburn . In: PTA Forum , 17/2014.