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Pharmacotherapy: Pharmacokinetics and Pharmacodynamics (including: ADE, TDM, DUE)
Adverse digestibility effects, drug-food interactions and long-term safety of proton pump inhibitors
  1. H. Jenzer,
  2. L. Sadeghi,
  3. C. Krause,
  4. P. Stute,
  5. M. Joray,
  6. M. Leuenberger,
  7. Z. Stanga
  1. 1Bern University of Applied Sciences – health division, aR&D Nutrition and Dietetics, Bern, Switzerland
  2. 2Bern University Women's Hospital, Department of Gynecologic Endocrinology and Reproductive Medicine, Bern, Switzerland
  3. 3Bern University Hospital, Division of Endocrinology Diabetes and Clinical Nutrition, Bern, Switzerland
  4. 4Bern University Hospital, Division of Endocrinology Diabetes and Clinical Nutrition and Department of Internal Medicine, Bern, Switzerland

Abstract

Background Gastric acidity is mandatory for pepsin activation, bactericidal effect, secretin and pancreatic enzymes' release. PPIs (proton pump inhibitors) change gastric pH permanently to >3-4.

Purpose The aim of this work is to assess the impact of permanent high gastric pH on absorption and bioavailability (except of CYP450-interactions) and to recommend nutrition support options.

Materials and methods A systematic online literature research was performed on usual platforms. Recommendations rely on a multidisciplinary focus group assessment.

Results Risk factors assigned to long-term inhibition of gastric acidity arise from

· cleavage-resistance of peptide and glycosidic bonds

· mucosal degeneration and leak

· loss of bactericidal action

and comprise

· bacterial overgrowth

· community and hospital-acquired pneumonia

· childhood asthma related to PPI treatments of mothers in pregnancy

· sensitisation to food allergens in the older and in pregnant women (progesterone slows down gastric emptying)

· deterioration of lactose intolerance, celiac disease, atrophic gastritis, rheumatoid arthritis, diabetes mellitus

· modified bioavailability

o malabsorption of micronutrients, for example vit C and B12, folate, Zn, Fe, Mg, Ca

o lower bioavailability, for example ketoconazole, itraconazole, posaconazole, (not: voriconazole), atazanvir, cefpodoxime, cinnarizine, enoxacin, dipyridamole

o higher bioavailability, for example nifedipine, digoxin, penicillins, erythromycin, alendronate.

To prevent these complications, the focus group recommends:

· alternative antacids, step-down, intermittent and on-demand strategies:

o MgCO3 and H2-antagonists have a shorter onset and time of pH>3-4 than pantoprazole 40mg (median pH=3.7, pH>4 for 10.8h) or esomeprazole 40mg (median pH=4.7, pH>4 for 16.1h).

· to avoid high allergenic food

o that is crustacean, eggs, fish, milk, peanuts, soybeans, tree nuts or fruits, and wheat

· buffering, pepsin replacement, stimulation of digestion and peristalsis

o Carbonated beverages, quinine water, aperitifs, appetisers, and bitter substances (amara)

o Prokinetic agents (domperidone, bromopride, metoclopramide, quinine, erythromycin)

o Mucosal protectors (curcumin, quercetin, alginates, pectins, glycyrrhizin)

o Melatonin (regulates digestion and has structural similarity to omeprazole)

o Pepsin in HCl preparations

· nutrition and dietary approach combined with physical activity

o High-fibre-, low-fat-, low-carb diet · reassessment of pharmacotherapy

o Weak acids (pKa<4.5) lose their undissociated state required for diffusion across membranes.

o Absorption is impaired by membrane-bound CYP3A4,5,7 and efflux transporter P-gp.

(a log-conc-diagram, structure formula, tables of relevant drugs and nutrients, as well as references are provided on the poster)

Conclusions PPI safety profiles are troubled by risk factors arising from inappropriate long-term use. Drugs may be more bioavailable as a result of mucosal hyperpermeability, or less bioavailable as a result of altered dissociation. Care should be given to substrates with pKa<4.5. At least children and pregnant women should prefer alternatives to PPIs.

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