Proton pump inhibitors (PPI) Domina Petric, MD

Pharmacokinetics Omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole and pantoprazole: substituted benzimidazoles that resemble H2 antagonists in structure with different mechanism of action.

Pharmacokinetics Omeprazole and lansoprazole are racemic mixtures of R- and S-isomers. Esomeprazole is the S-isomer of omeprazole and dexlansoprazole the R-isomer of lansoprazole. All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations.

Pharmacokinetics PPIs are administered as inactive prodrugs. Oral products are formulated for delayed release as acid-resistant, enteric-coated capsules or tablets.

Pharmacokinetics After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. For children or patients with dysphagia or enteral feeding tubes, capsules may be opened and the microgranules mixed with juice.

Pharmacokinetics Lansoprazole is also available as a tablet formulation that disintegrates in the mouth. It may be mixed with water and administered via oral syringe or enteral tube.

Pharmacokinetics Omeprazole is also available as a powder formulation (capsule or packet) that contains sodium bicarbonate (1100-1680 mg NaHCO3: 304-460 mg of sodium) to protect the naked drug from acid degradation.

Pharmacokinetics When administered on an empty stomach by mouth or enteral tube, this immediate-release suspension results in rapid omeprazole absorption (within 30 minutes) and onset of acid inhibition.

Pharmacokinetics PPIs are lipophilic weak bases (pKa 4-5). After intestinal absorption diffuse readily across lipid membranes into acidified compartment: the parietal cell canaliculus.

Pharmacokinetics The prodrug rapidly becomes protonated within the canaliculus and is concentrated more than 1000-fold by Henderson-Hasselbalch trapping. It rapidly undergoes a molecular conversion to the active form.

Pharmacokinetics The active form is a reactive thiophilic sulfenamide cation that forms a covalent disulfide bond with the H+/K+-ATPase. The active form irreversibly inactivates the enzyme.

Pharmacokinetics Drug pKa Bioavailability (%) t1/2 (h) Tmax (h) Usual dosage for peptic ulcer or GERD Omeprazole 4 40-65 0,5-1,0 1-3 20-40 mg qd Esomeprazole >80 1,5 1,6 Lansoprazole 1,0-2,0 1,7 30 mg qd Dexlansoprazole 5,0 30-60 mg qd Pantoprazole 3,9 77 1,0-1,9 2,5-4,0 40 mg qd Rabeprazole 5 52 3,1 20 mg qd

Pharmacokinetics The bioavailability of all agents is decreased approximately 50% by food. The drug should be administered on an empty stomach, 1 hour before meal.

Pharmacokinetics In a fasting state, only 10% of proton pumps are actively secreting acid and susceptible to inhibition. That is why PPIs should be administered 1 hour before a meal (usually breakfast).

Pharmacokinetics The drugs have a short serum half-life of about 1,5 hours. Acid inhibition lasts up to 24 hours owing to the irreversible inactivation of the proton pump. About 18 hours are required for synthesis of new H+/K+-ATPase pump molecules.

Pharmacokinetics Up to 3-4 days of daily medication are required before the full acid-inhibiting potential is reached. After stopping the drug, it takes 3-4 days for full acid secretion to return.

Pharmacokinetics PPIs undergo rapid first-pass and systemic hepatic metabolism and have negligible renal clearance. Dose reduction is not needed for patients with renal insufficiency or mild to moderate liver disease.

Pharmacokinetics To provide maximal inhibition during the first 24-48 hours of treatment, the intravenous formulations of esomeprazole and pantoprazole must be given as a continous infusion or as repeated bolus injections.

Pharmacodynamics PPIs inhibit both fasting and meal-stimulated secretion. In standard doses, PPIs inhibit 90-98% of 24-hour acid secretion.

Clinical use

GERD PPIs are the most effective agents for the treatment of: nonerosive and erosive reflux disease esophageal complications (peptic stricture, Barrett´s esophagus) extraesophageal manifestations of reflux disease

GERD Up to 15% of patients require twice-daily dosing. Once-daily dosing provides effective symptom relief and tissue healing in 85-90% of patients. Up to 15% of patients require twice-daily dosing.

GERD GERD symptoms recur in over 80% of patients within 6 months after discontinuation of a PPI. For patients with erosive esophagitis or esophageal complications, long-term daily maintenance therapy with full or half-dose is needed.

Barrett´s esophagus Massgeneral.org

GERD Many patients with nonerosive GERD may be treated with intermittent courses of PPIs (on demand).

GERD Sustained acid suppression with twice-daily PPIs for at least 3 months is used to treat extraesophageal complications: asthma chronic cough laryngitis noncardiac chest pain

Peptic ulcer disease All PPIs heal more than 90% of duodenal ulcers within 4 weeks and a similar percentage of gastric ulcers within 6-8 weeks.

H. pylori associated ulcers Therapeutic goals are: heal the ulcer and eradicate the microorganism. 2 AB + PPI +/- bismuth salts!

H. pylori associated ulcers PPIs promote eradication of H. pylori through these mechanisms: direct antimicrobial properties (minor) raising intragastric pH lowering the minimal inhibitory concentrations of AB (antibiotics)

H. pylori associated ulcers 14-day regimen of triple therapy: PPI twice daily clarithromycin 500 mg twice daily amoxicillin 1 g twice daily or metronidazole 500 mg twice daily Bismuth quadruple therapy with bismuth subcitrate.

H. pylori associated ulcers After completion of triple therapy, PPI should be continued once daily for a total of 4-6 weeks to ensure complete ulcer healing.

H. pylori associated ulcers Sequential treatment for 10 days: first 5 days PPI twice daily plus amoxicillin 1 g twice daily other 5 days PPI twice daily plus clarithromycin 500 mg twice daily plus tinidazole 500 mg twice daily

NSAID-associated ulcers In patients with NSAID-induced ulcers who require continued NSAID therapy, treatment with once or twice daily PPI promotes ulcer healing.

NSAID-associated ulcers Asymptomatic peptic ulceration develops in 10-20% of people taking frequent NSAIDs. Ulcer-related complications (bleeding, perforation) develop in 1-2% of persons per year.

NSAID-associated ulcers PPIs taken once daily are effective in reducing the incidence of ulcers and ulcer complications in patients taking aspirin or other NSAIDs.

Prevention of rebleeding from peptic ulcers Rebleeding of high-risk ulcers is reduced significantly with PPIs administered for 3-5 days either as high-dose oral therapy (omeprazole 40 mg orally twice daily) or as a continuous intravenous infusion.

Prevention of rebleeding from peptic ulcers Intragastric pH higher than 6 may enhance coagulation and platelet aggregation. Initial bolus administration of esomeprazole or pantoprazole 80 mg followed by constant infusion 8 mg/h is recommended.

Prevention of stress-related mucosal bleeding Oral immediate-release omeprazole formulation is administered by nasogastric tube twice daily on the first day, then once daily. For patients without a nasoenteric tube or with significant ileus, iv. H2 antagonists are preferred.

Gastrinoma, other hypersecretion Isolated gastrinomas: surgical resection. In patients with metastatic or unresectable gastrinomas, massive and hypersecretion results in peptic ulceration, erosive esophagitis and malabsorption.

Gastrinoma, other hypersecretion With PPIs, excellent acid suppression can be achieved. Dosage is titrated to reduce basal acid output to less than 5-10 mEq/h. Typical doses of omeprazole are 60-120 mg/day.

Adverse effects

General Diarrhea, headache and abdominal pain are reported in 1-5% of patients. Increasing cases of acute interstitial nephritis have been reported. Safety during pregnancy has not been established.

Nutrition Acid is important in releasing vitamin B12 from food. A minor reduction in oral cyanocobalamin absorption occurs during PPIs therapy. Subnormal B12 levels may occur with prolonged therapy.

Nutrition Acid also promotes absorption of food-bound minerals: non-heme iron insoluble calcium salts magnesium

Nutrition PPIs may reduce calcium absorption or inhibit osteoclast function, especially in the case of long term therapy: bone density control calcium supplements

Nutrition Cases of severe, life-threatening hypomagnesemia with secondary hypocalcemia have been reported.

Respiratory and enteric infections Gastric acid is an important barrier to colonization and infection of the stomach and intestine from ingested bacteria. There may be increased risk of both comunity-acquired respiratory infections and nosocomial pneumonia.

Respiratory and enteric infections There is a 2 to 3-fold increased risk for hospital and community acquired Clostridium difficile infection. There is also a small increased risk of other enteric infections: Salmonella, Shigella, E. coli and Campylobacter.

Increased serum gastrin Gastrin levels are regulated by intragastric activity. Acid suppression alters normal feedback inhibition so that median serum gastrin levels rise 1,5 to 2-fold in patients taking PPIs.

Increased serum gastrin Upon stopping the drug, the levels normalize within 4 weeks. The rise in serum gastrin level may stimulate hyperplasia of ECL and parietal cells which may cause transient rebound acid hypersecretion.

Other Among patients infected with H. pylori, long-term acid suppression leads to increased chronic inflammation in the gastric body and decreased inflammation in the antrum.

Other Long-term PPI therapy is associated with the development of small benign gastric fundic-gland polyps in a small number of patients.

Drug interactions Decreased gastric acidity may alter absorption of drugs for which intragastric acidity affects drug bioavailability: ketoconazole, intraconazole digoxin atazanavir

Drug interactions All PPIs are metabolized by hepatic P450 cytochromes, including CYP2C19 and CP3A4. Because of the short half-lives of PPIs, clinically significant drug interactions are rare.

Drug interactions Omeprazole may inhibit the metabolism of warfarin, diazepam and phenytoin. Esomeprazole may decrease metabolism of diazepam. Lansoprazole may enhance clearance of theophylline.

Drug interactions Rabeprazole and pantoprazole have no significant drug interactions! They are appropirate choice, for example, in patients taking warfarin.

Drug interactions Clopidogrel is a prodrug that requires activation by the hepatic P450 CYP2C19 isoenzyme. PPIs (especially omeprazole, esomeprazole, lansoprazole and dexlansoprazole) could reduce clopidogrel activation and its antiplatelet action.

Drug interactions Patients on clopidogrel should take PPIs with minimal CYP2C19 inhibition (pantoprazole, rabeprazole) if necessary: increased risk of gastrointestinal bleeding, chronic GERD or peptic ulcer disease.

Literature Katzung, Masters, Trevor. Basic and clinical pharmacology. Massgeneral.org Homenaturalcures.com