Proton Pump Inhibitors (PPIs)

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Chapter: Essential pharmacology : Drugs For Peptic Ulcer

Omeprazole : It is the prototype member of substituted benzimidazoles which inhibit the final common step in gastric acid secretion and have overtaken H 2 blockers for acid-peptic disorders.


PROTON PUMP INHIBITORS (PPIs)

 

Omeprazole

 

It is the prototype member of substituted benzimidazoles which inhibit the final common step in gastric acid secretion and have overtaken H 2 blockers for acid-peptic disorders. The only significant pharmacological action of omeprazole is dose dependent suppression of gastric acid secretion; without anticholinergic or H2 blocking action. It is a powerful inhibitor of gastric acid: can totally abolish HCl secretion, both resting as well as that stimulated by food or any of the secretagogues, without much effect on pepsin, intrinsic factor, juice volume and gastric motility.

 

Omeprazole is inactive at neutral pH, but at pH < 5 rearranges to two charged cationic forms (a sulphenic acid and a sulphenamide configurations) that react covalently with SH groups of the H+K+ATPase enzyme and inactivate it irreversibly, especially when two molecules of omeprazole react with one molecule of the enzyme. After diffusing into the parietal cell from blood, it gets concentrated in the acidic pH of the canaliculi because the charged forms generated there are unable to diffuse back. Moreover, it gets tightly bound to the enzyme. These features and the specific localization of H+K+ATPase to the apical membrane of the parietal cells confer high degree of selectivity of action to omeprazole. Acid secretion resumes only when new H+K+ATPase molecules are synthesized. It also inhibits gastric mucosal carbonic anhydrase.

 

 

The oral absorption of omeprazole is ~50%, because of instability at acidic pH. As the gastric pH rises, a higher fraction (up to 3/4) may be absorbed. Bioavailability of all PPIs is reduced by food; they should be taken in empty stomach, followed 1 hour later by a meal to activate the H+K+ ATPase and make it more susceptible to the PPI. Omeprazole is highly plasma protein bound, rapidly metabolised in liver by CYP2C19 and CYP3A4 (plasma t½ ~1 hr) and metabolites are excreted in urine. No dose modification is required in elderly or in renal/hepatic impairment. Because of tight binding to its target enzyme—it can be detected in the gastric mucosa long after its disappearance from plasma. As such, inhibition of HCl secretion occurs within 1 hr, reaches maximum at 2 hr, is still half maximal at 24 hr and lasts for 3 days. Because only actively acid secreting proton pumps are inhibited, and only few pumps may be active during the brief interval that the PPI is present (all have 1–2 hours plasma t½), antisecretory action increases on daily dosing to reach a plateau after 4 days. All PPIs produce 80–98% suppression of 24 hour acid output with conventional doses at steady state. Secretion resumes gradually over 3–5 days of stopping the drug.

 

Because of marked and long lasting acid suppression, compensatory hypergastrinemia has been observed. This has been found to induce proliferation of parietal cells and gastric carcinoid tumours in rats, but not in human beings. Though patients have been treated continuously for > 11 years without any problem, it may appear prudent to be apprehensive of prolonged achlorhydria and hyper-gastrinaemia, and if possible avoid long-term use of PPIs.

 

Uses

 

1. Peptic Ulcer: Omeprazole 20 mg OD is equally or more effective than H2 blockers. Relief of pain is rapid and excellent. Faster healing has been demonstrated with 40 mg/day: some duodenal ulcers heal even at 2 weeks and the remaining at 4 weeks. Gastric ulcer generally requires 4–8 weeks. It has caused healing of ulcers in patients not responding to H2 blockers. Continued treatment (20 mg daily or thrice weekly) can prevent relapse. PPIs are an integral component of anti-H. pylori therapy. PPIs are the drugs of choice for NSAID induced gastric/ duodenal ulcers. Healing may occur despite continued use of the NSAID.

 

2. Bleeding Peptic Ulcer: Acid enhances clot dissolution promoting ulcer bleed. Suppression of gastric acid has been found to facilitate clot formation reducing blood loss and rebleed. High dose i.v. PPI therapy (pantoprazole 40–120 mg/ day or rabeprazole 40–80 mg/day) profoundly inhibits gastric acid, and has been shown to reduce rebleeding after therapeutic endoscopy. Even in cases where the bleeding vessel could not be visualized, i.v. followed by oral PPI reduces recurrence and need for surgery.

 

3.  Stress Ulcers: Intravenous pantoprazole is as effective prophylactic (if not more) for stress ulcers as i.v. H2 blockers.

 

4. Gastroesophageal Reflux Disease (GERD): Omeprazole produces more complete round-the-clock inhibition of gastric acid resulting in rapid symptom relief and is more effective than H2 blockers in promoting healing of esophageal lesions. PPIs are the drugs of choice for patients with frequent or chronic symptoms and/or esophagitis/erosions; i.e. stage2 or stage3 GERD. Dose: 20–60 mg daily in 1 or 2 doses. Many patients require continued therapy since cause is not corrected.

 

5. Zollinger-Ellison Syndrome: Omeprazole is more effective than H2 blockers in controlling hyperacidity in ZE syndrome. However, 60–120 mg/day or more (in 2 divided doses) is often required for healing of ulcers. Inoperable cases have been treated for >6 years with sustained benefit and no adverse effects. Other gastric hypersecretory states like systemic mastocytosis, endocrine adenomas, etc. also respond well.

 

6. Aspiration Pneumonia: PPIs are an alternative to H2 blockers for prophylaxis of aspiration pneumonia due to prolonged anaesthesia.

 

OMIZAC, NILSEC 20 mg cap. OMEZ, OCID, OMEZOL 10, 20 mg caps, PROTOLOC 20, 40 mg caps containing enteric coated granules.

Capsules must not be opened or chewed; to be taken in the morning before meals.

 

Adverse Effects

 

These are minimal: nausea, loose stools, headache, abdominal pain, muscle and joint pain, dizziness are complained by 3–5%. Rashes (1.5% incidence), leucopenia and hepatic dysfunction are infrequent. On prolonged treatment atrophic gastritis has been reported occasionally.

 

Lately, few reports of gynaecomastia and erectile dysfunction, possibly due to reduced testosterone level, on prolonged use of omeprazole have appeared. Accelerated osteoporosis among elderly due to reduced calcium absorption has been recently associated with highdose long-term use of PPIs for GERD.

 

Interactions

 

Omeprazole inhibits oxidation of certain drugs: diazepam, phenytoin and warfarin levels may be increased. Clarithromycin inhibits omeprazole metabolism and increases its plasma concentration.

 

Esomeprazole

 

It is the Senantiomer of omeprazole; claimed to have higher oral bioavailability and to produce better control of intragastric pH than omeprazole in GERD patients because of longer t½. Higher healing rates of erosive esophagitis and better GERD symptom relief have been reported in comparative trials with omeprazole. Side effect and drug interaction profile is similar to the recemic drug.

 

Dose: 20–40 mg OD; NEXPRO, RACIPER, IZRA 20, 40 mg tabs.

 

Lansoprazole

 

Somewhat more potent than omeprazole but similar in properties. Inhibition of H+ K+ ATPase by lansoprazole is partly reversible. It has higher oral bioavailability, faster onset of action and slightly longer t½ than omeprazole. Dose should be reduced in liver disease. Side effects are similar, but drug interactions appear to be less significant; diazepam and phenytoin metabolism may be reduced.

Ulcer healing dose: 15–30 mg OD; LANZOL, LANZAP, LEVANT, LANPRO 15, 30 mg caps.

 

Pantoprazole

 

It is a newer H+ K+ ATPase inhibitor, similar in potency and clinical efficacy to omeprazole, but is more acid stable and has higher oral bioavailability. It is also available for i.v. administration; particularly employed in bleeding peptic ulcer and for prophylaxis of acute stress ulcers. It has lower affinity for cytochrome P450 than omeprazole or lansoprazole: risk of drug interactions is minimal.

 

Dose: 40 mg OD; PANTOCID, PANTODAC 40 mg enteric coated tab; PANTIUM 40 mg tab, 40 mg inj for i.v. use.

 

S-Pantoprazole

 

It is the active single enantiomer, twice as potent as the recemate.

 

PANPURE, ZOSECTA 20 mg tab.

 

Rabeprazole

 

This newer PPI is claimed to cause fastest acid suppression (due to higher pKa, it is more rapidly converted to the active species) and to aid gastric mucin synthesis. However, potency and efficacy are similar to omeprazole.

 

Dose: 20 mg OD; ZE syndrome — 60 mg/day. RABLET, PRORAB, RABELOC, RABICIP, RAZO 10, 20 mg tab; HAPPI 10, 20 mg tab, 20 mg/vial inj.

 

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