Mechanism of action
The different PPls, including omeprazole, lansoprazole, pantoprazole, rabeprazole and the stereo-isomeric compounds esomeprazole and dexlansoprazole are benzimidazole derivatives with a common structure differing in their substitutions on their pyridine and/or benzimidazole rings. Their pharmacological properties are similar (Table 1).
PPls are membrane permeable, acid-labile weak bases. Oral formulations are absorbed in the proximal small bowel. They are packaged in a variety of delivery systems to prevent premature activation and degradation by luminal gastric acid. IV formulations provide immediate acid suppression. After absorption, PPls they are carried in the systemic circulation to activated gastric parietal cells where they concentrate in the acidic secretory canniculi. Here they are cleaved (except esomeprazole and dexlansoprazole) into their active components, which bind covalently to cysteine residues on the H+/K+ ATPase. This binding inhibits acid secretion until replacement pumps can be synthesised, which takes up to 36 hours.
In order to bind, PPls require the active canaliculi expression of H+/K+ ATPases, which occurs in response to a meal. Not all parietal cells or their proton pumps are active after a single meal and only about two thirds of proton pumps are inhibited by a single PPI dose. With future meals, previously inactive enzymes are recruited into the secretory cannaliculi and proton exchange increases again. Consequently PPls should be dosed before a meal and the pharmacologic efficacy escalates after accumulating days of dosing.
PPls are highly proton bound and metabolised by the cytochrome (CYP) P450 enzyme system, which presents an opportunity for pharmacokinetic interactions with other co-administered drugs. The potential for drug interactions may be lower with rabeprazole and lansoprazole/ dexlansoprazole. Pantoprazole is primarily degraded by CYP2C19 0-demethylation and sulfate conjugation, which results in the lowest potential for CYP induction or inhibition. These PPls may be a preferred PPI choice when drug interactions are of concern (e.g., with clopidogrel).
Data suggest that rapid metabolisers may be less likely to respond to PPI treatment than slow metabolisers, especially when the PPI is used for H. pylori eradication.
Clinical advantages of PPls
Gastric acid secretion is a complex process regulated by at least three different stimuli on the parietal cell: paracrine actions of gastrin and histamine, and postganglionic muscarinic acetylecholine. Regardless of the nature of parietal cell stimulation, PPls effectively reduce acid secretion by blocking the final common pathway (H+/K+ ATPase). While histamine type 2 receptor antagonists (H2RAs) raise intragastric pH for only 8 hours, PPls maintain intragastric pH >4 for 15-21 hours daily and are more effective with respect to postprandial and nocturnal intragastric pH control. Whereas regular use of H2RAs (3-5 days) is associated with tachyphylaxis, which reduces their long-term effectiveness, the effect of PP ls is maintained over the long-term without need for dose escalation.
General clinical uses
1. Healing of PUD
Although the pathophysiologies of gastric and duodenal ulcer disease are different, sustained neutralisation of gastric acid (pH>3) for 18-20 hours per day is important for healing. PPls are significantly more effective than H2RAs in achieving ulcer healing, being effective in approximately 80% of patients. Maintenance treatment with a PPI may be important in high-risk groups, such as those with PUD-related complications (e.g., perforation, fibrosis), recurrences or H. pyloriÂnegative ulcers, although in H. pylori-positive PUD, if the bacterium is eradicated, prolonged treatment may be unnecessary.
2. Peptic ulcer-related gastrointestinal bleeding
Upper gastrointestinal bleeding due to PUD is associated with high morbidity, mortality and healthcare costs. Although pre-endoscopic PPI administration has not been conclusively shown to improve outcomes, it is not associated with appreciable risks in itself and may be recommended until the diagnosis can be ascertained. PPls should be administered after endoscopy in patients with confirmed PUD-related bleeding. In patients with high risk endoscopic stigmata (active bleeding, visible vessel or adherent clot) in comparison with placebo, IV PPI therapy administered for 72 hours after endoscopic haemostasis reduced rebleeding (number needed to treat, NNT 12), surgery (NNT 28) and mortality (NNT 45).
3. H. pylori eradication
PPls are synergistic with antibiotic therapy for eradication of H. pylori. They may increase the bioavailability of acid-labile antibiotics and may directly inhibit bacterial growth.
4. Prevention of NSAID-associated gastrointestinal ulcers
Patients at risk of NSAID-related gastrointestinal complications and who require NSAID therapy should be considered for prophylaxis. In high risk patients, omeprazole 20 mg was more effective than placebo in preventing PUD (5% vs. 17% developed ulcers at 6 months, repectively). In the placebo group, there was no difference between cyclo-oxygenase (COX)-1 and COX-2 inhibitors in the incidence of NSAID-related PUD, whereas PPI therapy significantly reduced ulcer formation regardless of whether a nonselective or selective NSAID had been used.
5. Zollinger-Ellison syndrome (ZES)
ZES is a rare condition and data are limited. In a 13-year case series involving 67 patients, high doses of PP ls maintained long-term symptom control in >90%. In some patients it was possible to down-titrate the PPI dose once ulcer healing and symptom resolution had occurred.
6. Erosive oesophagitis
In the Western world the prevalence of gastroesophageal reflux disease (GERD) is estimated at 10-20%. Regardless of the initial severity of oesophagitis, dose or treatment duration, PPls provide effective therapy for GERD with more rapid healing and symptom relief than with H2RAs or prokinetic agents. Furthermore, PPls are highly effective for maintenance of healing in erosive oesophagitis. Because effective maintenance of GERD can be achieved with halfthe healing dose of PPI, for long-term treatment PPI therapy should be reduced to the lowest dose necessary to control symptoms. Especially in milder GERD, some patients can be maintained with on-demand therapy.
7. Nonerosive reflux disease
Compared to patients with erosive oesophagitis, response rates to anti-secretory therapy are lower in patients with NERD. Nevertheless, PPls provide more effective heartburn control than either placebo or H2RAs. Unless there are indications for immediate upper endoscopy, professional societies recommend a trial of empiric therapy for undifferentiated GERD. In the absence of significant erosive disease, on-demand use of PPls may be helpful for symptom control when symptoms are intermittent and long standing.
8. Functional dyspepsia
Low dose PPls may be effective for epigastric distress syndrome and postprandial distress syndrome.
Clinical limitations of PPI therapy
There are limitations to PPI use in clinical practice, including the short plasma half-life and necessity for preprandial dosing, and 50% of patients taking PPI therapy for nonerosive GERD are dissatisfied with treatment due to unresolved symptoms. Among patients taking PPls twice daily, almost 40% increased their dose because of persistent nocturnal symptoms. Nocturnal acid breakthrough (recovery of gastric acid secretion) frequently occurs with once daily PPI dosing in the morning and breakthrough symptoms are common on a twice daily PPI regimen. Poor compliance, combined with a narrow window to provide efficacy due to short plasma half-life, may be an important cause of PPI failure.
Long-term use of PPls
Chronic use of high dose PP ls may affect absorption of calcium, magnesium and vitamin B 12. PP ls have been linked to a risk of hip fracture and although this association has not been conclusively proven, a warning has been added to the product labels for PPls. A possible link between PPI use and increased risk of pneumonia remains unproven and should not affect prescription for patients in whom they are indicated.
PPI use may increase susceptibility to enteric infections, with the most important being Clostridium difficile.
Drug-drug interactions may be a concern with PPls. In particular, there are reports of an interaction between omeprazole and clopidogrel, although this has not been proven in specific clinical studies. Nevertheless, lansoprazole, dexlansoprazole or pantoprazole may be preferred in patients receiving clopidogrel for cardiovascular protection. Prolonged use of PPls may be associated with low magnesium levels, especially where they are used in combination with digoxin or drugs that may cause hypomagnesemia. Other possible associations with PPI use include acute interstitial nephritis and B 12 deficiency.
Conclusions
Although very effective, PPls should be prescribed with careful attention to the appropriate indication, patient co-factors and the expected dose and duration of treatment.
