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Comparing Antisecretory Agents PPIs are more effective and long-lasting acid inhibitors than H2RAs. They are superior in healing both gastric and duodenal ulcer, although the advantage for GU is modest. Although H2RAs are less potent inhibitors of gastric acid secretion, ulcer healing rates are comparable to PPIs with a longer duration of treatment. The clearest advantages for PPIs over H2RAs are as components of H. pylori antibiotic regimens and for treatment of hypersecretory states such as gastrinoma. Side Effects of PPI’s: Pneumonia risk because of reduction of gastric acid allows colonisation of upper GI tract. Community acquired pneumonia and nosocomial pneumo - nia on ITU. Enteric infections- the risk of c diff as well as salmonella/ campylobacter and other gut pathogens is increased. Hypergastrinemia and carcinoid in rats on PPIs has been observed. Corpus gastritis and argyrophil cell hyperplasia, but no dysplasia or cancer- this has been observed in patients treated with omeprazole for up to 11 years. Chronic atrophic gastritis- occurs in 30% of patients on PPIs . Vitamin B12 malabsorption-this has been observed in patients on long term PPI. Not Iron absorption - iron absorption does not appear to be affected. Hypochlorhydria - this could reduce bone density by inhibiting calcium absorption and is associated with a slightly increased risk of hip fractures if >50 proportional to both PPI dose and duration of therapy. Severe reversible hypomagnesemia -has been described in case reports. In pregnancy H2 antagonists are safe and PPIs are probably safe but less experience. Treatment patterns for GORD with PPI The aim is to achieve remission. For Nonerosive gastroesophageal reflux disease PPIs are only useful for hypersensitive type. Prokinetic drugs increase LOS pressure, enhancing gastric emptying, or improving peristalsis. Prokinetic drugs are not recommended as monotherapy due to side effects. GABA agonists used to inhibit transient LOS relaxations- eg baclofen. Intermittent therapy may be useful in mild-moderate oesophagitis. With intermittent symptoms, the patient can try 2 week therapy, then only if symptoms return can try a further 2 week course. Intermittent PPI therapy cures 50% at 1 year. Maintenance Treatment with PPI’s at a higher dose are the best for healing and preventing oesophagitis. If recurrent symptoms in < 3months, need continuous PPI treatment. It is unknown if switching PPIs is clinically useful. “On-demand" use of PPIs might be useful for mild oesophagitis, but usually not effective; H2 receptor antags may be better for this. PPI’s
The phases of PPI action PPI’s Irreversibly bind to and inhibit the hydrogen-potassium ATPase pump on the luminal surface of the parietal cell membrane. It concentrates in the acidic compartments of the parietal cell. The prodrug is activated by the acid environment. A reactive sulfhydryl group forms a disulfide bond with a cysteine residue on the H-K-ATPase pump, thereby inactivating the enzyme. The parietal cell has to be producing acid (ie active) to be turned off. PPIs work poorly in fasting patients or if copresscribed another antisecretory agents (H2 receptor antagonists, anticholinergic agents, or somatostatin). If the parietal is inhibited in the six hours after PPI dosing, PPI efficacy will be compromised. PPIs are most effective when taken with or shortly before meals. Because the amount of H-K-ATPase present in the parietal cell is greatest after a prolonged fast, PPIs should be administered before the first meal of the day. PPI’s only inhibit active pumps so may need several doses to inhibit all pumps. Once-daily PPI dosing inhibits maximal acid output by about 66 % after five days so PRN PPI is not useful. Maximal acid secretory capacity may not be restored for 24 to 48 hours after discontinuing PPIs. B12 Ca Mg
Hypergastrin Atrophy
Refractory GORD Causes: Nocturnal acid breakthrough -Up to 70 % of patients taking PPIs bd gastric pH <4 lasting for >60 minutes, particularly at night. Incorrect timing with food as administration 15-30 minutes pre-meals is preferable. Effect of dosing interval — BD dosing may improve gastric acid suppression in some. Differences in metabolism -because of variability in cytochrome systems. Gastric acid hypersecretion eg Zollinger-Ellison or idiopathic. Helicobacter pylori - although its precise role in this context is unknown. Omeprazole resistance is a rare condition that is presumably caused by mutations of the proton pump. Affected patients can be treated with H2 antagonists. Delayed healing - those with severe esophagitis may take longer to heal than 8 weeks. Approaches to refractory GORD Consideration of Other Causes In patients in whom the adequacy of acid suppression is in question, do a 24-hour pH study while taking medications. The likelihod of 24 hour ph study on PPI abnormal is low, so should consider other causes too. Consideration of manometry. Esophageal multichannel intraluminal impedance. Increasing the frequency of dosing and offer bd treatment esp before dinner. Increasing the dose- can have a beneficial effect. The addition of a second, prokinetic drug eg domperidone-may be helpful but little evidence base. Switching to another drug —might help but no real evidence. Antireflux surgery - This should be considered in patients who require high doses of PPI to control symptoms, esp young patients who may require lifelong therapy.
NB bd lansoprazole is equivalent to switching to od 40mg esomeprazole.
H2 antagonists are not as effective as PPIs and patients can develop tolerance after 1 week.
Risk factors for poor response to medical therapy: Nocturnal reflux on 24 hour pH study. Structurally deficient LOS. Mixed duodenal and gastric reflux. Mucosal injury at presentation. PPI Comparison with Other PPI’s The most bioavailable are lansoprazole/ dexlansoprazole and pantoprazole. Rabeprazole has the fastest onset of action. Pantoprazole is the most ‘gastro-specific’; it binds to cysteine residues 813 and 822 within the alpha-subunit of the proton pump.
Written by Dr Sebastian Zeki
