Proton Pump Inhibitors

The PPIs—esomeprazole, lansoprazole, omeprazole, panto-prazole, rabeprazole, and dexlansoprazole—block gastric acid secretion by inhibiting gastric H+/K+-adenosine triphosphatase in gastric parietal cells.17 This produces a profound, long-lasting antisecretory effect capable of maintaining the gastric pH above 4, even during acid surges seen postprandially4,6

The PPIs are superior to H2RAs in patients with moderate-to-severe GERD. This includes not only patients with erosive esophagitis or complicated symptoms (Barrett's esophagus or strictures) but also those with symptomatic esophageal syndromes. Symptomatic relief is seen in approximately 83% of patients, and healing rates at 8 weeks as judged by endoscopy are 78%.1

A PPI should be given empirically to patients with troublesome symptoms of GERD. If the standard once-daily course of therapy is not effective in eliminating symptoms, then empiric therapy with twice-daily dosing should be given. Patients not responding to twice-daily PPI therapy should be considered treatment failures and further diagnostic evaluation should be performed.2

Whether PPIs can reverse Barrett's esophagus remains a topic for debate. The use of high-dose omeprazole (40 mg twice daily) caused partial regression of Barrett's esophagitis, but no change was noted in patients receiving ranitidine 150 mg twice daily.1 Others propose that islands of normal squamous cells that appear in patients with Barrett's esophagus after high-dose PPIs may be covering gastric mucosa and may mask the development of cancerous changes in the mucosa.18 It is unknown whether regression of Barrett's esophagus reduces the risk of adenocarcinoma, but aggressive therapy to suppress acid reflux early in the disease may help prevent Barrett's esophagus.

Comparable daily doses of PPIs are omeprazole 20 mg = esomeprazole 20 mg = lansoprazole 30 mg = dexlansoprazole 30 mg = rabeprazole 20 mg = pantoprazole 40 mg. The PPIs degrade in acidic environments and are therefore formulated in delayed-release capsules or tablets.19 Lansoprazole, esomeprazole, and omeprazole contain enteric-coated (pH-sensitive) granules in a capsule form. For patients unable to swallow the capsule or in pediatric patients, the contents of the capsule can be mixed in applesauce or placed in orange juice. Lansoprazole is also available in a packet for oral suspension and a delayed-release orally disintegrating tablet. Patients taking pan-toprazole or rabeprazole should be instructed not to crush, chew, or split the delayed-release tablets.

Omeprazole is also available in an immediate-release formulation combined with sodium bicarbonate (Zegerid). The proposed benefit of this combination product is fast onset of action and increase in pH by the sodium bicarbonate, which helps prevent degradation of omeprazole in the stomach. Sodium bicarbonate may also stimulate gastrin production, which may activate the proton pumps and optimize the effectiveness of omeprazole.

Pantoprazole and esomeprazole are available in IV formulations that offer an alternative route for patients unable to take oral medications. The IV product is not more effective than the oral forms and is significantly more expensive.

Patients should be instructed to take their PPI in the morning, 15 to 30 minutes before breakfast to maximize efficacy, because these agents inhibit only actively secreting proton pumps.6,20 While usually given prior to breakfast, patients with night-time symptoms may benefit from taking their PPI prior to the evening meal.1 If a second dose is needed, it should be administered before the evening meal and not at bedtime.1 Regardless of the time of day, PPIs should be given prior to a meal to gain the most benefit. The exception to this is the immediate-release omeprazole-sodium bicarbonate combination product, which can be given at bedtime.

The PPIs are generally well tolerated, and the choice of a particular agent is often based on cost and tolerability. The most common side effects are headache, diarrhea, constipation, and abdominal pain. All PPIs can decrease the absorption of drugs (e.g., ketoconazole) that require an acidic environment to be absorbed. All PPIs are metabolized by the cytochrome P-450 system to some extent. Omeprazole and lansoprazole are metabolizedbyCYP2C19 enzymes. Concerns have been raised in patients taking PPIs concurrently with clopidogrel, a prodrug, that must be converted to its active form by CYP2C19. Inhibition of CYP2C19 by PPIs has been suggested to decrease the effectiveness of clopidogrel and increase the risk of cardiac events. More study is needed to determine this effect. No interactions with lansoprazole, pan-

toprazole, or rabeprazole have been seen with CYP2C19 substrates such as diazepam,

warfarin, or phenytoin. Esomeprazole does not appear to interact with warfarin or phenytoin. Pantoprazole is metabolized by a cytosolic sulfotransferase and is there-

fore less likely to have significant drug interactions than other PPIs.

While generally not of major concern, omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin; lansoprazole may decrease theophylline concentrations. Drug interactions with omeprazole are of particular concern in patients who are considered "slow metabolizers," as are approximately 3% of the Caucasian population. Unfortunately, it is unclear which patients have the polymorphic gene variation that makes them slow metabolizers.20 Alternatively, patients who are considered rapid metabolizers, which is most common in the Asian population (12-20%), may


not respond as well as those who are considered slow metabolizers. This genetic variation among patients may alter the effect ofPPIs due to the ability oftheir enzyme

system to metabolize the drug. Esomeprazole is metabolized more by CYP3A4 en-

zymes and maybe affected less by the patient's genotype. Patients on potentially interacting drugs should be monitored for development of drug-related problems.

Other potential concerns with PPIs include hypergastrinemia, vitamin B12 deficiency, and risk for enteric infections or fractures. Prolonged hypergastrinemia leading to the development of colonic polyps and potentially adenocarcinoma in rats was

a concern that has proven to be unfounded with long-term use in humans. The FDA has stated that there is insufficient evidence linking PPI use to atrophic gastritis, intestinal metaplasia, or gastric cancer.26 PPIs may inhibit the secretion of intrinsic factor by the parietal cells, which may lead to decreased absorption ofvitamin B12 with subsequent deficiency. Patients receiving long-term PPI therapy should have periodic complete blood counts performed to detect signs of vitamin B12 deficiency. More recently, concerns include risk of enteric infections and risk of fractures with long-term use of PPIs. Although the incidence is low, further evaluation is needed to adequately quantify the risk of developing these effects. Routine bone density studies or calcium supplementation is not warranted based on PPI use alone.

Prokinetic Agents

The prokinetic agents include cisapride, metoclopramide, andbethanechol. The inferior efficacy and side-effect profiles of metoclopramide and bethanechol limit their use in the treatment of GERD, and they are not recommended.

Mucosa I Protect ants

Sucralfate, a nonabsorbable aluminum salt of sucrose octasulfate, has very limited value in the treatment of GERD and is not recommended.

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