on 31-Mar-2021 (Wed)

The choice of a specific oral PPI and whether over-the-counter (rather than prescription) PPIs are prescribed are often determined by patient preference and payer coverage. A systematic review of 12 randomized trials examining the relative effectiveness of different PPI doses and dosing regimens found no consistent difference in symptom resolution and esophagitis healing rates [17].

In patients unable to swallow pills or capsules, options include an oral suspension of lansoprazole and a powder formulation of omeprazole-sodium bicarbonate for oral suspension.

PPIs should be administered 30 to 60 minutes before breakfast for maximal inhibition of proton pumps. (See 'Pharmacology' above.)

Antisecretory drugs can be used with a PPI provided that there is a sufficient time interval between their administration. As an example, an H2RA can be taken before bedtime or during the night by individuals who report nocturnal breakthrough symptoms such as heartburn after taking a PPI in the morning or before dinner.

Switching PPIs is a reasonable strategy in patients with side-effects to an individual PPI and may be necessary due to cost differences. Although there is significant interindividual and intraindividual variability in intragastric pH control between PPIs, there are no consistent difference in relation to symptom resolution and esophagitis healing rates [17]. Switching PPIs in patients with well-controlled symptoms may also be associated with increased symptom severity and decreased patient satisfaction [20].

We gradually taper PPI therapy in patients treated with PPIs for longer than six months. For patients on a standard or high-dose PPI (eg, omeprazole 40 mg daily or twice daily), we decrease the dose by 50 percent every week. For patients on twice daily dosing, the initial reduction can be accomplished by decreasing the dosing to once in the morning before breakfast until the patient is on the lowest dose of the medication. Once on the lowest dose for one week, the patient is instructed to discontinue the PPI. However, no specific method for discontinuing PPI therapy has been proven effective, and no approach is universally accepted. [21,22].

Studies have demonstrated rebound gastric acid hypersecretion following discontinuation of PPIs in patients with long-term use. The reasons are not entirely clear, but appear to be due in part to the suppression of antral somatostatin expression, resulting in an increase in antral gastrin release and subsequent disruption of normal pH-related feedback inhibition of acid secretion that occurs after a meal [1].

ADVERSE EFFECTS — Long-term PPI use has been associated with several safety concerns. However, few of these concerns are supported by consistent data demonstrating a causal relationship.

PPI use has been associated with an increased risk of C. difficile infection, even in the absence of antibiotic use [23-33]. Associations with other enteric infections, including salmonellosis and campylobacteriosis, have also been reported [34-39]. However, the pathophysiologic mechanism involved in the increased risk of infection is unclear.

A 2017 meta-analysis of 50 observational studies found that PPI use was significantly associated with an increased risk of C. difficile infection (relative risk [RR] 1.3; 95% CI 1.1-14). The risk of C. difficile infection appears to be greater with PPIs as compared to H2 receptor antagonists [30,31].

Microscopic colitis — PPI use has been associated with microscopic colitis, including lymphocytic and collagenous colitis. In a case-control study that included 95 cases of microscopic colitis, exposure to PPIs was significantly higher in patients with microscopic colitis as compared with controls (38 versus 13 percent, OR 4.5, 95% CI 2.0-9.5) [41]. Similar results have been reported in other case-control studies, however, it is unclear if this association varies by PPI and if there is a dose-response relationship in either dose or duration of use [42,43].

Hypergastrinemia — Induction of hypergastrinemia has been associated with gastric carcinoid tumors in rats. However, these observations are not generalizable to species with gastrin physiology more analogous to humans [44]. While patients treated with omeprazole for up to 11 years have shown some enterochromaffin-like cell hyperplasia, no dysplasia or neoplastic changes have been observed [45]. An increased risk of colon cancer due to hypergastrinemia has also not been established [46]

Atrophic gastritis — Patients on long-term PPI therapy have a propensity to develop chronic atrophic gastritis. However, the risk of atrophic gastritis is small, and in the rare patient who develops atrophic gastritis, the clinical consequences are uncertain [45,47,48].

Intestinal colonization of multi-drug resistant organisms — PPIs may increase the risk of intestinal colonization with multi-drug resistant organisms. In a meta-analysis of 12 observational studies that included 22,305 patients, after adjusting for potential confounders, acid suppression increased the odds of intestinal carriage of multi-drug resistant organisms of the Enterobacterales order (producing extended-spectrum beta-lactamases, carbapenemases, or plasmid-mediated AmpC beta-lactamases) and of vancomycin-resistant enterococci (OR 1.74; 95%CI, 1.4-2.2) [49]. Possible mechanisms include an increase in bacteria that survive transit from the stomach to the intestine due to reduction in gastric acid by PPIs and direct alteration of the composition of intestinal microbiota, leading to a decrease in mean species diversity.

Magnesium malabsorption — PPIs can cause hypomagnesemia due to reduced intestinal absorption [50]. A meta-analysis of nine observational studies that included a total of 109,798 patients found that those who took a PPI had a significantly higher risk (RR 1.43, 95% CI, 1.08-1.88) of developing hypomagnesemia as compared with those who did not [51]. Clinical manifestations of hypomagnesemia include neuromuscular excitability (eg, tremor, tetany, convulsions), weakness, and apathy.

Severe PPI-induced hypomagnesemia has been associated with QT interval prolongation and torsades de pointes [ 52,53]. The risk of hypomagnesemia appears to be mainly in patients who have been on PPIs long-term (generally longer than one year) but cases have been reported within one year of starting PPI therapy [52,54].

Calcium and fracture risk — Although hypochlorhydria could theoretically reduce calcium absorption, the effect appears to be relevant only for the absorption of water insoluble calcium (eg, calcium carbonate) and can be overcome by ingestion of a slightly acidic meal [55]. The absorption of water soluble calcium salts or calcium in dairy products are not impacted by PPI-induced hypochlorhydria. When calcium supplementation is necessary in patients taking PPIs, we use calcium supplements that do not require acid for absorption, such as calcium citrate.

Vitamin B12 malabsorption — Long-term therapy with PPIs has been associated with vitamin B12 malabsorption [60,61]. However, absorption of oral B12 supplements is not affected.

Iron malabsorption — Gastric acid plays a role in the absorption of nonheme iron, and the use of PPIs has been associated with decreased iron absorption [62-66]. However, in most cases the decreased absorption does not appear to be of clinical significance. One exception may be in patients who require oral iron supplementation [65,67]. Such patients may need a higher dose or longer duration of supplementation [65]

Kidney disease — PPIs can cause acute interstitial nephritis (AIN) [68-71]. Similar to other cases of drug-induced AIN, AIN due to PPI use is not dose-dependent, and recurrence or exacerbation can occur with a second exposure to the same or a related drug.

Drug-induced lupus — In postmarketing safety surveillance, new onset of cutaneous lupus erythematosus and systemic lupus erythematosus (SLE), and exacerbation of existing disease have been reported in patients on PPIs [77-79]. Most cases of CLE-associated with PPI use are subacute and occur within weeks to years after continuous PPI therapy. PPI-associated SLE usually occurs days to years after initiating PPI treatment and typically presents with a rash. Most patients improve within 4 to 12 weeks of discontinuation of PPI therapy.

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Os Relatórios Contábeis de Propósito Geral das Entidades do Setor Público (RCPGs) devem ser elaborados com base no regime de competência.