Safety data required for proton-pump inhibitor use in children.

Abstract

Since 1976, proton-pump inhibitors (PPIs), the final common pathway of acid gastric secretion, have been the target of research in treating acid-related disorders. Molecules binding to cysteines in the gastric proton pump can block irreversibly the H+/K+ adenosine triphosphatase of the parietal cells. Proton-pump inhibitors have the best acid-inhibition potency because of their long duration of action and therefore are effective in treating acidrelated diseases. The literature on the efficacy and shortterm safety of omeprazole in pediatric patients is convincing: omeprazole gives rapid symptom relief in reflux esophagitis and, during maintenance treatment, induces fewer relapse episodes of mild or moderate reflux esophagitis than does ranitidine (1–3). However, this literature remains scarce compared with that pertaining to adults, especially concerning the newer pro-drugs such as esomeprazole, the S-isomer of omeprazole (4). Proton-pump inhibitors are absorbed as precursors that become active after conversion to sulfonamides by the acidity of the canaliculi of the parietal cells, in which their inhibitory action on the proton pump is effective at a rate depending on their dissociation constant (pKa). Therefore, the gastric mucosa must absorb the PPI as an inactive drug, without previous degradation by gastric acid, to avoid early conversion to a sulfonamide compound that occurs in the gastric lumen and not in the lumen of the canaliculi (Fig. 1). Compared with the classic form, the new multiple unit pellet system of omeprazole therapy, which contains a large number of small, individually enteric-coated micropellets is easier for small children to swallow and allows administration through a nasogastric tube. Despite the increasing use of several orally administrated PPIs in children and despite the manufacturers’ precautions and warnings (PPIs are not officially licensed for children in most countries), concern about the safety of long-term acid suppression remains a subject of controversy, not only in adult patients but especially in neonates and in children. Which safety data should be studied and which warnings should be issued for the use of PPIs in children? The aim of this article is to review the available data from the pediatric point of view and, when necessary, suggest further studies concerning 1) adequate indications for use in pediatric patients; 2) optimal dosage; 3) risk of adverse effects related to age or underlying disease; 4) metabolic pathways and drug interactions; and 5) consequences of the mechanisms of action and of permanent gastric-acid suppression on digestion, microflora, motility, and quality of mucus.