Peptic enzyme inhibitors

The analgesic effects of NSAIDs are attributed to inhibition of the COX-2 enzyme, whereas the negative GI effects are due to inhibition of COX-1.28 Patients taking oral anticoagulants, those with a history of peptic ulcer disease, or others at high risk for GI complications may be considered candidates for a COX-2 inhibitor or a combination of a nonselective NSAID with a gastroprotective agent such as a proton pump inhibitor (PPI). Because most PPIs are available by prescription only, such patients should be referred to a physician. 

The anti-ulcer agents omeprazole, lanzoprazole, and pantoprazole have been introduced during the past decade for the treatment of peptic ulcers. Gastric acid secretion is efficiently reduced by prazole inhibition of H+K+-ATPase in the parietal cells of the gastrointestinal mucosa [75]. The prazoles themselves are not active inhibitors of the enzyme, but are transformed to cyclic sulfenamides in the intracellular acidic compartment of parietal cells [76]. The active inhibitors are permanent cations at pH < 4, with limited possibilities of leaving the parietal cells, and thus are retained and activated at the site of action. In the neutral body compartments the prazoles are stable, and only trace amounts are converted to the active drugs. (For a review on omeprazole, see Ref. [77].)... 

Hunt (H54) reported the possible existence of a synergistic enzyme, which potentiated activity of crystalline hog pepsin at pH 2. He considered the potentiating effect of dilution on gastric juice peptic activity to be due not to dilution of the inhibitor, as assumed by Bucher et al. (B41, B42), but to the additional effect of the synergist. 

Proton pump inhibitors (gastric acid secretion inhibitors, gastric add pump inhibitors) inhibit gastric acid secretion 90% greater than the H2 blockers because they block the final step of acid production. Both omeprazole (Prilosec) and lansoprazole (Prevacid) are proton pump inhibitors used for the treatment of peptic ulcers and GERD. Those with hepatic impairment should take these drags with caution and have liver enzymes monitored regularly. 

Apart from the interaction between the side chains of the polypeptide substrate and the enzyme, there may be other interactions important for the efficiency of peptic catalysis. As was shown by Fruton t al. (11), if the methylene group in residue i is substituted for the carbonyl group, the substrate becomes an inhibitor. We found (12) that substitution of the -NH- group is residue P by an isosteric oxygen atom also resulted in a resistance to peptic hydrolysis. This compound was competitive inhibitor with Kj -K of the corresponding substrate (Table III). Therefore, formation of hydrogen bonds to the dipeptide region of the substrate is a prerequisite of peptic catalysis. 

Another criterion of a "transition state" inhibitor is the structural similarity of the compounds to the transition state in the catalysis of the enzyme. This is illustrated in Figure 3, where the structural similarity of a statyl residue and one of the proposed transition states of peptic catalysis (16) can be readily seen. 

---