Proton Pump Inhibitors

What are proton pump inhibitors? • They are used to reduce the production of stomach acid • They work by blocking the action of proton pumps, which are enzymes found in the lining of the stomach that pump protons into the stomach lumen to produce the stomach acid • PPIs are weakly basic at two parts of their structure. This means that, in acidic conditions, they can accept the protons, and become protonated, which enables them to bind to the proton pumps. • Examples include omeprazole, lansoprazole, pantoprazole • There are three receptors that stimulate acid secretion: histamine, gastrin and acetylcholine receptors • Therefore neither H2-receptor antagonists (which block histamine at H2 receptors in the stomach to reduce production of stomach acid from parietal cells) or PG receptor agonists (which mimic the action of prostaglandins at receptors in the stomach to inhibit secretion of stomach acid from parietal cells) can ever be What can we target to reduce stomach fully effective, because if one receptor acid secretion? is blocked, then there are always other receptors from which stimulation of acid secretion can occur • There is only one protein that pumps acid into the stomach and this H+/K+-ATPase is only present in parietal cells, so if we can inhibit this pump then we should affect all gastric H+ secretion without affecting other proton pumping processes elsewhere in the body. The proton pump is an ideal drug target. 1/7 How does omeprazole work? Pt1 Omeprazole arrives in the stomach, protected by its formulation. It is released in the duodenum where it crosses the intestinal epithelium by passively diffusing through the lipid bilayer of the epithelial cells. It then enters the bloodstream, from which it is transported to various tissues and organs including the stomach. Omeprazole is inactive until it reaches the acidic environment of the parietal cells in the stomach lining, where it is protonated (converted into its active form). It is protonated by the lone pair on the oxygen atom at the top of the molecule bringing down its electron density, causing the N atom to pick up and bind to a H+, allowing the molecule to act as a base. The N now has one extra bond and becomes positively charged. Hence, the pKaH/ basic properties of omeprazole allows it to be protonated. How does omeprazole work? Pt2 Once protonated, it reacts to give an intermediate called sulfenic acid, which binds irreversibly to the cysteine residues of the H+/K+ ATPase proton pump by forming a disulfide bridge (so the omeprazole is trapped here), and inhibits its function, blocking the final step in the production of stomach acid, preventing the secretion of hydrogen ions in the stomach lumen. 2/7 To allow it to withstand acidic conditions in the stomach and be absorbed in the duodenum. Once absorbed, omeprazole goes back to the stomach. Omeprazole needs to be absorbed and then go to the stomach, rather than act in the stomach as soon as it is swallowed. This is because omeprazole acts ON parietal cells, which are in the lining of the stomach. The best way to get here is through the bloodstream. Omeprazole would be able to move through the stomWhy does omeprazole have an enteric ach cell membranes normally to reach coating? the parietal cells, HOWEVER, if omeprazole didn't have the enteric coating, it would become protonated in the lumen of the stomach. This means that, in the protonated form, omeprazole cannot move through the cell membranes, so omeprazole wouldn't be able to get to the parietal cells from the stomach lumen. Therefore the omeprazole needs to remain protected until it has reached the location of the actual pumps, where it can now be protonated, so to do this, it is absorbed through the bloodstream. • The ratio of ionised:unionised species of omeprazole is around 363:1 (calculated using Henderson-Hasselbach equation). • The 363 ionised/ protonated molecules form an intermediate called sulfenic acid Can only protonated omeprazole molewhich irreversibly bind to the proton cules bind to proton pumps? pump • However, the 1 unprotonated molecule can still bind to the proton pump, even though it is much less likely (1 in 100000000 chance). It would do this by forming intermediates, until it forms 3/7 sulfenic acid which then can bind to the proton pump. The pyridine ring in omeprazole has a higher pKaH than the pyridine ring in timoprazole, meaning it has greater base strength. This is because omeprazole has a lone pair on the oxygen atom at the top of the pyridine ring which can bring down its electron density, helping the N atom to pick up and bind to a proton, increasing What is the difference between omepra- its basicity. Timoprazole doesn't have the zole and timoprazole? lone pair at the top of the molecule so there is no basicity increase, so it is not protonated as easily. This means that omeprazole has a greater ratio of ionised:unionised species in the gastric lumen- more omeprazole molecules are protonated. This means more omeprazole binds irreversibly to the proton pump and becomes trapped here, compared to timoprazole. 1. The PPI molecules become protonated and trapped in the stomach so cannot exit. What are the two reasons why PPIs are 2. A tiny fraction of the PPI molecule so effective? becomes protonated so generates a reactive intermediate which binds to the cysteine residues of the H+/K+ ATPase proton pump. 4/7 If the PPIs were not formulated with gastro-protection, they would not be able to move into the duodenum, be absorbed into the bloodstream and be transported to the parietal cells in the stomach lining to be protonated. The omeprazole taken orally (which is unprotonated) would form the reactive intermediates (eg sulfenamide, that forms from unprotonated omeprazole) in the stomach lumen. From here, the intermediates would likely Why are PPIs formulated as gastro-rereact with any nearby nucleophile, caussistant? ing the drug to be inactivated. We want the drug to be absorbed and reach the parietal cells in the lining of the stomach, and they wouldn't the able to do this if they become inactivated in the stomach before any of it is even absorbed. Therefore formulating PPIs as gastro resistant means that they avoid this degradation but can still access their target (although indirectly) What is the dose of omeprazole? • The dose of omeprazole is 10-20mg once daily. Omeprazole is given in a tiny dose compared to traditional antacids but is still able to reduce gastric acid secretion quite drastically. • Only a small amount is required because omeprazole binds irreversibly to the proton pump so has longer lasting effects. • However, as soon as food enters the body, gastrin and acetylcholine is released, so there is more translocation of proton pumps to the surface, and more acid is released. Therefore, once daily dosing of PPIs does not suppress acid secretion for a full 24 hours, potentially 5/7 leaving patients in discomfort overnight. • Also, omeprazole needs to be systematically absorbed in the duodenum before it can act, however if gastric emptying is delayed eg due to a consuming a high-fat meal, then the action of omeprazole is delayed. What medicine would be better to use than a PPI like omeprazole? • A medicine that gets straight to the stomach without systemic absorption, so is fast-acting, and that can stay in the stomach without getting degraded by acid, so is long-acting • One example of this is Vonoprazan • It is polar • It has a low IC50, indicating greater potency • It has a basic centre - the basic centre forms an ionic interaction with three carboxylic acids, so the basic properties of nitrogen in the compound is necessary for potent binding, and it means that vonoprazan is retained in the stomach and is long-acting - without the basic centre, the compound Why is vonoprazan effective in inhibiting would be inactive the proton pump? • It has two aromatic rings - the aromatic ring joined to the sulfur forms a pi-pi stack with an aromatic ring in the protein - without it, the compound would be much less potent • It has an SO2 group - this is necessary to hold the aromatic ring at the right angle to make the pi-pi interaction - without it, the compound would be much less potent 6/7 How does Vonoprazan compare to PPIs? • Vonoprazan stays in the stomach • Vonoprazan has a longer lasting effect than lansoprazole • Vonoprazan appears to be more clinically effective than lansoprazole, since it shows higher healing rates for oesophagitis patients and has higher H.pylori eradication rates • It must be a ring • It must have 4n+2 pi electrons (6, 10, What is the criteria for a compound to be 14, 18 etc) aromatic? - the pi electrons can be a lone pair eg on N, or can be in a double bond 7/7