Clinically Used Agents that Reduce Gastric acid Production

• Clinically used agents that reduce gastric acid production Simple chemical drugs: antacids o Work via local neutralisation of acid (do not prevent the over-production of acid) o Components: ▪ Aluminium hydroxides ▪ Magnesium hydroxides ▪ Calcium carbonate ▪ Sodium bicarbonate • Drugs that interfere with biological processes: o Muscarinic receptors antagonists o H2 receptor antagonists o Proton pump inhibitors Antacids • Magnesium salts o Forms: carbonate hydroxide, oxide, trisilicate o Dangerous when used with renal failure – failing kidney cannot excrete magnesium → accumulation o E.g. magnesium hydroxide (MOM); combination products such as Maalox, aluminium & magnesium • Calcium salts o Forms: many but carbonate is the most common o Use may result in kidney stones o Long duration of acid action may cause increase of gastric acid secretion (hyperacidity bound) o Often advertised as an extra source of dietary calcium • Sodium Bicarbonate o Highly soluble o Quick onset, but short duration o May cause metabolic alkalosis o Sodium content may cause problems in patients with hypertension or renal insufficiency • Aluminum salts o Forms: carbonate, hydroxide, phosphate o Have constipating effects o Often used with magnesium to counteract constipation o Example: aluminum carbonate Histamine H2 receptor antagonists • • • • • Competitively inhibit histamine actions at all H2 receptors Main clinical use is as inhibitors of gastric acid secretion Agents decrease both basal and food-stimulated acid secretion, while promoting healing of duodenal ulcers o Decrease food-stimulated acid secretion by 90% Drugs used are cimetidine (Tagamet) and ranitidine (Zantac) Use has declined with the availability of proton pump inhibitors Proton pump inhibitors (PPIs) • Reduce gastric acid secretion by up to 99% • Lack of the acid in the stomach will aid in the healing of duodenal ulcers and reduces pain from indigestion and heartburn, which can be exacerbated by stomach acid • E.g. omeprazole, lansoprazole, pantoprazole, rabeprazole • Act by irreversibly blocking the H+/K+ ATPase (gastric proton pump) of the gastric parietal cells o Covalent binding • Proton pump is the terminal stage in gastric acid secretion → directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion Acid catalysed activation of PPI • PPIs are prodrugs that get converted into the active compounds in the body • Conversion of prodrug to drug is acid-catalysed: Benzimidazoles (inactive prodrugds) are protonated at acidic pH on their pyridine nitrogen into Sulfenamides (active) • The acid induced protonation occurs only in the stomach which offers a suitably low pH (2) → PPis are not activated in non-acidic tissue e.g. kidneys Sulfenamide-SH group interaction (irreversible enzyme inhibition) • Major principle of inhibition is covalent binding of the drug to cysteine residues of the proton pump • Sulfenamides bind covalently to cysteine restudies of P-type ATPases e.g. proton pump (cysteine no. 813) • However, they may bind to glutathione → results in a loss of their inhibitory action • Target specificity: non-proton pump ATPases (e.g. Na/K, Ca/K ATPases) are not effected o They are also of p-type but are not affected by PPIs since they are more compact in their structure → PPIs do not get access to their cysteine Proton pump cycling (insertion into the acid canaliculi) • • Resting PPs are present in cytoplasmic tubules (pH 5) Upon stimulation they move to be inserted into secretory canaliculi (pH 1) o Activation of PPIs occurs only in the secretory canaliculi • PPIs are effective on stimulated proton pumps not on resting proton pumps • Full effect is delayed for 5-7 days Half-life of drug action • Drug elimination alone is not important for proton pump recovery since t1/2 of PPIs in plasma is very short (0.5-3 hrs) while t1/2 of recovery is much longer (e.g. 15 hrs for omeprazole) • Kd of an irreversible drug ~ 0 • Recovery is recovery of acid production action • • The rate of turnover of PPs is importance since binding of PPIs to PPs is covalent, however it is not the only factor since t1/2 of PPs is 48 hours > 15 hours of recovery o The body recovers from PPIs quicker than it can make new PPs This is because glutathione also has a cysteine that competes for PPIs in a sulfide exchange reaction Treatment of helicobacter pylori infection • H. pylori is an important causative factor in the production of gastric and duodenal ulcers and risk factor for gastric cancer (harms stomach and duodenal lining) • Ammonia produced to regulate pH is toxic to epithelial cells, as are biochemical produced by H. pylori such as proteases, vacuolating cytotoxin A (VacA), and certain phospholipases • Eradication of H. pylori infection promotes rapid and long-term healing of ulcers, and it is routine practice to test for the organism in patients presenting with suggestive symptoms • Organism can generally be eradicated with a 1- or 2- week regimen of 'triple therapy' o Comprises a PPI in combination with antibiotics amoxicillin and metronidazole or clarithromycin o PPIs are used because: ▪ HP is resistant to antibiotic at low pH since the antibiotics are broken down in an acidic environment → the higher the pH, the better the response to antibiotics. ▪ PPIs in the triple therapy can raise the pH in the stomach to 6 (at high dose)