Acid Peptic Disorders 2024.pdf

Pharmacology of Gastric Acid Lowering Drugs Mary Erclik PhD March 1st 2024  OUTLINE Drugs in the treatment of Peptic Ulcers (and GERD) - Proton Pump Inhibitors - Histamine Type 2 Receptor Antagonists (H2R antagonists) - Antacids - Mucosal Pro...

Pharmacology of Gastric Acid Lowering Drugs Mary Erclik PhD March 1st 2024  OUTLINE Drugs in the treatment of Peptic Ulcers (and GERD) - Proton Pump Inhibitors - Histamine Type 2 Receptor Antagonists (H2R antagonists) - Antacids - Mucosal Protective Agents - Therapy of H-Pylori infection Prokinetic Drugs (Treatment of GERD) - Dopamine Antagonists - Serotonin Agonists - Motilin Receptor agonists  OBJECTIVES - Recall the mechanism of action of acid-lowering drugs (including PPIs, H2- receptor blockers and antacids, other gastric protective drugs and prokinetic agents - Employ your knowledge of the mechanism of action of these drugs to their efficacy in reducing gastric acid, increasing gastric protection or displaying prokinetic activity - Employ your knowledge of the pharmacological properties of the these drugs to their role in the therapeutics of PUD and GERD Who were the scientists that determined the causal role of H-pylori in causing ulcers? What is the name the novel Potassium-Competitive Active Blocker (PCAB)? Which class of acid lowering drugs are pro-drugs that require activation? Which class of acid lowering drugs requires mostly renal elimination? What is 1 advantage PCABs have over PPIs? What drug demonstrates anti-microbial activity, stimulates bicarbonate secretion and forms a protective barrier along the surface of gastric epithelial cells?  Overview Physiology of Acid Production: - Gastric acid is produced by parietal cells in stomach fundus - Parietal cells are one of five cell types in gastric mucosa; they are responsible for producing acid The factors that regulate gastric acid production include: - Acetylcholine (+) - Histamine (+) - Gastrin (+) - GRP (+) - Excess acid (-) (via Somatostatin) - Gastric inhibitory peptide (GIP)(-) - Prostaglandin E2 (-) - EGF (-)  Overview Most common gastroinstestinal disorders: - Peptic ulcer disease (gastric or duodenal in origin) - Gastroesophageal reflux disease (GERD) - Drug-induced injury (ex. NSAIDS) - Hypersecretory states (Zollinger-Ellison disease) - Stress related mucosal injury Multiple Pathway Regulation of Physiological Effect B C A cAMP IP3 cAMP EFFECT Mechanism of Gastric Acid Lowering Drugs  H2 Receptor Antagonists - Volume of gastric secretion and concentration/acidity are both reduced - At therapeutic doses will inhibit 60-70% of 24-hr acid secretion - Particularly effective in treating basal acid secretion; this occurs mostly at night therefore should be administered before bed - Under prescription use they are indicated for peptic ulcers and GERD H2 Receptor Antagonists Potencies of agents vary considerably but all can be given in equipotent dosages Effect of H2-Antagonists on 24 hr acid secretion  Histamine Effects in the Body Source: Lullman, H. Color Atlas of Pharmacology. Thieme, 2005.  H2 Receptor Antagonists Ranitidine (Zantac) General - more potent and efficacious (4-10X) than cimetidine - little effect on cytochrome P450s - oral and IV use can be used by infants (starting at 1 month) for GERD - at high doses can affect clearance of warfarin, triazolam, glyburide and glipizide  H2 Receptor Antagonists Famotidine (Pepcid) - has greatest affinity for H2 receptor - less bioavailability than other H2-RA but has a longer half-life - no effect on cytochrome P450s - can also be used in children Nizatidine - has greatest bioavailability and antacids reduce absorption by 10% - largely excreted by kidneys (contraindicated with renal dysfunction) - no effect on cytochrome P450s  H2 Receptor Antagonists Adverse Effects - Minor side effects: diarrhea, headache, drowsiness, fatigue and constipation - Cimetidine inhibits binding of dihydrotestosterone to androgen receptors; may cause gynecomastia and impotence in men following long-term use - H2RAs cross the placenta; no indication that they harm the fetus but unless clearly needed they should be avoided during pregnancy - Can cause confusion, hallucinations and agitation when given IV - H2RAs are secreted in breast milk - H2RAs are primarily renally excreted therefore monitor with renal dysfunction - blockade of the H2 receptors in the heart may cause bradycardia  Proton Pump Inhibitors Proton Pump Inhibitors (PPIs) - considered major modality of treatment for acid-peptic disorders - Weak bases pKa 3.8 and 4.9 therefore they concentrate in acidic environment (1000 fold more concentrated in stomach than anywhere else in the body) - PPIs are generally administered as inactive pro-drugs; pro-drug is rapidly protonated and concentrated within parietal cells to form the active drug - the active drug interacts with the H/K ATPase, irreversibly inactivating the enzyme Mechanism of Proton Pump Inhibitors Olbe L, Carlsson E, Lindberg P, NRDD 2,132-139, 2003 Metabolic Activation of PPIs  PPIs PPIs - Omeprazole - Esomeprazole - Lansoprazole - Dexlansoprazole - Pantoprazole - Rabeprazole  PPIs - PPIs are more efficacious than H2-RAs - Indicated for the treatment of GERD and peptic ulcers, combination treatment of H-pylori infection - In fasting state only 10% of proton pumps are active and therefore susceptible to inhibition, therefore administer PPI 1 hr/before a meal - Short serum half-life (1-2 hours) but long duration of action due to irreversible binding of pump, therefore usually once a day dosing is sufficient - Not all pumps are active during the 1-2 plasma half-life; takes 2-3 days to reach steady state levels of acid secretion Pharmacokinetics: - rapid first-pass hepatic metabolism (dose modification may be necessary) - negligible renal clearance - Metabolized by CYP2C19 and CYP3A4 - Highly plasma protein bound - Polymorphisms in CYP2C19 may cause inter-patient differences in efficacy and toxicity - Omeprazole can inhibit CYP2C19 and may result in drug interactions; eg. clopidogrel  Adverse Effects of PPIs Adverse Effects Generally well tolerated Nausea, abdominal pain, flatulence, diarrhea Malfertheiner, P. et al. (2017) Proton-pump inhibitors: understanding the complications and risks Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2017.117 Activation of clopidogrel via cytochrome P450- Interaction with PPIs Malfertheiner, P. et al. (2017) Proton-pump inhibitors: understanding the complications and risks Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2017.117 Mechanism of Potassium-Competitive Active Blockers (PCAB) Aliment Pharmacol Ther, Volume: 53, Issue: 7, Pages: 794-809, First published: 16 February 2021, DOI: (10.1111/apt.16295) Comparison of PCAB and PPI MOA Journal of Neurogastroenterology and Motility 2018;24:334~344 https://doi.org/10.5056/jnm18029  Potassium-Competitive Active Blockers (PCAB): Vonoprazan Currently only approved in Japan; Looking for approval in North and South America Inhibits ability of H/K ATPase to bind to potassium, effectively inhibiting the pump Advantages over PPIs: - does not require protonation for activity therefore patients are not required to take with a meal - more consistent lowering of gastric pH means more effective in killing H- pylori and faster healing rates from bleeding - clinical data indicates less frequent bacterial resistance compared to PPI  Antacids - Used for centuries for simple, temporary relief of dyspepsia and acid-peptic disorders - Weak bases that react with gastric HCl to form a salt and water - Relatively safe and far less expensive than H2-RA and PPIs - Generally liquid antacids are more effective than tablets  Antacids - After a typical meal approximately 45 mEq of HCl is secreted - Acid neutralization capacity of antacids varies considerably; based on chemistry, formulation, route and time of administration - Significant binding of other drugs, particularly of metals/cations  Antacids Sodium Bicarbonate - Reacts rapidly with acid to produce carbon dioxide and NaCl - Formation of CO2 leads to gastric distension and belching - May lead to metabolic alkalosis if excess does not react - Rarely used alone due to risk of alkalosis  Antacids Calcium Carbonate - Less soluble, more slow-acting than sodium bicarbonate - Forms carbon dioxide and CaCl2 - Can cause gastric distension and belching - Excessive doses can lead to hypercalcemia and metabolic alkalosis  Antacids Mg/Al Hydroxides - React slowly to form chlorides and water - No gas generated; no distension - Metabolic alkalosis uncommon - Mg can cause diarrhea and Al causes constipation; often given together to offset effects on motility - Some clinicians do not recommend during pregnancy due to association of high doses of aluminum and fetal malformations  Antacids Drug Interactions - Can affect absorption or elimination of a number of other drugs; Therefore should be taken at least 2 to 3 hours apart - Antacids may decrease the efficacy of: - ACE inhibitors - quinolone antibiotics (ciproflaxacin, oflaxacin) - ASA (due to alkalinization of urine) - NSAIDS - levothyroxine - glyburide - misoprostol - Antacids may increase the absorption and efficacy of: - coumadin - L-Dopa  Mucosal Protective Agents: Prostaglandins - GI mucosa synthesize PGE1 and PGI2 - Misoprostol (PGE1 analog) exhibits both acid inhibitory and mucosal protective properties - Stimulates mucus and bicarbonate secretion - Often administered with NSAIDS  Mucosal Protective Agents: Bismuth Subsalicylate - Part of quadruple therapy for H-pylori infections - Has some antimicrobial activity - Inhibits pepsin activity - Increases mucous production - By binding to mucosal tissue glycoproteins it can coat and protect the ulcer Summary: Acid Lowering/ Protective Agents Prokinetic Agents GERD: Treatment  GERD: Treatment Approach GERD results when the protective mechanisms of the esophagus are overwhelmed by the aggressive factors derived from the stomach Current treatment options aim at reducing acid production, increasing the motility of the gut and increasing LES tone  GERD Treatment: Mechanism of Prokinetic Drugs  GERD Treatment Dopamine Receptor Antagonists Dopamine inhibits Ach release from myenteric plexus neurons and decrease lower esophageal sphincter tone; dopamine receptor antagonists reverse these effects In the gut the main receptor subtype is D2  Prokinetic Agents:D2 Antagonists Domperidone - Peripheral dopamine receptor antagonist; limited CNS effects - Increases esophageal peristalsis; increases LES tone; increases gastric emptying rate - Also used to increase lactation in nursing mothers Adverse Effects - Far fewer than metoclopramide due to lack of penetration of CNS - Headache and dizziness  Prokinetic Agents- 5-HT Agonists ECL cells produce 5-HT in response to chemical and mechanical stimulation 5-HT stimulates peristalsis 5-HT agonists must be selective for specific receptor subtypes (5-HT4 R agonism) to be effective as a prokinetic agent Cisapride and tegaserod withdrawn or limited due to cardiotoxicity Prucalopride currently available  Prokinetic Agents: Erythromycin Erythromycin: - Macrolide antibiotic - Ligand for the motilin receptor - Increases LES tone; increases gastric emptying rate and increases intestinal peristalsis - Antibiotic, therefore short-term use only - Hepatic excretion, inhibits CYP3A4 Adverse Effects - torsade de pointes and QT prolongation - abdominal pain, cramps, vomiting and diarrhea  Summary - Hypersecretory conditions can be treated with acid-lowering lowering drugs such as PPIs and H2R antagonists, protective agents and prokinetic drugs - Proton pump inhibitors are the most efficacious class of drugs at lowering gastric pH because they inhibit the terminal target in acid secretion, the H+/K+ ATPase - Mucosal protective agents increase the protective mechanisms of the gastric lining - Prokinetic agents enhance the transit of gastric contents to reduce the risk of reflux into the esophagus