IPFC 2 2024 PUD/GERD Pharmacology PDF

PUD/GERD Pharmacology 1 Overview ▪ Review of acid secretion ▪ Pharmacology of agents to treat PUD/GERD, and dyspepsia 2 Recommended Reading ▪ Basic and Clinical Pharmacology, 15e, Chapter 62 (sections 1-3) ▪ The Pharmacological Basis...

PUD/GERD Pharmacology 1 Overview ▪ Review of acid secretion ▪ Pharmacology of agents to treat PUD/GERD, and dyspepsia 2 Recommended Reading ▪ Basic and Clinical Pharmacology, 15e, Chapter 62 (sections 1-3) ▪ The Pharmacological Basis of Therapeutics, 14e, Chapter 53 3  “VI DE O #1” 4  “VI DE O #1” 5 Proton Pump Inhibitors - MOA “VI DE O #2 ▪ Include omeprazole, esomeprazole (the S isomer of omeprazole), pantoprazole, and others ” ▪ Although structurally-related to H2 receptor antagonists, they have no affinity for the H2 histamine receptor ▪ Instead, they have specific and selective effects on the gastric proton pump (selective even for this pump vs. other proton pumps in the body) ▪ Most are prodrugs to avoid breakdown prior to being absorbed and reaching their site of action, other approaches include various enteric-coated formulations 6  “VI DE O #2 ” 7 Proton Pump Inhibitors - PK Notes “VI DE O #2 ” 8 Proton Pump Inhibitors - PK Notes “VI DE O #2 ▪ Minor drug-nutrient interaction with vitamin B12 (requires acidic conditions for digestion/absorption), similar effects on iron, calcium, magnesium ” ▪ Absorption interactions related to reductions in acidity may also occur for drugs such as ketoconazole, digoxin, and others ▪ Almost no renal clearance - extensively metabolized including on first-pass, by CYP2C19 and 3A4 ▪ Short plasma half-lives but longer durations of effect due to irreversible inhibition of the proton pump 9 Proton Pump Inhibitors - PK Notes “VI DE ▪ E.g. Clopidogrel drug interaction O #2 ▪ Clopidogrel is an antiplatelet administered as a prodrug activated vis CYP2C19” metabolism ▪ Omeprazole, esomeprazole, lansoprazole, and dexlansoprazole are CYP2C19 inhibitors and they reduce the efficacy of clopidogrel ▪ Although the evidence is mixed, some studies have suggested an increased risk of negative cardiovascular outcomes due to this drug interaction 10 Proton Pump Inhibitors - Toxicity Notes “VI DE ▪ The most common ADRs are diarrhea and headache O #2 ▪ ” Retrospective association studies have linked PPIs to kidney dysfunction, fractures, and infection ▪ The increased incidence of fractures may be due to the inhibition of calcium absorption ▪ The increased incidence of infection may be due to changes in gut flora 11 Histamine type 2 receptor antagonists - MOA ▪ Competitive H2 receptor antagonist ▪ Primary activity is via blockade of those receptors on parietal cells ▪ Very selective i.e. few off-target effects ▪ Highest efficacy against nocturnal secretion but inhibits all acid secretion 12 Histamine type 2 receptor antagonists - MOA 13 Histamine type 2 receptor antagonists - MOA 14 Histamine type 2 receptor antagonists - Toxicity ▪ Very low incidence of adverse effects such as diarrhea or constipation, headache, muscle pain ▪ The first H2 blocker, cimetidine, has more adverse effects including androgen receptor antagonism, increase prolactin levels, and inhibition of estradiol metabolism ▪ Cimetidine also has numerous drug interactions that the other do not because it inhibits CYP 1A2, 2C9, 2D6, and 3A4 15 Antacids ▪ Commonly used for self-limited and/or intermittent GERD ▪ Bases are ingested, result in a direct interaction with H+ to form salt and water (with or without CO2 production) ▪ May also stimulate prostaglandin production ▪ One meal can result in ~ 45 mEq of HCl secretion, most doses of antacids contain 3-4x mEq of base salts 16 Antacids ▪ E.g. sodium bicarbonate ▪ One of the first antacids ▪ Carbon dioxide is produced as a by-product of the acid-base reactions, resulting bloating, distension, and belching ▪ May be absorbed systemically to cause metabolic alkalosis, particularly in patients with reduced renal function ▪ E.g. calcium carbonate ▪ Also forms carbon dioxide, but the overall reaction and CO2 production is slower compared to sodium bicarbonate 17 Antacids ▪ E.g. magnesium/aluminum hydroxide ▪ No CO2 production ▪ Very low risk of metabolic alkalosis ▪ Bases administered in combination because magnesium salts produced after the acid-base reaction can result in osmotic diarrhea and aluminum salts can cause constipation 18 Misoprostol ▪ Methyl-PGE1 analogue ▪ Very short serum half-life ▪ Decreases acid secretion, promotes bicarbonate and mucous secretion ▪ Activates the PGE2 receptor ▪ May stimulate uterine contractions therefore contraindicated in pregnancy and used with caution in women of childbearing age 19 Bismuth compounds ▪ Mechanisms of action may include: ▪ Coats erosions and ulcers ▪ Stimulates prostaglandin production ▪ Stimulates mucous and bicarbonate secretion ▪ Decreases GI secretions to treat diarrhea ▪ Direct antimicrobial effects, including against H. pylori ▪ ADRs include blackening of the stool, darkening of the tongue 20 Sucralfate ▪ Sucrose complexed with aluminum hydroxide that forms a viscous solution when mixed with water ▪ Thought to bind and coat areas of the GI tract with greatest negative charge, possibly the areas around ulcers 21 Promotility Agents - Dopamine Receptor Antagonists ▪ Dopamine inhibits cholinergic smooth muscle stimulation, therefore blockade of D2 receptors is prokinetic ▪ Result is increased peristalsis in the esophagus, increased esophageal tone, promotes gastric emptying ▪ Relatively smaller effect on small intestine ▪ Also antiemetic, due to central blockade of D2 receptors in the CTZ 22 Promotility Agents - Dopamine Receptor Antagonists ▪ Adverse effects involve the CNS primarily: ▪ Restlessness, drowsiness, insomnia, anxiety, agitation, all more pronounced in the elderly ▪ EPS effects at high doses and some reports of tardive dyskinesia after prolonged use therefore long-term use is not recommended, particularly in the elderly ▪ Elevated prolactin levels can result in galactorrhea, gynecomastia, impotence, and menstrual disorders ▪ Domperidone causes fewer adverse effects because it does not extensively cross the BBB 23 Promotility Agents - Other ▪ Cisapride and prucalopride ▪ Both are 5-HT4 receptor agonists that result in prokinetic activity ▪ Cisapride was removed from the market/restricted due to rare but fatal cardiac arrhythmia ▪ Alosetron ▪ 5-HT3 receptor antagonists are known for their antiemetic properties, but may also provide some prokinetic activity ▪ Erythromycin ▪ Macrolide antibiotic displays pro kinetic activity by mimicking the actions of motilin, a small peptide (22 residues) secreted by the GI tract to act as a increase motility ▪ May work “too well”, moving undigested food into the small intestine ▪ Tolerance also develops 24