Drugs used in acid-peptic disease

Types drugs that neutralise gastric acid (antacids) reduce gastric acid secretion via proton pump inhibition via effects on histamine, cholinergic and prostaglandin receptors enhance mucosal defences through cytoprotective or possibly antimicrobial activities ANTACIDS mechanism of action weak bases react with gastric hydrochloric acid to form salt and water, reducing gastric acidity reduction of pepsin activity at above pH 4.0 mucosal protection through stimulation of prostaglandin production or through binding of injurious substance principal constituent magnesium or aluminium hydroxide, alone or in combination with sodium bicarbonate or a calcium salt combinations have been developed to maximise effectiveness and minimise inconvenience the net buffering capacity is determined by the ability to neutralise gastric acid and the duration of medications residence in the stomach

NC Hwang 2009

magnesium hydroxide + aluminium hydroxide alkalinize urine to alter excretion of drugs sensitive to urinary pH salicylates GASTRIC ANTI-SECRETORY DRUGS gastric acid secretion is under the control of 3 principal agonists histamine acetylcholine gastrin final common pathway through the proton pump, H+/K+ ATPase modalities H2 antagonists antimuscarinic agents proton pump inhibitor physiologic control of H+ secretion

pharmacologic control of H+ secretion

tablet formulations are generally weak in their neutralising capacity not recommended for the treatment of active peptic ulcer adverse effects change in bowel habits cation absorption (sodium, magnesium, aluminium, calcium) only significant in patients with renal impairment systemic alkalosis drug interactions interaction with other drugs used in acid-peptic disease both proton pump inhibitor and sucralfate require acidic medium for activity may adsorb drugs in gastrointestinal tract, thus reducing absorption digoxin, iron, itraconazole, ketoconazole, quinolones (ciprofloxacin, norfloxacin, enoxacin), tetracycline speed gastric emptying, thus delivering drugs to absorption sites in the intestines more quickly

H2 RECEPTOR ANTAGONISTS inhibitors of the action of histamine at H2-receptors on the gastric parietal cells inhibiting acid secretion and hence volume of gastric secretion classification competitive, surmountable, reversible cimetidine, ranitidine, famotidine, nizatidine unsurmountable, irreversible long-acting tiotidine, loxtidine

Drugs used in acid-peptic disease

structure all structurally dissimilar cimetidine contains an imidazole ring and is structurally similar to histamine ranitidine contains a furan ring famotidine and nizatidine contain a thiazole ring imidazole, furan, thiazole, serve as an aromatic nucleus of histamine H2-receptor antagonists furan and thiazole derivatives are more potent than imidazole derivative cimetidine

NC Hwang 2009

ranitidine rapidly absorbed from intestine 50% bioavailability, increased in cirrhosis 15% bound to plasma protein Vd 1.3 L/kg clearance 10 ml/min/kg t 2 hours, increased in uraemia, cirrhosis 70% excreted unchanged in the urine famotidine rapidly absorbed from intestine 50% bioavailability, increased in cirrhosis 15% bound to plasma protein Vd 1.3 L/kg clearance 7 ml/min/kg t 4 hours, increased in uraemia, cirrhosis 70% excreted unchanged in the urine nizatidine rapidly absorbed from intestine 90% bioavailability, increased in cirrhosis 30% bound to plasma protein, mainly 1acid glycoprotein Vd 1.2 L/kg clearance 10 ml/min/kg, t 1.5 hours, increased in uraemia, cirrhosis more than 90% of an oral dose is excreted in the urine within 12 hours, 60% unchanged ANTIMUSCARINIC AGENTS rarely used, if at all, as adjuncts to H2-receptor antagonists pirenzipine, is relatively selective for gastric M1 muscarinic receptors PROTON PUMP INHIBITORS omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole all are substituted benzimidazoles that reversibly inhibits the gastric parietal cell proton pump, H+/K+ ATPase omeprazole is a racemic mixture of R- and S- isomers esomeprazole is the S-isomer of omeprazole all administered as a lipophilic prodrugs to protect the acid-labile prodrug from rapid destruction within the gastic lumen, they are formulated as acidresistant enteric coated formulations mechanism of action after passing through the stomach and entering the alkaline intestinal lumen, the enteric coating dissolves and the prodrug is absorbed as lipophilic weak bases with pKa 4-5, diffuse rapidly across lipid membranes into acidified compartment, such as the parietal cell canaliculus in acidic environment the prodrug is activated activation hindered by presence of H2 receptor antagonists within the acid compartment, the prodrug rapidly becomes protonated, converts into active, reactive thiophilic sulphonamide cation, and is concentrated > 1000 fold within the parietal canaliculus the sulphonamide reacts with H+/K+ ATPase, forms a covalent disulphide linkage, irreversibly inactivates the enzyme H+ secretion is reduced, but not gastric volume

mechanism of action direct effect of H2 receptor blockade reduction in parietal cell cAMP concentrations attenuate the intracellular activation of protein kinases by gastrin and acetylcholine effects over 90% reduction in basal food-stimulated, and nocturnal secretion of gastric acid after a single dose blockade of cardiac and mast cell H2 receptormediated effects not clinically significant ranitidine and nizatidine increase antral contractility direct effects on smooth muscle cholinergic receptors indirect effects by increasing cholinergic neurotransmission (possibly via inhibitory action on acetylcholinesterase) indications in acid-peptic disease, especially duodenal ulcer, these drugs reduce symptoms and accelerate healing, and prevent recurrences in Zollinger-Ellison syndrome in gastro-oesophageal reflux disease pharmacokinetics cimetidine rapidly absorbed from intestine 85% bioavailability 19% bound to plasma protein Vd 1 L/kg clearance 8 ml/min/kg, decreased in uraemia t 2 hours, increased in uraemia 50% excreted unchanged in urine, 13% as sulphoxide

Drugs used in acid-peptic disease

all have short half-lives, but, a single daily dose of omeprazole can inhibit 100% of gastric acid secretion, as at least 18 h are required for synthesis of new H+/K+ ATPase pharmacokinetics rapidly absorbed 40-90% bioavailability, increased in elderly and cirrhosis 95% (highly) protein bound Vd 0.3 L/kg clearance 7.5 ml/min/kg extensively metabolised by CYP2C19, CYP3A4 sulphated metabolites excreted in urine or faeces as sulphone, -sulphide, hydroxyt 1-2 h, increased in elderly and cirrhosis deficiency in CYP2C19, clearance is 1 ml/min/kg, t is 2.7 hours

NC Hwang 2009

SOMATOSTATIN ANALOG Octreotide a long acting synthetic somatostatin analog significantly inhibit secretion of several circulating peptide hormones, and gastric and pancreatic secretions also a growth hormone antagonist/inhibitor requires parenteral administration pharmacokinetics bioavailability <2% after oral administration, 100% after subcutaneous administration 65% bound to plasma protein Vd 0.35 L/kg clearance is 2.7 ml/min/kg t of 1.5 hours 10-20% excreted in the urine MUCOSAL PROTECTIVE AGENTS Sucralfate aluminium sucrose sulphate, a sulphated disaccharide developed for use in peptic ulcer disease mechanism of action polymerisation and selective binding to necrotic ulcer tissue, where it may act as a barrier to acid, pepsin, and bile directly adsorb bile salts stimulate endogenous prostaglandin synthesis requires acid pH to be activated should not be administered with antacids, H2 receptor antagonists, or proton pump inhibitors absorption poorly absorbed systemically, though rising plasma concentrations documented in patients with renal failure drug interactions reduce absorption of orally administered drugs actions inhibited by drugs which raise gastric pH Colloid bismuth compounds mechanism of action selective binding to ulcer, coating it and protecting it from acid and pepsin inhibition of pepsin activity stimulation of mucous production increase prostaglandin production may have antimicrobial activity against Helicobacter pylori in combination with metronidazole and tetracycline tripotassium dicitrato bismuthate decrease absorption of tetracycline

adverse effects headache, dizziness, depression hypersensitivity rashes, pruritus, bronchospasm nausea, vomiting, constipation, flatulence, abdominal pain, diarrhoea muscle and joint pain blurred vision dry mouth precautions liver disease pregnancy and in breast-feeding gastric malignancy drug interactions omeprazole inhibits P450 and prolongs metabolism of certain drugs (warfarin, digoxin, diazepam, phenytoin, clopidogrel) absorption reduced with concurrent administration of antacids, H2-receptor antagonists, sucralfate PROSTAGLANDINS Misoprostol a methyl analog of prostaglandin E1 approved for prevention of ulcers induced by the administration of non-steroidal anti-inflammatory drugs mechanism of action cytoprotective inhibition of gastric secretion mediated through inhibition of histamine-stimulated cAMP production, the major second messenger for histamine-induced acid secretion adverse effects diarrhoea, uterine contraction