Drugs used in the treatment of gastrointestinal diseases

Phr.Volkan KAHRAMAN

GI DISEASES

•Gastroesophageal Reflux Disease (GERD)

•Peptic Ulcer Disease (PUD)

•Duodenal Ulcer

•Nausea

•Emesis

DRUGS USED IN ACID-PEPTIC DISEASES

• Acid-peptic diseases include gastroesophageal reflux, peptic ulcer (gastric and duodenal), and stress-related mucosal injury.

• In all these conditions, mucosal erosions or ulceration arise when the caustic effects of aggressive factors (acid, pepsin, bile) overwhelm the defensive factors of the gastrointestinal mucosa (mucus and bicarbonate secretion, prostaglandins, blood flow, and the processes of restitution and regeneration after cellular injury).

DRUGS USED IN ACID-PEPTIC DISEASES

• Over 90% of peptic ulcers are caused by infection with the bacterium Helicobacter pylori or by use of nonsteroidal anti-inflammatory drugs (NSAIDs).

• Drugs used in the treatment of acid-peptic disorders may be divided into two classes: agents that reduce intragastric acidity and agents that promote mucosal defense.

PHYSIOLOGY OF ACID SECRETION

• The parietal cell contains receptors for gastrin (CCK-B), histamine (H2), and acetylcholine (muscarinic).

• When acetylcholine (from vagal postganglionic nerves) or gastrin (released from antral G cells into the blood) bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+,K+ ATPase (the proton pump) on the canalicular surface.

PHYSIOLOGY OF ACID SECRETION

• In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells.

• ECL cells also have receptors for gastrin and acetylcholine, which stimulate histamine release.

• Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP) and activates protein kinases that stimulate acid secretion by the H+,K+ ATPase.

PHYSIOLOGY OF ACID SECRETION

• In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation.

• In contrast, acetylcholine provides potent direct parietal cell stimulation.

GERD (Gastroesophageal Reflux Disease)

• The goals of GERD therapy are complete resolution of symptoms and healing of esophagitis.

• Proton pump inhibitors clearly are more effective than H2 receptor antagonists in achieving these goals.

• Healing rates after 4 weeks and 8 weeks of therapy with PPIs are 80% and 90%,respectively;the corresponding healing rates with H2 antagonists are 50% and 75%.

PEPTIC ULCER DISEASE

• Imbalance between mucosal defense factors ( bicarbonate,mucin,prostaglandin,NO,and other peptides and growth factors) and injurious factors (acid and pepsin).

• On average,patients with duodenal ulcers produce more acid than do control subjects,particularly at night.

• H.pylori and exogenous agents such as NSAIDs interact in complex ways to cause and ulcer.

PEPTIC ULCER DISEASE

• Up to 60% of peptic ulcers are associated with H.pylori infection of the stomach.

• This infection may lead to impaired production of somatostatin by D cells and,in time,decreased inhibiton of gastrin production,resulting in increased acid production and reduced durodenal bicarbonate production.

• NSAIDs also are very frequently associated with peptic ulcers and bleeding.

PROTON PUMP INHIBITORS

• The most potent supressors of gastric acid secretion are inhibitors of the gastric H+ , K+ -ATPase( proton pump.

• In typical doses,these drugs diminish the daily production of acid by 80-95%.

• Six proton pump inhibitors are available;

• Omeprazole,Esomeprazole,Lansoprazole, Dexlansoprazole,Rabeprazole and Pantoprazole.

PROTON PUMP INHIBITORS

• These drugs have different substitutions on their chemical structures but are remarkably similar in their pharmacological properties.

• These drugs ideally should be given 30 minutes before meals.

• These drugs are extensively metabolized by CYC2C19 and CYP3A4.

PROTON PUMP INHIBITORS

• Among the PPIs,only omeprazole inhibits CYP2C19 (decreasing clearance of disulfiram,phenytoin) and induces CYP1A2(increasing clearance imipramine, several antipsychotic drugs,theophylline).

• Most common seen adverse effects;nausea, abdominal pain,constipation,flatulance,and diarrhea

H2 RECEPTOR ANTAGONISTS

• The H2 receptor antagonists inhibit acid production by reversibly competing with histamine for binding H2 receptors on the basolateral membrane of parietal cells.

• Increasingly,however,PPIs are replacing the H2 receptor antagonists in clinical pratice.

H2 RECEPTOR ANTAGONISTS

• 4 different H2 receptor antagonists are available:

• Cimetidine,Ranitidine,Famotidine,and Nizatidine.

• These drugs are less potent than PPIs but still suppress 24-hour gastric acid secretion by 70%.

• I.v. And i.m. Preperations of cimetidine,ranitidine, and famotidine are available.

H2 RECEPTOR ANTAGONISTS

• When the oral route is not an option,these drugs can be given in intermittent i.v. boluses or by continuous infusion.

H2 RECEPTOR ANTAGONISTS

• Like PPIs,H2 receptor antagonists generally are well tolerated.

• Side effects usually are minor and include diarrhea, headache,drowsiness,fatigue,muscular pain,and constipation.

• Cimetidine inhibits CYC2C9 and CYP2D6,and thereby can increase the levels of a variety of drugs that are substrates for these enzymes.

MISOPROSTOL

• PGE2 can prevent gastric injury by cytoprotective effects that include stimulation of mucin and bicarbonate secretion and increased mucosal blood flow.

• Oral doses of 100-200µg significantly inhibit basal acid secretion or food-stimulated acid secretion.

• The usual recommended dose for ulcer prophylaxis is 200µg four times a day.

• Misoprostol is contraindicated during pregnancy because it can increase uterine contractility.

SUCRALFATE

• In acid enviroment(ph≤4) sucralfate undergoes extensive cross-linking to produce a viscous,sticky polymer that adheres to epithelial cells and ulcer craters for up to 6 hours after a single dose.

• Should be taken on an empty stomach 1 hour before meals.

• The usual dose is 1 g 4 times daily.

• Constipation is the most seen adverse effect.

ANTACIDS

• The rationale for the use of antacids in peptic ulcer disease lies in the assumption that buffering of H+ in the stomach permits healing.

• Healing rates are comparable with those observed after the use of H2 blocking agents.

• Sodium bicarbonate,Calcium carbonate, magnesium hydroxide,and aluminium hydroxide.

• If diarrhea occurs or if there is renal failure , a magnesium based preperation should be discontinued.

ANTACIDS

• Combination of Mg and Al hydroxide provide a relatively balanced and sustained neutralizing capacity and are preferred by most experts.

• In general antacids ahould be administered in suspension form because this probably has a greater neutralizing capacity than powder or tablet dosage forms.

• If tablets are used,they should be thoroughly chewed for maximum effect.

ANTACIDS

Mg/Al hydroxide+Carbonate hydrate

Calcium carbonate,Sodium alginate,Sodium bicarbonate

Calcium carbonate,Magnesium Carbonate