Pharma - 4th Asessment - Git Lecture Slides -i - 27 Jan 2007

GASTROINTESTINAL DRUGS Dr. Mariam Yousif PHARMACOLOGY & TOXICOLOGY DEPARTMENT )27/1/2007(

OBJECTIVES I. Peptic ulcer * Definition & Pathophysiology * Therapeutic strategies * Drug treatment A. Antimicrobial therapy )treatment of H. pylori( B. Drugs that inhibit or neutralize gastric acid secretion 1. Proton-Pump Inhibitors )PPI( 2. H2-receptor antagonists 3. Antacids C. Cytoprotective agents

II. Antiemetic Drugs III. Laxatives )Purgatives( 1. Bulk Laxatives 2. Osmotic Laxatives 3. Faecal Softeners 4. Stimulant Purgatives IV. Antidiarrhoeal agents 1. Antimotility agents 2. Adsorbents

I. Peptic Ulcer A peptic ulcer is an open sore or raw area in the lining of the stomach (gastric) or the upper part of the small intestine (duodenal).

Location of peptic ulcers

Peptic ulcer is the most common chronic illness of the digestive system , it recurs and affects at least 10% of the population in developed countries.

Peptic ulcer seen under endoscopy

Pathophysiology Peptic ulcer results when the normal balance of factors that damage or protect the gastrointestinal mucosal barrier is disturbed.

Infection of the gastric mucosa with Helicobacter pylori is generally considered a major cause.

Other factors: An imbalance between mucosaldamaging mechanisms )acid and pepsin( and mucosal-protecting mechanisms )mucus, bicarbonate, local synthesis of PGE2 and I2, and nitric oxide(. NSAIDs: decrease synthesis of PGs, abrogate mucosal protecting mechanisms.

Therapeutic Strategies For Treatment Of Peptic Ulcer To balance the aggressive factors )Helicobacter pylori infection, gastric acid secretion( against defensive or cytoprotective factors )bicarbonate secretion, mucus secretion, prostaglandins(. The goals of therapy are relief from pain, promotion of healing and prevention of recurrence.

 Gastric acid secretion by parietal cells of the gastric mucosa is controlled by acetylcholine, histamine, prostaglandins E2 and I2; and gastrin.  The binding of acetylcholine, histamine or gastrin results in the activation of a H+/K+-ATPase proton pump that secretes HCl into the lumen of the stomach.  Prostaglandins E2 and I2 diminish gastric acid production.

Acid secretion from the parietal cell. )a( Gastrin )G( and acetylcholine )Ach( stimulate the parietal cell directly to increase acid secretion, and also stimulate the enterochromaffin-like )ECL( cells to secrete histamine, which then acts upon the H2 receptors of the parietal cell )b(. The H+/K+ ATPase pump in tuberovesicles, which fuse with the canalicular membrane upon stimulation and release H+ into the lumen; Cl- is transported into the lumen by a separate carrier system. The parietal cell also has receptors for PGE2 and their stimulation inhibits acid secretion.

The important approaches in the treatment: 1. To eradicate the bacterial infection )most important(. 2. To reduce gastric acid secretion or neutralize it. 3. To provide agents that protect the gastric mucosa from damage.

A. Eradication of Helicobacter pylori infection )antimicrobial therapy(  H. pylori is a gram-negative rod that colonizes the mucus on the luminal surface of the gastric epithelium.  H. pylori infection causes inflammatory gastritis and is a putative contributor to peptic ulcer disease and gastric lymphoma.

Helicobacter Pylori )HP( Closely Associated with the Disease In 1983, researchers in Australia discovered a bacterium residing in the stomach of patients with chronic gastritis )inflammation of the stomach(. Further studies showed that this bacterium, subsequently called Helicobacter pylori )fig. 2(, was found in at least 90 per cent of patients suffering from peptic ulcers. The bacteria protect themselves from the high acidity in the stomach by producing 'urease' in the gastric mucosa, which is an enzyme that metabolizes urea and neutralizes gastric acid. They also elaborate various toxic substances which induce inflammation and cause cell damage in the stomach and the duodenum.

Helicobacter pylori seen under an electronic microscope

 Optimal therapy of patients with peptic ulcer disease )both duodenal and gastric ulcers( who are infected with H. pylori requires antimicrobial treatment.  Eradication of H. pylori reduces ulcer recurrence rates.

A variety of regimes that constitute 'triple therapy' are utilized as 'best' therapy )combination therapy( Metronidazole or amoxicillin plus clarythromycin plus omeprazole [a PPI )proton pump inhibitor(]

Given twice daily for 14 days

- Single agent therapy of H. pylori infections has proven less effective )20-40% eradication rates(

-Eradication rate is greater than 90% with the triple regime. -A two-week course of triple therapy is chosen based on efficacy and cost. - Elimination of the bacillus can produce longterm remission of ulcers. -Many patients can not tolerate metronidazole because of its side effects.

Other combinations: Clarythromycin, tetracycline and omeprazole

-In resistant cases, a PPI is also used as part of 'quadruple therapy' with both amoxicilin and clarythromycin plus metronidazole.

-Combinations of the H2 receptor antagonist ranitidine with bismuth are also available, given with clarythromycin.

Recommended regimens for H. pylorieradication Acid suppressantAntibiotic Amoxycillin Metronidazole

Clarythromycin

Esomeprazole ----20mg twice daily daily

1g twice daily ------

Lansoprazole----30mg twice daily daily 500mg twice daily daily

500mg twice daily

500mg twice daily

1g twice daily

400mg twice

-----

400mg twice

------1g twice daily

500mg 3 times daily 400mg twice daily

400mg twice

500mg twice daily

1g twice daily

Omeprazole ---20mg twice daily

500mg twice daily

500mg twice daily -----------

400mg 3 times daily

B. Drugs used to inhibit or neutralize gastric acid secretion

.1)Proton-Pump Inhibitors )PPI e.g.’s Omeprazole Lansoprazole

.1)Proton-Pump Inhibitors )PPI  Act by irreversible inhibition of the H+/K+-ATPase )the proton pump(, the terminal step in the acid secretory pathway.

 Administered orally as capsules containing entericcoated granules as degrade rapidly at low pH.

 Inhibit acid secretion by more than 90%. PPIs are more effective at healing ulcers than H2 receptor antagonists.

 PPIs have a longer duration of action than H2 receptor antagonists and are given once daily. Their longer duration of action is due to their irreversible inhibition of the H+/K+ ATPase pump.

The clinical uses of Omeprazole include a. Peptic ulcers resistant to H2-receptor antagonists. b. Reflux oesophagitis. c. As one component of therapy for Helicobacter pylori infection. d. Zollinger-Ellison syndrome

A major cause of peptic ulcer, although far less common than H.pylori or NSAIDS, is Zollinger-Ellison syndrome. A large amount of excess acid is produced in response to the overproduction of the hormone gastrin, which in turn is caused by tumors on the pancreas or duodenum. These tumors are usually malignant, must be removed and acid production suppressed to relieve the recurrence of the ulcers.

Drug interactions Omeprazole inhibits cytochrome P-450 liver enzymes and reduces the metabolism of drugs such as warfarin and phenytoin.

2. H2- receptor antagonists )e.g. Ranitidine, Cimetidine, Famotidine(

 Inhibit histamine actions at H2-receptors.

 Given orally and are well absorbed.  Suppression of acid secretion is less than with a PPI because only the histamine component is inhibited.

 Clinical use include peptic ulcer and reflux oesophagitis.

Drug interactions Cimetidine inhibits cytochrome P-450 liver enzymes and reduces the metabolism of drugs such as warfarin and phenytoin.

.3Antacids  Weak bases that act by neutralizing gastric acid.  The commonly used are salts of magnesium & aluminum such as aluminum hydroxide or magnesium hydroxide )milk of magnesia(.  Used to relieve the pain and not to heal the ulcer.  Usually advised to avoid concurrent administration of antacids and other drugs.

C.Drugs which protect the mucosa  Cytoprotective compounds: enhance the mucosal protection mechanisms and provide a physical barrier over the surface of the ulcer.

.1Bismuth chelate  Bismuth chelate or colloidal bismuth is used in combination regimens to treat H. pylori involvement in peptic ulcer.  Has toxic effects on the H. pylori.  Other actions: coating the ulcer base forming a protective barrier and stimulating bicarbonate secretion.  Bismuth produces black tongue and stools.

.2Sucralfate A complex of aluminum hydroxide and sulphated sucrose.  Forms complex gels with mucus, thus decrease the degradation of mucus by pepsin. Given orally.  Forms a viscous paste in the acid environment of the stomach, antacids reduce its efficacy.

3. Misoprostol - A stable analogue of prostaglandin E1. - Inhibits gastric acid secretion, increases the secretion of mucus and bicarbonate. - Only used to prevent gastric damage that can occur with chronic use of NSAIDs. - Produces uterine contractions )abortifacient(, contraindicated during pregnancy. Abuse to induce abortion. - Unwanted effects: diarrhoea and abdominal cramps.

Drug List Amoxicillin Clarythromycin Ranitidine Omeprazole Antacids (Magnesium hydroxide, Aluminum hydroxide), Bismuth chelate Sucralfate Misoprostol