Pharmacology of GIT

Assistant Professor Dr. Shamil AL-Neaimy MBchB, MSc, PhD Dept Assistant Professor Dr. Shamil AL-Neaimy MBchB, MSc, PhD Dept. of Pharmacology College of Medicine University of Mosul

المعدة بيت الداء والحمية رأس الدواء المعدة بيت الداء والحمية رأس الدواء

Peptic ulcer Psychosomatic disorder in about 10% of adults, due to imbalance between gastric acid secretion and mucosal resistance (production of mucus and bicarbonate).

Predisposing factors 1- H. Pylori : in 70% of G. U and 90% of D Predisposing factors 1- H. Pylori : in 70% of G.U and 90% of D.U 2- Stress 3- Diet: spices, pickles 4- Alcohol 5- Smoking 6- Drugs: NSAIDs (Aspirin)

Classification of treatment of P.U: Four groups of drugs 1- Antimicrobial therapy 2-Drugs that decrease gastric acid secretion. 3- Drugs that neutralize gastric acid. 4- Drugs that enhance mucosal defense.

Antimicrobial agents Optimal therapy for patients with peptic ulcer disease who are infected with H. pylori requires antimicrobial treatment. Eradication of H. pylori results in rapid healing of active peptic ulcers and low recurrence rates.

Currently, either triple therapy consisting of a PPI with either metronidazole or amoxicillin plus clarithromycin, or quadruple therapy of bismuth subsalicylate and metronidazole plus tetracycline plus a PPI, are administered for a 2-week course. This usually results in a 90 percent or greater eradication rate.

I- Drugs that decrease gastric acid secretion: 1- H2 receptor blockers 2- Anticholinergics (Antimuscarinic) 3- Proton pump inhibitors

H2- receptors blockers: Mechanism of Action: H2 blockers inhibit acid secretion stimulated by histamine, gastrin, and Cholinomimetics (basal, food and vagal stimulated). They reduce volume of acid secreted and concentration of pepsin..

The gastric acid secretion is under control of three agonists: Histamine, Ach, and Gastrin, that they have receptors for each one on the parietal cells.

Histamine is the final mediator (1st messenger) in the process of gastric acid secretion, so it increases the affinity of M3 and G - receptors for Ach and gastrin respectively leading to stimulation of 2nd messenger (cyclic AMP, cyclic GMP, and calcium Ion) resulting in acid secretion

1x 4-10x 20-50x Daily dosage Relative potency Trade name H2-receptor Blockers Daily dosage Relative potency Trade name Scientific name 800 mg H.S or 400 mg Bid 1x Tagamet Cimetidine 300 mg H.S or 150 mg Bid 4-10x Zantac Ranitidine 40 mg H.S or 20 mg Bid 20-50x Pepcid Famotidine Axid Nizatidine

Pharmacological Actions: i. GIT: - Decrease volume of gastric acid secretion and concentration of pepsin (90% of the basal, food stimulated and nocturnal) after single dose. ii. CVS: (in therapeutic doses) - Cimetidine and ranitidine have little effect on C.O and B.P - Famotidine decreases C.O - Nizatidine decreases H.R and C.O

iii. Immune system: - enhancing certain immune response by blocking histamine receptors that decreases mediators release mast cells and basophiles. iv. Effects not related to H2 blocking: - Cimetidine binds to androgen receptors causing gynaecomastia. - Cimetidine and (to a lesser extent) ranitidine inhibit cytochrome P450 system of enzymes but not famotidine and Nizatidine. - All of the drugs (except famotidine) inhibit first pass metabolism of ethanol in the liver.

Indications: 1- G.U 2- D.U 3- Gastro esophageal reflex disease (GERD). 4- hypersecretory conditions : a- Zollinger – Ellison syndrome ( gastrin secreting tumor) b- systemic mastocytosis c- multiple endocrine neoplasia ( MEN ) . 5- pre-anesthesia: (emergency and labour) to decrease incidence of mendelson's syndrome (aspirating gastric acid causing aspirating pneumonitis). 6- Controlling symptoms of gastric carcinoma. 7- Hiatus hernia (H.H). 8- Stress ulcer. 9- Iatrogenic ulcer.

Side Effects: I- CNS: sedation, delirium, slurred speech. Associated mostly with cimetidine, rarely with ranitidine, and not with famotidine and Nizatidine. II- ENDOCRINE: (only cimetidine) antiandrogenic effect in male (Gynaecomastia, low sperm count, and impotence), in female ( galactorrhea ).

III- BLOOD: blood dyscrasia (agranulocytosis, thrombocytopenia Neutropenia and aplastic anemia) associated mostly with Cimetidine, rarely with ranitidine, and not with famotidine and Nizatidine. IV- LIVER: Cimetidine --------- reversible cholestatic effect Ranitidine --------- reversible hepatitis +/- jaundice Famotidine and Nizatidine ------ changing liver enzyme test.

Drug Interactions: I- All (except famotidine) inhibit first pass effect of ethanol that increases its bioavailability (toxicity). II - Cimetidine inhibits P450 cytochrome system leading to increase toxicity of : calcium channel blockers , benzodiazepines , tricyclic antidepressants , propranolol ,labetolol , Xylocaine , quinidine , thiophylline , caffeine , warfarine , and metronidazole.

Proton pump inhibitors: Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole Esomeprazole, MOA: They inhibit gastric acid secretion by inhibiting H+/K+ ATPase enzyme in parietal cells Indications: P.U, GERD, Zollinger – Ellison syndrome.

Side Effects: 1.gastric carcinoid tumors 2.low vitamin B12 3.incomplete absorption of calcium carbonate products 4.Erythema multiformis (E.M), gynecomastia, bronchospasm, leukopenia, thrombocytopenia, photosensitivity, Alopecia.

II- Neutralization of gastric acid: Antacids: Basic substances that decrease acidity by neutralizing HCL, thus protecting ulcer from acid and pepsin by increasing PH (as pepsin is inactive when PH > 5), also pepsin is inactivated by Al and Mg salts. .

MOA They provide mucosal protection either through stimulation of P.G production or by binding to identified injurious substance

Classification: - Systemic: absorbable but cause metabolic alkalosis (sodium bicarbonate) -Non -systemic: non significantly absorbed, not affect acid – base Balance (Mg and Al salts) Amount of antacid given depends on: 1- The rate of acid secretion 2- Presence of food 3- Rate of gastric emptying

III-Enhancement of mucosal resistance: 1- Bismuth chelate: -Acts by chelating with protein in the ulcer base to form a coat that protects from acid, bile and pepsin. -Stimulation of production of mucous and prostaglandin synthesis -Also has antimicrobial activity against H. pylori. .

Indications: D. U and G. U (therapeutic activity equal to H2 blockers Indications: D.U and G.U (therapeutic activity equal to H2 blockers. But relapse of ulcer less than H2 blockers) Side Effects: Darkening of tongue, teeth and stool. Arthropathy and encephalopathy. Contraindications: Renal failure and pregnancy.

2. Sucralfate: MOA: Stimulate prostaglandin synthesis and bind to pepsin and bile acid. Indications: P.U, GERD, GI bleeding, stress ulcer and U.C Side Effects: Constipation, vertigo and skin rash Contraindications: Renal failure Drug interaction: Impaired absorption of digoxin, warfarin, Iron, and NSAIDs

3. Misoprostol: Synthetic analog of PGE1, it prevents G 3. Misoprostol: Synthetic analog of PGE1, it prevents G.U in patients taking NSAIDs, chronic D.U and G.U. MOA: It inhibits acid secretion stimulated by histamine Side Effects: Dysmenorhea and rash Contraindications: Pregnancy