Drugs for peptic ulcer, emesis and reflux disorders

Dr. Rishi Pal

Assistant Professor

Physiology of gastric secretion

Stomach secretes 2-3 liters of gastric juice /day.

Chief/peptic cells secrete pepsinogen. Parietal or oxyntic cells secrete acid and IF. Superficial epithelial cells secrete alkaline

mucus and bicarbonates.

Regulation of gastric acid secretion

Ach Histamine Gastrin prostaglandin-E2

Phases of gastric acid secretion Basal, cephalic and hormonal Membrane bound proton pump (H+) K+ ATPase

Peptic ulcer

Damage to the mucosa and deeper tissue exposed to acid and pepsin is known as peptic ulcer.

Causes of peptic ulcer :-

1. H. pylori infection

2. Use of NSAIDS

3. Stress

Classification of the drugs used in peptic ulcer

Drugs that inhibit gastric acid secretion1. Proton pump inhibitors: omeprazole, esomeprazole,

lansoprazole, pantoprazole, rabeprazole.

2. H2-receptor antagonists: cimetidine, ranitidine,

3. famotidine, roxatidine,nizatidine

4. Antimuscarinic agents (anticholinergics): pirenzepine, telenzepine

5. Prostaglandin analogs: misoprostol, enprostil.

Anti-peptic ulcer drugs

Ulcer protective sucralfate, and bismuth subcitrate (CBS)

Drugs that neutralize gastric acid (antacids)

a) Systemic antacids: sodium bicarbonate and sodium citrate.

b) Non systemic antacids: magnesium hydroxide, magnesium trisilicate, aluminum hydroxide, and calcium carbonate.

Anti-peptic ulcer drug

Anti- H. pylori drugs Amoxicillin, tetracycline, clarithromycin,

metronidazole, tinidazole, bismuth subsalicylate, H2-antagonists and PPIs.

Proton pump inhibitors

Proton pump, K+-ATPase membrane bound enzyme play an important role in the final step of gastric acid secretion (basal and stimulated).

Omeprazole is the prototype drug: these are prodrugs and activated to sulfenamide at acidic pH. Activated form binds covalently with SH group of H+ pump and irreversibly inactivates it.

PPIs administered orally 30 min. before meal. Half life short (1.5 hr), acid secretion suppressed for upto 24 hr.

Enteric coated form or powder containing sodium bicarbonate.

i.v. formulations available for esomeprazole, lansoprazole, pantoprazole and rabiprazole.

They are highly bound to plasma proteins; extensively metabolized in liver and metabolites secreted in urine.

Therapeutic uses of PPIs

1. Peptic ulcer disease Duodenal ulcer disease Gastric ulcer Acute bleeding ulcer H. pylori-associated ulcer Stress ulcers (curling ulcers) NSAIDs induced ulcers 2. Gastroesophegial reflux disease (GERD)3. Zollinger’-Ellison syndrome.

Adverse effects of PPIs

Headache, diarrhoea and abdominal pain. Skin rashes and arthralgia. May decrease vit B12 absorption Increase rate of infection and fracture of bones. Drug interactions: omeprazole can inhibit metabolism

of phenytoin, warfarin, diazepam. PPIs decreases bioavailability of itraconazole, iron salts, etc

H2-Receptor antagonists

Mechanism of action: Competitively block H2 receptors on parietal

cells. Suppress all phases of acid secretion. Most effective in suppressing nocturnal acid

secretion. Less potent than PPIs.

Administered orally and well absorbed. Metabolized in liver. Cimetidine, ranitidine and famotidine

available for i.v. administration Nizatidine has high bioavailability (100%)

Therapeutic uses of H2 blockers

Peptic ulcer disease Duodenal ulcer disease Gastric ulcer Acute bleeding ulcer H. pylori -associated ulcer Stress ulcers (curling ulcers) NSAIDs induced ulcers 2. Gastroesophegial reflux disease (GERD)3. Zollinger’-Ellison syndrome.

Anticholinergic agents

Pirenzepine Telenzepine Selective M1-receptor blocker Inhibit acid secretion Not commonly used because of their low

efficacy and anticholinergic effects.

Prostaglandin analogues

Misoprostol effective orally for prevention and treatment of NSAID-induced duodenal ulcers.

Inhibit gastric acid secretion. Increase bicarbonate and mucus secretion. Common side effects: Diarrhoea and abdominal cramps. Containdicated in pregnancy

Ulcer protective

Sucralfate : it is complex aluminum hydroxide and sulphated sucrose.

Polymerized to form sticky gel that adheres to the ulcer base and protects it.

Form barrier against acid-pepsin.

Increase mucus-bicarbonate secretion.

Given orally empty stomach.

Reduced absorption of digoxin, tetracyclines, ketoconazole, fluoroquinolones. etc.

Concurrent use of PPIs, H2 blocker should be avoided.

Bismuth containing preparation

Bismuth salisylates and colloidal bismuth subcitrate.

React with protein in the base of ulcer and protect it from peptic digestion.

Stimulates secretion of PGE2, mucus and bicarbonate.

Anti-microbial effects against H. pylori.

Drugs that neutralized gastric acid

Ideal antacids1. Insoluble and neutralize acid

2. Should not liberate CO2

3. Non-absorbable

4. Should not disturb acid-base balance

Types of antacids

Systemic: sodium bicarbonate and sodium citrate

Non systemic: magnesium hydroxide, magnesium trisilicate, aluminum hydroxide gel and calcium carbonate.

Antifoaming agents

Methylpolysiloxane Oxethazaine Sodium alginate

Anti H. pylori agents

Gram negative, rod shaped bacteria associated with gastritis, duodenal ulcer, gastric ulcer and gastric carcinoma.

Cause mucosal inflammation Ammonia produced by urease activity

damage cells.

Combination therapy

To prevent or delay development of resistant organism.

Prevent relapse Promote rapid ulcer healing Eradicate H. pylori infection

Treatment for 1 or 2 weeks required

Triple therapy x 14 days Lansoprazole 30 mg BD+ clarithromycin 500 mg BD +

Amoxicillin 1 g BD

Quadruple therapy x 14 days lansoprazole 30 mg BD + bismuth subsalicylate 525 mg QID +

tetracycline 500 mg QID + Metronidazole 500 TDS

After completion of above regimen, PPIs should be continued for six more weeks.

Emetics and antiemetics pathways

Emetics and antiemetics

Mechanism of vomiting Pregnancy, infection, drugs, radiation, painful

stimuli, motion sickness, metabolic and emotional disturbances.

Neurotransmitters involved Ach, histamine,5HT and dopamine.

Emetics

Mustard Common salt Ipecac Apomorphine

Used for certain poisoning cases

Contraindications for emetics

Emetics Children Unconscious patient Corrosive and caustic poisoning CNS Poisoning Kerosene poisoning

Antiemetics

Classification of antiemetics Anticholinergics: scopolamine, dicycloamine Antihistamines (H1-blockers): dimenhydrinate,

diphenhydramine, cyclizine,meclizine, hydroxyzine,promethazine,doxylamine, cinnarizine

5HT3-receptor antagonists: ondansetron, granisetron, dolasetron, palonosetron

Antiemetics

Prokinetic agents: metoclopramide, domperidone

Neuroleptics: chlorpromazine, fluphenazin, prochlorperazine, haloperidol

Cannabinoids: dronabinol Adjuvant antiemetics: glucocorticoids,

benzodiazepines

Anticholinergics as antiemetic

Scopolamine for motion sickness, it blocks afferent impulses from vestibular apparatus to the vomiting center by its anticholinergic action.

Its sedative effects also contributes for its antiemetic effect.

Scopolamine not effective in other types of vomiting.

Antihistamine H1 blocker as antiemetic

Motion sickness, morning sickness, post operative and other types of vomiting.

Dimenhydrinate, diphenhydramine, doxylamine, promethazine, cyclizine, meclizine.

Have sedative and anticholenergic action. Meclizine has longer duration of action.

5HT3-receptor antagonist as antiemetic

Ondensetron is prototype drug Granisetron, dolasetron,palanosetron. Blockade of 5HT3 receptor on vagal afferent in the

gut also block 5HT3 receptors in CTZ & STN.

Used for anticancer drug-induced nausea and vomiting, effective in hyperemesis of pregnancy, postoperative and post radiation vomiting but not effective in motion sickness.

5HT3 receptor antagonist

Prokinetic drugs

Drugs promote coordinated movements of upper GIT and hasten gastric emptying are called prokinetic drugs.

Metoclopramide: D2 receptor antagonist Have central and peripheral action. Enhance release of Ach from myentric

neurons. Used in GERD

Mechanisms

Prokinetic effects

Neuroleptics

Prochlorperazine Used for vomiting due to systemic infection,

drugs, uraemia.

Cannabinoids: dronabinol used for cancer chemotherapy

Adjuvant antiemetics: glucocorticoids, benzodiazepines.

Anti emetics