ANTI ULCER DRUGS References: Lippincott's Illustrated Reviews: Pharmacology, 4th Edition. Melmon and Morrelli's Clinical Pharmacology, 4th Edition Dr Manikandan,JIPMER, India, Antiulcer Drugs

ANTI ULCER DRUGS Expected learning outcomes: UNIT: 10 Expected learning outcomes: 1. Define ulcer and Describe pathophysiology of ulcer. 2. Compare and contrast Gastric and Duodenal ulcers. 3. Identify the classification of drugs used to treat PUD. 4. State prototype drugs used in each classification and their details. 5. Evaluate therapeutic goals for PUD in various clinical situations. 6. Apply pharmaceutical process for the welfare of the clients receiving drug therapy for PUD. References: Lippincott's Illustrated Reviews: Pharmacology, 4th Edition. Melmon and Morrelli's Clinical Pharmacology, 4th Edition Dr Manikandan,JIPMER, India, Antiulcer Drugs

Can you label the parts? 1 2 4 3

Overview of Ulcers Peptic ulcer is an open sore or raw area on the lining of stomach(Gastric ulcer), Or on the duodenum (Duodenal ulcer).   GASTRIC ULCER DUODENAL ULCER Site In stomach generally duodenal bulb Pain 15-30 minutes after meals, relieved by vomiting relieved by meals Vomiting common uncommon Pathology may be benign or malignant almost never malignant Gender More common in women More common in men

Auto regulation of acid secretion Food stimulates release of gastrin from antral G cells (G). Gastrin stimulates enterochromaffin-like cells (ECL) to release histamine, which stimulates parietal cells (P) in the gastric corpus to secrete acid. Acid stimulates release of somatostatin from somatostatin cells (S) in the antrum, inhibiting further gastrin release. BMJ 2001; 323 : 980 doi: 10.1136/bmj.323.7319.980 (Published 27 October 2001)

Ranitidine Proglumide Ca++ Ca++ Misoprostol Ranitidine See Animation PGE2 Gastrin Histamine _ + Proglumide ACh _ _ H2 M3 Adenyl cyclase + Gastrin receptor PGE receptor + + Ca++ ATP cAMP Ca++ + + + Protein Kinase (Activated) K+ H+ + K Parietal cell Proton pump _ Lumen of stomach Omeprazole _ Gastric acid Antacid

Can you identify these people ? Nobel prize Medicine – 2005 Discovery of H.pylori & its role in ulcer Barry J Marshall J. Robin Warren

Antacids Duration of action : 30 min when taken in empty stomach Weak bases that neutralise acid Also inhibit formation of pepsin (As pepsinogen converted to pepsin at acidic pH) Present day antacids : Aluminium Hydroxide Magnesium Hydroxide OTC drug for symptomatic relief of dyspepsia Duration of action : 30 min when taken in empty stomach 2 hrs when taken after a meal Side effects : Al3+ antacids – constipation (As they relax gastric smooth muscle & delay gastric emptying) Mg2+ antacids – Osmotic diarrhoea . In renal failure Al3+ antacid – Aluminium toxicity & Encephalopathy

Antacids – Common additives & Interactions Simethicone – Decrease surface tension ,thereby reduce bubble formation Added to prevent reflux . Alginates- Form a layer of foam on top of gastric contents & reduce reflux Oxethazaine – Surface anaesthetic Adsorb drugs and form insoluble complexes that are not absorbed . Clinical importance : Interactions can be avoided by taking antacids 2 hrs before or after ingestion of other drugs .

Now answer this question Is it rational to combine aluminum hydroxide and magnesium hydroxide in antacid preparations ? Combination provides a relatively fast and sustained neutralising capacity . (Magnesium Hydroxide – Rapidly acting Aluminium Hydroxide - Slowly acting ) Combination preserves normal bowel function. (Aluminium Hydroxide – constipation Magnesium hydroxide – diarrhoea )

Histamine H2 Receptor Antagonist Reversible competitive inhibitors of H2 receptor Highly selective, No action on H1 or H3 receptors Very effective in inhibiting nocturnal acid secretion (as it depends largely on Histamine ) Modest impact on meal stimulated acid secretion (As it depends on gastrin, acetyl choline and histamine) H2 Blockers–Side effects & Interactions Extremely safe drugs Cimetidine causes gynecomastia, galactorrhea (as it is antiandrogenic & increases prolactin level) Cimetidine inhibits CYP450 & increases conc. of Warfarin, Theophylline, Phenytoin, Ethanol.

Now answer this question Your friend wants to take a H2 antagonist before he takes alcohol to avoid gastric irritation .He consults you .Which H2 antagonist will you ask him to take ? Answer : Famotidine Explanation : All H2 antagonist except famotidine inhibit gastric first pass metabolism of ethanol and increase its bioavailability .

Proton Pump Inhibitors Most effective drugs in antiulcer therapy Irreversible inhibitor of H+ K+ ATPase Prodrugs requiring activation in acid environment Weakly basic drugs & so accumulate in canaliculi of parietal cell Activated in canaliculi & binds covalently to extracellular domain of H+ K+ ATPase Acid secretion resumes only after synthesis of new molecules Half life is about 1.5 hrs

Proton Pump Inhibitors Now answer this question Omeprazole 20 mg o.d. Esomeprazole 20 - 40 mg o.d. Lansoprazole 30 mg o.d. Pantoprazole 40 mg o.d. Rabeprazole 20 mg o.d. Now answer this question It is given in the previous slides that the half life of proton pump inhibitors is 1.5 hours only and these drugs are generally given once daily. How this can be justified ? Answer : P.P.I - Irreversible inhibitors of H+K+ATPase (Hit and run drugs)

Proton Pump Inhibitors – Kinetics Given as enteric coated granules in capsule or enteric coated tablets Pantoprazole also given intravenously Half life – 1.5 hrs Since it requires acid for activation - given 1 hr before meals Other acid suppressing agents not coadministered

P.P.I. – Side effects & Interactions Extremely safe drugs Causes hypergastrinemia which leads to carcinod tumor in rats But no evidence of such tumors in man Inhibit CYP 450 & hence metabolsim of warfarin, phenytoin, etc Pantoprazole & Rabeprazole have no significant interactions

Now Answer this Question A patient comes to your clinic at midnight complaining of heart burn. You want to relieve his pain immediately. What drug will you choose? Answer : Antacids Explanation : Antacids neutralise the already secreted acid in the stomach. All other drugs act by stopping acid secretion and so may not relieve symptoms atleast for 45 min.

Mucosal Protective Agents Sucralfate Salt of sucrose complexed to sulfated aluminium hydroxide In acidic pH polymerises to viscous gel that adheres to ulcer crater Taken on empty stomach 1 hr. before meals Concurrent antacids, H2 antagonist avoided ( as it needs acid for activation ) Sucralfate Misoprostol Colloidal Bismuth compounds

Mucosal Protective Agents Colloidal Bismuth Compounds Misoprostol PGE1 analogue Modest acid inhibition Stimulate mucus & bicarbonate secretion Enhance mucusal blood flow Approved for prevention of NSAID induced ulcer Diarrhoea & cramping abd. pain – 20 % Not so popular as P.P.I are more effective & better tolerated Colloidal Bismuth Compounds Coats ulcer, stimulates mucus & bicarbonate secretion Direct antimicrobial activity against H.pylori May cause blackening of stools & tongue Not used for long periods – bismuth toxicity

Now answer this question A pregnant lady (first trimester) comes to you with peptic ulcer disease. Which drug will you prescribe for her ? Answer : Antacids or Sucralfate Explanation ; H2 antagonists cross placenta and are also secreted in breast milk. Safety of Proton pump inhibitors not established in pregnancy. Misoprostol causes abortion .

Triple Therapy The BEST among all the Triple therapy regimen is Omeprazole / Lansoprazole - 20 / 30 mg bd Clarithromycin - 500 mg bd Amoxycillin / Metronidazole - 1gm / 500 mg bd Given for 14 days followed by P.P.I for 4 – 6 weeks Short regimens for 7 – 10 days not very effective

Triple Therapy vs Sequential Therapy The BEST Triple therapy regimen Omeprazole / Lansoprazole - 20 / 30 mg bd Clarithromycin - 500 mg bd Amoxycillin / Metronidazole- 1gm / 500 mg bd Recent Meta analysis: 25% of patients are resistant Sequential Therapy: PPI+Amoxycillin for first 5 Days AND PPI+Clarithromycin+Tinidazole/Metronidazole for next 5 Days Sequential therapy is better than Triple therapy. Nadim S. Jafri Ann Intern Med. 2008;148:923-931.

Quadruple Therapy Given when Triple Therapy fails Omeprazole / Lansoprazole - 20 / 30 mg bd Bismuth subsalycilate - 2 tabs qid Metronidazole - 250 mg qid Tetracycline - 500 mg qid

Now you have learnt about drugs used for treating peptic ulcer Now you have learnt about drugs used for treating peptic ulcer ? Are there any drugs that can cause peptic ulcer ? Drugs causing peptic ulcer Non Steroidal Anti Inflammatory Drugs (NSAIDs) Glucocorticoids Cytotoxic agents

Antiemetics References: Lippincott's Illustrated Reviews: Pharmacology, 4th Edition. Melmon and Morrelli's Clinical Pharmacology, 4th Edition Dr Manikandan,JIPMER, India, Antiulcer Drugs

UNIT 11: Antiemetic Drugs UNIT INSTRUCTIONAL OUTCOMES: At the end of this unit, the student should be able to, Discuss pathophysiology of vomiting List drugs used as antiemetic Drugs State vital information about the drugs used as antiemetic Drugs Apply pharmacological knowledge gained in the clinical scenario.

Pathophysiology of Emesis Chemoreceptor Trigger Zone (CTZ) Cerebral cortex Cancer chemotherapy Opioids Smell Sight Thought Anticipatory emesis Chemoreceptor Trigger Zone (CTZ) Vestibular nuclei Vomiting Centre (medulla) Motion sickness Muscarinic Histaminic H1 (Outside BBB) Muscarinic, 5 HT3 & Histaminic H1 Dopamine D2 5 HT3,,Opioid Receptors Chemo & radio therapy Gastroenteritis Pharynx & GIT 5 HT3 receptors

Now answer this question Which group of drugs can be used as antiemetics ? Serotonin 5 HT3 Antagonists Dopamine D2 Antagonist Anticholinergics H1 Antihistaminics Cannabinoids

Serotonin 5 HT3 Antagonist Potent antiemetics Even though 5 HT3 receptors are present in vomiting centre & CTZ, the antiemetic action is restricted to emesis caused by vagal stimulation. High first pass metabolism Excreted by liver & kidney No dose reduction in renal insufficiency but needed in hepatic insufficiency Given once or twice daily – orally or intravenously.

Drugs Available Ondansetron 32 mg / day Granisetron 10 mg / kg / day Dolasetron 1.8 mg / kg / day Indications Chemotherapy induced nausea & vomiting – given 30 min. before chemotherapy. Postoperative & postradiation nausea & vomiting Adverse Effects Excellent safety profile Headache & constipation All three drugs cause prolongation of QT interval, but more pronounced with dolasetron.

Dopamine D2 Antagonist Antagonise D2 receptors in CTZ. Drugs available Metoclopramide 2.5 mg b.d Domperidone 10 mg b.d Both drugs are also prokinetic agents due to their 5 HT4 agonist activity. Domperidone – oral ; Metoclopramide – oral & i.v Metoclopramide crosses BBB but domperidone cannot.

Phenothiazines & Butyrophenones Prochlorperazine Promethazine Phenothiazines are antipsychotic with potent antiemetic property due to D2 antagonism. Butyrophenone Droperidol Droperidol used for postop. nausea & vomiting, but cause QT prolongation.

H1 Antihistaminics Most effective drugs for motion sickness Drugs available Meclizine Cyclizine Dimenhydrinate Diphenydramine Promethazine – Used in pregnancy, used by NASA for space motion sickness

Anticholinergics Cannabinoids Scopolamine (hyoscine) – used as transdermal patch for motion sickness Cannabinoids Dronabinol – used as adjuvant in chemotherapy induced vomiting.It is a psychoactive substance Nabilone What’s Latest? Aprepitant…(nk-1 receptor Blocker) Rational Thinking: Atropine b. Scopolamine (TDP)

Summary Source: Henry Hitner and Barbara Nagle, Pharmacology, An Introduction, 6th Edition

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