2MB+GI+Pharmacology+2+-+acid+peptic.pdf

Drugs to treat acid-peptic disorders Prof. L.J. Egan Peptic Ulcer Disease Stomach Duodenum PUD: Location PUD: Pathogenesis  Normal defences against ulcers      Mucus Bicarbonate layer Blood flow Cell renewal Prostaglandins  Pathogenic factors    Excess acid Helicobacter infection NSAIDs Ul...

Drugs to treat acid-peptic disorders Prof. L.J. Egan Peptic Ulcer Disease Stomach Duodenum PUD: Location PUD: Pathogenesis  Normal defences against ulcers      Mucus Bicarbonate layer Blood flow Cell renewal Prostaglandins  Pathogenic factors    Excess acid Helicobacter infection NSAIDs Ulcer occurs when pathogenic factors outweigh defences Most commonly: Helicobacter infection and NSAIDs Less commonly: ↓ Mucous or blood flow Helicobacter pylori Gram – bacillus Spiral-shaped Motile Causes chronic gastritis Helicobacter pylori and PUD: the evidence    H. pylori is present in most patients who have a DU that is not related to NSAID use. H. pylori infection is detectable before the occurrence of DU and appears to be a risk factor for the disorder. Eradication of H. pylori prevents disease recurrence. Nobel Prize Medicine/Physiology 2005 "for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease" Dr. Barry Marshall PUD and NSAIDs    Compelling epidemiology links NSAID use to PUD NSAIDs decrease protective prostaglandin production in the stomach (systemic effect) Maybe additional direct irritant effect (local effect) Excess acid/other factors  Zollinger-Ellison syndrome  Gastrinoma Therapeutic strategies in PUD    Inhibit gastric acid Eradicate H. pylori infection Prevent NSAID complications Gastric acid secretion: mechanism Active transport Exchange pH 7 Exchange pH 1 Gastric acid secretion: regulation Acid secretagogues Histamine Acetylcholine Gastrin cAMP Ca++ Ca++ Inhibition of gastric acid    Antacids H2 receptor antagonists Proton pump inhibitors Antacids Antacids   Neutralize gastric acid and raise pH Salts of     Magnesium (diarrhoeagenic) Aluminium (constipating) Sodium hydroxide Useful preparations often combine various antacids together Maalox: Each 5 ml of oral solution contains: Aluminium hydroxide 175mg Magnesium hydroxide 200mg Also Gaviscon Rennies Others………. H2 receptor antagonists    Competitive antagonists of the receptor Inhibit basal acid secretion Decrease acid secretion in response to     Histamine Gastrin Acetylcholine Examples   Cimetidine Ranitidine Cimetidine and ranitidine    High oral bioavailability Usually given twice daily Low side effect profile    Cimetidine    Diarrhoea Rash Inhibits CYP450  Drug interactions (↑ Warfarin and TCA levels) Available OTC Renal excretion – reduce dose in renal insufficiency Nobel Prize for Medicine: James Black  At the beginning of the 1960s, James Black developed the drug propranolol, which is a beta-blocker that has a calming effect on the heart by blocking the receptor for adrenaline. At the beginning of the 1970s he developed the drug Cimetidine that suppresses the formation of gastric acid and is used to fight ulcers. Proton pump inhibitors      Omeprazole, lansoprazole, rabeprazole…….. Irreversible inhibition of the H+/K+-ATPase (the proton pump) Final common pathway of basal and induced acid secretion Prodrugs Weak bases, accumulate in the acid environment of the canaliculi of the stimulated parietal cell where they are activated Omeprazole     Prototype PPI Best taken 30 minutes before a meal Also IV Adverse effects      Very well tolerated Diarrhoea Allergic skin rash S-enantiomer available also (esomeprazole) Metabolized by CYP2C19 PPIs: Plasma half life & duration of action  Typical half life   Duration of action   1-1.5 hours 24-36 hours Mechanism    Canalicular trapping by protonation (weak base in an acidic pH) Irreversible inhibition of H+/K+ ATPase Requires new pump synthesis Acid suppression in PUD: long-term outcomes   Recurrence rate > 30% Requires long-term H2RA or PPI therapy    Expense Inconvenience Potential for side effects Concerning acid suppression, which statement is true? 1. 2. 3. 4. 5. Antacids block gastric acid secretion Cimetidine inhibits the final common pathway for acid secretion Acid inhibition causes malabsorption Omeprazole has a long plasma half life, explaining its 24h duration of action Omeprazole is trapped in the parietal cell and irreversibly inhibits the proton pump Therapeutic strategies in PUD    Inhibit gastric acid Eradicate H. pylori infection Prevent NSAID complications H. pylori eradication    Multi-drug regimens Variable efficacy Gradual increase in prevalence of drug-resistant strains Eradication regimens  PCN Tolerant    PPI b.d. Clarithromycin Amoxicillin  PCN allergic    PPI b.d. Clarithromycin Metronidazole 7-14 days therapy 80-90% eradication rate Therapeutic strategies in PUD    Inhibit gastric acid Eradicate H. pylori infection Prevent NSAID complications NSAIDs & PUD  NSAIDs      Aspirin Non-aspirin anti-inflammatory pain killers Used to treat pain, especially arthritic pain Block the actions of cyclo-oxygenase ↓ levels of PGE2   ↓ Mucous and bicarbonate secretion  acid production Misoprostol      Stable analogue of PGE2 Oral – produces high concentration at gastro-duodenal mucosa Mitigates harmful effects of NSAIDs on PG production in stomach Decreases rate of NSAID-induced ulceration Usefulness limited by   Diarrhoea Effects on cervix Pharmacological treatment of PUD: Summary  Identify cause of ulcer     Heal ulcer by suppression of gastric acid (PPI usually) Maintain healing by continued suppression of gastric acid   H. pylori NSAIDs Or Eradicate cause:   stop NSAIDs or co-administer misoprostol Eradicate H. pylori Falling incidence of PUD  Decrease due to    Cimetidine H2RA Omeprazole PPI H. pylori eradication Which statement is false? 1. 2. 3. 4. 5. Peptic ulcers can be caused by an infection with H pylori Eradication of H pylori with 2 antibiotics and a PPI is 100% effective Misoprostol blocks prostaglandin receptors NSAIDs decrease gastro-protective prostaglandins PPIs are available over the counter Gastro-oesophageal reflux disease     Incompetence of lower oesophageal sphincter (obesity, drugs, heredity…….) Reflux of acidic gastric contents into lower oesophagus Heartburn Complications   Stricture Barretts oesophagus & cancer Gastro-oesophageal reflux disease  Diagnosis    Heartburn symptoms Reflux oesophagitis Gold standard test   24 hour oesophageal pH De Meester score GORD: Treatment  Prevent acid reflux     Weight loss, drug avoidance, elevate head of bed etc Surgical fundoplication Increase tone of LOS Medical  Suppress gastric acidity (requires chronic therapy)   PPI H2RA THANKS FOR YOUR ATTENTION!