H2 Blockers & Proton Pump Inhibitors PDF

Academic logo H2 Blockers & Proton Pump Inhibitors This lecture was presented by: Dr.Alaa Alanteet Dr. Mohammed Almutairi • • • • • • EDITING FILE Main text Male slide Female slide Important Dr, notes Extra info Objectives Understand the key points of pathophysiology of the peptic ulcer disease...

Academic logo H2 Blockers & Proton Pump Inhibitors This lecture was presented by: Dr.Alaa Alanteet Dr. Mohammed Almutairi • • • • • • EDITING FILE Main text Male slide Female slide Important Dr, notes Extra info Objectives Understand the key points of pathophysiology of the peptic ulcer disease Enumerate various classes of drugs used in peptic ulcer disease Know the characteristic pharmacokinetics, pharmacodynamics and side effects of drugs used in peptic ulcer disease. Know the cytoprotective drugs mainly misoprostol and its use in NSAIDsinduced peptic ulcer. Identify different antacids that are used to relief pain of peptic ulcer. Identify potential adverse drug interactions of anti-ulcer drugs. ‫★ = اﻻﺷﯾﺎء اﻟﻠﻲ رﻛز ﻋﻠﯾﮭﺎ دﻛﺗور اﻟﻌﯾﺎل‬ Summery Dr. Fouda Video For more quizzes & mnemonics check our channel :) ! Peptic Ulcer Disease (PUD) Definition A localized lesion of the mucous membrane of the stomach (gastric ulcer) or duodenum (duodenal ulcer), typically extending through the muscularis mucosa. Pathophysiology ◎ Old theory: is imbalance between: 1. Aggressive factors (acid & pepsin) 2. Defensive factors (e.g. prostaglandins, mucus & bicarbonate lyer) ◎ However, nowadays, it seems that H. pylori theory is very important. which is the major etiological factor in peptic ulcer disease (95% in duodenal and 80% in gastric ulcer). Defensive factors Aggressive factors ◎ Normal aggressive factors: 1. Mucus and bicarbonate* ion secretions protect mucosa 1. Hydrochloric acid (HCL) 2. Pepsin ◎ Destroys gastric and duodenal mucosa ◎ Aggravating causes of PUD 1. H. Pylori infection 2. NSAIDs*, Aspirin 3. cigarettes, alcohol 4. impaired regulation of acid-pepsin secretion. * because NSAIDs will ↓Prostaglandins which are protective factors ★ Could come as SAQ 2. Prostaglandins (PGE2 & PGI2) Protect mucosa by: ◦ Inhibiting acid secretion ◦ ↑ mucus & bicarbonate production ◦ Enhancing mucosal blood flow (V.D) ◎ Factors Impaired the defense: Ischemia, shock, delayed gastric emptying, duodenal-gastric reflux. * If there is an increase in an acidic substance in the body, the body will secrete an alkaline substance to do neutralisation the HCl * Click here for the slide picture Etiology of PU H. pylori infection Caffeine Alcohol Drugs (e.g. NSAIDs, corticosteroids) Smoking Hypersecretory states (Zollinger Ellison syndrome) Diet Genetic factors Peptic Ulcer Disease (PUD) Etiology of PU cont… Zollinger Ellison Syndrome ◎ is a disease in which Gastrin-secreting tumors (gastrinoma) cause the stomach to produce too much acid, resulting in peptic ulcers. Symptoms include abdominal pain and diarrhea. ◎ Gastrin produces: ◦ Parietal cell hyperplasia (trophic factor) ◦ Excessive gastric acid production ◦ Diarrhea Gastric secretions Pepsinogens (Chief cells) HCl and intrinsic factor (Parietal cells) Mucus, bicarbonate (mucus-secreting cells) Regulation of gastric secretions Parietal cells secrete acid in response to: 1 Ach (neurotransmitter): M3 receptors 2 Gastrin (hormone): CCK 2 receptors (cholecystokinin) 3 Histamine (local hormone): H2 receptors 4 Proton pump (H+/ K+ ATPase) Treatment of P.U Neutralizing Agents Mucosal cytoprotective agents “create a balance between acid & base” “used when the problem is in the defensive mechanism not in the HCl it self” antacids Prostaglandin analogues (NaHCO3) Hyposecretory drugs ↓ gastric acid secretion → Promote healing & relieve “when the cause is ↑ pain production of HCl itself” ◦ Proton pump inhibitors ◦ H2 receptor blockers ◦ Antimuscarinic drugs H. pylori infections: Eradication by Antibiotics & Antacid The prazoles ! Drug M.O.A Proton Pump Inhibitors (PPIs) Omeprazole Lansoprazole Pantoprazole Rabeprazole Acts by irreversible inhibition of proton pump (H+/ K+ ATPase) that is responsible for final step in gastric acid secretion from the parietal cell (they covalently bind to the pump) P.K. ◦ Given orally as enteric coated formulations (unstable in acidic medium in stomach) ◦ Pro-drugs (converted to the active form after administration in gastric gland -parietal cells-) ◦ Rapidly absorbed from the intestine then distributed in blood then activated in stomach ◦ Activated within the acidic medium of parietal cell canaliculi (the site of action) ◦ At neutral pH, PPIs are inactivated -it require Hcl (acid medium)◦ Should not be combined with H2 blockers -because they inhibit liver enzymes - or antacids because they reduce HCl → inactivation of PPIs ◦ Bioavailability is reduced by food → given one hour before the meal ◦ Have long duration of action (>12-24h) → once daily dose is sufficient ◦ Metabolized in the liver by Cyt-P450 (the cause of drug-drug interactions) → dose reduction is required in severe liver failure P.D. ◦ They are the most potent inhibitors of acid secretion available today. ◦ Produce marked inhibition of basal & meal stimulated-acid secretion (90-98%). ◦ Reduce pepsin activity. ◦ Promote mucosal healing & decrease pain. ◦ Proton pump inhibitors heal ulcers faster than H2 blockers and have H. pylori inhibitory properties (antibacterial action) ◦ Eradication of H. pylori (combined with antimicrobial drugs). ◦ Resistant severe peptic ulcer (4-8 weeks). ◦ PPIs are the most effective drugs however, we usually start with H2 blockers first (as PPIs are Uses very expensive & reserved for severe cases only). ◦ Gastroesophageal reflux disease (GERD) (both Prokinetic and Hyposecretory drugs can be used in GERD) ◦ Hypersecretory conditions as Zollinger Ellison syndrome & gastrinoma (first choice) (↓HCl production) ◦ CNS: headache ◦ GIT: diarrhea, abdominal pain ◦ Achlorhydria (absence of HCl) & Hypergastrinemia (Explanation: ↓HCL → ↑gastrin ADRs formation by feedback stimulation → accumulation of gastrin → hypergastrinemia) ◦ Gastric mucosal hyperplasia caused by hypergastrinemia ◦ Infections: caused by Achorohydra & Hypergastrinemia - Increased bacterial flora - Increased risk of community-acquired respiratory infections & nosocomial Pneumonia ◦ Long term use can lead to: (3↓) - ↓ Production of intrinsic factors from stomach wall → Vitamin B12 deficiency - ↓ Magnesium → Hypomagnesemia - ↓ Calcium → Osteoporosis -for Ca++ to be absorbed, it must dissolve in acidic medium◎Precaution: do not combine Omeprazole (CYP2C19 inhibitor) and clopidogrel (antiplatelet), because (CYP2C19) is required for activation of clopidogrel. H2 Receptor Blockers The tidines! Cimetidine Drugs M.O.A Most ADRs Ranitidine Famotidine Nizatidine Most potent Greatest Bioavailability They ★ reversibly and competitively block H2 receptors on the parietal cells ◦ Good oral absorption. ◦ Given before meals. ★ Famotidine is the most potent drug. ◦ Exposed to first pass metabolism, except nizatidine which has the greatest bioavailability ◦ Duration of action (4-12 h). ◦ Metabolized by liver. ◦ Excreted mainly in urine. P.K Uses ◦ GERD (heartburn / dyspepsia). ◦ Acute ulcer healing in moderate cases (if severe → PPI) - Duodenal ulcer (6-8 weeks). - Benign gastric ulcer (8-12 weeks). ◦ Prevention of bleeding from stress-related gastritis. ◦ Preanesthetic medication (to prevent aspiration pneumonitis). ◦ Post–ulcer healing maintenance therapy to prevent relapse. ◦ ↓ Basal and food stimulated-acid secretion. ◦ Block 90% of nocturnal acid secretion (which depend largely on histamine) & 60-70% of total 24hr acid secretion → better to be given before night sleep. ◦ ↓ pepsin activity. ◦ Promote mucosal healing & decrease pain. P.D ADRs ◦ GIT disturbance: Nausea & vomiting. ◦ CNS effects: Headache - confusion (in elderly, hepatic dysfunction and renal dysfunction) ◦ Bradycardia and hypotension in rapid I.V. (so must inject slowly) ◦ Only Cimetidine: all the below is in cimetidine 1. CYT-P450 inhibition → ↓ metabolism of warfarin, phenytoin, benzodiazepines 2. Endocrine effects: - Galactorrhea (Hyperprolactinemia) - Antiandrogenic actions (gynecomastia–impotence) due to inhibition of dihydrotestosterone binding to androgen Receptors. “★Cimetidine” ◎Precaution: dose reduction in severe renal or hepatic failure and elderly. H2 receptor blockers Cimetidine Ranitidine Famotidine Nizatidine Efficacy +++ +++ +++ +++ Potency + ++ +++ ++ Dose (Don’t memorize) 400 mg bid 150 mg bid 20 mg bid 150 mg bid CYT-P450 ++ - - - Antiandrogenic ++ - - - Drug interactions Many No No No Prostaglandin Analogues Misoprostol Drug MOA P.K ◦ Prostaglandin analogues (PGE1). (analogue means similar) ◦ ↓HCL secretion (because it ↓CAMP ) ◦ ↑ Protective measures (↑mucous / bicarbonate & gastric mucosal blood flow). Orally, must be taken 3-4 times/day. Uses ◦ Used for NSAIDs - induced peptic ulcer (NSAIDs ↓PG) ◦ Labor induction ADRs ◦ Abdominal cramps; diarrhea -Dr. Fouda: anything ↓HCl will cause diarrhea★ Uterine contraction (dysmenorrhea or abortion) (Because it is an abortifacient # in pregnancy) ★ Vaginal bleeding. Antacids (Inorganic Salts) Drug NaHCO3 CaCO3 Al(OH)3* Mg(OH)2* Sodium bicarbonate Calcium carbonate Aluminum hydroxide Magnesium hydroxide MOA Acts by direct chemical neutralization of HCl (because they alkaline) & ↓ pepsin activity. Uses ◦ Not considered a treatment of peptic ulcer. ◦ Used to relieve pain of peptic ulcer & for dyspepsia (temporary, no effect on secretions) ◦ All antacids ↓absorption of some drugs (↓HCl) as tetracycline, fluoroquinolones, iron ADRs ◦ Effective, but systemic alkalosis may occur. ★ # in CVD patients Na causes salt & water retention→ hypertension ◦ Hypercalcemia → Milk-alkali syndrome** ◦ ↓absorption of tetracycline ◦ Renal failure * Aluminum cause constipation while Magnesium cause diarrhea so they are mixed in 1 tablet to cancel out each other’s ADRs. Summary from slides ★ Constipation ◦ Hypophosphatemia (weakness, malaise, anorexia) ◦ Seizure in renal patients ★ Diarrhea ◦ Hypotension ◦ Cardiac arrest **Patient with PU usually administer large amount of milk & antacid to relieve symptoms of hyperacidity. excess milk → hypercalcemia excess antacid → alkalosis ★ Test for H. pylori prior to beginning therapy. ◦ Acid-reducing medications are prescribed in case of PUD without H pylori infections ◦ Acid-reducing medications for PUD include: - H2 receptor blockers. “‫”ارﺧص‬ - PPIs should be used for acute therapy only if H2RAs fail or cannot be used, or as part of treatment for H. pylori. “if not improved” ◦ Complete H. pylori eradication is required to prevent relapse. ◦ PUD with H pylori infections can be treated with triple therapy or quadruple therapy MCQ 1. Which of the following is an adverse effect associated with long-term use of proton pump inhibitors? A. Diarrhea B. Abdominal pain C. Hypomagnesemia D. Headache 2. Which H2 receptor blocker has the greatest bioavailability? A. Cimetidine B. Ranitidine C. Famotidine D. Nizatidine 3. What is the mechanism of action of proton pump inhibitors (PPIs)? A. Reversible inhibition of H2 receptors B. reversible inhibition of proton pump C. Irreversible inhibition of proton pump D. Inhibition of prostaglandin synthesis 4. Which of the following is considered a aggressive factor in peptic ulcer disease? A. Hydrochloric acid (HCl) B. Prostaglandins C. Mucus and bicarbonate D. Blood flow 5. Which of the following drugs is commonly used as a mucosal cytoprotective agent in peptic ulcer disease? A. Omeprazole B. Misoprostol C. Ranitidine D. Pantoprazole 6. Which of the following is a potential adverse effect associated with H2 receptor blockers? A. Hypomagnesemia B. Headache C. Diarrhea D. Thrombocytopenia 7. What is the main mechanism of action of antacids in relieving pain in peptic ulcer disease? A. Inhibition of acid secretion B. Neutralization of gastric acid C. Enhancement of mucus production D. Promotion of mucosal healing 1:C ,2:D ,3:C ,4:A ,5:B ,6:B ,7:B SAQ Mr. Johnson, a 55-year-old male, presents to the clinic with complaints of recurrent abdominal pain & discomfort. He reports a burning sensation in his stomach, especially after meals. He has a history of smoking and occasional alcohol consumption. Physical examination reveals epigastric tenderness. 01 1. What is the most likely diagnosis of Mr. Johnson's symptoms? 2. Name 2 aggressive factors that contribute to the development of peptic ulcer disease? 3. Which defensive factors protect the gastric mucosa from damage? 4. What is the major causative factor in peptic ulcer disease, particularly in duodenal ulcers? 5. How do NSAIDs contribute to the development of peptic ulcers? 6. Which class of drugs is known to inhibit acid secretion and promote mucosal healing in peptic ulcer disease? 7. What are the potential adverse effects of question 6? Ms. Rodriguez, a 40-year-old female, presents to the clinic with abdominal pain and black, tarry stools. She has a medical history of chronic NSAID use for her chronic arthritis. On examination, she appears pale and has a rapid heart rate. Abdominal examination reveals epigastric tenderness and a positive stool guaiac test. 02 1. What is the most likely diagnosis for Ms. Rodriguez's symptoms? 2. Explain the pathophysiology of the condition mentioned in question 1. 3. How do NSAIDs contribute to the development of the condition? 4. Name two defensive factors that protect the gastric mucosa. 5. Which drug class is commonly used for treating the condition mentioned in question 1? 6. Describe the mechanism of action of the drug in question 5? 7. What are the potential adverse effects of histamine H2 receptor blockers commonly used in the treatment of the condition? Case Scenario 1 Answers: 1. peptic ulcer disease. 2. hydrochloric acid (HCl) and pepsin. 3. mucus and bicarbonate ion secretions. 4. Helicobacter pylori (H. pylori) infection. 5. by ↓ production of prostaglandins, which are protective factors for the gastric mucosa. 6. Proton pump inhibitors (PPIs) 7. headache, diarrhea, abdominal pain, achlorhydria, hypergastrinemia, gastric mucosal hyperplasia, ↑ risk of infections, ↓ Vit B12, Mg, and Ca. Case Scenario 2 Answers: 1. gastrointestinal bleeding, possibly due to a peptic ulcer. 2. imbalance between aggressive factors (such as HCl & pepsin) and defensive factors (including mucus & bicarbonate) in the gastric mucosa → erosion & ulceration. 3. by ↓ production of prostaglandins, which are protective factors for the gastric mucosa. 4. mucus and bicarbonate secretions. 5. prostaglandins analogues (Misoprostol) 6. Prostaglandin analogues (PGE1), ↓HCL secretion,↑ Protective measures (↑mucous / bicarbonate & gastric mucosal blood flow). 7. Abdominal cramps; diarrhea, Uterine contraction (dysmenorrhea or abortion), Vaginal bleeding. Team Leaders Muhnnad Al-Otaibi Reema Almotairi Sarah Alajaji Team members Maryam Alghannam Alanoud Abdullah Aroub Almahmoud Nourah alarifi Layan Sulaiman Renad Alotaibi Aishah Boureggah Wafa Alakeel Areej Alquarini Wasan Alanazi Lama Alotaibi Ayedh Alqantash Jana alshiban Nazmi A Alqutub Layan Alruwaili Yousef badgesh Sara Alharbi Mohammed Alqutub Fatimah Alghamdi Fahad Aldhafian Special thanks to Norah Almania for the amazing logo