GIT Drugs PDF

# Peptic Ulcer & Gastrophagial Reflex ## Main Causes of Peptic Ulcer (2) 1. Gram negative helicobacter pylori (H.pylori) 2. NSAID ## Treatment Approach 1. Eliminating H.pylori infection 2. Reduce gastric acid secretion (PPIs, H₂ receptor antagonists) 3. Protecting gastric mucosa (Misopr...

# Peptic Ulcer & Gastrophagial Reflex ## Main Causes of Peptic Ulcer (2) 1. Gram negative helicobacter pylori (H.pylori) 2. NSAID ## Treatment Approach 1. Eliminating H.pylori infection 2. Reduce gastric acid secretion (PPIs, H₂ receptor antagonists) 3. Protecting gastric mucosa (Misoprostol & Sucralfate) ## Antimicrobial Agents - Usually combined therapy - First line therapy is a quadruple of: - Bismuth subasalicylate - Metronidazole - Tetracylicne with PPI (Proton pump inhibitors) - Triple therapy consists of PPI, Amoxicillin (Metronidazole in penicillin allergy), Clarithromycin ## H₂ Receptor Antagonists - Gastric acid secretion stimulators are: ACH, Histamine, Gastrin - Activating ptn kinase leading to H⁺/K⁼ adenosine triphosphate (ATPase) proton pump to secret hydrogen in exchange with K ions into the stomach lumen - 70% of gastric acid secretion is reduced ### MOA - Selective H2 receptors (no H1 effects) - Competitve antagonism with histamine - Reversible ### Therapeutic Uses (3) 1. Peptic ulcer: Reccurance in common in H.pylori is used as monotherapy, NSAIDs give PPIs (more effective) 2. Acute stress ulcers: I.V, tolerance occurs fast (replace with PPIs) 3. Gastrophagial reflux disease(GERD): Effective, decrease acid secretion (takes 45 minutes to relive symptoms), PPIs is the best choice ### Kinetics - Administered orally - Highly soluble (brest milk, placenta) - Excreted in urine - I.V forms available in Cimetidine, Ranitidine, Famotidine ### Adverse Effects - Ciametidine endocrine effects (e.g. gynaecomastia, galactorrhe *continous release of milk*) - CNS effects *increased in elderly usually after I.V* - Interfere with drugs requiring acid environment - Ciametidine inhibits many CYP450 isoenzymes (other drug accumulation e.g. warfarin, phenytoin, clopidogrel) ## H⁺/K⁺ ATPase Pump Inhibitors (PPIs) - Supress the secretion of hydrogen ions into the gastric lumen - They work on the final step of gastric acid secretion ### Actions - Prodrugs - Absorbed and activated in the parital cells - 90% of gastric acid secretion is inhibited - Omeprazole combined with CHOO3 for faster absorption ### Therapeutic Uses - Preffered in GERD, Erosive esophagitis, Active duodenal ulcer, Pathologic hypersecretory conditions (Zollinger-Ellison syndrome) - Reduce bleeding risk in ulcers due to Aspirin ir NSAID - Stress ulcer prophlyaxis (e.g. before surgery stress) - Must be combined with Antimicrobial in H.pylori ### Kinetics - Administered orally - Before food (30 - 60 min) Except Dexlansoprazole - I.V forms are available in Esomeprazole, Lansoprazole, Pantoprazole - Low half life BUT Long duration of action (covalent bond) ### Adverse Effects - CYP2C19 is inhibited by Omeprazole, Esomeprazole - Bone fractures (> 1 year) - Decrease vit B12 absorption (due to interference with intrinsic factor secretion which need acid environment) - Decrease Calcium absorption (due to High gastric pH) *calcium citrate as a supplement* - Diarrhea - Clostridium difficile colitis - Hypomagnesmia - Pneumonia ## Prostaglandins (Misoprostol) - Prostaglandin E is produced by gastric mucosa and inhibits acid secretion and stimulates mucus and bicarbonate secretion ### Actions - Misoprostol works on prostaglandin E1 - Prevent NSAID induced gastric ulcer - Can be used as prophylactic treatment - Contraindicated in pregnancy (uterine contractions-> miscarriage) - Diarrhea (common) ## Antacids - Weak bases - Inhibit pepsin by increasing pH >4 ### Chemistry - Food dependence mechanism - Food increase the duration of action - May cause alkalosis and hypernatriemia ### Therapeutic Uses - Symptomatic relief in peptic ulcer, heart burn, and GERD - After meal (max efficacy) - Calcium carbonate used to prevent osteoporosis ### Adverse Effects - Constipation in Aluminium hydroxide - Diarrhea in Magnesium hydroxide - Accumulation of cations may occur in renal imperment ## Mucosal Protective Agents (Cytoprotecive Compounds) ### Scralfate - Aluminium hydroxide and sulfated sucrose - Creates a physical barrier to protect the ulcer from pepsin and acid - Acidic environment is a must (not combined with PPIs, H₂, antagonists, antacids) - Multiple daily dosing ## Bismuth Subasalicylate - One of the quadruple therapy that is used to treat H.pylori related peptic ulcer - Pepsin inhibitor - Increase mucus secretion - Interacts with glycoproteins in necrotic mucosal tissue to coat and protect ulcer ## Drugs Control Chemotherapy Induced Nausea and Vomiting (CINV) ### Mechanisms That Trigger Vomiting - Area postrema (CVO) *chemoreceptor trigger zone CTZ* - Lateral reticular formation of the medulla (motor control) ### Vomiting Mediators - D2 - 5-HT3 - *Chemotherapy may damage GIT directly= vomiting response* ## Antiemetic Drugs (Anti-vomiting) ### Phenothiazines (Prochlorperazine) - Block dopamine receptors in the CTZ - Effective in low or moderately emetogemic chemotherapeutic agents ### 5-HT3 Receptor Blockers - Periphery block (visceral vagal afferent fibers) - CTZ block - Long duration of action - I.V and oral forms - Prophylactic prior chemotherapy, effective in all grades of emetogenic therapy - Extensively metabolized in liver, excreated in urine - Ondansetron, Granisetron prevent emesis in 50-60% Cisplatin treated patients - Ondansetron dosage adjustment in hepatic insufficiency - QT prolongation in high dose of Ondansetron and Dolasetron - I.V. Dolasetron is prohibited in CINV prophylaxis ### Substituted Benzamides (Metoclopramide) - Inhibits dopamine in the CTZ - High dose to be effective against the etmogenic cisplatin 30-40% - Adverse effects include (Extrapyramidal symptoms) - Enhance gastric motility ### Butyropenones (Droperidol, Haloperidol) - Block dopamine receptors - Droperidol used in sedation - May prolonge QT interval ### Benzothiazepines (Lorazepam, Alprazolam) - Low potency - Used in anticipated vomiting - Contraindicated with alcohol (CNS sedation) ### Corticosteroids (Dexamethasone, Methylprednisolone) - Effective against mildly to moderately emetogenic chemotherapy - Block prostaglandins (main mechanism is unknown) ### Substance P/Neurokinin-1 Receptor Antagonists - They target the neurokinn receptor in the vomiting center and block the actions of sbstance P - Highly or moderately emetogemic chemotherapy - Usually combined with Dexamethasone and 5-HT3 antagonists - Effective for the delayed phase of CINV (after 24h of chemotherapy) - Aprepitant, Rolapitant metabolized by CYP3A4 - Aprepitant is an CYP3A4 and CYP2C9 inducer - Rolapitant is an CYP2D6 inhibitor - Adverse effects include: Fatigue, Diarrhea, Abdominal pain, hiccups ## Antidiarrheals ### Antimotility Agents - Control diarrhea - Inhibit ACh release - Loperamide in acute diarrhea (including traveler's diarrhea) - May cause Toxic megacolon (prohibited in childrens and patients with severe colitis ### Adsorbents (Aluminum hydroxide, Methylcellulose) - Control diarrhea - Have many mechanisms: - Absorb intestinal toxins or microorganisms - Coat or protect the intestinal mucosa. - Less effective than antimotility, may interfere with the absorption of other drugs ### Agents That Modify Fluid and Electrolyte Transport (Bismuth subsalicylate) - Used in traveler's diarrhea - Decrease fluid secretion in the bowel - May cause black tongue and stools ## Laxatives (Anticonstipation) ### Irritants And Stimulants (3) 1. Senna - Bowel evacuation within 6-12h - Cause water and electrolye secretion into the bowel - Can be combined with stool softener (Docusate) - Useful in opiod induced constipation 2. Bisacodyl - Available as suppositories & entric coated tablets - Potent colon stimulant -Acts directly on nerve fibers in the mucosa of the colon 3. Castor oil: - Broken down in the small intestine to ricinoleic acid-> - Very irritating to the stomach - Prohibited in pregnancy (uterine contractions) - Not commonly used ### Bulk Laxatives (Methylcellulose, Psyllium) - Form gels in the large intestine - Cause water retention amd intestinal distension - Leading to increasing peristalsis activity - Psyllium may reduce absorption of other oral drugs (2hour interval) ### Saline and Osmotic Laxatives - Increase intistinal activity by osmotic mechanism - Electorlytes solutions with Polyethylene glycol (PGE) used as colonic lavage, used to prepare the gut for radiological or endoscopic procedures - PEG powder only used as laxative (less potent to others) - Lactulose can't be hydrolized by Gl enzymes; oral form reach the colon and degrade by colonic bacteria into (lactic, formic, acetic acids) - Lactulose also used in heptic encephalopathy (reducing ammonia level) ### Stool Softener (Docusate) - Mixed with the stool -> softer feces - Docusate sodium or calcium forms are available - Days to action - Prohibited with mineral oil (oil absorption risk) ### Lubricant Laxatives (Glycerin suppositories, Mineral oil) - Facilitate stool passage - Mineral oil is administrated orally in upright position (to avoid aspiration-> lipid Pneumonia) ### Chloride Channel Activators (Lubiprostone) - Increase fluid secretion in the interstitial lumen - Used in Chronic constipation, Irritable bowel syndrome with constipation (IBS-C) - No drug-drug interactions ## Inflammatory Bowel Disease (IBD) - Immune mediated GIT inflammation (due to bacteria....) - IBD subtype are (Crohn's disease *CD*, Ulcerative colitis *UC* - CD affect any portion of the GIT from motuh to anus - CD inflammation characterized in the mucosal layer ## Drugs Used in IBD (4) ### 1. 5-Aminosalicylates (5-ASA) - Two compunds are availave AZO compounds and MESALAMINE compounds - AZO compunds are prodrugs including Balsalazide, Osalazine, Sulfasalazine - Sulfasalazine is a prodrug consisting 5-ASA linked to sulfapyridine - Sulafpyridine= adverse effects #### Actions - Anti-inflammatory and immunosupressive properties - Main mechanism is Unknown #### Therapeutic Uses - Mainstay of treated in UC - This class is not effective in CD #### Kinetics - Mesalamine kinetics vary and depends on the route of administration - Absorption increase in severe disease and decrease with decreasing pH - Local effect in UC - Sulfasalazine with sulfapyridine orally absorption from (60 to 80%) #### Adverse Effects - Adverse effects in Sulfasalazine occur in up to 45% of patients (due to Sulfapyridine) - Sulfasalazine impair male fertility - Sulfasalazine inhibits interstitial folate absorption - Headache, Nause, Fatigue are common & dose related in 5-ASA - Severe adverse effects include: hemolytic anemia, myelosuppression, hepatitis, pneumonitis, neurotoxicity, rash, Stevens-Johnson syndrome - STOP treatment in the first sign of skin rash or hypersensitivity ### 2. Corticosteroids - Budesonides have minimal systemic effects (low bioavailability-> high 1st pass metabolism) - Budesonides delayed release is delivered in ileum and proximal large bowel used in ileocecal CD - Budesonides extended release is delivered through the colon used in UC patients with pancolitis ### 3. Biological Agents - TNF-alpha inhibitors - Infliximab and Adalimumab for moderate-severe CD and UC - Certolizumab for moderate-severe CD ONLY - Golimumab for moderate-severe UC only - First line for CD patients - Second line for UC patients after 5-ASAs - By the time the drug lose its efficacy - Alpha-4 integrin inhibitors (Vedolizam) - Alpha-4 integrin are adhesion molecules that promote leukocytes migration to the sites of inflammation - Vedolizumab binds to alpha-4/beta-7 and is indicaated for refractory UC and CD #### Adverse Effects - Headache - Arthralgia - Nausea - Fatigue and musculoskeletal pain ### 4. Immunomodilators - Methotrexate (MTX) - Inhibits the production of folinic acid - ONLY I.M or Subcutaneous administration has efficacy in CD (unknown MOA) - Not recommended in UC maintenance #### Adverse Effects - Nause - Vomiting - Abdominal discomfort - serum amniotransferase elevation - Rash - Folic administration reduce Gl adverse effects - Thiopurines (Azathioprine, 6-Mecraptopurine) - Administered orally - Corticosteroids-sparing effects in UC and CD - First line as monotherapy - Limited due to HIGH toxicity including-> Bone marrow supression, hepatotoxicity ## Irritable Bowel Syndrome (IBS) - Chronic abdominal pain - Classified into (IBS-C *constipation*, IBS-D *diarrhea*)