Pharmacology MED310: Gastrointestinal Track - PDF

Pharmacology MED310 Pharmacology of Gastrointestinal Track Dr. Panayiota Christodoulou Drugs Acting on the Gastrointestinal Tract Drugs affecting the GI System are used for the treatment of:  Bowel motility disorders – i.e., gastroparesis, constipation, and diarrhea  Gastric acidity  Gastroesop...

Pharmacology MED310 Pharmacology of Gastrointestinal Track Dr. Panayiota Christodoulou Drugs Acting on the Gastrointestinal Tract Drugs affecting the GI System are used for the treatment of:  Bowel motility disorders – i.e., gastroparesis, constipation, and diarrhea  Gastric acidity  Gastroesophageal reflux disease (GERD)  Peptic ulcers  Nausea and vomiting Drugs Acting on the Gastrointestinal Tract The gastrointestinal tract The GI tract includes: • Mouth (oral cavity) • Pharynx • Esophagus • Stomach • Small intestine (duodenum, jejunum, and ileum) • Large intestine (cecum and colon) Exocrine glands: 1. The salivary glands 2. The liver 3. The pancreas 4. The gallbladder Parasympathetic Sympathetic Innervation of the Gastrointestinal Tract EXTRINSIC Sympathetic neurons (blue) project to the gut: Decrease gut motility, contraction of sphincters Parasympathetic neurons (pink): Increase secretions and gut motility, relaxation of sphincters Parasympathetic The GI tract Innervation of the gastrointestinal tract • Vagal afferent neurons (green) in the nodose and inferior jugular ganglia and • Spinal afferent neurons (green) in the dorsal root ganglia ✓ Receive sensory information from the gut. Afferent neurons Gastric Acid is Produced by Parietal Cells Stimulation of parietal cells by:  The vagus nerve  Histamine  Gastrin ➔Carbonic anhydrase forms HCO3and H+ from H2O and CO2 ➔ H+/K+-ATPase pumps H+ out of parietal cells into stomach lumen ➔ HCO3- - secreted into the bloodstream Gastric acid = HCl Where does Cl- come from? Parietal cells secrete it by simple diffusion Gastric secretion Normal gastric pH is 2.0 to 3.0 → Why is gastric mucosa not damaged by this harsh environment? Mechanisms to protect the gastric mucosa from the acidic stomach environment:  Mucus secretion → barrier between gastric acid and stomach mucosa  HCO3- secretion → neutralize H+  gastric epithelium is mostly impenetrable to H+ What happens if H+ do penetrate? - rich mucosal blood supply → any H+ will be rapidly removed Drugs for gastrointestinal disorders Drugs used for: 1) Peptic ulcers and gastroesophageal reflux disease (GERD) 2) Chemotherapy-induced emesis 3) Diarrhea 4) Constipation Peptic ulcer Ulcer = lesion extending through the mucosa and submucosa into deeper structures of the wall of the GI tract Most common locations of gastric and duodenal ulcers Causes of peptic ulcer: • Infection with gram-negative Helicobacter pylori • Use of nonsteroidal antiinflammatory drugs (NSAIDs) • Increased hydrochloric acid secretion (stress) • Inadequate mucosal defense against gastric acid (stress) • Tumors (rare) Gastric and Duodenal Ulcer Ulcers can also be caused by Zollinger–Ellison syndrome = gastrin-secreting pancreatic adenomas → multiple ulcers in the stomach and duodenum  breakdown of the mucosal barrier (mucus and HCO3–)  barrier – normally protects stomach from low pH  Also, may be accompanied by increase the secretion of gastric acid and pepsin  gastric ulcers - often caused by Helicobacter pylori  duodenal ulcers – also often due to H. pylori + HCO3– in duodenum → Excess H+ from stomach not neutralized Peptic ulcer Treatment of peptic ulcer 1) Eradicating the H. pylori infection 2) Reducing secretion of gastric acid with the use of proton pump inhibitors or H2-receptor antagonists 3) Providing agents that protect the gastric mucosa from damage such as misoprostol and sucralfate 4) Neutralizing gastric nonabsorbable antacids acid with Guidelines - Evaluation and Management of a Patients with Dyspeptic or Ulcer-like symptoms - NUD = non-ucler dyspepsia - PPI – proton pump inhibitor - H2RA – H2 receptor antagonists Gastroesophageal reflux disease (GERD) Stomach acid continuously refluxes into the esophagus → pain, heartburn, inflammation and → pain is worsened by stooping and ingesting hot drinks Exacerbating factors  Increase intra-abdominal pressure (due to obesity, big meals, tight clothing)  Decrease tone of lower esophageal sphincter (LES) (due to pregnancy, hiatus hernia, fatty meals and smoking, and tricyclic antidepressants and anticholinergic drugs) Gastroesophageal reflux disease (GERD) Treatment of GERD 1) Improve defense mechanisms 2) Decrease aggressive factors – i.e., gastric reflux → antacids, H2 receptor antagonists, PPIs, etc → strengthen the lower esophageal sphincter (prokinetic drugs) 3) If pharmacology is insufficient in symptomatic control – surgery to tighten the sphincter (also strengthen lower esophageal sphincter) Proton pump inhibitors (H+/K+-ATPase) Dexlansoprazol, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole ➢ Bids to H+/K+-ATPase → suppress the secretion of hydrogen ions into the gastric lumen ➢ PPIs are prodrugs (acid-resistant enteric coating) ➢ The coating is removed in the duodenum (transported to parietal cells) ➢ Forms a stable, irreversible covalent bond with H+/K+-ATPase ➢ 18 hours for the enzyme to be resynthesized ➢ PPIs inhibit both basal and stimulated gastric acid secretion by 90% Proton pump inhibitors (H+/K+-ATPase) Omeprazole - prodrug activated in parietal cells forms covalent bond with H+/K+ ATPase H+/K+-ATPase = Hydrogen potassium ATPase Proton Pump • Transmembrane protein in parietal cells • Antiporter - H+ out, K+ in • Works against the electrochemical gradient → Energy is needed → Energy – provided by ATP hydrolysis Proton pump inhibitors - Characteristics 1st choice for acid suppression ➢ Prophylaxis and treatment of GERD, Erosive esophagitis, Active Duodenal Ulcer, and Pathologic Hypersecretory Conditions (e.g., Zollinger-Ellison syndrome) ➢ Reduce the risk of bleeding from NSAID-induced ulcers ➢ Stress ulcer treatment Pharmacokinetics:  Orally effective (before largest meal → 30 - 60min)  Metabolized by the CYP450 system → Omeprazole and Esomeprazole may decrease the effectiveness of Clopidogrel (inhibit CYP2C19 – potential DDIs)  t1/2 - few hours  BUT irreversible inhibitors – so not a big issue  Metabolites excreted in the urine and feces Proton pump inhibitors - Adverse effects • Diarrhea • Clostridium difficile colitis • Hypomagnesemia • Increased risk of fractures of the hip, wrist, and spine → Duration 1 year or greater • Increase the risk of fractures → Prolonged acid suppression may lead to: - vitamin B12 (acid required for absorption) - calcium absorption (acid required for absorption) → Alternative: Calcium Citrate (citrate ➔ absorption not affected by gastric pH) K+- Competitive Acid Blockers (P-CABs) Are all Proton Pump Inhibitors Irreversible?  K+-Competitive acid blockers (P-CABs)  compete with K+ → inhibitors of the H+/K+–ATPase → inhibit gastric acid (HCl) secretion into the lumen of the stomach e.g. Vonoprazan, Tegoprazan – currently approved in some Asian countries Histamine Effects 1. Cardiovascular system: Vasodilation→ Decrease blood pressure Which receptors should we  capillary permeability ➔ may lead to edema inhibit to limit gastric acid 2. Smooth muscle: secretions? Vascular – Dilation Bronchial – Contraction Uterine – Contraction Gastrointestinal – Contraction 3. Gastrointestinal system Stimulates gastric acid secretion 4. Peripheral nervous system (PNS) Sensitizes sensory nerve endings → pain and itching 5. Enhances platelets aggregation 6. Inflammatory mediator Histamine - Overview  Histamine formation - by tissue mast cells and basophils (some neurons) – from histidine-by-histidine decarboxylase  Histamine release is stimulated by immunoglobulin E (IgE) complexes, activated complement, burns, inflammation, and some drugs  Histamine release is inhibited by epinephrine, prostaglandin E2, and feedback inhibition from histamine itself  Breakdown - ring methylation and oxidative deamination - Metabolites - excreted in urine Histamine activates H2 Receptors Histamine binds H2 Receptors H2 Receptors are coupled to Gs Adenylyl cyclase is activated Increase cAMP Activation of protein kinase A Translocation of H+/K+ ATPasecontaining tubulovesicles to plasma membrane Active H+/K+ ATPase Histamine activates H2 Receptors • Histamine-induced, cAMP-dependent PKA activation promotes the trafficking of H+/K+-ATPase-enriched vesicles towards the apical membrane of parietal cells • TRPML1 –Transient Receptor Potential Mucolipin 1– is a Ca2+ channel that is essential for vesicle exocytosis → gastric acid secretion • Inhibitors of TRPML1 may be the future of therapy H2 receptors antagonists • Gastric acid secretion by parietal cells of the gastric mucosa is stimulated by acetylcholine, histamine, and gastrin • The receptor-mediated binding of acetylcholine, histamine, or gastrin cause the activation of protein kinases, which stimulates the H+/K+–adenosine triphosphatase (Hydrogen/Potassium - ATPase) proton pump (hydrogen ions exchange for K+) ➢ Drugs: 1. 2. 3. 4. Cimetidine (first H2 receptor antagonist) Famotidine Nizatidine Ranitidine (reducing acid secretion by approximately 70% ) H2 receptors antagonists – Mechanism of Action = H2 antihistamines e.g., Cimetidine, Ranitidine, Famotidine, Nizatidine Mechanism of Action  competitive antagonists at the H2 receptor → inhibit histamine-induced gastric acid secretion Pharmacokinetics • Ranitidine – more potent than Cimetidine → less dosing frequency • Oral administration • Urine excretion • t1/2 increased in patient with renal dysfunction → Dose adjustment • Ranitidine and Nizatidine have been pulled from the market in 2019 • No longer 1st choice → PPIs have taken over Comparison Between Histamine (H2) Receptor Antagonists and Proton Pump Inhibitor Effects on Gastric Acid Secretion 24hr median intragastric acidity Red – before treatment Blue – after 1 month of ranitidine (150mg 2x daily) Green - omeprazole (20mg 1x daily)  H2-receptor antagonists – marked effect on nocturnal acid secretion but only a modest effect on meal-stimulated secretion  Proton pump inhibitors (PPIs) markedly suppress BOTH meal-stimulated and nocturnal acid secretion H2-receptors antagonists -Therapeutic uses Peptic ulcer • Effective in promoting the healing of duodenal and gastric ulcers • Recurrence is common after treatment with H2 antagonists is stopped • Patients with NSAID-induced ulcers should be treated with PPIs (better than H2 antagonists) Acute stress ulcers • H2 blockers are given as intravenous infusion to prevent and manage acute stress ulcers • PPIs have gained favor for this indication because tolerance may occur with these agents in this setting Gastroesophageal reflux disease (GERD) • Low doses of H2 antagonists is used for the prevention and treatment of heartburn (GERD) • H2-receptor antagonists act by stopping acid secretion • Antacids more quickly and efficiently neutralize secreted acid in the stomach, their action is temporary (PPIs preferable) H2-receptors antagonists – Adverse Effects • Cimetidine - Endocrine effects (gynecomastia, and galactorrhea) → acts as a nonsteroidal antiandrogen • Headache • Dizziness • Diarrhea • Muscular pain • Drugs such as Ketoconazole, which depend on an acidic medium for gastric absorption, may not be efficiently absorbed if taken with H2 blockers • Cimetidine – inhibits CYP450 → Drug - drug interactions (Warfarin, Phenytoin) H2 Receptor Antagonists Vs Proton Pump Inhibitor • Proton pump inhibitors block the H+-K+-ATPase pump on gastric parietal cells • H2 receptor antagonists act to block histamine receptors on parietal cells ✓ Both Omeprazole and Ranitidine ultimately lower gastric acid production PPIs are more effective than H2 antagonists in suppressing gastric acid production and healing peptic ulcers Prostaglandins • Prostaglandin E, inhibits secretion of HCl and stimulates secretion of mucus and bicarbonate ➢ Misoprostol (analog of prostaglandin E1) is approved for the prevention of NSAID-induced gastric ulcers Uses: - Peptic ulcers Side effects: - Diarrhea (limits use) and abdominal cramping - It is contraindicated in pregnancy → stimulate uterine contractions → miscarriage → premature labor PPIs are preferred agents for the prevention of NSAID-induced ulcers Nonsteroidal Anti-inflammatory Drugs (NSAIDs) lead to Ulcer Formation NSAIDs inhibit cyclooxygenase → inhibit prostaglandin formation → less mucus production + more gastric acid secretion Prostaglandins are protective - Promote mucus secretion from surface epithelial cells and bicarbonate secretion) -Inhibit gastric acid secretion from parietal cells in the stomach Nonsteroidal Anti-inflammatory Drugs (NSAIDs) lead to Ulcer Formation NSAIDs inhibit cyclooxygenase → inhibit prostaglandin formation → less mucus production + more gastric acid secretion NSAIDs → Prostaglandins → less mucus production + more gastric acid secretion Misoprostol: - semisynthetic prostaglandin derivative → mimics prostaglandins High-to-Moderate Risk Patients  Those with chronic NSAID use  The elderly  Patients with ulcer history In rheumatoid arthritis patients with chronic NSAID use Overview Gastric Antacids ➢ Partially neutralize gastric acid and inhibit pepsin activity (weak bases) → aim to protect the stomach mucosa ➢ Must be taken frequently to maintain increased stomach Ph ➢ Efficacy depends on its capacity to neutralize gastric HCl ➢ Indications - peptic ulcers, acid indigestion, hyperchlorhydria (i.e., excess HCl in the stomach) ➢ Subdivided into systemic and non-systemic Drugs: • Aluminum hydroxide • Magnesium hydroxide Non-systemic Antacids • Calcium carbonate • Sodium bicarbonate, (systemic Antacid) can produce transient metabolic alkalosis and is not recommended for long-term us ✓ Food delays stomach emptying allowing more time for the antacid to react Non-systemic Antacids – constipation - laxative - constipation Combined mixtures to avoid these side effects! = not absorbed into the systemic circulation  anionic group i.e., OH- or CO32- combines with H+ → gastric acid - neutralized  cationic group i.e., Ca2+, Mg2+ - combines with HCO3- (from pancreas) → insoluble basic compound – formed → excreted in feces  do not produce metabolic alkalosis Non-systemic Antacids 1. Magnesium Hydroxide i.e., Milk of Magnesia - Mg(OH)2 - Mg2+ - antacid + laxative - caution - impaired renal function → retention of Mg2+ may cause cardiovascular and neurologic toxicity 2. Calcium Carbonate – CaCO3 - Ca2+ salts - precipitate in GI→ constipation - caution - too much dairy → hypercalcemia - may lead to bone weakness, kidney stones, etc - high neutralizing capacity - may cause rebound acid secretion if used chronically 3. Aluminum Hydroxide – Al(OH)3 - OH- reacts with H+ - may inhibit pepsin - may stimulate stomach mucus secretion - Al3+ salts - long lasting in stomach - react slowly with Cl- Side Effects - constipation - interferes with PO43- absorption in bone → osteomalacia - Decrease absorption of tetracyclines and other antibiotics Systemic Antacids = absorbed into the systemic circulation e.g., sodium bicarbonate  anionic group – HCO3- - combines with H+ - rapidly → gastric acid – neutralized → a lot of CO2 → belching → stomach distention – caution if gastric ulcer that can perforate present  cationic group – Na+ - does NOT combine with HCO3- from pancreas – Na+ and HCO3- - absorbed in duodenum producing a metabolic alkalosis Antacids-Therapeutic uses • Provide symptomatic relief of: - Peptic Ulcer Disease (PUD) - Heartburn - GERD • Promote healing of duodenal ulcers • Used as last-line therapy for acute gastric ulcers • They should be administered after meals for maximum effectiveness • Calcium carbonate preparations → calcium supplements for the treatment of osteoporosis Antacids-Adverse effects • Aluminum hydroxide causes constipation • Magnesium hydroxide causes diarrhea • Absorption of the cations from antacids (Mg2+, Al3+, Ca2+) → Adverse effects in patients with renal failure • Systemic alkalosis • Liberates CO2, causing belching and flatulence • Neurologic or Cardiovascular toxicity (absorption and retention of Mg2+) Summary - Antacids - Anion - combines with H+ - neutralizing gastric acid - Cation - absorbed with HCO3– or excreted as an insoluble precipitate with HCO3– Mucosal protective agents AIM - Improve defense mechanisms → Preventing mucosal injury → Reducing inflammation → Healing existing ulcers Uses: - Peptic Ulcers - NSAID-induced ulcers - GERD Bismuth Subsalicylate - a Mucosal Protective Agent Bismuth Subsalicylate - over-the-counter preparations Mechanism of action - unclear • Antimicrobial - when H. pylori exposed to bismuth: → antimicrobial activities → effects on iron uptake by bacteria → Iron is required for growth because it is a cofactor for many essential enzymatic processes → effects of bismuth on bacteria → iron limitation • Inhibition of pepsin activity • Increase mucous secretion • Interaction with glycoproteins in necrotic mucosal tissue → coats ulcer Unwanted effects • Nausea • Vomiting • Blackening of the tongue and feces • Very little is absorbed, but if renal excretion is impaired →encephalopathy Sucralfate – a Mucosal Protective Agent Sucralfate = complex of sulfated sucrose and polyaluminum hydroxide - If gastric acid (low pH) → cross-linking → paste formed - Paste can adhere to the mucosal defect and exposed deeper layers → This coating of the ulcer protects it from acids and pepsin → Improves healing Sucralfate – a Mucosal Protective Agent Sucralfate is not absorbed (3-5% only → urine excreted unchanged)  Does not inhibit acid secretion  Does not neutralize acid  Low pH is required for activation → cannot be used together with gastric neutralizing agents (i.e., antacids) or gastric secretion lowering agents (i.e., PPIs and H2 receptor antagonists)  Putative drug-drug interactions (DDIs)  binds digoxin and tetracyclines → Decrease absorption of these drugs  Used to treat peptic ulcers (clinically – when proton pump inhibitors do not work) Side effects: Constipation Excreted in the feces – 48hrs Drugs acting on the gastrointestinal tract: Peptic ulcer H. Pylori Predispose Patients to Ulcers 55 to 65% of patients with peptic ulcers carry H. pylori infections ➢ H. pylori = gram-negative spiral bacillus ➢ Effects of H. pylori  Secrete inflammatory mediators → Increase gastrin release from G cells  H. pylori urease activity → produces aluminum hydroxide → Increase gastric pH → Increase gastrin secretion Antimicrobial agents • Optimal therapy for patients with peptic ulcer disease infected with H. pylori requires antimicrobial treatment • Endoscopic biopsy of the gastric mucosa or various noninvasive methods are used (serologic tests and urea breath tests) • Eradication of H. pylori results in rapid healing of active peptic ulcers and low recurrence rates • Quadruple therapy is administered for a 2-week course • Triple therapy for 2 weeks (when rates of clarithromycin resistance are low ) • Treatment with a single antimicrobial drug is less effective, results in antimicrobial resistance, and is not recommended H. Pylori treatment options • • • • • Antimicrobials H2-receptor antagonists Proton pump inhibitors Prostaglandins Antacids Antimicrobial agents (For H. pylori) ➢ Metronidazole ➢ Amoxicillin ➢ Clarithromycin ➢ Tetracyclines ➢ Bismuth compounds Quadruple therapy: 1. Bismuth subsalicylate 2. Metronidazole 3. Tetracycline 4. PPI (Proton pump inhibitor) Triple therapy: 1. Amoxicillin 2. Clarithromycin 3. PPI (Proton pump inhibitor) Laxatives and Cathartic Drugs = drugs that promote defecation  Laxatives → the excretion of a soft, formed stool  Cathartics → fluid evacuation Possible Causes of Constipation Drugs Causing Constipation Laxatives and Cathartic Drugs Uses  Radiologic exams of GI tract  Bowel surgery  Proctologic exam  Avoid straining at stool - esp. patients with a hernia or cardiovascular disease  Anorectal disorders – hemorrhoids  After anti-helminthic therapy i.e., parasite irradication  After poisoning - drugs or food Contraindications  Colic i.e., attacks of severe abdominal pain  Nausea + cramps  Undiagnosed abdominal pain  Patients with symptoms of appendicitis Laxatives and Cathartic Drugs • Irritants and Stimulants (Senna, Bisacodyl, Castor oil) • Bulk Laxatives (Bran, Methylcellulose, Psyllium) • Saline and Osmotic Laxatives (Magnesium citrate, Magnesium hydroxide, Sodium phosphate) • Stool Softeners (Docusate sodium, Docusate calcium, Docusate potassium) • Lubricant Laxatives (Mineral oil and Glycerin suppositories) Stimulation of Peristalsis by Mucosal Irritation Irritant laxatives → Irritant action on the intestinal mucosa → Fluid absorbed < Fluid secreted → Intestinal lumen is filled → Stimulates reflex peristalsis Irritant laxatives also directly stimulate peristalsis What is peristalsis? The Peristaltic Reflex Passage of bolus triggers → Stretching of the intestinal wall → Triggers a reflex 1. Circular muscles - Behind bolus - contract - In front of bolus – relax 2. Longitudinal muscles - Behind bolus – relaxed - In front bolus – contracted → Bolus is propelled forward Stimulation of Peristalsis by an Intraluminal Bolus Distention of the intestinal wall by fecal matter ➔ Mechanoreceptors – activated ➔ Neuronally-mediated ascending reflex contraction of intestinal smooth muscle and a descending relaxation Contact (Stimulant–Irritant) Cathartics • Increase intestinal motor activity (peristalsis) • Increase water and electrolyte accumulation in the colon Castor Oil  From the seeds of Ricinus Communis  Prodrug → Activated by hydrolysis by pancreatic lipases → Ricinoleic acid – irritant agent → 1-3hrs after administration – irritant acts on the small intestine Side effects  Disagreeable taste  Should NOT be used just prior to bedtime Bisacodyl – a diphenylmethane • 6-8hrs after oral administration – irritant acts on the small intestine (Before bedtime) • Rectal suppositories - effective within 1hr Anthraquinones – e.g., Cascara, Aloe, and Senna • 6-8hrs after oral administration – irritant acts on the small intestine (Before bedtime) Side effects  Electrolyte imbalance from excessive catharsis Bulk-forming Laxatives = absorb and retain water ➔Fecal material becomes hydrated and soft ➔May also reflexively stimulate peristalsis – as expand upon water absorption - insoluble and non-absorbable from the intestine e.g., Bran (and Other Dietary Fiber), Methylcellulose, Carboxymethylcellulose, and Psyllium Preparations - Naturally occurring or synthetic polysaccharides - Work within 1 - 3 days Sodium Side effects and precautions: - Caution: may reduce the absorption of some drugs as some drugs bind to these → other drugs should not be taken orally within 2hrs of these - May cause intestinal obstruction Saline (Osmotic) Cathartics e.g., Magnesium Hydroxide, Sodium Phosphate, and Polyethylene Glycol Mechanism of action ➔ Water to be retained through an osmotic effect ➔ Increase water ➔ Stretching of the bowel lumen ➔ Increase Peristalsis Pharmacokinetics  Poor and slow absorption from the GI  20% of Mg2+ - absorbed - for magnesium hydroxide BUT rapidly excreted if normal renal function ➔Water retention → → Increase peristalsis ➔Water removal < 3 hours Side effects  Electrolyte imbalance  Cerebral failure – for sodium phosphate  Mg2+ intoxication (for magnesium hydroxide)- if renal function is impaired → weakness, nausea, vomiting, and respiratory depression Stool Softeners = Also known as emollient laxatives or surfactants • Keep feces soft so tenesmus is avoided - no direct or reflex stimulation of peristalsis Docusate (docusate sodium or docusate calcium preparations) - Lowers surface tension → Increase water penetration into feces - Effects – within 1 to 2 days - Minimal laxative effects – avoid tenesmus - Prophylaxis rather than acute treatment - Contraindicated with mineral oil → potential for absorption of the mineral oil Lubricant Laxatives = slow down reabsorption of water, lubricants, act by facilitating the passage of hard stools Mineral Oil = a mixture of liquid hydrocarbons obtained from petroleum Glycerin Suppositories = remove poo from the back passage Side effects  Lipid pneumonia in elderly or debilitated patients if oil is aspirated (should be taken orally in an upright position)  Potential foreign-body reactions in mesenteric lymph nodes, liver, spleen, and intestinal mucosa  Potential of blocked absorption of essential fat-soluble substances (vitamins A, D, and K, and carotene) Laxatives - Summary Prokinetic (Gastric Motility Promoting) Drugs Drugs that increase gastric motility can be beneficial if:  Strengthen lower esophageal sphincter → GERD  Promote gastric emptying → Gastroparesis + Postsurgical gastric emptying delay Stimulate small intestine → postoperative ileus, chronic intestinal pseudoobstruction Stimulate colonic transit → constipation Gastroparesis = delayed gastric emptying Causes: → Diabetes mellitus – most common → Smooth muscle disorders → Nervous system disorders → Idiopathic Stimulation of Peristalsis by an Intraluminal Bolus Distention of the intestinal wall by fecal matter ➔ Mechanoreceptors – activated ➔ Neuronally-mediated ascending reflex contraction of intestinal smooth muscle and a descending relaxation Stimulation of Peristalsis by an Intraluminal Bolus Gut distension ➔ Enterochromaffin cells (EC) release serotonin (5-HT) ➔ 5-HT stimulates intrinsic + extrinsic primary afferent neurons (PAN) ➔ IPAN neurons release Acetylcholine and Calcitonin gene-related peptide (CGRP) ➔ the enteric nervous system is activated ➔ reflex activity Motilin – stimulates excitatory neurons and muscle cells What are the inhibitory neurons?  Inhibitory neurons - dopaminergic ➔ Dopamine → gastric contractility → LES contractility Prokinetic Drugs – D2 Receptor Antagonists Metoclopramide and Domperidone  Dopaminergic neurons – inhibitory → Acetylcholine release  Ach – normally stimulates motility → Dopamine → Motility  Reversible D2 dopamine receptor antagonists → Indirectly ACh release ➔ GI motility and lower esophageal sphincter tone Clinical uses: - Gastroparesis (due to surgery or diabetes) - Gastroesophageal reflux disease - Chronic dyspepsia - Antiemetic Side effects – Extrapyramidal - like those seen with typical antipsychotics i.e. parkinsonism, dystonia, tardive dyskinesia (if used long-term) – Sedation – Prolactin secretion → advantage clinically to stimulate postpartum lactation Prokinetic Drugs – Cholinergic Agents  M3 mAChR stimulation → Prokinetic effects • Bathanechol - M3 mAChR agonist → Good enough in the past for GERD and gastroparesis BUT now seldom used due to side effects • Neostigmine  Competitive acetylcholinesterase inhibitor → Indirect cholinergic agonist Uses: Hospitalized patients – acute colonic pseudo-obstruction 2mg neostigmine → prompt colonic evacuation of flatus and feces Side effects: Cholinergic side effects - Nausea - Vomiting - Diarrhea - Excessive salivation - Bradycardia Prokinetic Drugs - Erythromycin Erythromycin = Macrolide What are macrolides normally used for? → Macrolides – protein synthesis inhibitors – antimicrobial drugs  1989 – Erythromycin is also an agonist to Motilin receptors → Increase GI motility  Later – many erythromycin derivatives – also motilin R agonists  Side effects - nausea, vomiting, and abdominal cramps Antidiarrheal Agents Aims • Prevent dehydration and electrolyte imbalance (due to severe diarrhea) • Prevent excessive bowel movements in bowel motility disorders SHOULD NOT BE USED IF: → Bloody diarrhea → High fever → Systemic toxicity (since can worsen the underlying condition) Should antibacterial drugs be used? NO unless – bacteria are the CAUSE (RARE) • Antibacterials will deplete intestinal flora → Pathogenic bacteria – free to proliferate → Diarrhea Drugs Causing Diarrhea Recommendations for Treating Acute Diarrhea Recommendations for Treating Chronic Diarrhea Possible Causes of Chronic Diarrhea  Intestinal infections (bacterial or protozoal)  Inflammatory disease (Crohn’s disease or ulcerative colitis  Malabsorption (lactose intolerance)  Secretory hormonal tumor  Drugs  Laxative abuse  Motility disturbance (due to diabetes mellitus, irritable bowel syndrome, or hyperthyroidism) Antidiarrheals - Site of Action Diarrhea is caused by:  Decreased ability of enterocytes to absorb NaCl and H2O (due to toxins)  Increased fluid secretion into the lumen (due to mucosal inflammation, viruses, bacterial toxins) - Increase luminal fluid - Peristalsis – stimulated  Adsorbents bind toxins - NaCl + H2O can be reabsorbed  Opioids activate inhibitory pathways - propulsion and peristalsis inhibited  Glucose-containing oral rehydration solutions - Glucose is absorbed - Glucose drags water with it Antidiarrheals – Antimotility Agents = Increased motility of GIT and decreased absorption of fluid 1. Antimotility agents 2. Adsorbents 3. Agents that modify fluid and electrolyte transport Antimotility agents Diphenoxylate, Loperamide (acute diarrhea) • Both are analogs of meperidine and have opioid-like actions on the gut • Activate presynaptic opioid receptors in the enteric nervous system → decrease peristalsis • Lack analgesic effects (usual doses) Side effects: drowsiness, abdominal cramps, dizziness Toxic megacolon → should not be used in children or in patients with severe colitis Antidiarrheals – Adsorbents Aluminum hydroxide, Methylcellulose = Adsorbents absorb bacterial toxins and fluid in the gut Clinical Uses • Acute diarrheal • Severe diarrhea or dysentery Mechanism of action: • By adsorbing intestinal toxins or microorganisms • By coating or protecting the intestinal mucosa → Less effective than antimotility agents Side effects  NOT absorbed → no systemic side effects  Constipation Antidiarrheals - Agents that modify fluid and electrolyte transport Bismuth subsalicylate Clinical Uses • Traveler’s diarrhea • Decreases fluid secretion in the bowel Mechanism of action • Due to its salicylate component as well as its coating action Adverse effects • Black tongue • Black stools Antidiarrheals – Opioid Agonists Opioids decrease propulsion and peristalsis → GI contents are delayed in passage → Feces have sufficient time become desiccated → Desiccated feces – pass colon slower Clinical Uses:  Acute diarrhea – NOT for enteric infections  Opium alkaloids (codeine, morphine) - severe diarrhea or dysentery  Chronic therapy should be avoided due to risk of dependence Loperamide  Nonprescription, No analgesic effects  Does not cross BBB – endothelial cells of BBB actually pump it back out → No risk of dependence  for IBS + prophylaxis and treatment of traveler’s diarrhea Diphenoxylate  No analgesic effects  High doses → CNS effects → risk of dependence  Formulated with atropine to avoid overdose Irritable bowel syndrome (IBS) = is characterized by bouts of diarrhea, constipation or abdominal pain → uncertain etiology but psychological factors may play a part therapy Chronic idiopathic condition - Not associated with pathophysiological changes in gut structure - Diagnosed only when all else has been excluded Symptoms: • Abdominal pain • Bloating • Cramps associated with bowel habit alteration i.e., Constipation or diarrhea Treatment – depends on symptoms (type and severity) • Mild – diet alterations • Moderate → severe - pharmacology Drugs for Irritable bowel syndrome (IBS) Antispasmodics Laxatives – if constipation  Severe cases with diarrhea → 5HT3 receptor antagonists  Aim - Decrease pain and intestinal motility Alosetron – approved specifically for this type of IBS - potent and selective for 5HT3 receptors - Side effect: severe diarrhea Ondansetron, Palonosetron, Dolasetron - also 5HT3 antagonists – not studied in IBS but used to prevent and treat nausea and emesis Antispasmodics = anticholinergic drugs  Dicyclomine and Hyoscyamine - Inhibit mAChR – enteric plexus and smooth muscle BUT efficacy for relieving abdominal symptoms – not convincing → AVOID Drugs for Irritable bowel syndrome (IBS) Classified as: Constipation predominant (IBS-C), Diarrhea predominant (IBS-D) Inflammatory Bowel Disease (IBD) ➢ Conditions characterized by immune-mediated GI tract inflammation Crohn’s disease (CD) • Affect any portion of the GI tract (characterized by transmural inflammation) Ulcerative colitis (UC) • Affects the rectum or other parts of the colon (characterized by inflammation limited to the mucosal layer) Drugs for Inflammatory Bowel Disease (IBD) Maintenance of remission in both ulcerative colitis and Crohn's disease is achieved with: • • • • 5-aminosalicylates (5 ASAs) Corticosteroids Biologic agents Immunomodulators Aminosalicylates Mesalamine, Balsalazide, Olsalazine, and Sulfasalazine Mesalamine = 5-aminosalicylic acid (5-ASA) = active moiety of all the aminosalicylates used to treat inflammatory bowel disease 5-ASA - inhibits prostaglandin and leukotriene synthesis within the intestinal tract (mainly - terminal ileum and colon) → Decrease inflammation Balsalazide, Olsalazine, and Sulfasalazine = prodrugs Clinical use: Mild to moderate ulcerative colitis Side effects: - nausea - vomiting - diarrhea - headache - abdominal pain - bone marrow suppression Drug Treatment of Crohn Disease and Ulcerative Colitis Drug Treatment of Crohn Disease and Ulcerative Colitis Tumor Necrosis Factor-α Inhibitors Inflammatory bowel disease is mediated by TNFα → neutralizing TNFα – beneficial ✓ How can we neutralize TNFα? - monoclonal antibodies (mAb) or antibody fragments (F(ab) generated against TNFα (mAb and F(ab) can only be given by injection) Clinical uses:  Moderate to severe Crohn disease unresponsive to other therapies (adalimumab, certolizumab pegol, and infliximab)  Moderate to severe ulcerative colitis not responsive to other drugs (infliximab) Side effects  Immunosuppressants → increased respiratory infections Drug Treatment of Crohn Disease and Ulcerative Colitis Other Biologics Aimed at Decreasing Inflammation Inflammatory bowel disease is mediated by α4-containing integrin receptors and specific interleukins (IL-12 and IL-23) Vedolizumab  α4-containing integrin receptors – essential for leukocyte migration  Vedolizumab - specific for the a4β7 integrin receptor ➔ Inhibits leukocyte migration ➔ Inhibit inflammation Ustekinumab  IL-12 and IL-23 promote lymphocyte activation  Ustekinumab – neutralizes IL-12 and IL-23 ➔ Inhibits lymphocyte activation ➔ Inhibit inflammation Drug Treatment of Crohn Disease and Ulcerative Colitis Corticosteroids Corticosteroids  inflammation  reduce connective tissue proliferation Prednisone and Budesonide → Induce remission in acute persistent inflammatory bowel disease  used systemically until adequate control of inflammation is achieved THEN dose or stop ➔ avoid side effects Summary – Drugs used for Gastrointestinal Disorders Summary – Drugs used for Gastrointestinal Disorders Summary – Drugs used for Gastrointestinal Disorders Summary – Drugs used for Gastrointestinal Disorders Summary – Drugs used for Gastrointestinal Disorders Question A couple celebrating their 30th wedding anniversary are given a trip to Peru to visit Machu Picchu. Because of past experiences while traveling, they ask their doctor to prescribe an agent in case they experience diarrhea. Which drug would be effective? A. Omeprazole B. Loperamide C. Famotidine D. Lubiprostone Question A 45-year-old woman complains of severe persistent heartburn and an unpleasant, acid-like taste in her mouth. The clinician suspects that she has gastroesophageal reflux disease. Which drug is most appropriate? A. An antacid such as aluminum hydroxide B. Nizatidine C. Amoxicillin D. Esomeprazole Question An elderly woman with a recent history of myocardial infarction is seeking a medication to help treat her occasional heartburn. She is currently taking several medications, including aspirin, clopidogrel, simvastatin, metoprolol, and lisinopril. Which drug should be avoided in this patient? A. Calcium citrate B. Famotidine C. Omeprazole D. Ranitidine Question Which agent for gastrointestinal problems is contraindicated in pregnancy? A. Calcium carbonate B. Famotidine C. Lansoprazole D. Misoprostol Question Which drug has been known to cause discoloration of the tongue? A. B. C. D. Amoxicillin Omeprazole Bismuth subsalicylate Lubiprostone