PMCOL 344: Scientific Basis of Pharmacology II Past Paper 2025 PDF
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University of Alberta
2025
PMCOL
Dr. William F. Colmers
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This document is a past paper for the PMCOL 344: Scientific Basis of Pharmacology II course in 2025. It covers topics such as GI Pharmacology, clotting, immunopharmacology, and assessments. The paper has questions.
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PMCOL 344: Scientific Basis of Pharmacology II 2025 Dr. William F. Colmers Professor, Pharmacology & Neuroscience [email protected] 2025 © PMCOL 344 General Pharmacology 1 PMCOL...
PMCOL 344: Scientific Basis of Pharmacology II 2025 Dr. William F. Colmers Professor, Pharmacology & Neuroscience [email protected] 2025 © PMCOL 344 General Pharmacology 1 PMCOL 344 Winter 2025 Continues on from PMCOL 343 Topics covered include: GI Pharmacology (Colmers) Clotting and Haematopoeisis (Plane) Antineoplastic drugs and Antiviral drugs (Hammond) Immunopharmacology (Posse de Chaves) Pharmacology of Metabolic Disorders (Gruber) Antiinfectives (Sandini) 2025 © PMCOL 344 General Pharmacology 2 PMCOL 344 Scientific Basis of Pharmacology, Part II As in PMCOL 343, all topics taught will include a grounding in the underlying pathophysiology Aim is to explain the rationale for treatments, leading to better understanding of the pharmacology Course material provided online (lecture slides and any other material provided by instructors) Textbook not required, but course is based on “Rang & Dale” text Online copy available for free on library website (see syllabus) 2025 © PMCOL 344 General Pharmacology 3 PMCOL 344 Winter 2025 Assessments Midterm 1 (30% of mark) February 12 (50 min) Material taught up to and including Feb 10th MCQs – (If online - ExamLock and SEM) Midterm 2 (20% of mark) March 14th (50 min) Material taught up to and including March 0th MCQs – (If online - ExamLock and SEM) Final examination (50% of mark, cumulative!!) TBA (Registrar’s office determines) 2 hours Emphasis on last section of course, but significant amounts of material examined in the midterms MCQs - (If online - ExamLock and SEM) 2025 © PMCOL 344 General Pharmacology 4 PMCOL 344 Winter 2024 Instructor contact information is in the Syllabus on eClass Read the Syllabus for course rules and more details! Really, please read the #&@! syllabus! Really!! 2025 © PMCOL 344 General Pharmacology 5 Why GI Pharmacology? GI drugs represent ~8 - 10% of all prescriptions Comprise >30% of OTC preparations, e.g. Laxatives Antacids Gas relievers Anti-diarrheals Haemorrhoid treatments 2025 © PMCOL 344 General Pharmacology 6 Role of GI tract in Physiology Mediates digestion and absorption of nutrients and orally-available drugs Elimination of waste and toxins (defecation and vomiting) Endocrine system 5-HT (> 90% of body 5-HT is in the enteric NS) Gastrin Ghrelin Cholecystokinin 2025 © PMCOL 344 General Pharmacology 7 Digestive System Digestive System consists of: The digestive tract (hollow organ) Mouth Esophagus Stomach Intestines Plus organs of digestion Tongue Salivary glands Pancreas Gallbladder Liver 2025 © PMCOL 344 General Pharmacology 8 GI Tract Histological Anatomy 2025 © PMCOL 344 General Pharmacology 9 Enteric Nervous System Intrinsic neural network within the wall of the GIT Regulates motility, secretion, blood flow and immune responses. Integrated with, regulated by, autonomic nervous system (ANS) Can act independent of CNS Submucosal plexus Innervates epithelia and muscle cells Myenteric plexus Regulates gut motility and secretion Lies between muscle layers 2025 © PMCOL 344 General Pharmacology 10 Enteric Nervous System ENS receives: Vagal Parasympathetic fibers (Acetylcholine – Ach) Mainly excitatory – Increase gut motility, dilate sphincters (facilitate transit), increase secretions Sympathetic fibers (Noradrenaline) Decrease gut motility, constrict sphincters ENS also comprises sensory nerves signaling mechanical and chemical stimuli Mediate spinal and brainstem reflexes regulating digestive function Provide input to central autonomic circuits that regulate feeding and illness behaviors Transmit both painful and non-painful sensation 2025 © PMCOL 344 General Pharmacology 11 Gut motility Motility Moves food from mouth to anus (= peristalsis) Mixes food to facilitate digestion (more surface area of food for acid and enzymes to act on) (=segmentation) Determined by smooth muscle properties and modified by chemical inputs Nerves Hormones Paracrine signals Different regions – different types of motility Tonic contractions in sphincters Phasic contractions in small intestine and colon 2025 © PMCOL 344 General Pharmacology 12 Small intestine motility * * * Rhythmic electrical activity accompanies contractions * * Phasic activity driven by slow * * * * waves Slow waves show some * * spiking activity (trace 1, 3rd and 4th events, propagation slows with more distal * segments (traces 5,6) When slow wave reaches Spike potentials and slow waves from threshold, VGCCs open, Ca2+ progressively (1 → 6) distal sites in the enters, APs fire (*) and human small intestine muscles contract. Curved line (1 → 4) shows apparent distalward propagation From Johnson, Gastrointestinal Physiology 9th Edition Elsevier 2019 2025 © PMCOL 344 General Pharmacology 13 Patterns of Motility Isolated contraction Moves contents both orally and aborally Segmentation mixes contents over a short length of intestine (time sequence, left to right) Peristalsis Propels contents aborally Involves contraction and relaxation 2025 © PMCOL 344 General Pharmacology 14 Motility caused by coordinated activity Longitudinal and circular muscles coordinate movement to produce either segmentation of peristalsis. Contraction wave in ring muscle, moving aborally behind an aboral relaxation wave, causes peristalsis. Alternating ring contractions help mix contents during segmentation. Peristaltic reflex: triggered by mechanical stretch and mucosal stimulation Activates excitatory motoneurons above bolus (5-HT released from enterochromaffin cells Activates inhibitor motor neurons below (relaxes gut wall below bolus) 2025 © PMCOL 344 General Pharmacology 15 Gut-Brain-Energy Axis Hormones secreted by gut during eating can affect gut function, e.g.: Gastrin (made in mucosal enteroendocrine cells) - stimulates acid secretion by parietal cells in stomach 5-HT from enterochromaffin cells - increases ACh release from nerves in ENS Motilin from mucosal cells - stimulates contraction of GI smooth muscle Also act at other tissues, e.g. Cholecystokinin (CCK) from small intestine enteroendocrine cells - stimulates pancreatic enzyme secretion Glucagon-like peptide 1 (GLP-1) stimulated insulin release, - inhibits glucagon release, promotes satiety (big target now!) 2025 © PMCOL 344 General Pharmacology 16 Enteroendocytes Release Hormones Enteroendocrine cells respond to nutrients, neurotransmitters, local signals to release hormones H.M Cox https://doi.org/10.1016/j.coph.2016.08.010 2025 © PMCOL 344 General Pharmacology 17 Gut-Brain-Energy Axis 2025 © PMCOL 344 General Pharmacology 18 Gastric Acid Secretion, Ulcers and Acid Reflux Dr. W.F. Colmers PMCOL 344 2025 © PMCOL 344 General Pharmacology 1 Gastric Secretions Human stomach secretes ~2.5 liters gastric juice per day Peptic (Chief) cells: Pro-enzymes like prorennin, pepsinogen Parietal cells: HCl, pH ≈ 1 – 2 Why are stomach secretions so acidic? Promotes proteolysis (e.g. conversion of pepsinogen to pepsin) Kills pathogens Aids in iron absorption: Acidic environment favors Fe2+ form, which is better absorbed than Fe3+ form 2025 © PMCOL 344 General Pharmacology 2 Why is stomach wall safe from acid content? Protective mechanisms: Mucosal cells secrete prostaglandins (PGs) such as PGE2 and PGI2 which: Act on receptors on mucosal cells to stimulate secretion of mucus (EP4 receptors) & bicarbonate ions (EP1/2 receptors) Mucosal surface forms gel-like protective surface, pH 6-7 (vs. stomach lumen, pH 1 – 2) Act on EP2/3 receptors on enterochromaffin-like (ECL) cells to inhibit release of histamine Histamine stimulates acid production via H2 receptors Act on vascular EP2/4 receptors to cause vasodilation and thus improve blood flow to the mucosal layer 2025 © PMCOL 344 General Pharmacology 3 HCl Secretion by parietal cells - mechanism Parietal cells secrete 150 mM HCl, pH 90%, increase pH above 4 Decrease pepsin activity Promote healing of ulcers 2025 © PMCOL 344 General Pharmacology 20 Classic example of structure- based drug design – James Black (Nobel Prize 1988) KD of cimetidine for histamine receptors H1 – 0.45 mM H2 – 0.80 µM H3 - 33 µM 2025 © PMCOL 344 General Pharmacology 21 Inhibits some cytochrome P450 enzymes (CYP2C9, 2D6 and 3A4) so potentiates actions of other drugs which are normally broken down by these enzymes such as: oral anticoagulant warfarin calcium channel antagonist felodipine lovastatin anti‐epileptic phenytoin benzodiazepines and tricyclic anti‐depressants Can cause reversible gynaecomastia in men affinity for estrogen receptors and increases prolactin secretion 2025 © PMCOL 344 General Pharmacology 22 Neutralize acid: Antacids Basic inorganic salts: taken orally to directly neutralize gastric acid and thus also inhibit peptide enzymes (need a pH> 5) Chemical antagonism Not absorbed At sufficient doses for prolonged periods can result in healing of ulcers Mixture of salts of magnesium (causes diarrhea) and aluminum hydroxide (causes constipation) help preserve normal bowel function Al(OH)3 + 3HCl → AlCl3 + 3H2O 2025 © PMCOL 344 General Pharmacology 23 Neutralize acid: Antacids Alginates: negatively charged polysaccharides from algal cell walls, absorb water to form a viscous gum May possibly increase viscosity and adherence of mucus to the stomach lining? CaCO3 MgCO3 + alginic acid MgCO3 + Al(OH)3 2025 © PMCOL 344 General Pharmacology 24 Protection of the mucosa Enhance endogenous mucosal protective mechanisms &/ or provide physical barrier over ulcer Bismuth chelate (colloid): Used with triple therapy to treat H. pylori Kills bacteria & prevents adherence Sucralfate: complex of Al(OH)3 and sulfated sucrose which releases Al in acidic environment to leave negatively-charged complex which binds to proteins and glycoproteins in mucous to form gel Both can affect absorption of other drugs and also believed to: adsorb pepsin, enhance PG synthesis, stimulate HCO3 -secretion? 2025 © PMCOL 344 General Pharmacology 25 Protection of the mucosa PGs inhibit HCl release from parietal cells, enhance mucous production & mucosal blood flow, stimulate HCO3- release But PGs short‐lived Misoprostol Stable analog of PGE1 greatly reduced metabolism by oxidation Can stimulate uterine contractions so not used in pregnancy 2025 © PMCOL 344 General Pharmacology 26 Protection of the mucosa: Misoprostol Promotes healing of ulcers & prevents damage caused by NSAIDs Act on EP1/2 receptors on mucosal cells to increase HCO3-, on EP4 receptors to increase mucous production Act on EP2/3 receptors on ECL cells to inhibit histamine production X via inhibition of adenylyl cyclase 2025 © PMCOL 344 General Pharmacology 27 What you need to know: The mechanisms by which acid is secreted by parietal cells & the pharmacology of how this process is regulated by endogenous mediators Causes of ulcers (H. pylori, NSAIDs, stress) The mechanisms of action of drugs currently used to treat ulcers and GERD 2025 © PMCOL 344 General Pharmacology 28 Sample question A 48 year-old man presents to his GP because of embarrassment over breast enlargement. He has a peptic ulcer for which he has been taking medication. What drug is he most likely taking and what is the cause of the breast enlargement? (2 marks) Cimetidine, H2 receptor antagonist which has affinity for estrogen receptors 2025 © PMCOL 344 General Pharmacology 29 Vomiting and Anti-emetics Dr. W.F. Colmers PMCOL 344 2025 © PMCOL 344 General Pharmacology 1 Vomiting Vomiting (Emesis): Forceful evacuation of gastric contents through mouth Physiological response to: irritating substances in gut or blood stream excessive vestibular stimulation (motion sickness) psychological stimuli (e.g. fear, odors) Nausea: Feeling of impending vomiting Harder to control pharmacologically Most anti-emetics not anti‐nauseant 2025 © PMCOL 344 General Pharmacology 2 Learning Objectives Following this class you should be able to: Describe the main features of the vomiting reflex Understand the mechanism of action of anti-emetic drugs 2025 © PMCOL 344 General Pharmacology 3 Why are drugs that modulate vomiting clinically useful? Physiological response to ingestion of toxic substance Emetic drugs Induce vomiting to prevent absorption of ingested toxic substances Ipecac Unwanted effect of clinically used drugs, e.g. chemotherapy (70--‐80%), opioids, anaesthetics Motion sickness, pregnancy, migraine, bacterial & viral infections Vomiting reduces effectiveness of treatments, can cause dehydration and nutrient depletion Anti-emetic Drugs 2025 © PMCOL 344 General Pharmacology 4 Reflex mechanism of Vomiting Vomiting regulated centrally by medulla Chemoreceptor trigger zone (CTZ) Blood--‐brain barrier near to CTZ relatively permeable, allowing circulating emetogenic mediators to act, also receives inputs from vestibular nuclei and directly from GI tract Vomiting center Receives impulses from CTZ, GI tract and higher cortical centers and co-ordinates physical act of vomiting Vestibular nuclei Inputs from labyrinth (inner ear) 2025 © PMCOL 344 General Pharmacology 5 Vomiting 2025 © PMCOL 344 General Pharmacology 6 Vomiting neural control circuitry 2025 © PMCOL 344 General Pharmacology 7 Anti-emetics: Muscarinic receptor antagonists Selective, competitive, orthosteric antagonists e.g. Hyoscine Act at vomiting centre & vestibular nuclei Given prophylactically for X X motion sickness & post‐op emesis Side effects predictable e.g. dry mouth, blurred vision, sedation, constipation 2025 © PMCOL 344 General Pharmacology 8 Anti-emetics: 5-HT3 receptor antagonists Selective, competitive, orthosteric antagonists e.g. Ondansetron Act at CTZ & visceral afferents Useful for chemotherapy – induced emesis as chemo X agents (e.g. cisplatin) release 5-HT from enterochromaffin cells & directly stimulates CTZ plus visceral nerves Not as effective against motion sickness? Long QT syndrome 2025 © PMCOL 344 General Pharmacology 9 Anti-emetics: dopamine (D2) receptor antagonists Selective, competitive, orthosteric antagonists e.g. Metoclopramide, domperidone For metoclopramide CTZ is primary site of action Can be used for chemotherapy‐ X induced vomiting but is less effective than 5-HT3 receptor antagonists Also acts on GI tract to increase motility – moves contents downwards Domperidone doesn’t cross Can cross BBB so can cause BBB, so no CNS effects, but movement disorders does increases gut motility 2025 © PMCOL 344 General Pharmacology 10 Other anti-emetics Antipsychotic phenothiazines (e.g. chlorpromazine) Used for treatment of more severe nausea and vomiting associated with cancer, radiation therapy, cytotoxic drugs, opioids and anaesthetics and other drugs D2 receptor antagonists: Act in CTZ, but can also block histamine and muscarinic receptors Limitations caused by unwanted effects Cannabinoids (marijuana derivatives, e.g. nabilone): act in CTZ Glucocorticoids (e.g. dexamethasone) used with chemotherapy, mechanism unclear NK1 receptor antagonists (e.g. aprepitant): action at CTZ and vomiting center, used in combination with dexamethasone and ondansetron for chemotherapy-induced vomiting 2025 © PMCOL 344 General Pharmacology 11 What you need to know: The pharmacology of the vomiting reflex The mechanisms of action of the major classes of emetic and antiemetic drugs 2025 © PMCOL 344 General Pharmacology 12 Sample question A 68-year old woman undergoing chemotherapy with cisplatin is suffering from severe vomiting. What would be the most effective medication to counteract the emesis and what is its mechanism of action? (2 marks) 5-HT3 receptor antagonists. Act primarily at the CTZ and also visceral afferents. Useful, because chemo drugs release 5-HT from enterochromaffin cells which directly stimulates CTZ 2025 © PMCOL 344 General Pharmacology 13 Intestinal Fluid Balance and Anti-Diarrheal Drugs PMCOL 344 2025 Dr. W.F. Colmers 2025 © PMCOL 344 General Pharmacology 1 Learning objective Following this class you should be able to: Describe the mechanisms responsible for maintenance of normal intestinal fluid balance Describe the mechanisms underlying the currently used treatments for diarrhea 2025 © PMCOL 344 General Pharmacology 2 Diarrhea Diarrhea – frequent passage of liquid feces May be accompanied by abdominal cramps and nausea Physiological mechanism to rid gut of irritating substances Caused by infection, anxiety, drugs, inflammatory disease Primary cause of death in infants in developing countries 2025 © PMCOL 344 General Pharmacology 3 Diarrhea Results from disordered water and electrolyte transport in the small intestine Increased gut motility Increased fluid secretion Decreased absorption of fluid Leads to loss of electrolytes (especially Na+) and H2O 2025 © PMCOL 344 General Pharmacology 4 Intestinal Fluid Balance Adult human takes in ≥2 liters of fluid daily Saliva and secretions from stomach, pancreas and liver add ~7 liters, total of ~9 liters that enter the small intestine daily H2O and electrolytes are simultaneously absorbed in the intestine and secreted in bowel Normally absorption > secretion >90% of fluid entering small intestine is absorbed, with only ~ 1 liter reaching the large intestine Further absorption occurs in the large intestine Only 100 to 200 mls of H2O excreted in stool 2025 © PMCOL 344 General Pharmacology 5 Intestinal Fluid Balance Any change in 2-directional flow of H2O and electrolytes in small intestine causes increased volume of fluid to enter the large intestine When this volume exceeds absorptive capacity → diarrhea Intestinal epithelial cells express ion channels, pumps and transporters both on luminal and basolateral membranes Absorption of H2O from small intestine caused by osmotic gradients created when solutes are absorbed from lumen Water always follows solutes! 2025 © PMCOL 344 General Pharmacology 6 Absorption of H2O and Electrolytes Na+ enters epithelial cells via Na+ channels (ENaC), or can be co-transported with glucose or amino acids Na+ transported out of epithelial cells into extracellular fluid (ECF) by Na+/K+-ATPase Increases ECF osmolarity, H2O follows passively Water never moves through water channels alone- it always follows the movement of ions (aquaporins) 2025 © PMCOL 344 General Pharmacology 7 Secretion of H2O and electrolytes Secretion of H2O and electrolytes occurs in small intestine where NaCl is transported from ECF into epithelial cells Na+ is pumped back into the ECF by Na+/K+-ATPase and Cl- passes into the lumen via the CFTR channel Cl- movement creates an osmotic gradient and H2O and other electrolytes flow passively from the ECF via intercellular channels 2025 © PMCOL 344 General Pharmacology 8 2 Types of diarrhea - mechanisms Secretory diarrhea: abnormal secretion of H2O and salts into small intestine Occurs when absorption of Na+ is impaired while secretion of Cl- continues or is increased Net fluid secretion results, leading to loss of H2O and salts as watery stools Causes dehydration May result from the action on the bowel mucosa of bacterial toxins E.g. cholera toxins irreversibly activate Gs-proteins to increase cAMP and thus activate CFTR (Cl- channel) 2025 © PMCOL 344 General Pharmacology 9 2 Types of diarrhea - mechanisms Osmotic diarrhea: Can occur when poorly-absorbed, osmotically active substance is ingested e.g. sorbitol, mannitol H2O moves from ECF into gut lumen until osmolarity of intestinal content = that of ECF Increases volume of stool and causes dehydration owing to loss of H2O Here there is a looser coupling between movement of NaCl and H2O Loss of body H2O is greater than loss of NaCl, so hypernatremia also develops Normally, water moves with Na+, but here the water moves because of the osmotic load in the gut 2025 © PMCOL 344 General Pharmacology 10 Treatment of diarrhea First priority: Oral rehydration Restore fluid and electrolyte balance Addition of glucose (and some amino acids) enhances Na+ absorption via a co-transporter and thus also H2O uptake 2025 © PMCOL 344 General Pharmacology 11 Treatment of Diarrhea Anti-infective agents Most GI infections are viral, while bacterial infections normally resolve quickly without antibiotics Therefore, anti-infectives not often used Some common bacterial infections may need treatment: E. coli Salmonella Shigella Campylobacter Details of anti-infective actions are covered later in this course 2025 © PMCOL 344 General Pharmacology 12 Treatment of diarrhea: Spasmolytics Rationale: Relaxation of gut smooth muscle ↓ Decrease in gut motility ↓ Increase in transit time ↓ Increased time for reabsorption of water 2025 © PMCOL 344 General Pharmacology 13 Treatment of diarrhea: Muscarinic antagonists ACh is primary stimulatory neurotransmitter in gut X X Contraction ENS ACh Muscarinic antagonists (atropine, etc.) block action of ACh so relax gut muscle and decrease motility Side effects significant and predictable, so these drugs are rarely used 2025 © PMCOL 344 General Pharmacology 14 Treatment of diarrhea: Opioid receptor agonists Effects of opiates on gut function are complex Opioid neuropeptides are released and act locally Opioid drugs act much more widely, so can essentially confuse system Opioid agonists affect multiple GI functions Motility, secretion and transport of electrolytes and fluid by activation of opiate receptors (µ, δ and κ) A number of mechanisms, since receptors are localized in several cell types within GI tract Primary site of action probably at ENS inhibitory presynaptic receptors to reduce ACh release 2025 © PMCOL 344 General Pharmacology 15 Treatment of Diarrhea: Opiates Contraction ENS ACh Contraction ENS Opioid ACh Net effect is to increase segmentation and decrease peristalsis Decreases propulsive movement Increase transit time so water absorption increased 2025 © PMCOL 344 General Pharmacology 16 Treatment of diarrhea: Opiates Symptomatic relief Morphine: major unwanted effect is constipation Codeine, diphenoxalate (more CNS effects at higher concentrations) For diarrhea treatment, no need for CNS actions Loperamide Structurally similar to pethidine (synthetic opioid agonist), but does not cross BBB Effects due only to actions on peripheral opioid receptors in GI muscle and ENS Very limited (i.e. virtually none) CNS effects Most commonly used for travellers diarrhea Also reduces frequency of cramps, shortens duration of illness but can cause constipation 2025 © PMCOL 344 General Pharmacology 17 Treatment of diarrhea: Adsorbents Bind up H2O in gut Symptomatic relief does not reduce dehydration, efficacy not proven in clinical trials Examples: kaolin, pectin, chalk, charcoal, methylcellulose Could also potentially adsorb pathogens or toxins (e.g charcoal) Could also potentially coat and protect mucosa 2025 © PMCOL 344 General Pharmacology 18 What you need to know: The mechanisms for maintaining normal intestinal fluid balance The types of diarrhea The mechanisms underlying the currently used treatments for diarrhea 2025 © PMCOL 344 General Pharmacology 19 Sample question A couple on vacation in Peru are suffering from diarrhea. What would be the drug of choice for treatment and how does it act (3 marks) Loperamide, an opioid receptor agonist, acts at presynaptic receptors in the ENS to reduce ACh release Overall effect is to increase segmentation, and decrease peristalsis, thereby decreasing propulsive movement. This gives the GI tract more time to resorb water from gut contents (Also – loperamide is an OTC preparation, since it can’t be abused) 2025 © PMCOL 344 General Pharmacology 20 Laxatives and GI motility enhancers Dr. W.F. Colmers PMCOL 344 2025 2025 © PMCOL 344 General Pharmacology 1 Constipation Constipation: Slowed passage of food through GI tract 50+% of people affected Causes: Drugs like opiates, antidepressants and iron supplements Diet, hydration state and exercise Hormones, IBS 2025 © PMCOL 344 General Pharmacology 2 Learning objectives Following this section of this class you should be able to: Describe the mechanism of action of laxatives and agents that enhance GI motility 2025 © PMCOL 344 General Pharmacology 3 Drugs which alter the transit of food through gut Purgatives: Accelerate passage of food through intestine and evacuation of bowels Bulk laxatives, osmotic laxatives, stimulating purgatives, stool softeners Used to relieve constipation or to clear bowel prior to surgery or examination Agents that increase motility of GI tract without causing purgation (evacuation): D2 antagonists 2025 © PMCOL 344 General Pharmacology 4 Purgatives: Bulk Laxatives Bulk Laxatives like methyl cellulose, ispaghula husk Polysaccharide polymers that are not broken down by digestion in the upper part of the GI tract Form bulky hydrated mass in gut lumen Mechanical distension promotes peristaltic reflex Slow action (several days) but are not absorbed, so no unwanted effects 2025 © PMCOL 344 General Pharmacology 5 Purgatives: Osmotic laxatives Osmotic laxatives like lactulose (disaccharide of fructose and galactose, macrogols (inert ethylene glycol polymers) Poorly absorbed, so produce osmotic load in lumen that draws water into gut lumen Softens stool and stretches gut to promote peristalsis and defecation Takes 2-3 days to act but not absorbed, so no unwanted effects 2025 © PMCOL 344 General Pharmacology 6 Purgatives: Stimulant laxatives Increase electrolyte and water secretion and/or increase peristalsis Example: Bisacodyl – given as a suppository can stimulate defecation in 15 minutes Senna Active component (a glycoside) directly stimulates nerves in myenteric plexus to increase peristalsis and defecation Used in combination with stool softeners (e.g. docusate) for chronic opioid-induced constipation With all purgatives, prolonged use can lead to dependence 2025 © PMCOL 344 General Pharmacology 7 Drugs which increase GI motility Contraction ENS ACh Cholinomimetics (muscarinic agonists) and cholinesterase inhibitors enhance GI contractions but do so in an uncoordinated fashion → little or no net propulsive activity GI tract also produces 50% of the body’s dopamine Changes in GI function in Parkinson’s 2025 © PMCOL 344 General Pharmacology 8 Drugs which increase GI motility: D2 antagonists Dopamine mediates negative feedback mechanism to modulate gut motility – released at the same time as ACh during peristalsis to cause muscle relaxation and inhibiton of ACh release D2R D2 agonist relaxation ENS D2R ACh D2 antagonists block effects of endogenous dopamine D2 antagonists inhibit smooth muscle relaxation and enhance ACh release → increased contractility and peristalsis These drugs only affect response to endogenous dopamine, so ACh release is normal 2025 © PMCOL 344 General Pharmacology 9 D2 antagonists Actions are therefore negated by anticholinergic drugs like atropine If you block muscarinic receptors, then D2 antagonists have little effect This shows that the potentiating effects of D2 blockers on ACh release (presynaptic D2Rs) is more important than the block of dopamine-mediated relaxation (postsynaptic D2Rs) However, cholinergic drugs alone are not effective in relieving constipation – increase contractility but not propulsion 2025 © PMCOL 344 General Pharmacology 10 Drugs that increase GI motility: D2 antagonists Prototype: metoclopomide Increase gastric emptying Relaxes pyloric sphincter as well as smooth muscle Also used as antiemetics due to action in CTZ Decrease absorption of drugs notmally absorbed in stomach (specifically weak acids) Crosses BBB, so long-term use can cause dyskinesias Domperidone does not cross BBB, so no dyskinesias Used also to stimulate lactation in new mothers by stimulating prolactin release from pituitary lactotrophs – tonic dopamine release from hypothalamus acts on lactotroph D2 receptors 2025 © PMCOL 344 General Pharmacology 11 Drugs which increase GI motility: 5-HT4 agonists 5-HT released from enterochromaffin cells Food constituents, stretching of gut wall trigger release Released also by endogenous mediators such as gastrin Important part of peristaltic reflex Stimulates sensory nerves in myenteric plexus Presynaptic 5-HT4 receptors in myenteric plexus enhance ACh release 5-HT4 Contraction ENS ACh 2025 © PMCOL 344 General Pharmacology 12 Drugs which increase GI motility : 5-HT4 agonists Good target: in comparative studies of GI motility, cisapride “clearly superior to other treatments” However, was withdrawn due to fatal cardiac arrhythmias (LQT syndrome) due to block of cardiac HERG channel Tegaserod also withdrawn due to “adverse cardiac events” but is still available for patients that cannot be effectively treated with anything else Prucalopride in Canada and US So far, not linked to increased risk of cardiac events 2025 © PMCOL 344 General Pharmacology 13 Chronic Bowel Disease and Its Treatment Dr. W.F. Colmers PMCOL 344 2024 2025 © PMCOL 344 General Pharmacology 15 Chronic Bowel Diseases: IBS Irritable Bowel Syndrome Possible Causes: “Colon, or large intestine particularly sensitive and reactive to certain foods and stress” Possible alterations in 5-HT reuptake into neurons Bacterial infection Possibly hormones NOT Inflammatory Bowel Disease Alterations in GI tract motility Increased motility → diarrhea Decreased motility → constipation 2025 © PMCOL 344 General Pharmacology 16 IBS types with respect to stool 2025 © PMCOL 344 General Pharmacology 17 Treatment for IBS Symptomatic treatment: Diet Stress management Laxatives and/or antidiarrheals 2025 © PMCOL 344 General Pharmacology 18 Treatments for IBS PG analogues: Lubiprostone for constipation-dominant IBS Analogue of PGE1 ↑cAMP (via EP4 receptors) to activate epithelial Cl- channels (CFTR) to stimulate fluid secretion. Increases fluid in stool to stretch gut and speed up transit of gut contents Cl- movement creates an osmotic gradient, H2O and other electrolytes flow passively from the ECF into the lumen through channels Poorly absorbed, so selective for gut 2025 © PMCOL 344 General Pharmacology 19 Ulcerative colitis and Crohn’s disease Ulcerative Colitis (UC): Inflammatory disorder causing ulcers in the lining of rectum and colon Ulcers form at sites where inflammation leads to cell death Inflammation in colon causes frequent emptying → diarrhea Ulcerative colitis 2025 © PMCOL 344 General Pharmacology 20 Ulcerative colitis and Crohn’s disease Crohn’s disease: Inflammatory disorder Differs from UC: Inflammation deeper within intestinal wall Occurs not just in colon but elsewhere in GI tract, e.g., small intestine, mouth, esophagus and stomach Crohn’s and UC both associated with increased risk of cancer Both require long-term treatment with anti- inflammatory and immunosuppressant drugs (covered in later lectures) Crohn’s disease 2025 © PMCOL 344 General Pharmacology 21 Therapeutic strategies for UC and Crohn’s disease Anti-diarrheals: Symptomatic relief, do not affect etiology of disease Glucocorticoids: Potent anti-inflammatory and immunosuppressant agents (PMCOL 343) E.g. Prednisolone Bind to members of nuclear receptor superfamily – modify gene transcription Anti-inflammatory – inhibit all stages of the inflammatory process For mild forms of UC, these drugs used in rectal enemas For severe UC and Crohn’s, given orally Can induce remission but long-term use limited by unwanted effects 2025 © PMCOL 344 General Pharmacology 22 Therapeutic strategies for UC and Crohn’s disease Aminosalicylates Maintenance of remission of both UC and Crohn’s disease can be achieved with aminosalicylates Sulfasalazine: Not well absorbed in gut. The active moiety 5-aminosalicylic acid (5-ASA; mesalazine) is released in the colon by bacteria Not absorbed Localized anti-inflammatory agent Scavenge free radicals Inhibit prostaglandin synthesis 5-ASA Sulfapyridine (sulfonamide – unwanted effects) (Preparations of mesalazine itself and other pro-drugs available) 2025 © PMCOL 344 General Pharmacology 23 Newer treatments for IBD - biologicals Biopharmaceuticals (humanized antibodies) targeting components of the inflammatory pathway (expensive!) Anti-Tumor necrosis factor-α (TNF- α) Infliximab Adalimumab Golimumab Anti-α4β7 integrin on T-helper lymphocytes Vedolizumab Anti-protein subunit of interleukin (IL)-12 and IL-23 Blocks interleukin binding to IL-12Rβ1 receptors on immune cells Ustekinumab 2025 © PMCOL 344 General Pharmacology 24 Sample question What pharmacological approaches can be used to increase the rate of GI transit in constipation D2 receptor antagonists, 5-HT4 receptor antagonists Osmotic laxatives Bulk laxatives What is the mechanism of action of sulfasalazine? Localized anti-inflammatory actions including scavenging of free radicals and inhibition of prostaglandin synthesis 2025 © PMCOL 344 General Pharmacology 25