Pharmacology Quiz: Gastrointestinal Agents
26 Questions
0 Views

Choose a study mode

Play Quiz
Study Flashcards
Spaced Repetition
Chat to Lesson

Podcast

Play an AI-generated podcast conversation about this lesson

Questions and Answers

Prolonged use of purgatives can lead to which of the following?

  • Increased energy levels
  • Dependence (correct)
  • Improved sleep quality
  • Increased appetite

    • Which of the following describes the mechanism of action of sucralfate in treating ulcers?

  • It releases aluminum in an acidic environment to form a negatively-charged complex that binds to proteins and glycoproteins in mucus. (correct)
  • It inhibits histamine production in ECL cells.
  • It directly neutralizes gastric acid.
  • It kills H. pylori bacteria.

    • Prostaglandins influence gastric acid secretion by:

  • Decreasing blood flow to the mucosal layer.
  • Acting on EP2/3 receptors on ECL cells to inhibit histamine release. (correct)
  • Stimulating histamine release from ECL cells.
  • Activating vascular EP1 receptors to cause vasoconstriction.

    • Cholinomimetics enhance GI contractions in a coordinated fashion, resulting in effective propulsive activity.

    <p>False (B)</p> Signup and view all the answers

    Misoprostol is safe to use during pregnancy to prevent NSAID-induced ulcers.

    <p>False (B)</p> Signup and view all the answers

    Parietal cells secrete 150 mM HCl, resulting in a stomach pH above 4.

    <p>False (B)</p> Signup and view all the answers

    What are two mechanisms, other than direct acid neutralization, by which some anti-ulcer medications protect the gastric mucosa?

    <p>Enhancing prostaglandin synthesis and stimulating bicarbonate secretion.</p> Signup and view all the answers

    What is the effect of D2 antagonists on smooth muscle relaxation and acetylcholine (ACh) release in the gastrointestinal tract?

    <p>D2 antagonists inhibit smooth muscle relaxation and enhance ACh release, leading to increased contractility and peristalsis.</p> Signup and view all the answers

    What is the mechanism of action of antacids in neutralizing gastric acid?

    <p>Antacids are basic inorganic salts that directly neutralize gastric acid.</p> Signup and view all the answers

    D2 antagonist effects are negated by drugs like ______.

    <p>atropine</p> Signup and view all the answers

    Bismuth chelate is used in triple therapy to treat H. ________ infections.

    <p>pylori</p> Signup and view all the answers

    According to the sample question, what side effect did the 48 year-old man experience from his peptic ulcer medication?

    <p>Breast Enlargement (B)</p> Signup and view all the answers

    Match the following drugs with their primary action on GI motility:

    <p>Metoclopramide = D2 antagonist; increases gastric emptying and acts as an antiemetic Domperidone = D2 antagonist; does not cross BBB, stimulates prolactin release Prucalopride = 5-HT4 agonist; currently available for treating GI motility issues Cisapride = 5-HT4 agonist; withdrawn due to cardiac arrhythmias</p> Signup and view all the answers

    Cimetidine inhibits cytochrome P450 enzymes, potentially potentiating the effects of drugs like warfarin, felodipine and ______.

    <p>lovastatin</p> Signup and view all the answers

    Match the following drug-related effects with their corresponding mechanisms:

    <p>Antacids = Neutralize gastric acid Cimetidine = Inhibits cytochrome P450 enzymes Alginates = Form a viscous gum in the stomach Prostaglandins = Inhibit histamine release from ECL cells</p> Signup and view all the answers

    Match the substance with its function in the context of gastric protection:

    <p>Prostaglandins = Inhibit HCl release from parietal cells Mucous = Provides a physical barrier to protect the stomach lining Bicarbonate = Neutralizes acid near the mucosal surface Bismuth chelate = Kills bacteria &amp; prevents adherance</p> Signup and view all the answers

    Metoclopramide increases gastric emptying by:

    <p>Relaxing the pyloric sphincter (A)</p> Signup and view all the answers

    Domperidone easily crosses the blood-brain barrier (BBB), resulting in a high risk of dyskinesias with long-term use.

    <p>False (B)</p> Signup and view all the answers

    Misoprostol acts on EP1/2 receptors on mucosal cells to increase ________ production.

    <p>HCO3-</p> Signup and view all the answers

    Which of the following is a potential side effect of cimetidine with respect to male patients?

    <p>Reversible gynaecomastia. (B)</p> Signup and view all the answers

    Misoprostol is a short-lived analog of PGE1 that is rapidly metabolized by oxidation

    <p>False (B)</p> Signup and view all the answers

    What is the role of 5-HT4 receptors in the myenteric plexus concerning acetylcholine (ACh) release?

    <p>Presynaptic 5-HT4 receptors in the myenteric plexus enhance ACh release.</p> Signup and view all the answers

    Antacids are absorbed systemically to neutralize gastric acid.

    <p>False (B)</p> Signup and view all the answers

    The release of 5-HT from enterochromaffin cells is triggered by food constituents and ______ of the gut wall..

    <p>stretching</p> Signup and view all the answers

    At what pH do antacids need to raise the stomach lumen's levels to in order to inhibit pepsin activity?

    <p>Above 5</p> Signup and view all the answers

    Why was Cisapride withdrawn from the market?

    <p>Fatal cardiac arrhythmias (B)</p> Signup and view all the answers

    Flashcards

    HCl Secretion

    Parietal cells secrete 150 mM HCl, maintaining pH around 1-2 to aid digestion and prevent bacterial growth.

    EP2/3 receptors

    Receptors on ECL cells that, when activated, inhibit histamine release, reducing acid secretion.

    Histamine role in digestion

    Histamine stimulates acid production through H2 receptors on parietal cells, increasing stomach acidity.

    Cimetidine

    A drug that blocks H2 receptors, reducing stomach acid secretion; it inhibits certain cytochrome P450 enzymes.

    Signup and view all the flashcards

    Antacids

    Basic inorganic salts taken orally to neutralize gastric acid and inhibit digestive enzymes, requiring pH>5.

    Signup and view all the flashcards

    Alginates

    Negatively charged polysaccharides from algal cell walls that may increase mucus viscosity in the stomach.

    Signup and view all the flashcards

    Cytochrome P450 enzymes

    A group of enzymes involved in drug metabolism; some drugs like cimetidine inhibit these enzymes.

    Signup and view all the flashcards

    Gynaecomastia

    Reversible breast enlargement in men, possibly caused by certain drugs like cimetidine affecting estrogen receptors.

    Signup and view all the flashcards

    Cholinomimetics

    Drugs that mimic acetylcholine effects, enhancing GI contractions.

    Signup and view all the flashcards

    D2 antagonists

    Drugs that block dopamine receptors, increasing GI motility.

    Signup and view all the flashcards

    Role of dopamine in GI

    Dopamine modulates gut motility, relaxing muscles during peristalsis.

    Signup and view all the flashcards

    Metoclopramide

    A D2 antagonist that increases gastric emptying and acts as antiemetic.

    Signup and view all the flashcards

    Domperidone

    A D2 antagonist that does not cross BBB, avoiding dyskinesias.

    Signup and view all the flashcards

    5-HT4 agonists

    Drugs that enhance ACh release, boosting GI motility via serotonin.

    Signup and view all the flashcards

    Cisapride

    5-HT4 agonist withdrawn due to cardiac risks, but effective for GI motility.

    Signup and view all the flashcards

    Tegaserod

    Withdrawn 5-HT4 agonist linked to adverse cardiac events but still available as a last resort.

    Signup and view all the flashcards

    Prucalopride

    A newer 5-HT4 agonist, not linked to cardiac risks for constipation treatment.

    Signup and view all the flashcards

    Cholinergic drugs

    Enhance contractility but not effective alone for constipation relief.

    Signup and view all the flashcards

    Mucosal protection

    Mechanisms that protect the stomach lining from damage.

    Signup and view all the flashcards

    Bismuth chelate

    A colloid used in triple therapy for H.pylori that kills bacteria.

    Signup and view all the flashcards

    Sucralfate

    A complex that binds to ulcers and forms a protective gel.

    Signup and view all the flashcards

    Prostaglandins (PGs)

    Compounds that inhibit HCl release and promote mucous production.

    Signup and view all the flashcards

    Misoprostol

    A synthetic PGE1 analog used to protect the stomach lining.

    Signup and view all the flashcards

    H.pylori

    Bacteria often responsible for causing peptic ulcers.

    Signup and view all the flashcards

    NSAIDs

    Non-steroidal anti-inflammatory drugs that can cause ulcers.

    Signup and view all the flashcards

    EP receptors

    Receptors acted on by Misoprostol to promote mucosal protection.

    Signup and view all the flashcards

    Study Notes

    PMCOL 344: Scientific Basis of Pharmacology II 2025

    • This course continues 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), and Antiinfectives (Sandini).
    • All topics include grounding in underlying pathophysiology.
    • The aim is to explain the rationale for treatments, leading to better understanding of pharmacology.
    • Course material is provided online (lecture slides and any other material from instructors).
    • A textbook is not required, but the course is based on "Rang & Dale" text. An online copy is available on the library website (see syllabus).

    Assessments

    • Midterm 1: 30% of the mark, February 12th (50 minutes), Material taught up to and including February 10th, MCQs (online- ExamLock and SEM).
    • Midterm 2: 20% of the mark, March 14th (50 minutes), Material taught up to and including March Oth, MCQs (online- ExamLock and SEM).
    • Final Examination: 50% of the mark, cumulative, TBA (Registrar's office determines), 2 hours.
    • Emphasis is on the last section of the course, but significant amounts of material are examined in the midterms. MCQs, (If online - ExamLock and SEM).

    Additional Information

    • Instructor contact information is in the syllabus on eClass.
    • Students should read the syllabus for course rules and more details.
    • GI drugs represent approximately 8-10% of all prescriptions and more than 30% of OTC preparations (e.g., laxatives, antacids, gas relievers, anti-diarrheals, haemorrhoid treatments).
    • The Gl tract mediates digestion and absorption of nutrients and orally-available drugs, and also eliminates waste and toxins (defecation and vomiting).
    • The Gl tract contains endocrine system components, including 5-HT (>90% of body 5-HT is in the enteric NS), gastrin, ghrelin, and cholecystokinin.

    GI Tract Histological Anatomy

    • The Gl tract has a submucosa with glands.
    • The mucosa includes epithelium, lamina propria, and muscularis mucosae.
    • The muscularis has circular and longitudinal muscle layers.
    • The serosa contains areolar connective tissue and epithelium.

    Enteric Nervous System

    • The ENS is an intrinsic neural network within the wall of the Gl tract.
    • It regulates motility, secretion, blood flow, and immune responses, and is integrated with and regulated by the autonomic nervous system (ANS).
    • The ENS can act independently of the CNS.
    • The submucosal plexus innervates epithelia and muscle cells.
    • The myenteric plexus regulates gut motility and secretion and lies between muscle layers.

    Gut motility

    • Motility moves food from mouth to anus (peristalsis); mixes food to facilitate digestion (segmentation); and is determined by smooth muscle properties modified by chemical and nerve inputs, and hormones.
    • Different regions of the GI tract have different types of motility (e.g., tonic contractions in sphincters, phasic contractions in the small intestine and colon).

    Small intestine motility

    • Rhythmic electrical activity accompanies contractions.
    • Phasic activity is driven by slow waves.
    • Slow waves exhibit spiking activity (trace 1, 3rd and 4th events) and propagation slows with more distal segments.
    • When the slow wave reaches threshold, VGCCs open, Ca2+ enters, and APs fire leading to muscle contraction.

    Patterns of motility

    • Isolated contraction moves contents both orally and aborally.
    • Segmentation mixes contents over short length of intestine.
    • Peristalsis propels contents aborally and involves contraction and relaxation.

    Gut-Brain-Energy Axis

    • Hormones secreted by the gut during eating can affect gut function.
    • Gastrin stimulates acid secretion by parietal cells in the stomach.
    • 5-HT from enterochromaffin cells increases ACh release from nerves in ENS.
    • Motilin from mucosal cells stimulates contraction of GI smooth muscle.
    • Cholecystokinin (CCK) from small intestine enteroendocrine cells stimulates pancreatic enzyme secretion.
    • Glucagon-like peptide 1 (GLP-1) stimulated insulin release, inhibits glucagon release, and promotes satiety.

    Enteroendocytes Release Hormones

    • Enteroendocrine cells respond to nutrients, neurotransmitters, and local signals to release hormones.

    Gastroesophageal Reflux Disease (GERD)

    • The stomach secretes ~2.5 liters of gastric juice per day.
    • Peptic (chief) cells secrete pro-enzymes like prorennin and pepsinogen.
    • Parietal cells secrete HCl, maintaining a pH of approximately 1-2 in the stomach.
    • Stomach secretions are acidic to promote proteolysis (e.g., pepsinogen to pepsin) and kill pathogens.
    • Acidic conditions facilitate iron absorption (Fe2+ form is better absorbed than Fe3+ form).
    • The stomach wall is protected from acid by mucosal cells secreting prostaglandins (e.g., PGE2 and PGI2), which stimulate mucus and bicarbonate ion secretion.
    • Mucosal surface forms a gel-like protective layer (pH 6-7).
    • Histamine stimulates acid production via H2 receptors.
    • Vascular EP2/4 receptors increase blood flow to the mucosal layer to aid in this protection.

    HCI Secretion by parietal cells

    • Parietal cells secrete 150 mM HCl.
    • H + and Cl- are actively secreted by parietal cells.
    • K+ is exchanged for H+ by H+/K+ ATPase.
    • Carbonic anhydrase generates H+and HCO3- from H2O and CO2.
    • HCO3- exchanges for Cl-.

    HCI Secretion by parietal cells - Stimulation

    • Histamine, basally released from ECL cells, acts on parietal cell H2 receptors to activate proton pump via Gs, cAMP.
    • Gastrin, secreted by G cells in response to nerve stimulation and stomach contents (e.g., amino acids and Ca2+), acts on CCK2 receptors on ECL cells to elevate [Ca2+] stimulating histamine release.

    HCI Secretion by parietal cells - Inhibition

    • ACh, released from postganglionic cholinergic neurons, acts on parietal cell M3 receptors to stimulate proton pump via elevation of [Ca2+].
    • Prostaglandins inhibit histamine production, increase HCO3- and mucous secretion, and vasodilation.
    • Tonic release of somatostatin from D cells acts on SST2 receptors on G cells to inhibit gastrin release, ECL cells to inhibit histamine release and parietal cells to inhibit acid secretion

    Causes of ulcers

    • Possible causes are stress, Cyclooxygenase (COX) inhibition by NSAIDs, and Helicobacter pylori infection (primary underlying factor in ~80-90% of gastric ulcers and ~95% of duodenal ulcers).
    • Stomach acid, when it passes into the duodenum, is usually protected by high levels of bicarbonate secretion.

    Treatment Goals

    • Relieve symptoms.
    • Allow damaged tissue to heal.
    • Eliminate the cause.

    Helicobacter pylori

    • Discovered in 1982 by Marshall & Warren.
    • Awarded the Nobel Prize in 2005.
    • Corkscrew-shaped, Gram-negative bacterium.
    • Present in ~50% of the population.
    • Lifetime prevalence of peptic ulcer disease (PUD) is ~20% in H. pylori-infected populations.
    • Causes asymptomatic inflammation of the stomach lining (gastritis) and, eventually, ulcers and is linked to cancer.
    • The WHO classifies it as a Class 1 carcinogen, equivalent to cigarette smoking
    • PUD-linked death rate ~1.2/100,000 in Canada (2017).

    Helicobacter pylori survival mechanisms

    • H. pylori survives the stomach's acidic environment by burrowing into stomach mucous, allowing acid and pepsin to reach the stomach epithelium.
    • Urease converts urea to HCO3- and ammonia to neutralize acid (form NH4+ = ammonium).
    • Breakdown of amino acids from food generates high levels of urea in the stomach.
    • H. pylori produces toxins that kill epithelial cells and causes local inflammation.

    Urea breath test for H. pylori

    • Used as a quick, cheap, and non-invasive alternative to endoscopy.
    • A solution containing urea labelled with 13C or 14C is consumed.
    • Exhaled breath is collected and analyzed for labelled CO2.

    Triple Therapy (ulcers)

    • Treatment course, usually effective for 2 weeks, includes a proton pump inhibitor (e.g., omeprazole), clarithromycin (macrolide – inhibits bacterial protein synthesis), and amoxicillin (broad spectrum penicillin – inhibits bacterial wall synthesis).
    • Can cure ulcers if H. pylori is the cause.

    Proton pump inhibitors

    • H+/K+ ATPase is the last step in gastric acid secretion pathway.
    • Proton pump inhibitors are prodrugs whose active moieties bind covalently with cysteines in the active site on the outside of the cell, inhibiting both basal and stimulated acid secretion.
    • First-line therapy.
    • Prototype: Omeprazole. It is irreversible therefore long-acting.t1/2= 1 hour, but single dose reduces acid secretion for 2-3 days. Weak base (pKa ~8), ionized form accumulates on outside of cell in acid enviroment. This promotes conversion of prodrug

    Pharmacokinetic interactions

    • Omeprazole inhibits some cytochrome P450 enzymes, potentiating actions of other drugs (e.g., warfarin, clopidogrel, phenytoin, benzodiazepines, and tricyclic antidepressants).
    • Potential for increased CV risk with PPI use.

    H2 receptor antagonists

    • Selective, competitive orthosteric antagonists at H2 receptors on parietal cells.
    • Prototype: Cimetidine.
    • Inhibit both histamine- and gastrin-stimulated acid secretion.
    • Given orally, decrease basal and stimulated acid secretion (>90%), increases pH above 4.
    • Decrease pepsin activity and promote healing of ulcers.

    Classic example of structure-based drug design

    • James Black (Nobel Prize 1988).
    • Shows the Kp of cimetidine for histamine receptors: H1 = 0.45 mM, H2 = 0.80 µM, and H3 = 33 µM.

    Additional inhibition of HCI secretion

    • 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 gynecomastia in men due to affinity for estrogen receptors and increased prolactin secretion

    Neutralize acid: Antacids

    • Basic inorganic salts taken orally to neutralize gastric acid and inhibit peptide enzymes (need pH > 5).
    • Chemical antagonism.
    • At sufficient doses for prolonged periods, can result in healing of ulcers.
    • Mixture of magnesium and aluminum hydroxide salts preserves normal bowel function (Al(OH)3 + 3HCI → AICI3 + 3H2O).
    • Alginates are negatively charged polysaccharides from algal cell walls that absorb water to form a viscous gum. May possibly increase viscosity and adherence of mucus to the stomach lining.

    Protection of the mucosa

    • Enhance endogenous mucosal protective mechanisms.
    • Bismuth chelate (colloid): used with triple therapy to treat H. pylori, kills bacteria and prevents adherence.
    • Sucralfate is a complex of Al(OH)3 and sulfated sucrose, which releases Al in acidic environments to form a negatively-charged complex that binds to proteins and glycoproteins in mucous to form a gel.
    • Both bismuth chelate and sucralfate can affect absorption of other drugs and also adsorb pepsin.
    • Prostaglandins (PGs) inhibit HCl release, enhance mucous production and mucosal blood flow, and stimulate HCO3 release but are short-lived.
    • Misoprostol is a stable analog of PGE1 with greatly reduced metabolism by oxidation, acting on EP1/2 receptors on mucosal cells, on EP4 receptors to increase mucous production, and on EP2/3 receptors on ECL cells to inhibit histamine production via inhibition of adenylyl cyclase. Promotes healing of ulcers and prevents damage by NSAIDs.
    • The mechanisms by which acid is secreted and how processes are regulated are key.
    • Causes of ulcers (H. pylori, NSAIDs, stress) and mechanisms of action of drugs are key to understand.

    Vomiting and Anti-emetics

    • Vomiting (emesis): forceful evacuation of gastric contents.

    • Physiological response to irritating substances in the gut/blood stream, excessive vestibular stimulation (motion sickness), psychological stimuli (fear, odors).

    • Physiological response to ingestion of toxic substances – emetic drugs induce vomiting to prevent absorption of ingested toxins (e.g., ipecac).

    • Unwanted effects of clinically used drugs (e.g., chemotherapy, opioids, anesthetics), motion sickness (e.g., pregnancy, migraine, bacterial & viral infections) can cause vomiting, reducing effectiveness of treatments and causing dehydration and nutrient depletion.

    • Vomiting regulated centrally by the medulla.

    • Chemoreceptor trigger zone (CTZ): near the CTZ in the blood-brain barrier, which is relatively permeable, allowing circulation of emetogenic mediators.

    • Vomiting center receives impulses from the CTZ, GI tract, and higher cortical centers and coordinates the physical act of vomiting.

    • Vestibular nuclei receive inputs from the labyrinth (inner ear).

    Anti-emetics: Muscarinic receptor antagonists

    • Selective, competitive, orthosteric antagonists that act at the vomiting center and vestibular nuclei, useful for motion sickness and post-op emesis. These drugs are predictable, hence, they cause dry mouth, blurred vision, sedation, and constipation.

    Anti-emetics: 5-HT3 receptor antagonists

    • Selective, competitive, orthosteric antagonists that act at the CTZ and visceral afferents; useful in treating chemotherapy-induced vomiting, acting on enterochromaffin (EC) cells. They are less effective against motion sickness, and can cause Long QT syndrome.

    Anti-emetics: Dopamine (D2) receptor antagonists

    • Selective, competitive, orthosteric antagonists that act primarily at the CTZ; useful for chemotherapy-induced vomiting and less effective than 5-HT3 antagonists, but acting on GI tract to increase motility. They can cross the BBB, causing movement disorders. Prototypes: Metoclopramide, domperidone.

    Other anti-emetics

    • Antipsychotic phenothiazines (e.g., chlorpromazine): used for severe nausea and vomiting associated with conditions like cancer, radiation, cytotoxic, opioid or anesthetic medications.
    • D2 receptor antagonists, acting on the CTZ, can block histamine and muscarinic receptors, but have limitations because of unwanted effects.
    • Cannabinoids (e.g., nabilone) act on the CTZ for nausea and vomiting relief.
    • Glucocorticoids (e.g., dexamethasone) are used with chemotherapy, but their mechanism is unclear.
    • NK1 receptor antagonists (e.g., aprepitant) act on the CTZ and vomiting center, often used in combination with other drugs.

    Intestinal Fluid Balance and Anti-Diarrheal Drugs

    • Adult humans ingest ~2 liters of fluid daily, and ~9 liters enter the small intestine daily (including saliva and secretions from the stomach, pancreas, and liver). Absorption normally exceeds secretion (e.g., ~90% of fluid from small intestine is absorbed vs. ~1 liter remaining for large intestine absorption). H2O and electrolytes are simultaneously absorbed and secreted.
    • Small intestinal epithelial cells express ion channels, pumps, and transporters.
    • Water always follows solutes. Disruptions to this balance cause diarrhea.
    • Diarrhea results from disordered water and electrolyte transport in the small intestine. This leads to increased gut motility, increased fluid secretion, and decreased fluid absorption, leading to fluid and electrolyte loss, most notably Na+ and H2O.

    2 Types of Diarrhea - Mechanisms

    • Secretory diarrhea results from abnormal secretion of water and salts into the small intestine. This occurs when salt absorption is impaired while chloride secretions continue or increase net fluid secretion, causing watery stools and dehydration. Toxins can trigger this (e.g., cholera toxins).
    • Osmotic diarrhea occurs when poorly absorbed substances (e.g., sorbitol, mannitol) are ingested, drawing water into the gut lumen and leading to loose stools and dehydration. This can happen with improper food handling.

    Treatment of diarrhea

    • First priority for diarrhea treatment is to restore fluid and electrolyte balance through oral rehydration. The addition of glucose (and some amino acids) enhances Na+ absorption for better fluid reabsorption intake.

    Anti-infective agents (treatment for diarrhea)

    • Most GI infections are viral, and therefore anti-infectives are not often used.
    • Some common bacterial infections (e.g., E. coli, Salmonella, Shigella, Campylobacter) may need treatment

    Treatment of diarrhea: Spasmolytics

    • Rationale for spasmolytics in treating diarrhea is based on relaxation of gut smooth muscle leading to a decrease in gut motility and an increase in transit time, increasing the time available for water reabsorption.

    Treatment of diarrhea: Muscarinic antagonists

    • ACh is a primary stimulatory neurotransmitter in the gut. Muscarinic antagonists (e.g., atropine) block the action of ACh to relax gut muscle and decrease motility. Side effects are significant, making these rarely used.

    Treatment of diarrhea: Opioid receptor agonists

    • Opiates affect multiple GI functions (motility, secretion, electrolyte and fluid transport). Opioid drugs affect the entire gut system more broadly and hence can be used, though not consistently, to treat diarrheal symptoms resulting from the issues discussed above. They generally act by inhibiting presynaptic receptors to reduce ACh release and increase segmentation vs. peristalsis.

    Treatment of diarrhea: Adsorbents

    • Adsorbents in treating diarrhea bind water in the gut without reducing dehydration necessarily. They are symptomatic care, and efficacy is typically not proven, though they might adsorb pathogens and toxins, for example.

    What you need to know (Intestinal fluid balance/diarrheal issues)

    • Understand the mechanisms for maintaining normal intestinal fluid balance.
    • Understand the types of diarrhea (secretory and osmotic, and how to distinguish them)
    • Understand the mechanisms underlying currently used treatments for diarrhea.

    Sample question (Intestinal fluid balance)

    • Loperamide, an opioid receptor agonist, acts on presynaptic receptors in the ENS to reduce ACh release. This leads to increased segmentation and decreased peristalsis, which gives the GI tract more time to resorb water from gut contents. Because it avoids affecting the CNS, it is an OTC drug.

    Laxatives and GI motility enhancers

    • Constipation affects ~50% of adults. It is a slowed passage of food through the GI tract. Causes include opioids, antidepressants, iron supplements, diet, hydration state, and exercise, and hormones (e.g., IBS).
    • Purgatives accelerate intestinal transit and bowel evacuation (bulk laxatives, osmotic laxatives, and stimulant laxatives).
    • Bulk laxatives are non-absorbable substances that form a bulking mass in the gut. This mechanical distension promotes peristalsis. Examples include methyl cellulose and ispaghula husk.
    • Osmotic laxatives are poorly absorbed substances such as lactulose or macrogols which create osmotic loads, drawing water into the gut to soften stools.
    • Stimulant laxatives, such as bisacodyl or senna, directly stimulate myenteric plexus nerves to increase gut peristalsis and defecation. Prolonged use of any purgative (laxative) can result in dependence.

    Drugs which increase GI motility

    • Cholinomimetics (muscarinic agonists) and cholinesterase inhibitors enhance GI contractions but have limited net propulsive activity. They are not used for constipation often due to uncoordinated contractions.
    • The Gl tract generates ~ 50% of the body’s dopamine.
    • D2 antagonists block effects of endogenous dopamine, acting on smooth muscle relaxation and increasing ACh release, and thus increasing contractility and peristalsis, though often have unwanted side effect consequences. Prototypes: Metoclopramide, domperidone.
    • 5-HT4 agonists stimulate sensory nerves in the myenteric plexus and presynaptic 5-HT4 receptors, enhancing ACh release. Prototypes include cisapride (withdrawn due to cardiac arrhythmias), tegaserod (also withdrawn due to adverse cardiac events), prucalopride (not yet linked to increased cardiac risk)

    Chronic Bowel Diseases: IBS

    • Irritable bowel syndrome (IBS) involves a colon or large intestine particularly sensitive and reactive to certain foods, stress, possible alterations in 5-HT reuptake into neurons and bacteria, possibly hormones, and generally does not involve inflammation.
    • IBS classification is based on whether the diarrhea and constipation are dominant symptoms (constipation-dominant, diarrhea-dominant, and mixed).
    • Treatment options for IBS include diet, stress management, laxatives, antidiarrheal agents, for example.

    Treatments for IBS

    • PG (prostaglandin) analogues like Lubiprostone: analogue of PGE1,↑ cAMP (via EP4 receptors) to activate epithelial Cl- channels (CFTR), resulting in increased fluid secretion, which increases fluid in stool to stretch gut and increase transit of gut contents. Cl- gradient created for improved absorption. Poorly absorbed for selectivity in the gut.

    Ulcerative colitis and Crohn's disease

    • Ulcerative colitis (UC): inflammatory disorder causing ulcers in the rectum and colon lining. Ulcers result from inflammation leading to cell death at sites of inflammation which causes frequent bowel emptying as diarrhea.
    • Crohn’s disease: inflammation that happens deeper within the intestinal wall and can occur throughout the entire GI tract (small intestine, mouth, esophagus and stomach), and has an increased risk of associated cancer. Differing from UC by not being confined to the colon.
    • Chronic treatment options for UC and Crohn's disease include anti-diarrheals for symptomatic relief, glucocorticoids (prednisolone), aminosalicylates (sulfasalazine: poorly absorbed, but the active moiety 5-ASA, is released in the colon; localized anti-inflammatory, scavenges free radicals and inhibits prostaglandin synthesis), and newer biological treatments like anti-TNF alpha agents (e.g., infliximab, adalimumab, golimumab), anti-integrin agents (e.g., vedolizumab), and anti-protein subunit of interleukin agents (e.g., ustekinumab).

    Studying That Suits You

    Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

    Quiz Team

    Related Documents

    PMCOL 344: Scientific Basis of Pharmacology II Past Paper 2025 PDF

    Description

    Test your knowledge on the pharmacology of gastrointestinal agents with this quiz. It covers topics such as purgatives, ulcer treatments, and the influence of various medications on gastric functions. Understanding how these drugs work will enhance your grasp of gastrointestinal pharmacotherapy.

    More Like This

    Use Quizgecko on...
    Browser
    Open
    Browser
    Browser