Gastrointestinal Therapeutics – Part 1 PDF

You are listening to My Surrey Attendance Code: ‘Sick as a dog’ By Aerosmith Xx-xx-xx Gastrointestinal Therapeutics – Part 1 Dr Martin Hawes Senior Lecturer...

You are listening to My Surrey Attendance Code: ‘Sick as a dog’ By Aerosmith Xx-xx-xx Gastrointestinal Therapeutics – Part 1 Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics Monday, 14 October 2024 1  Learning Outcomes 1. State the principle functional problems caused by disease of the gastrointestinal system 2. Identify drugs that can be used to modify gastrointestinal function 3. Identify drugs that can be used to treat gastrointestinal disease 4. Give examples of possible uses of these agents to treat the most common diseases in domesticated species 5. Understand the pharmacological principles of antiparasitic treatments Monday, 14 October 2024 2  Link to other modules VMS1003 VMS1004 VMS2003 Monday, 14 October 2024 3  Therapeutics Antiemetics Emetics Acid blockers and gastro-protectants Prokinetics Laxatives Antidiarrhoeals Monday, 14 October 2024 4  Emetics and anti-emetics Vomiting (emesis) - complex reflex pathway evolved to protect animals from ingested toxins, but also associated with wide range of medical conditions Main targets for emetics / antiemetics: Cats & Dogs Neurokinin-1 receptors (NK1) Serotonin receptors (5-HT) Histamine-1 receptors (H1) Cats Sympathomimetic (α2 ) Dogs Dopamine receptors (D2) Remember me? Cats are not small dogs Pharmacology of emetics/antiemetics Adapted from Washabau and Day, 2013 Monday, 14 October 2024 5  Emetics and anti-emetics Vomiting (emesis) - complex reflex pathway evolved to protect animals from ingested toxins, but also associated with wide range of medical conditions Main targets for emetics / antiemetics: Cats & Dogs Neurokinin-1 receptors (NK1) Serotonin receptors (5-HT) Histamine-1 receptors (H1) Cats Sympathomimetic (α2 ) Dogs Dopamine receptors (D2) Remember me? Cats are not small dogs Pharmacology of emetics/antiemetics Adapted from Washabau and Day, 2013 Monday, 14 October 2024 6  Emetics and anti-emetics Vomiting (emesis) - complex reflex pathway evolved to protect animals from ingested toxins, but also associated with wide range of medical conditions Main targets for emetics / antiemetics: Cats & Dogs Neurokinin-1 receptors (NK1) Serotonin receptors (5-HT) Histamine-1 receptors (H1) Cats Sympathomimetic (α2 ) Dogs Dopamine receptors (D2) Remember me? Cats are not small dogs Pharmacology of emetics/antiemetics Adapted from Washabau and Day, 2013 Monday, 14 October 2024 7  Anti-emetics metoclopramide - dopamine (D2) antagonist - supresses CRTZ and upper GI pro-kinetic stimulant – increases ACh release in upper GI tract - NB – exclude GI obstruction before use maropitant – NK1 receptor antagonist – 24 hour action ondansetron – anti-serotonergic (5-HT). Expensive, used for patients unable to tolerate, or not controlled by, metoclopramide or maropitant metoclopramide maropitant Parvovirus Ouch! Can be painful Motion sickness when injected Monday, 14 October 2024 8  Emetics Used primarily to induce vomiting following poisoning Only useful if instigated within ~ 2-3 hours of ingestion Do not induce vomiting if poison is corrosive, severe CNS depression, seizuring, reduced gag reflex, bradycardia apomorphine , ropinirole - dopamine (D2) agonist (stimulates CRTZ dogs) xylazine - α2-adrenergic agonist (stimulates emetic centre cats) Hydrogen peroxide 3% solution oral alternative (stimulates CN IX at pharynx) apomorphine ropinirole xylazine Monday, 14 October 2024 9  Acid blockers and mucosal-protectants Acid blockade is important part of healing oesophageal and gastric ulceration and for treatment of gastritis. Main targets for drug therapy: Histamine (H2) receptors H+K+-ATPase proton pump Protectants aid the normal GI barrier function. Main aims/targets for drug therapy: Creating a physical barrier Acid neutralization Prostaglandin E & its production Regulation of gastric acid regulation Taken from Rang et al , 2016 Monday, 14 October 2024 10  Acid blockers and mucosal-protectants cimetidine, ranitidineH famotidineH – histamine H2 receptor antagonists – decreases stomach acid production omeprazole – proton pump inhibitor – supresses stomach acid secretion sucralfateH – complex which reacts with stomach acid to form a paste - binds to proteins in ulcers forming a protective barrier to aid healing cimetidine omeprazole Gastric ulcer Monday, 14 October 2024 11  Acid blockers and mucosal-protectants Antacids – aluminium hydroxide, magnesium hydroxide, calcium carbonate - not easy to administer, frequent administration, not palatable Misoprostol – synthetic prostaglandin E1 analogue. Useful for ulcers caused by NSAID. Caution – can cause abortion Ruminal lactic acidosis Monday, 14 October 2024 12  Pro-kinetics and anti-diarrhoeals Prokinetics – increased motility – e.g. management of ileus +/- constipation Anti-diarrhoeals – decreased motility – management of diarrhoea Enteric Nervous System Autonomic Nervous System ACh NE Secretions and Sensing environment Motility Increased motility Reduced motility Adapted from Washabau and Day, 2013 Sphincter relaxation Sphincter constriction Increased blood flow Reduced blood flow Increased secretions Reduced secretions Monday, 14 October 2024 13  Prokinetics metoclopramide - increases ACh release in upper GI tract. Useful for preventing gastro-oesophageal reflux & promoting gastric emptying cisaprideH – increases ACh release - was most effective prokinetic but withdrawn from human medicine (QT-prolongation). ‘Veterinary special’ ranitidineH - histamine H2 receptor antagonist, but anticholinesterase activity gives weak prokinetic activity, stimulating gastric emptying erythromycin – macrolide antibiotic, but is also a motilin receptor agonist – NB responsible antibacterial use lidocaine – infusion in horses improves intraoperative gastric motility Rabbit GI Equine ileus tract stasis Monday, 14 October 2024 14  Laxatives Promote elimination or increase fluid content of stools. Used for constipation, clear bowel prior to radiography / surgery Bulk forming laxatives - Mostly plant fibres (e.g. bran) are hydrophilic and not digested - bulk stimulates peristalsis Lubricants – e.g. liquid paraffin - coat the stool with a water- immiscible film, preventing water loss and ease stool passage lactulose – fermented in the large intestine to acetate and lactate with consequent osmotic laxative effect. Adjust based on individual response Who ate all the crickets? lactulose Who, who, who? Monday, 14 October 2024 15  Anti-diarrhoeals / anti-spadmodics Anti-diarrhoeals act by reducing peristalsis to enhance water reabsorption, demulcent activity or water adsorption loperamideH and diphenoxylateH – opioid agonists – anti- secretary, decrease propulsive intestinal contractions and increase segmentation, increase tone of GI sphincters hyoscine – antimuscarinic – antispasmodic for equine colic Other anti-diarrhoeals (e.g. metronidazole) treat cause Kaolin-pectin formulations - demulcent and adsorbent hyoscine loperamide Monday, 14 October 2024 16  Key Points LO – Identify drugs that can be used to modify gastrointestinal function or disease and their pharmacological principles. Give examples of possible uses of these agents to treat the most common diseases in domesticated species Emetics and antiemetics are used to trigger or stop vomiting. The principle targets include NK1 , 5-HT, H1, α2 and D2 receptors in CRTZ or emetic centre. Species differences are important in the choice of agent Metoclopramide (D2 antagonist), maropitant (NK1 antagonist) and ondansetron (5-HT3 receptor antagonist) are the main veterinary antiemetics Apomorphine (D2 agonist) and xylazine (α2-adrenergic agonist) are used as emetics in dogs and cats respectively Monday, 14 October 2024 17  Key Points LO – Identify drugs that can be used to modify gastrointestinal function or disease and their pharmacological principles. Give examples of possible uses of these agents to treat the most common diseases in domesticated species Prokinetics increase GI motility through actions on the autonomic or enteric nervous systems and are used to treat ileus +/- constipation. Metoclopramide and cisapride increase the release of ACh, ranitidine has anticholinesterase activity, erythromycin is a motilin receptor agonist. The exact mechanism of lidocaine’s use as a prokinetic is unknown. Monday, 14 October 2024 18  Key Points LO – Identify drugs that can be used to modify gastrointestinal function or disease and their pharmacological principles. Give examples of possible uses of these agents to treat the most common diseases in domesticated species Anti-diarrhoeals act by reducing peristalsis to enhance water reabsorption, demulcent activity or water adsorption Loperamide is an opioid agonist with multiple antidiarrhoeal effects (anti-secretary, decreases propulsive intestinal contractions, increases segmentation, increases tone of GI sphincters), hyoscine is an antimuscarinic, kaolin-pectin formulations are widely used (though evidence lacking) and have demulcent and adsorbent properties Monday, 14 October 2024 19  Key Points LO – Identify drugs that can be used to modify gastrointestinal function or disease and their pharmacological principles. Give examples of possible uses of these agents to treat the most common diseases in domesticated species Laxatives promote elimination or increase fluid content of stools. They are used to relieve constipation, clear the bowel prior to radiography / surgery Bulk forming laxatives (e.g. bran) are hydrophilic and not digested, the resultant bulk stimulates peristalsis Lubricants(e.g. liquid paraffin) coat the stool with a water- immiscible film, preventing water loss and ease the passage of the stool by lubrication Lactulose is a non-absorbable sugar fermented in the large intestine to acetate and lactate with consequent osmotic laxative effect. Monday, 14 October 2024 20  Key Points LO – Identify drugs that can be used to modify gastrointestinal function or disease and their pharmacological principles. Give examples of possible uses of these agents to treat the most common diseases in domesticated species Acid secretion blockade is an important part of healing oesophageal and gastric ulceration and for treatment of gastritis. Main targets for drug therapy are histamine H2 receptors (e.g. cimetidine and ranitidine) and the H+K+-ATPase proton pump (omeprazole). Gastro-protectants aid the normal GI barrier function. Main aims/targets for drug therapy include creating a physical barrier (sucralfate), acid neutralization (aluminium and magnesium antacids, calcium carbonate) and synthetic prostaglandin E (misoprostol) Monday, 14 October 2024 21