Gastrointestinal Pharmacology – Clinical Applications

2/13/2024 Gastrointestinal Pharmacology – Clinical Applications Nolie K Parnell, DVM, DACVIM Purdue University G 132 X 49333 Purdue SAIM Top GI Medications Capromorelin/Mirtazapine Cerenia Cisapride Metoclopramide Ondansetron Pantoprazole Prednisone/ prednisolone Probiotics (Visbiome/Proviable) 1 2/...

2/13/2024 Gastrointestinal Pharmacology – Clinical Applications Nolie K Parnell, DVM, DACVIM Purdue University G 132 X 49333 Purdue SAIM Top GI Medications Capromorelin/Mirtazapine Cerenia Cisapride Metoclopramide Ondansetron Pantoprazole Prednisone/ prednisolone Probiotics (Visbiome/Proviable) 1 2/13/2024 What Is A GI Protectant (GIP)? Antacids Oldest group of GIPs Not practical for the majority of dog/cat patients Histamine type-2 receptor antagonists H2 – Receptor Antagonist/ H2RA Proton pump inhibitors PPIs Misoprostol Sucralfate Why Use GI Protectants? GI Ulceration (GUE) High-dose corticosteroids Non-steroidal anti-inflammatory drugs Primary gastrointestinal tract disease Endoparasitism underappreciated AKI Other Esophagitis Gastroesophageal Reflux (reflux esophagitis) Bilious vomiting Unknown if CKD Literature suggests not associated Hepatic disease Ex. Intrahepatic shunt Hypovolemic or hypotensive shock Hypoadrenocorticism Hit-by-car Sepsis 2 2/13/2024 Medical Conditions Associated with Gastrointestinal Ulceration (GUE) True incidence of GUE is unknown Under-reported due to variability of clinical signs Under-reported due to % of pets mildly effected 88% of dogs had GUE in stomach 6% had GUE of stomach and duodenum 12% had GUE duodenum alone Disease Odds Ratio NSAID Admin 6.3 (95% CI) Glucocorticoid Admin 3.0 (95% CI) GI Neoplasia 13.5 % (95% CI) GI Mechanical Dz *foreign bodies *GDV 4.8 % (95% CI) JVIM:Volume35, Issue6 November/December 2021 Pages 2697-2704 Gastrointestinal Ulceration & Erosion (GUE) 3 2/13/2024 Gastric Acid Production Parietal cell produces HCl. 3 receptors communicates with vasculature in submucosa: histamine 2, gastrin, & muscarinic. H+/K+ Pump at lumen surface. ATP dependent. Exchange of H+ (out) for KCl (in). Cl- diffuses back out of parietal cell. www.hopkins-gi.org Groups of GI Protectants Class of RX Example Action H2RA Famotidine Inhibit HCl acid secretion PPI Omeprazole Inhibit HCl acid secretion Prostaglandin Analogue Misoprostol Cytoprotective due to prostaglandin E1 analogue (↑ bicarbonate secretion, ↓pepsin content, preservation of tight junctions, ↑mucosal blood flow) and ↓ gastric acid secretion Antacids Tums Stimulate local prostaglandin synthesis; ↓ pepsin activity; binds bile acids in stomach Miscellaneous Sucralfate Multiple (pH buffering, binds to mucosal defect, etc) 4 2/13/2024 GOALS of GIPS Increase intragastric pH  3 for 75% of day (approximately 18 hours) Increase intragastric pH  4 for 67% of day (approximately 16 hours) Promote repair of injured mucosal tissue Prevention of GUE is not realistic for majority of GIPS Exception: misoprostol and high-dose aspirin and no evidence misoprostol prevents GUE from glucocorticoids Sucralfate Complex salt Composed of sucrose octasulfate and aluminum hydroxide Mechanism of action is multifactorial Adheres to ulcer site-protective not just a “Band-Aid” Cytoprotective prostaglandin E2 and I2 Antacid properties 5 2/13/2024 Sucralfate Requires an acidic environment to be effective Side Effects Relatively safe Drug interactions (interferes with absorption) Ciprofloxacin, doxycycline If needed, give these medications 2 hours before sucralfate Constipation +/- decrease gastric emptying Sucralfate Humans report an analgesic effect for esophagitis and posttonsillectomy Is this secondary to creating a barrier? No evidence combination therapy of sucralfate with PPI or H2RA for treatment of GUE is beneficial or indicated PPIs are superior to sucralfate for management of GUE Some evidence that intact tablets may not fully disintegrate and liquid suspension is more reliable 6 2/13/2024 H2-Receptor Antagonist H2- Receptor Antagonists Drug Trade Name Potency Dosing Frequency Cytochrome P450 Available Forms Cimetidine Tagamet Least TID- 4x day Yes OTC, Rx Ranitidine Zantac 5x Cimetidine BID Yes, small OTC, Rx Famotidine Pepcid 20xCimetidine 1-2x day No OTC, Rx All have both oral and parenteral forms 7 2/13/2024 H2-receptor Antagonist Comparison of H2RAs to each other All are equally effective in decreasing gastric acidity Continuous H2RA administration results in pharmacological tolerance Gastrin-induced up-regulation of enterochromaffin-like cell synthesis of histamine which competes with the antagonist at the parietal cell Dogs: occurs within 13 days and clinical observed by Day 3 Cats: unclear but between Day 1 - 13 Clinical Efficacy: lack of benefit of H2RAs for management of GUE or reflux esophagitis JVIM.2018;32:1823-1840 ACVIM Consensus Statement JVIM.2018;32:1823-1840 8 2/13/2024 Proton Pump Inhibitors Result is to  acid production Binds at the secretory surface (apical membrane) of parietal cell Inhibits the enzyme hydrogenpotassium adenosine triphosphate (H+/K+ ATPase) Inhibits transport of hydrogen ions into the lumen of stomach Omeprazole Accumulates in acidic compartment of parietal cell (unique to parietal cell) Does not affect other proton pump systems Drug is degraded in an acid environment 9 2/13/2024 What Are Your PPI Options? Drug Class Dose Frequency/Route Availability Omeprazole Prilosec 0.7 – 1 mg/kg PO once daily to *BID Rx , Generic, OTC Omeprazole Generic 0.7 – 1 mg/kg PO once daily OTC Pantoprazole Protonix 1 mg/kg PO, IV once daily Rx, Generic Lansoprazole Prevacid®24H R 1 – 2 mg/kg PO once daily Rx, Generic, OTC Esomperazole Nexium 0.7- 1 mg/kg PO, IV once daily Rx Conclusion: PPIs administered twice daily are superior to other GIPs for treatment of GUE 10 2/13/2024 Clinical concerns for PPIs Breaking or crushing an enteric-coated form or using compounded formulation may diminish protective effect Administering enteric-coated form preferred Decreases lag-time for achieving max effect Humans Long-term use and increased risk for fractures Long-term use and increased risk of pneumonia Omeprazole prophylaxis induces fecal dysbiosis Clinical concerns for PPIs Drug interactions with PPIs Impact on Cytochrome P450 (CYP) and gastric pH Antifungals (poor absorption w/ exception of fluconazole and itraconazole solution) Iron – changes in gastric pH Mycophenolate – changes in gastric pH Clopidogrel - (CYP) – potentially ↓ antiplatelet activity PPI should be gradually tapered after administration of  4 weeks to avoid rebound gastric acid hypersecretion ↓50% on a weekly basis Discontinue evening dose as first step JVIM.2018;32:1823-1840 11 2/13/2024 Use of GIPs in Medical Conditions other than GUE Use of GIPs in Medical Conditions other than GUE 12 2/13/2024 Howl #841-256 2 yr old, MN DSH Howl’s Endoscopy 13 2/13/2024 Erosive gastritis Erosive esophagitis Gastroesophageal Reflux What Is Your Treatment Plan? 14 2/13/2024 Howl’s Treatment Plan Icu treatment plan At-home treatment plan Maropitant Pantoprazole Metoclopramide Omeprazole Cisapride Prokinetic Therapy Rationale To manipulate gastric or gastrointestinal motility Primary dysmotilities create significant morbidity and can be frustrating to treat Secondary motility disorders also occur Post-operative ileus Ileus associated with opioid analgesics Secondary to inflammation of the GI tract 15 2/13/2024 What Prokinetics Are Available? Metoclopramide Cisapride Erythromycin Azithromycin Use cautiously (microbial stewardship) Pyridostigmine Side effects outweigh benefits except with Myasthenia Gravis patients Ranitidine (weak prokinetic, should not be used as first option) Human: 5-HT4 receptor antagonists (ex. prucoalopride) No veterinary option at this time other than cisapride) Human: NK1 receptor antagonist (gastroparesis) Unknown if veterinary option improves gastric motility at this time Gastroesophageal Reflux Disease (GERD) 1. Increase intragastric pH  4 2. Improve/increase lower esophageal sphincter tone 3. Improve Gastric Emptying 1. 2. Pharmacology Diet 16 2/13/2024 Gastroesophageal Reflux Esophageal Inflammation ↓ lower esophageal sphincter tone Pharmacologic Management Prokinetics Improve gastric emptying so  likelihood that gastric contents will be refluxed  lower esophageal sphincter pressures Metoclopramide 0.2-0.4 mg/kg PO QID Cisapride 0.5-1.0 mg/kg PO BID-TID Must be compounded 17 2/13/2024 Metoclopramide Dopaminergic antagonist Both prokinetic & antiemetic Emesis via CRTZ pathway Indications Gastroesophageal reflux Delayed gastric emptying Emesis ? for postoperative ileus Most likely only effective for proximal GI (stomach, duodenum) Minimal effect in Jejunum Reglan 0.1-1.0 mg/kg IM, SQ, PO 1.0-2.0 mg/kg/day CRI Metoclopramide Adverse Reactions dog: mentation & behavior changes cat: frenzied behavior or disorientation dog/cat: constipation with chronic use Contraindications Seizures Structural obstruction Gastrointestinal hemorrhage 18 2/13/2024 Serotonergic Agents: Cisapride Approved for use in the USA in 1993 FDA withdrew drug 1999 Serotonergic effects on smooth muscle (5-HT4 receptors) Must be compounded Cisapride Clinical Application Esophageal disease Cat vs. dog esophageal muscle Increases LES pressure Gastroesophageal reflux Postoperative ileus Idiopathic Feline Megacolon Gastric disease Delayed gastric emptying Cisapride 0.2-0.5 mg/kg PO BID-TID 19 2/13/2024 “Casey” Smith 4 year old castrated male DSH Clinical Presentation: no defecation x 7 days vomiting x 3 days anorexic, lethargic x 2 days Physical Examination: obese dehydrated (5-7%) stool-filled colon 20 2/13/2024 “Casey” Smith Diagnosis: obstipation secondary to idiopathic megacolon Initial Treatment: Intravenous fluids to address dehydration Enema(s) Manual evacuation the following day Long-term treatment: Diet manipulation with fiber Lactulose Cisapride 21 2/13/2024 Abby Goodwin 18 month old spayed female Boston Terrier CC: Acute onset of vomiting History: 6 hours before was found eating left-overs left on counter Physical Examination: no abdominal pain, no signs of systemic illness Treatment Plan (Supportive): Maropitant SQ Diet change for 72 hours (low fat, highly digestible) Betty Lawson 10 year old spayed female Boxer CC: protracted vomiting, weakness, anorexia, mixed bowel diarrhea, weight loss History: 2-3 week hx of progress GI signs; anorexia for 4 days 22 2/13/2024 Why Use Antiemetics? Reduces frequency of vomiting Possibly eliminate vomiting entirely IMPACT Relieves a stressful/emotional situation for an owner Reduces severity of dehydration & electrolyte imbalances Allows animal to rest Possibly decrease time in hospital What Antiemetics Are Available? Alpha-2-Adrenergic Antagonists Dopaminergic Antagonists Serotonergic (5-HT3) antagonists (Neurokinin)NK-1 receptor antagonist H2RAs are often referred to as antiemetics but they are NOT Do NOT use: Anticholinergics atropine 23 2/13/2024 Cerenia™ (maropitant citrate) FDA approved anti-emetic for dogs and cats Oral use in dogs SQ or IV in dogs and cats NK1 receptor antagonist, blocks binding of substance P within the emetic center Provides broad-spectrum effectiveness against central and peripheral causes of vomiting Oral and injectable formulations Maropitant Indications Vomiting Motion sickness Nausea Dosing Information Dosing varies based on route of administration Oral dose higher than parenteral due to first-pass metabolism Parenteral 1 mg/kg Oral 2 mg/kg Dosing varies based on targeted treatment Length of time to administer varies based on age Not FDA approved for puppies  2 months of age Puppies 2 -7 months of age: approval up to 5 consecutive days Puppies  7 months: until resolution of vomiting Motion Sickness 8.0 mg/kg PO once daily x 2 days Fast 1 hour prior to administration Administer 2 hours prior to travel 24 2/13/2024 Maropitant EBM has shown maropitant also has mild visceral analgesia FYI: SQ administration can sting (ouch!) in some patients Cats seem especially sensitive Maropitant has been safely administered chronically in CKD felines Used prior to general anesthesia to reduce vomiting 2 mg/kg PO the night before GA “Betty” Pertinent Test Results Cobalamin < 250 µg/ml Hypoalbuminemia Alb = 1.9 mg/dl Endoscopy Thickened rugal folds Infiltrative duodenal mass Histopathology LSA 25 2/13/2024 Serotonin Antagonists Receptors located peripherally and centrally Antiemetic and anti-nausea Effective in conditions which cause the release of serotonin Chemotherapy GI inflammation Ondansetron (Zofran) 0.5-1.0 mg/kg PO BID 0.1-0.5 mg/kg IV BID Dolasetron (Anzemet) 0.6-1.0 mg/kg PO BID 0.6mg/kg IV q 24 hours Serotonin Antagonists Receptors located peripherally and centrally Antiemetic and anti-nausea Effective in conditions which cause the release of serotonin Chemotherapy GI inflammation Ondansetron (Zofran) 0.5-1.0 mg/kg PO BID 0.1-0.5 mg/kg IV BID Dolasetron (Anzemet) 0.6-1.0 mg/kg PO BID 0.6mg/kg IV q 24 hours 26