GIT Disorders: Therapy Principles

• The digestive tract serves as the main path for administering drugs to animals.
• Treatment for digestive issues poses unique challenges because of specific GIT characteristics.
• Drugs can alter the function of the GIT, affecting drug absorption rates.
• Oral drug administration may cause drug-drug and drug-food interactions that impact absorption and efficacy.
• Vomiting and diarrhea can affect how well orally given drugs work.
• Drugs can influence gut microflora, or vice versa.
• Focus will be on treating digestive disorders and medications' impact on the digestive system.

Principles of Therapy for GIT Disorders

• A selective and effective therapeutic approach requires understanding individual patient's pathophysiology and clinical signs.
• Symptomatic relief addresses the patient's discomfort but is not a definitive treatment.
• Eliminating offending agents might resolve clinical signs, negating the need for further medication.
• Therapy might require interrupting normal physiological processes, such as using anti-inflammatory drugs to reduce inflammation.
• Accurate diagnosis of chronic diseases should be the priority.

Drug Categories

• Emetics induce vomiting
• Antiemetics prevent vomiting
• Antacids neutralize excessive gastric acidity
• Adsorbents are chemically inert and adsorb dissolved or suspended substances like gases, toxins, and bacteria.
• Astringents cause protein precipitation on cell surfaces, reducing membrane permeability without killing cells.
• Cytoprotectants create a protective layer on skin or mucous membranes to prevent irritation.
• Carminitives are flavorings that help expel gas and reduce foam.
• Cathartics speed up the passage of material through the GIT and aid defecation.

Vomiting Reflex

• Vomiting is a reflex controlled by the vomiting center in the medulla oblongata.
• The vomiting center can be directly or indirectly stimulated via the chemoreceptor trigger zone (CTZ).
• Neurotransmitters such as acetylcholine (muscarinic receptors) and substance P (NK-1 receptors) directly stimulate the emetic center to induce vomiting.
• The CTZ is stimulated by dopamine (D2 receptors), α2-adrenergic drugs (NE receptors), serotonin (5-HT3 receptors), acetylcholine (M1 receptors), enkephalins, and histamine (H1 and H2 receptors); the CTZ stimulates the vomiting center.
• Effective antiemetics works by blocking neurotransmitter receptors, while emetics act by stimulating them.

Emetics

• Emetics are used to protect the GIT by causing vomiting in cases of harmful substance ingestion.
• Emetics are used when evacuation of the stomach is necessary; such as; poisoning with non-corrosive materials, drug overdose or emptying the stomach before anesthesia.
• Do not induce emesis when a corrosive substance is ingested.

Types of Emetics

• Centrally acting emetics stimulate the vomiting center in the medulla oblongata.
• Locally acting emetics induce emesis by irritating the pharynx, esophagus, stomach, or duodenum.

Centrally acting emetics

• Apomorphine hydrochloride is a synthetic morphine derivative and central dopamine agonist.
• Apomorphine stimulates dopamine receptors in the CTZ, which then stimulates the vomiting center.
• It is administered subconjunctivally, on the gingival membrane, IV or SC.
• Vomiting occurs 2-10 minutes post-administration
• IM route is less effective.
• Apomorphine is less preferred in cats due to CNS excitation.
• Xylazine is a sedative-analgesic that causes vomiting in dogs occasionally, while in cats induces vomiting 100% of the time.
• Xylazine binds to α2-adrenergic receptors in the CTZ, stimulating the emetic center.
• Contains emetine, a toxic alkaloid that irritates the stomach and acts on the CTZ center. Ipecac is no longer for "home use" in humans and animals.
• Prostaglandin F2-alpha causes vomiting, but it is not used as an emetic. A side effect.

Locally acting emetics

• Useful in emergency cases when parenteral emetics are not available.
• Pet owners may administer at home.
• The following are local emetics that can be used at home:
• 3% hydrogen peroxide can be mixed with saline (1mL peroxide to 3mL saline) and given orally (5ml) to dogs/cats, may induce vomiting in 5-10min.
• Be careful, as aspiration may lead to death
• Sodium chloride (1 tsp to the back of the tongue)
• Copper or Zinc sulfate (50ml of 1% solution)
• Freshly ground mustard seeds mixed with tepid water may induce variably effective vomition.

Antiemetics

• Vomiting is physically exhausting for small animals, causing dehydration, electrolyte imbalances, and aspiration pneumonia.
• Antiemetics control excessive vomiting.
• Common indications include motion sickness and vomiting related to metabolic diseases, radiation, or chemotherapy.
• Antiemetics should not be used for more than 3 days, as they may mask underlying disorders.

Types of Antiemetics

• Centrally acting antiemetics and locally acting antiemetics

Centrally acting antiemetics

• Prokinetics (Metoclopramide, Cisapride, Domperidone)
• Antihistamines (Meclizine, Buclizine, Diphenhydramine, Cyclizine)
• Phenothiazines (Acepromazine, Chlorpromazine, Promethazine, Trifluperazine, Triflupromazine)
• Serotonin 5-HT3 receptor antagonists (Ondansetron, Granisetron, Palonosetron, Dolasetron)
• NK-1 receptor antagonist (Maropitant citrate)

Locally acting antiemetics

• Protectants: kaolin
• Pectin
• Bismuth salts
• Topical anesthetics: benzocaine

Centrally Acting Antiemetics

• Control vomiting by blocking dopaminergic receptors in the CTZ or depressing the emetic center.
• Metoclopramide is a prokinetic exerts its antiemetic effect via three mechanisms:
• Low doses inhibit dopaminergic transmission in the CNS
• High doses inhibit serotonin receptors in the CRTZ
• Metoclopramide increases gastric and upper duodenal emptying.
• This drug sensitizes gut smooth muscles to acetylcholine and improves coordination of esophageal, gastric, and duodenal peristaltic contractions (prokinetic action).
• Metoclopramide is commonly used in dogs with intractable emesis caused by parvovirus, cancer therapy, and chronic gastritis.
• Is less effective in cats because CTZ D2 dopamine receptors are not very important in mediating humoral emesis.

Cisapride

• Enhance the release of myenteric acetylcholine
• Treats dysmotility disorders including constipation and megacolon in cats, delayed gastric emptying in dogs, and idiopathic postoperative ileus in horses.
• It is also a prokinetic but unlike metoclopramide, enhancement of gut motility includes the large colon.
• Domperidone is a dopaminergic antagonists, but it does not penetrate well into the CNS with less antiemetic effect than metoclopramide.
• Antihistamines block histamine receptors in the vomiting center, especially for motion sickness, and have antimuscarinic effects.
• Phenothiazine tranquilizers block dopamine receptors in the emetic center and stimulate vomiting at the DA2 receptor.
• New centrally acting antiemetics include serotonin antagonists (5-HT3) and the NK 1 receptor antagonist, maropitant.
• Ondansetron is the most popular serotonin antagonist used by veterinarians and is a selective inhibitor of serotonin (5-HT3) receptors both centrally and peripherally.
• Ondansetron is used for nausea and vomiting related to emetogenic cancer chemotherapy, gastroenteritis, pancreatitis, and inflammatory bowel disease
• Maropitant Citrate was approved for use as an antiemetic in both dogs and cats and works by mimicking substance P's structure and binding to the NK-1 receptors, preventing stimulation of the vomit center.
• Locally acting antiemetics protect the GI epithelium.

Anti-ulcer Drugs

• Ulcers are erosions of mucosa in the GIT, named by location: gastric, duodenal, esophageal.
• Ulcers form due to metabolic disease, drug therapy (NSAIDs), stress, and increased hydrochloric acid release.
• Histamine, gastrin, and acetylcholine stimulate the parietal cells to secrete hydrochloric acid.
• A thick mucus layer protects the mucosal lining.
• Antiulcer drugs discussed: antacids, histamine-2 antagonists, mucosal protective drugs, prostaglandin analogs, and proton pump inhibitors.
• Anti-ulcer drugs indicated for hyperchlorhydria, peptic ulcers, gastritis, reflux esophagitis, chronic renal failure, grain overload, and toxemia.
• Antacids promote ulcer healing and can interact with other drugs.

Action Mechanism of Antacids

• Act by neutralizing HCl in the stomach, forming water and neutral salt and reducing pepsin activity.
• Types of Antacids those that are absorbed in the blood (systemic antacids) and those that remain primarily in the Gl tract (local antacids).
• Systemic antacids are water soluble, anionic portions are readily absorbed. They have a rapid effect and short duration of action. Example: Sodium bicarbonate solution can produce systemic alkalosis and may burden the kidneys
• Local antacids are alkaline salts, such as aluminum and magnesium hydroxide, provide acid neutralization with minimal side effects.
• Inhibitors of Gastric Acid Secretion block H2 receptors in gastric mucosa, decreasing HCl secretion .Examples: Cimetidine, Ranitidine, Famotidine, Nizatidine
• Proton pump inhibitors (PPIs) are more effective than histamine type-2 antagonists and bind irreversibly to the H+-K+-ATPase enzyme on parietal cells, preventing HCl secretion: Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole, and Esomeprazole.
• Prostaglandin analogs are synthetic prostaglandins with gastric mucosa protective effects, examples include Misoprostol (Cytotec) to prevent duodenal hemorrhage.
• Astringents coagulate mucosal surface proteins to form a protective layer, reduction absorption of toxic material, arrest minor bleeding and reduction of inflammation
• Mucosal protectants coat the GIT to protect against irritation, known as pepsin inhibitors.

Sucralfate

• Sucralfate is a complex of aluminum hydroxide and sulfated sucrose that adheres to the ulcer to protect it from stomach acid and pepsin. Sucrose octasulfate polymerizes into a viscous, sticky substance that creates a protective effect by binding to ulcerated mucosa.
• Treats gastric ulcers and prevents NSAID induced ulcers.
• Pectin is a carbohydrate combined with adsorbent Kaolin.
• Bismuth subsalicylate has mucosal protectant and adsorbent properties where bismuth coats the ulcer base, adsorbs pepsin, enhances prostaglandin synthesis, and stimulates bicarbonate secretion.
• Effective treatment for acute diarrhea .

Adsorbents

• Adsorbents are inert substances that are not absorbed and either line the mucosa or adsorb gases, toxins, and bacteria
• They physically bind chemical compounds and eliminate them in feces.
• Kaolin adsorbents is an aluminum silicate combined with pectin for diarrhea.
• Attapulgite hydrates magnesium aluminum salicylate and is used to adsorb bacterial toxins.
• Activated charcoal is a residue of destructive distillation that has a broad-spectrum activity rapidly.
• Carminitives promote expulsion of gas and reduce foam formation, includes: Simethicon, Poloxalene, Turpentine,Camphor, Peppermint, Anise and Capsicum
• Laxatives Also called stool loosening drugs, laxatives and cathartics increase the motility of bowel and change the character of the stool:

Indications

• Constipation
• Removal of toxic materials from GIT
• Softening stools
• Removing gut edema

Classification based Intensity of Effect

• Laxatives (mild)
• Cathartics (mild to severe)
• Purgative drastic (severe)

Classification based MOA

• Stimulant
• Bulk
• Osmotic
• Lubricant (emollient)
• Fecal softeners

Stimulant cathartics

• Cause irritation of mucosal lining, initiating myenteric reflex to increase peristalsis.
• They increase fluid accumulation in the gut lumen and inhibits water absorption.
• Types of stimulant cathartics: emodin, resinous, irritant oils and miscellaneous with example drugs and their properties.
• Hydrophilic colloids are nonabsorbed synthetics that attract water and are milder than stimulant cathartics.
• Osmotic cathartics are hyperosmolar and pull water into the colon: examples include salts, saline products, lactulose and glycerine salts.
• Emollient Lubricant act by coating the surface of the stool with a water-immiscible film, increasing water content and lubricant action.
• Fecal softeners make the fecal material soft for easy defecation.

Anti-Diarrheal Drugs

• In some instances treatment is required in diarrhoeal cases that may temporarily relieve clinical signs.
• Treatment for diarrhea may include the use of antimicrobials, motility modifiers, and intestinal protectants
• Motility modifiers includes of two types: prokinetics and antispasmodics
• Anticholinergics are used to reduce intestinal motility and secretions and act through M1 or M3 receptors
• Opiates decreases intestinal secretion,decreases the flow of feces, however, they increase segmental contractions.
• Caution! Opiates are generally in infectious diarrhea because may significantly slow GI transit and increase absorption of bacterial toxins.

Probiotics

• Probiotics may benefit cases from the disruption of normal flora, Lactobacillus spp., Enterococcus faecium, and Bifidobacterium spp
• Probiotics compete with pathogenic bacteria for colonizing sites.

Appetite Stimulating Drugs

• Drug therapy may be used to stimulate appetite to prevent more invasive procedures.