Pharmacology of the Digestive System PDF

PHARMACOLOGY AND THERAPEUTICS II PHARMACOLOGY OF THE DIGESTIVE SYSTEM Catarina Jota Baptista Assistant Professor DVM, MSc, PhD in Veterinary Sciences [email protected] (For teaching purposes o...

PHARMACOLOGY AND THERAPEUTICS II PHARMACOLOGY OF THE DIGESTIVE SYSTEM Catarina Jota Baptista Assistant Professor DVM, MSc, PhD in Veterinary Sciences [email protected] (For teaching purposes only) BIBLIOGRAPHY Principal Secundary TABLE OF CONTENTS Quick revision: anatomy of and physiology of the Appetite stimulants digestive system Antiobesity drugs Antibiotic therapy of the digestive system Hepatic drugs Antiinflamatory & analgesic therapy of the Pancreatic drugs digestive system IBD therapy Mouth (anti-sialogens and teeth therapy) Vomit (emetic and anti-emetic drugs) Anti-ulcer and anti-acid drugs Anti-diarreal drugs Laxatives and prokinetics ANATOMY Source: Applied Pharmacology for Veterinary Technicians ANATOMY Source: Applied Pharmacology for Veterinary Technicians PHYSIOLOGY ANTIBIOTICS In: Handbook of Veterinary Pharmacology ANTIBIOTICS Ampicillin (+/- sulbactam) Amoxiciline (+/- clavulamic acid) Metronidazole Tylosin Enrofloxacin (…) In: Gimes, Millie; Lidbury, Jonathan (2020) Antibiotics in canine GI disease: when to use and when to ditch, DVM360, 51 (3) ANTI-INFLAMMATORY + ANALGESIA Glucocorticoid therapy is used for chronic inflammatory conditions (e.g IBD, chronic gastritis, chronic hepatitis) or acute conditions not associated with infectious diseases in dogs. Flunixin meglumine, or phenylbutazone are given IM or IV to horses for the control of colic pain. N-butylscopolammonium bromide (Buscopan) is an antispasmodic drug used in horses for control of the abdominal pain of colic. Morphine is used IM in dogs and cats, and butorphanol is administered IV to horses to control colic pain. Opioids must be used carefully because they may provoke ileus. MOUTH ANTI-SIALOGENS Used in very specific situations, for example to limit excess saliva when placing an endotracheal tube. Glycopyrrolate Atropine These are anticholinergic drugs, so they block the effects of acetylcholine on parasympathetic nerve endings. The effect of anticholinergic drugs is to reduce gastrointestinal motility and secretions (including saliva). Although they are used to decrease salivation, they can also have other effects associated with suppression of the parasympathetic nervous system, including constipation, tachycardia, dryness of the mucous membranes, urine retention and pupil dilation. The effects of the parasympathetic nervous system also decrease secretions and peristalsis in the intestine, so they may work as anti-diarrheal. TEETH Dental cleaning Based on an antiseptic (such as chlorhexidine), dental polishing products (pastes, cookies etc...), toothpaste for brushing... Examples: C.E.T.® Dentifrice; Oravet® Dental; Nolvadent® Oral Cleansing Solution; CHX® Oral Cleansing Solution; MaxiGuard® Oral Cleansing (...) Fluoride supplementation Fluoride Gel 0.4%; C.E.T. FluraFom® Mouth & dental infections Clindamycin, Doxycycline, Amoxicillin + clavulanic acid VOMIT VOMIT VOMIT EMETIC DRUGS ANTI-EMETIC DRUGS EMETIC DRUGS CENTRAL EMETIC DRUGS PERIPHERIC EMETIC DRUGS CENTRAL EMETIC DRUGS Apomorphine Apomorphine is a dopamine agonist, it stimulates dopamine chemoreceptors directly. Dopamine is an important neurotransmitter in vomiting in dogs, but not so much in cats. Apomorphine is, therefore, less effective in cats than in dogs. Apomorphine is administered orally, subcutaneously, intravenously or topically in the conjunctival sac. Its efficacy is unpredictable when administered orally and the IM route is less effective. Vomiting occurs quickly after administration, usually within 5 to 10 minutes when administered orally, or 10 to 20 minutes when administered subconjunctivally. CENTRAL EMETIC DRUGS Xylazine (Xilazin®, Rompun®, AnaSed®) This effect is considered an adverse effect of its use as a sedative. The mechanism of xylazine's emetic action is not fully understood. It is considered the emetic of choice for cats. Xylazine does not induce vomiting in horses. In cattle, sheep or goats, it is not very effective because they rarely vomit. In large animals, esophageal intubation is preferable to induce emesis. PERIPHERIC EMETIC DRUGS Hydrogen Peroxide (3%) Stimulates the afferent nerves through gastric irritation. Hydrogen peroxide (3%) is applied to the back of the pharynx to stimulate vomiting via cranial nerve IX and, in small doses, is relatively non-toxic. Small doses (5-10 mL administered by syringe) of hydrogen peroxide can be administered until emesis occurs. It is not recommended for cats, and some cats develop hemorrhagic gastritis secondary to its use. It should be administered with caution as it can lead to aspiration pneumonia. Homemade salt and mustard Not recommended. ANTI-EMETIC DRUGS Phenothiazine Derivatives Antihistamines (less effective in animals, compared to humans) Antimuscarinic drugs Serotonin antagonists Metoclopramide Maropitant PHENOTHIAZINE DERIVATIVES Mechanism of action They act centrally, mainly by two mechanisms in the emetic centre: blocking dopamine receptors blocking alpha-adrenergic receptors (α1). Some phenothiazines also block the histaminic and muscarinic receptors. Because of this broad action, and ability to inhibit vomiting from a variety of stimuli, this group of drugs has been called “broad-spectrum” antiemetics. PHENOTHIAZINE DERIVATIVES Acepromazine, Promethazine Tranquillizer with multisystemic effects. Used as a sedative, tranquilizer, an anaesthetic adjuvant and has antiemetic effects. Used to control vomiting caused by motion sickness and nausea. It comes in tablet and injectable forms. Adverse side effects: sedation, ataxia and hypotension, penile prolapse in horses. ANTIMUSCARINIC (ANTICHOLINERGIC) DRUGS These drugs decrease vomiting from various causes, including vestibular stimulation (motion sickness) and stimulation of the CRTZ. In people, scopolamine has been one of the most effective agents for treating motion sickness (Transderm-Scop®), but it is less effective in dogs and cats. Adverse effects: xerostomia (anti-sialogens), decreased stomach emptying, ileus, urine retention, and constipation, including potential for ileus. These agents should be used cautiously in patients with glaucoma because there is a risk of increased intraocular pressure. Atropine Scopolamine Aminopentamide Isopropamide Not very used as anti-emetic drugs! SEROTONIN ANTAGONISTS Serotonin receptors are found in the vagus nerve terminals and in the chemoreceptor zone. Blocking these receptors causes antiemetic activity. They are mainly used for severe vomiting in dogs and cats, especially when associated with chemotherapy. Ondansetron Tablets, oral solution and solution for injection. Dolasetron Intravenous Granisetron Oral tablet and solution, transdermal patch, injectable solutions. METOCLOPRAMIDE It is a procainamide derivative and has central and peripheral anti-emetic activity. Centrally, it blocks dopamine receptors, Peripherally it increases gastric contraction, speeds up gastric emptying, increases peristalsis of the small intestine and causes relaxation of the pyloric sphincter. It also inhibits serotonin receptors Metoclopramide is a broad-spectrum antiemetic that has been popular in small animal medicine, particularly for animals that vomit because of drug therapy (e.g., cancer drugs) or gastrointestinal disease. This drug is available in various forms, both injectable and oral. METOCLOPRAMIDE Metoclopramide is used as an antiemetic for infectious enteritis, uremic vomiting and vomiting associated with chemotherapy. It is also used to treat gastric motility disorders. However, its use became less frequent when Maropitant appeared at the market. The increase in GI motility may produce some abdominal discomfort. Because metoclopramide stimulates upper GI motility, it should not be administered if there is an obstruction. It is totally contraindicated in cases of suspected intestinal obstruction or occlusion (e.g. foreign bodies, torsions, invaginations, etc.). MAROPITANT Cerenia®, Prevomax®, Vetemex®, Vemonil® Approved specifically for veterinary medicine and widely used in oral or injectable form in a variety of situations, but mainly acute. The efficacy of maropitant is attributed to its central site of action. It blocks neurokinin-1 (NK-1) receptors in the area of the brain called the nucleus tractus solitarius – the site known as the emetic center. Input into the emetic center may come from different sources: gastrointestinal tract, higher brain centers, CRTZ, and vestibular apparatus (motion sickness). Because NK-1 inhibitors – such as maropitant – block input from multiple sources, they are considered broad spectrum in action. MAROPITANT It also has analgesic properties (visceral pain), but it is less effective in reducing nausea. Maropitant is, therefore, an effective antiemetic for pancreatitis, enteritis, copper sulfate and apomorphine-induced vomiting, and motion sickness to treat and prevent chemotherapy-induced (e.g. cisplatin) vomiting, especially in dogs. Maropitant is extensively metabolized by the liver and there is little clearance by the kidney; therefore, no dose adjustments are needed in https://www.cliniciansbrief.com/article/maropitant-novel-antiemetic patients with compromised kidney function. However, the use in chronic hepatic disease must be used with caution. Adverse effects are rare but include pain at the injection site, hypersalivation, and diarrhoea. ANTI-ULCER AND ANTI-ACID DRUGS ANTI-ULCER AND ANTI-ACID DRUGS ANTI-ULCER AND ANTI-ACID DRUGS ANTI-ACIDS Magnesium hydroxide (Magnalax®) In ruminants, magnesium hydroxide is used to increase rumen pH in cases of ruminal acidosis. Magnesium hydroxide is also an osmotic laxative. Magnesium antacids containing magnesium are contra-indicated in animals with kidney disease because they can develop electrolyte imbalances. ANTI-ACIDS Magnesium hydroxide combined with aluminum hydroxide In horses and dogs, it helps managing gastric ulcers. H2 BLOCKERS Cimetidine It was the first H2 blocker developed. It is available in tablet, oral solution and injectable form. The other drugs in this group are considered more effective, thus making the use of cimetidine infrequent. H2 BLOCKERS Ranitidine Ranitidine is more potent and has a longer duration of action than cimetidine. Stimulates gastric emptying and intestinal motility. It is also available as a tablet, oral solution and injection. H2 BLOCKERS Famotidine Famotidine is more potent and has fewer adverse effects than ranitidine. It is available in coated tablets, oral powder and injectable forms. H2 BLOCKERS PROSTAGLANDIN ANALOGS Misoprostol Misoprostol is a prostaglandin analogue that acts like endogenous prostaglandins, suppressing gastric acid production and increasing mucus production in the gastrointestinal tract. It is an oral tablet that is most often used in veterinary medicine to prevent gastric ulceration in animals taking NSAIDs, especially in horses. This medicine is contraindicated in pregnant animals, and pregnant women should be warned about handling this medicine. Adverse effects include gastrointestinal signs such as diarrhoea, vomiting and abdominal pain. MUCOSAL PROTECTIVE DRUGS Sucralfate It is a non-absorbable chemical derivative of sucrose that combines with proteins to form an adherent barrier that covers the ulcer and protects it from gastric acid, pepsin and bile salts, acting as a “biological bandage”. It is used to treat esophagitis, gastric or duodenal ulcers and uremic gastritis. Sucralfate is available in powder and tablets. Adverse effects are rare and limited to the gastrointestinal tract (constipation). As sucralfate binds to ulcers in an acidic environment, it should generally not be administered simultaneously as drugs that increase gastric pH. Zheng, Hengqi & Len, Mary & Pattamanuch, Nicole. (2021). Effective Use of Topical Sucralfate in the Conservative Management of Expanded Gastrostomy Tract Reduction. JPGN Reports. 2. e111. 10.1097/PG9.0000000000000111. PROTON PUMP INHIBITORS They bind irreversibly to the proton pump (H+K+ATPase) on the surface of the stomach's parietal cells. This inhibits the transport of hydrogen ions into the stomach so that the cell cannot secrete HCl. The production of gastric acid is reduced, which allows the stomach and esophagus to heal. They are most effective when taken about 30 minutes before a meal; administration with food decreases absorption. Occasionally, they can cause diarrhea, vomiting or flatulence in dogs and cats. Omeprazole Widely used in dogs and cats. Also in horses and foals over 4 weeks old. Lansoprazole or esomeprazole ANTI-DIARRHEAL DRUGS ANTI-DIARRHEAL DRUGS Anticholinergics Protectants and Absorbents Prebiotics and Probiotics Motility reducers (Opiates) ANTICHOLINERGICS Already covered in anti-sialogens. This group of drugs blocks the release of acetylcholine from parasympathetic nerve endings, thus reducing the parasympathetic stimulation of gastrointestinal motility and secretions. They are rarely used in mild diarrhoea due to their non-specific action. Atropine Hyoscyamine Isopropamide Propantheline N-butylescopolammonium bromide (Buscopan®) PROTECTANTS AND ABSORBENTS They protect the inflamed mucosa and bind to bacteria or their toxins to prevent their absorption by the intestinal mucosa. Their effectiveness is questionable. Bismuth salicylate Little used in cats (toxicity). Protective, anti-bacterial and anti-inflammatory effect (like Aspirin). Kaolin/pectin Protective effect Activated charcoal In situations of poisoning, to prevent absorption of the toxic substance ingested. PREBIOTICS AND PROBIOTICS These are growth factors or beneficial bacteria (Lactobacillus spp., Enterococcus faecium, Bifidobacterium spp.) that compete with pathogenic bacteria for colonization sites and nutrients, altering the microenvironment, reducing local inflammation and altering immune responses. Usually used to correct imbalances in the gastrointestinal mucosa caused by prolonged diarrhoea or antibiotic therapy. Because they promote a health intestinal environment they will contribute to a normal motility and faecal texture. Available in various formulations such as pastes, powders, syrups, tablets... MOTILITY REDUCERS (OPIATES) They are effective agents in controlling diarrhoea because: 1.increase segmental contractions 2.decrease intestinal secretions 3.increase intestinal absorption Many clinicians consider opiates to be the drugs of choice for the control of diarrhea in dogs. They are also used to treat diarrhea in calves. Use in cats and horses is controversial due to their tendency to cause CNS stimulation, constipation, sedation and “paralytic ileus”. Completely contraindicated in diarrhea of toxic and infectious origin! Diphenoxylate (Lomotil®) Loperamide (Imodium®) CONSTIPATION/OBSTIPATION  LAXATIVES (ACTING ON THE FECAL MASS) CONSTIPATION/ OBSTIPATION PROKINETICS (ACTING ON THE PERSITALTISM MOVEMENT) LAXATIVES LAXATIVES Hyperosmotics/osmotics Faecal mass expanders (or Bulk Laxatives) Stimulants (or irritants) Emollients (softners + lubricants) HYPEROSMOTIC/OSMOTIC They are composed of salts, lactulose, glycerine/glycerol and honey. They are highly concentrated and draw water into the colon by osmosis, increasing the faeces’ water content and faecal volume, which stimulates the intestinal stretch receptors to promote peristalsis. In the case of salts, repeated and prolonged use can lead to electrolyte imbalances and should be limited in dehydrated animals, those with heart failure or CKD. Lactulose Also useful in cases of hepatic encephalopathy, as it helps to reduce blood ammonia levels. Sodium phosphate and sodium biphosphate Not recommended for cats as they can cause hyperphosphataemia and hypocalcaemia. Magnesium sulphate Magnesium hydroxide Polyethylene glycol (PEG) FAECAL MASS EXPANDERS Fibrous substances added to the diet that absorb water in the intestine increase faecal volume and stimulate peristalsis, resulting in the production of large, soft faeces. Animals should be well hydrated before starting fibre supplementation to minimise the potential for fibre impaction in the constipated colon. They are effective, well tolerated with few adverse effects. Metamucil Psyllium Bran Vetasyl Fiber STIMULANTS/IRRITANTS They increase peristalsis by chemically irritating the sensory nerve endings in the intestinal mucosa. Their site of action can vary, from affecting only the large or small intestine, to affecting the entire gastrointestinal tract. They can cause abdominal discomfort. Bisacodyl (Dulcolax ®) It is an effective stimulant laxative in cats when administered with fibre supplementation for the long-term control of constipation. Castor oil EMOLLIENT (LUBRICANTS + SOFTENERS) They are faecal softeners, lubricants and humectants. Emollients increase lipid absorption and impair water absorption and are not absorbed systemically, so they have fewer adverse effects than osmotic laxatives. Adverse effects are rare, but at high doses abdominal cramps and diarrhoea are possible. Docusate sodium, oral and in enema form (Pet-Ema®, Docu-Soft ). Calcium docusate, normal and soft gel capsules. Petroleum, mineral oil, or petrolatum is the active ingredient in products used to prevent and treat hairballs in cats (CatLax®, Defurr®). Petroleum in liquid form is mineral oil, and it is usually administered to horses as a laxative by nasogastric tube during colic episodes. PROKINETICS PROKINETICS Dopaminergic antagonists Serotoninergic drugs Cholinergic DOPAMINERGIC ANTAGONISTS They stimulate motility in the cardia, stomach and small intestine. Metoclopramide It is a dopamine antagonist, and serotonin antagonist at these high doses. Domperidone It can be used to regulate gastrointestinal motility in horses, cats and dogs. METOCLOPRAMIDE Use in Small Animals It is of little benefit to increase stomach emptying in disorders of gastroparesis or chronic regurgitation. It also has been used to stimulate normal upper motility following surgery (e.g., corrective surgery or gastric dilatation). Use in Horses It may stimulate small intestine – but not large bowel, but this has little benefit for horses with intestinal ileus. Undesirable side effects in horses include behavioural changes and abdominal pain. Use in Ruminants It may increase the motility of the rumen in cattle and sheep. It has been used successfully in some cattle with functional pyloric stenosis but was not effective in calves. DOMPERIDONE It does not cross the blood–brain barrier. Therefore, adverse CNS effects are not as much of a problem compared to metoclopramide in horses. An additional effect is to stimulate lactation. Use in Horses Domperidone has been investigated for use in horses to treat fescue toxicity and agalactia. The action of domperidone to increase lactation is through the stimulation of prolactin. Another use of domperidone is to increase digital laminar microvascular blood flow in horses. SEROTONINERGIC DRUGS Cisapride Stimulates the motility of the proximal and distal gastrointestinal tract. Oral absorption is variable because of extensive metabolism. The oral absorption in dogs and cats ranges from 30 to 60%. Use in dogs Clinical use in dogs has included treatment for gastroesophageal reflux, delayed gastric emptying, and small bowel motility disorders. Compared to metoclopramide, cisapride is more effective for increasing lower esophageal sphincter tone in dogs, which helps prevent reflux esophagitis. Use in cats Cisapride has been used for treating chronic constipation in cats, including in the colon. By contrast, metoclopramide has no effect on colonic smooth muscle. SEROTONINERGIC DRUGS Use in Horses Cisapride increases the motility of the left dorsal colon and improves ileo-ceco-colonic junction coordination. In contrast to metoclopramide, cisapride has fewer side effects at doses needed to affect the GI tract and greater effects on the jejunum and colon than metoclopramide. Oral administration is usually not possible in horses with gastric reflux because absorption will be questionable. CHOLINERGIC DRUGS Bethanechol It binds to muscarinic receptors and initiates GI smooth muscle contractions and it has been used to non-specifically stimulate smooth muscle. In contrast to cisapride or metoclopramide, bethanechol has a more pronounced effect on the motility of the ileocecocolic region in cattle. In horses, bethanechol increases gastric emptying. Dexpanthenol Post-operative treatment of paralytic ileus - or retention of flatus or faeces - and equine colic (without obstruction). APPETITE STIMULANT Important during prolonged illnesses and recovery processes. Cats undergoing prolonged fasting or inadequate nutrition can develop hepatic lipidosis. Diazepam - a drug that produces a transient stimulation of appetite when administered intravenously. Oxazepam - oral use in dogs and cats. Cyproheptadine - oral antihistamine and serotonin antagonist used as an appetite stimulant mainly in cats. Mirtazapine - oral use in dogs and cats, transdermal (in the ear) in cats. Capromorelin - oral use only in dogs ANTIOBESITY DRUGS Dirlotapide Dirlotapide is a selective microsomal triglyceride transfer protein (MTP) inhibitor that blocks the assembly and release of lipoprotein particles into the bloodstream (via the lymphatic system) in dogs. Its unique mechanism of action provides for potential weight loss by reducing appetite and by decreasing fat absorption. Dirlotapide acts locally in the gut to reduce appetite, increase fecal fat, and produce weight loss. The drug undergoes enterohepatic circulation and is primarily excreted in the feces, with small amounts excreted in the bile and urine. The most commonly reported adverse effects include vomiting, diarrhea, anorexia, and lethargy. INFLAMMATORY BOWEL DISEASE (IBD) Sulfassalazine Treatment of ulcerative, idiopathic and plasmacytic–lymphocytic colitis after dietary therapy has been attempted. It is not as effective for the small intestine. It combines sulfapyridine (antibiotic) and 5-aminosalicylic acid (mesalamine, an anti-inflammatory). The bond is broken by bacteria in the colon to release the two drugs. The sulfonamide component is absorbed into the circulation while the salicylic acid component remains active in the GI tract. Less than half of the salicylate component is absorbed systemically. Adverse effects: The sulfonamide component is absorbed and can produce keratoconjunctivitis sicca in dogs. This drug cannot be used in patients that have allergic reactions to sulfonamides.  INFLAMMATORY BOWEL DISEASE (IBD) Immunomodelators Glucocorticoids (mentioned in previous slides) Azathioprine It is metabolized to active metabolites that inhibit activated lymphocytes thereby suppressing lymphocyte response. It has caused other GI problems during therapy (e.g., diarrhea during the initial therapy and liver injury with longer use); therefore, careful monitoring during treatment is recommended. Cats are more sensitive to the adverse effects than dogs. INFLAMMATORY BOWEL DISEASE (IBD) Immunomodelators Chlorambucil Chlorambucil is used in combination with prednisolone for treatment of chronic enteropathy and inflammatory bowel disease. In one study, the combination of chlorambucil–prednisolone was more effective than the combination of azathioprine– prednisolone for treating chronic enteropathy and protein-losing enteropathy in dogs. Cyclosporine Cyclosporine has been used to treat diarrhea caused by IBD and perianal fistulas associated with ulcerative colitis in dogs. The success is attributed to the ability of cyclosporine to suppress T-cell mediated activity in the bowel, and to suppress inflammatory cytokines HEPATIC DRUGS Glucocorticoids Antioxidants Anti-copper agents Ursodeoxycholic acid Antifibrotic agents Hepatic encephalopathy therapy Source: Handbook of Veterinary Pharmacology GLUCOCORTICOIDS Steroid therapy is the most used therapy for chronic hepatitis in dogs, as well as important for use in chronic GI tract inflammation. They have anti-inflammatory effects but also antifibrotic and choleretic effects. Prednisone must be metabolized into prednisolone by the liver so it is best to use prednisolone in case of liver disease. Source: Handbook of Veterinary Pharmacology ANTIOXIDANTS Oxidative stress and damage caused by free oxygen radicals may be a contributory cause of liver disease. The main antioxidants are vitamins C and E, silymarin, and S-adenosyl-Lmethionine (SAMe). SAMe is a normal metabolite in the hepatocytes and is important in the defence against free radicals. Silymarin (silibinin) has several pharmacological actions that may be useful in treating liver disease. It inhibits lipid peroxidase and beta-glucuronidase and the cytotoxic actions of tumour necrosis factor (TNF). Source: Handbook of Veterinary Pharmacology ANTI-COPPER AGENTS Hereditary copper toxicosis occurs in Bedlington terriers, and copper accumulation may also occur secondary to diseases in which cholestasis is a prominent feature. Chelating drugs, such as D-penicillamine, can actively bind free extracellular copper and facilitate its excretion in the urine. Chelators bind free copper actively and are an effective way to quickly remove increased intracellular copper that causes hepatic damage. Zinc gluconate or acetate is another anti-copper medication. Zinc induces metallothionein in the enterocytes. This protein binds copper, preventing its absorption. Copper is sequestered within senescent enterocytes and shed into the intestinal lumen. Source: Handbook of Veterinary Pharmacology URSODEOXYCHOLIC ACID Ursodeoxycholic acid (UDCA), ursodiol, is one of the natural bile acids in the enterohepatic circulation. UCDA has multiple drug actions, including protection of hepatic cells from apoptosis, choleretic (induction of bile flow), suppression of hepatic synthesis and secretion of cholesterol, modulation of the immune system to reduce inflammation, and increasing the production of glutathione and metallothionein, which prevent oxidative damage. Source: Handbook of Veterinary Pharmacology ANTIFIBROTIC AGENTS Fibrosis may follow a variety of chronic liver insults and result in cirrhosis and the incapacity of the liver to regenerate. Increased lipid peroxidation of hepatocytes (e.g., hepatocellular damage) activates the mesenchymal hepatic stellate cells to produce fibrinogenic substances and extracellular collagen matrix. Colchicine is the only drug used specifically to stop and reduce fibrosis. It is thought to act by stimulating collagenase activity. However, its use is not strongly advocated since clinical studies have not been performed to prove its efficacy. Source: Handbook of Veterinary Pharmacology HEPATIC ENCEPHALOPATHY THERAPY Hepatic encephalopathy may occur due to both congenital and acquired hepatic diseases. Ammonia and aromatic amino acids are the two main factors contributing to HE. Lactulose and soluble fibers will reduce ammonia metabolism. These agents are metabolized by the colonic bacterial flora to produce acids that reduce the pH of the colonic contents. Metronidazole is efficacious against most obligate anaerobes, some of which are urease producers. These may contribute to ammonia production and exacerbation of HE. Thus, metronidazole is an antibiotic used as adjuvant therapy in HE. Source: Handbook of Veterinary Pharmacology EXOCRINE PACREAS SUPPLEMENT Pancreatic lipase – exocrine pancreatic insufficiency  ACUTE PANCREATITIS Fuzapladib is conditionally FDA-approved (pending full demonstration of effectiveness) to control clinical signs in dogs with acute pancreatitis. Fuzapladib limits the neutrophil-mediated inflammatory response in dogs with pancreatitis and may reduce pancreatic lesion size and extrapancreatic organ involvement. Fuzapladib is contraindicated in dogs hypersensitive to it. This drug has not been studied in dogs with cardiac, hepatic, or renal disease; dogs