Gastrointestinal Therapeutics 2 PDF

Gastrointestinal Therapeutics 2 Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics The very hungry CATerpillar Monday, 14 October 2024...

Gastrointestinal Therapeutics 2 Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics The very hungry CATerpillar Monday, 14 October 2024 1  Learning Outcomes 1. Identify drugs that can be used to modify gastrointestinal function and their pharmacological principles 2. Identify drugs that may be employed to treat gastrointestinal disease and their pharmacological principles 3. Give examples of possible uses of these agents to treat the most common diseases in domesticated species 4. Understand the pharmacological principles of antiparasitic treatments Monday, 14 October 2024 2  Drugs to treat GI disease Appetite Reduced e.g. disease of many body systems (particularly chronic inflammatory, infectious, neoplastic), chemotherapy- associated Excessive e.g. obesity Intestinal microbiota Imbalance e.g. chronic enteropathy, exocrine pancreatic insufficiency (EPI), antibiotic responsive diarrhoea, motility disturbance, specific infectious agents Endoparasitism Nematodes, cestodes, Giardia Monday, 14 October 2024 3  Appetite stimulants Anorexia usually secondary to another condition Complex pathways Psychological & behavioural / physiological & metabolic / neurotransmitters Approaches to tempt eating Wet food Warm food Small portions Wide, shallow bowls Remove after 20-30 mins Hand feeding Hopkins et al (2016) https://www.ncbi.nlm.nih.gov/books/NBK278931/ Monday, 14 October 2024 4  Appetite stimulants mirtazapine – noradrenaline and serotonergic antagonist with appetite-stimulant, anti-emetic and anti-nausea effects Effects typically seen within 30 minutes cyproheptadine – non-selective serotonergic antagonist Can take up to 24 hours to be effective diazepam used historically but should be avoided due to risk of acute hepatic necrosis. Steroids also used historically capromorelin – ghrelin agonist approved this year (June!!) capromorelin mirtazapine Cat’s concept of Labrador’s concept a small portion of a small portion Monday, 14 October 2024 5  Intestinal microbiota Bacterial communities on intestinal mucosal surfaces. Bacterial cells outnumber host cells by 10 times. Interaction with host is usually beneficial Modifying the microbiota (and host immune response?) Prebiotics - Selectively fermented ingredients that support beneficial micro- organisms e.g. fructo-oligosaccharides (FOS) Probiotics - Live microorganisms, in adequate amounts confer a health benefit on the host e.g. Enterococcus faecium Synbiotics - preparations containing both prebiotics and probiotics Monday, 14 October 2024 6  Antibiotic and gastrointestinal disease Restrict antibiotics to times of need e.g. Specific infections Haemorrhagic diarrhoea ARD / SIBO metronidazole bactericidal for Gram +ve / Gram –ve anaerobes Inhibits nucleic acid function by preventing DNA repair At high doses antiprotozoal – used for Giardia infection Appears to modulate the immune system – beneficial in ARD (IBD) metronidazole Monday, 14 October 2024 7  Acute Haemorrhagic Diarrhoea Syndrome (aka HGE) Cause uncertain - association with toxin produced by Clostridium perfringens Peracute onset of bloody diarrhoea and vomiting Dehydration, tachycardia, weak pulses, shock in severe cases Diagnosis - compatible clinical signs (haemoconcentration and normal TP) and exclusion of other causes e.g. Addison's disease, parvoviral enteritis, intussusception, pancreatitis There is typically haemoconcentration with normal plasma proteins. Treatment - needs to be aggressive and is primarily symptomatic/supportive IV fluids Antiemetics e.g. maropitant Antibiotics - controversial Monday, 14 October 2024 8  Broad Spectrum Anthelmintics Drug Class Benzimidazoles Imidazothiazoles Macrocyclic lactones Amino acetonitrile derivatives Spiroindoles Monday, 14 October 2024 9  Guidelines Monday, 14 October 2024 10  Benzimidazoles Benzimidazoles include albendazole, fenbendazole etc. Febantel (in Drontal) is a prodrug Benzimidazoles bind to parasite tubulin leading to inhibition of glucose uptake, glycogen depletion and death Effective against nematodes, cestodes and Giardia spp. β-tubulin Taenia spp. but not Dipylidium Horse faeces with typically red-coloured caninum cyathostomin stages Monday, 14 October 2024 11  Benzimidazoles Kill worms slowly, prolonged exposure increases efficacy Ruminants/equids more sensitive than carnivores – rumen/caecum acts as reservoir fenbendazole is safe for puppies and kittens and lactating bitches/queens Dose puppies/kittens at 2, 5, 8 and 12 weeks of age albendazole fenbendazole Monday, 14 October 2024 12  Benzimidazoles triclabendazole differs from other benzimidazoles in that it is a narrow spectrum anthelmintic. Accumulates in both immature and adult stages of Fasciola hepatica triclabendazole is only drug effective against early immature fluke i.e. 2 weeks and older, through to adults. Other flukicides e.g. closantel and oxyclozanide are effective against adult flukes, nitroxynil against late immature stages triclabendazole Fasciola hepatica www.cattleparasites.org.uk Monday, 14 October 2024 13  Nicotinic agonists Nicotinic agonists – act at nicotinic ACh receptors (ion channels) and cause a rapid and reversible spastic paralysis. The following classes are selective for nematode muscles Imidazothiazoles – include levamisole Tetrahydropyrimidines – include pyrantel levamisole pyrantel Monday, 14 October 2024 14  Macrocyclic Lactones Derived from compounds produced by Streptomyces fungi Avermectins - include ivermectin and selamectin Milbemycins - include moxidectin and milbemycin Avermectins Milbemycins ivermectin selamectin moxidectin milbemycin Monday, 14 October 2024 15  Macrocyclic Lactones Open invertebrate specific glutamate-chloride channels in post- synaptic membrane (nematodes but not cestodes) leading to hyperpolarisation, flaccid paralysis and death Persistent activity used for preventative worm strategies (prophylaxis) http://www.wormbook.org/chapters/www_gaba/gaba.html Monday, 14 October 2024 16  Macrocyclic lactone - Toxicity Monday, 14 October 2024 17  Narrow spectrum - Isoquinolines praziquantel causes severe damage to the parasite integument, resulting in tetanic muscular contraction and paralysis. Mechanism unproven but thought to be related to changes in divalent cation fluxes, especially Ca+ praziquantel Monday, 14 October 2024 18  Antiprotozoal agents Coccidiosis / toxoplasmosis / neosporosis trimethoprim/sulphonamide (TMPS) inhibits folate synthesis (and purine synthesis toltrazuril - anticoccidial active against Eimeria spp. Affects the fine structure of the developmental stages of coccidia. TMPS toltrazuril Eimeria oocyte Toxoplasma Neospora Giardiasis metronidazole or fenbendazole Giardia cyst trophozoite Monday, 14 October 2024 19  Key Points LO – Identify drugs that may be employed to treat gastrointestinal disease and their pharmacological principles. Give examples of possible uses of these agents to treat the most common diseases in domesticated species Anorexia is usually secondary to another condition. Mirtazapine is a noradrenaline and serotonergic agonist with appetite-stimulant, anti-emetic and anti-nausea effects. Diazepam and steroids are also widely used but no longer recommended. Intestinal microbiota play an essential role in GI homeostasis - the microbiota composition can be altered in GI disease. Pre- and probiotics can be used to help restore normal composition Antibiotics should be restricted to treatment of specific infections and conditions such as HGE, ARD and SIBO Metronidazole is bactericidal for many Gram +ve and –ve anaerobes and has antiprotozoal and anti-inflammatory actions Monday, 14 October 2024 20  Key Points LO – Understand the pharmacological principles of antiparasitic treatments Similar to antibiotics, anthelmintics should be used responsibly to reduce the risk of development of resistance (see SCOPS, COWS guidance). Benzimidazoles (Group 1 white drenches) are broad spectrum anthelmintics that act by binding to parasite tubulin and are effective against nematodes and cestodes (Taenia spp.). Fenbendazole is safe for puppies and kittens and lactating bitches/queens. Triclabendazole is narrow spectrum against immature and adult stages of the fluke life cycle. Nicotinic agonists (Group 2 yellow drenches), such as levamisole and pyrantel, cause a spastic paralysis in nemotodes. Monday, 14 October 2024 21  Key Points LO – Understand the pharmacological principles of antiparasitic treatments Macrocyclic lactones (Group 3 clear drenches) open invertebrate specific glutamate-chloride channels in post- synaptic membrane leading to hyperpolarisation, flaccid paralysis and death. Two main classes of MLs: the avermectins (e.g. ivermectin and selamectin) and the milbemycins (e.g. moxidectin and milbemycin). Mutations in the MDR-1 gene (also known as ABCB1 mutation) cause sensitivity to MLs in many herding breed dogs, including Rough Collies, Shetland Sheep dogs and Old English Sheep Dogs. Monday, 14 October 2024 22  Key Points LO – Understand the pharmacological principles of antiparasitic treatments Praziquantel is a narrow spectrum tape wormer, which causes severe damage to the parasite integument, resulting in tetanic muscular contraction and paralysis Antiprotozoal treatments include trimethoprim/sulphonamide and related compounds, which inhibit synthesis of folate required for nucleic acid synthesis, and toltrazuril, which induces changes in the fine structure of the developmental stages of coccidia. Monday, 14 October 2024 23  Further Reading Riviere, J.E. et al., 2009. Veterinary pharmacology and therapeutics 9th ed., Ames, Iowa: Wiley-Blackwell. Edward Hall, James Simpson, and David Williams. BSAVA Manual of Canine and Feline Gastroenterology. Second ed. 2005. BSAVA Manual Ser. Web. Sustainable parasite control strategies for cattle (COWS) accessible online at http://www.cattleparasites.org.uk Sustainable parasite control in sheep (SCOPS) accessible online at http://www.scops.org.uk/ A guide to the treatment and control of equine gastrointestinal parasite infections (ESCCAP Guideline 8) accessible online at https://www.esccap.org/guidelines/ Monday, 14 October 2024 24  GI parasite Cats & Dogs – Roundworm Nematodes e.g. Toxocara canis, Toxocara leonine, Toxocara cati Monday, 14 October 2024 25  GI parasite Cats & Dogs – Hookworm nematodes e.g. Ancylostoma caninum, Uncinaria stenocephala, Ancylostoma tubaeforme Monday, 14 October 2024 26  GI parasite Cats & Dogs – Tapeworm cestodes e.g. Taenia taeniaeformis, Dipylidium caninum, Echinococcus granulosus Monday, 14 October 2024 27  Anthelmintics in Ruminants - Sheep Monday, 14 October 2024 28  Anthelmintics in Ruminants - Cattle Monday, 14 October 2024 29  Anthelmintics in Horses Monday, 14 October 2024 30  Equine GI parasite infections (ESCCAP Guideline 8) Monday, 14 October 2024 31