Endocrine Pharmacology II PDF

for teaching purposes only Endocrine Pharmacology II Nuno Coelho Pharmacology and therapeutics II 3rd year – Veterinary Medicine  for teaching purposes only 3 Thyroid hormone and antithyroid drugs ...

for teaching purposes only Endocrine Pharmacology II Nuno Coelho Pharmacology and therapeutics II 3rd year – Veterinary Medicine  for teaching purposes only 3 Thyroid hormone and antithyroid drugs  for teaching purposes only 1) ENDOCRINE SYSTEM Pituitary Thyroid reproductive endocrinology Pancreas  Summary 1) Introduction a brief explanation about how the thyroid hormones are synthesized and regulated 2) Factors that change the metabolism of thyroid drugs 3) Effect of the thyroid hormones in the body 4) Drugs associated with thyroid hormones for teaching purposes only  for teaching purposes only 1) Introduction Diseases of the thyroid are common in veterinary medicine Hyperthyroidism of the cat vs hypothyroidism of the dog the typical colloid-containing follicles in the thyroid the gland T3 (tri-iodothyronine) and T4 (thyroxine) are the two main thyroid hormones produced by the thyroid gland  1) Introduction the typical colloid-containing follicles in the thyroid the gland for teaching purposes only  1) Introduction Synthesis of thyroid hormones – several steps involved 1. Thyroglobulin is synthesized in the RER of the follicular cell (thyroid gland) and secreted into lumen (stored as colloid) 2. Iodide from blood enters follicular cells via Na+/I- symport (NIS) 3. Iodide exit to colloid in transporter pendrin 4. iodide is oxidized by enzyme thyroid peroxidase (TPO): converted from iodide (I-) to iodine (I2) 5. I2 is incorporated in tyrosine residue of thyroglobulin, by thyroid peroxidase, and forms monoiodotyrosine (MIT) and Osmosis, 2023 diiodotyrosine (DIT) 6. DIT and MIT couple - 2 molecules of DIT combine to form T4, and MIT+DIT form T3 for teaching purposes only thyroglobulin now contains T3, T4, MIT, DIT  1) Introduction Regulation of the synthesis and release of thyroid hormones Osmosis, 2023 Thyroid releasing hormones (TRH) secreted by hypothalamus (when T3 and T4 blood levels are low) Thyroid stimulating hormone (TSH) released by pituitary (after stimulated by TRH) TSH stimulate thyroid hormones synthesis in follicle (among other things) Regulation by feedback negative: T3 and T4 (high amounts) will inhibit TRH and TSH for teaching purposes only  1) Introduction Thyroid secretion and transport Thyroid hormones are stored in colloid until stimulated for secretion Osmosis, 2023 TSH stimulation endocytosis (pinocytosis) of iodinated thyroglobulin from colloid thyroglobulin is hydrolysed in lysosomes thyroid hormones travel in release of T3 and T4 (deiodination – removal of iodide) blood bound to thyroxine- that are secreted to circulation binding protein (TBP) for teaching purposes only  for teaching purposes only 1) Introduction Lecturio, 2023 T4 is the main secretory product, but less potent (with less physiological influence), being converted in the target tissues into the more active form (T3) by 5’-deiodinase T3 binds to THR (thyroid hormone receptor) in nucleus, forming a transcription factor complex – binds thyroid response elements (TRE), promoting ultimately in the production of proteins relevant in the metabolis  2) Factors that change thyroid hormone metabolism Changes with: illness and malnutrition drugs for teaching purposes only  2) Factors that change thyroid hormone metabolism Changes with: illness and malnutrition chronic starvation, malnutrition, diabets mellitus, liver and kidney disease can decrease serum T3 concentrations adaptive mechanism the body uses to keep protein and blunt the metabolic rate during illness for teaching purposes only  2) Factors that change thyroid hormone metabolism several drugs impair plasma os tissue binding of the hormones or alter their metabolism Scott-Moncrieff, 2012 for teaching purposes only  2) Factors that change thyroid hormone metabolism Scott-Moncrieff, 2012 for teaching purposes only  3) Effects of the thyroid hormones Riviere, 2018 for teaching purposes only  for teaching purposes only 3) Effects of the thyroid hormones calorigenesis and 10 thermoregulation 1 endocrine immunologica 9 2 growth and l and maturation hematological 8 reproductive dermatological 3 effects on lipids and 4 7 GI carbohydrates 5 6 neuromuscular cardiovascular  4) Drugs associated with thyroid hormones 1) Thyroid hormone preparations 2) antithyroid drugs for teaching purposes only  4.1) Thyroid hormone preparations crude hormones prepared from thyroid gland synthetic L-thyroxine (T4) Thyroid hormone preparations synthetic L- triiodothyronine (T3) combinations of T3 and T4 for teaching purposes only  4.1) Thyroid hormone preparations crude hormones prepared from thyroid gland hormone products derived from desiccated thyroid tissue not used anymore for replacement therapy in small animals because of the small costs, still persists in some cases for large animals disadvantages: highly variable content of T3 and T4 and short shelf-life but is able to normalize hormonal concentrations for teaching purposes only  4.1) Thyroid hormone preparations synthetic L-thyroxine (T4) hormone of choice for hormonal replacement in all species (hypothyroidism) formulated as levothyroxine sodium – PO – Thyroxavet, Leventa, Kelevo, Canitroid, Thyron Vet, Thyrota; Dog, Cat and also for Horses (Powder) an injectable form is also available T4 is the main secretory product of the thyroid and can be considered a pro-hormone, being converted to T3 in the organism for teaching purposes only  4.1) Thyroid hormone preparations Riviere, 2018 for teaching purposes only  apenas fins pedagógicos 4.1) Thyroid hormone preparations Tri-iodothyronine – T3 Synthetic salt of the endogenous T3 hormone – Liothyronine sodium – Triostat, Cytomel (humanos) Not the first choice – used if animals do not respond to synthetic T4 short half-life (requires Tx TID) and can cause iatrogenic hyperthyroidism  for teaching purposes only 4.1) Thyroid hormone preparations Levothyroxine in dogs oral replacement doses for T4 in the dog range between 0.02 and 0.04 mg/kg daily resolve clinical signs in most of dogs 4 weeks after treatment maximum concentration 3h after administration and half life of 11.6h; food may delay absorption some authors refer that the daily dose can be distributed in BID Levothyroxine in cats initial dose of 0.05–0.1 mg twice daily – then, based on clinical response and post-pill serum T4 evaluation, adjust! Levothyroxine in horses - levothyroxine has been 20 μg/kg/day orally  4.1) Thyroid hormone preparations Therapeutic considerations althouh being resistant to thyrotoxic signs, can develop thyrotoxicosis: signs consist in nervousness weight loss, polyurya, polydipsia, more panting and fever; confirm diagnosis with T4 and T3 serum concentrations and amelioration with stoping temporarly the administration Usually this treatment is for the rest of animal’s life Important to monitor therapy (amelioration signs) and eventually serum T4 and serum TSH concentrations (normally decreased after L-thyroxine for teaching purposes only  4.2) Antithyroid drugs What do plants from genus Brassica have in common with inhibitors of thyroid peroxidase (TPO) antithyroid activity for teaching purposes only  4.2) Antithyroid drugs Riviere, 2018 Antithyroid thioureylene or thionamide drugs are direct inhibitors of TPO, leading to a reduction in the organification and coupling steps of thyroid hormone synthesis for teaching purposes only  4.2) Antithyroid drugs Mechanism of action: After administration, these drugs are concentrated by the thyroid gland, and inhibit the synthesis of thyroid hormones by: 1. blocking the incorporation of iodine into the tyrosyl groups in thyroglobulin 2. preventing the coupling of iodotyrosyl groups (mono- and diiodotyrosines) to form the ether linkage of T4 and T3 3. direct interactions with the thyroglobulin molecule Gerhardt, 2023 for teaching purposes only  4.2) Antithyroid drugs Propylthiouracil (PTU) Apart from inhibiting TPO, also inhibits Deiodinase 1 Its use has been decreasing – serious side effects – autoimmune effects – hemolytic anemia and immune-mediated thrombocytopenia for teaching purposes only  for teaching purposes only 4.2) Antithyroid drugs Methimazole/Thiamazole Felimazole, Apelka the drug of choice for hyperthyroidism of cats – PO (tablets or oral solution) or transdermal Starting with BID or TID, but as a therapeutic is observed, SID therapy could be implemented- better for owner compliance check periodically for serum T4 and signs of toxicity Adverse effects: anorexia, vomiting, lethargy, excoriations, bleeding, hepatopathy, thrombocytopenia, , agranulocytosis, leukopenia, eosinophilia; some resolve after 1 month (particularly GI ones) less common, but serious – hepatic toxicity: increased levels of ALT, AST, alkaline phosphatase and bilirubin  4.2) Antithyroid drugs Carbimazole (Vidalta, neomercazole, carbazole) derivative of methimazole, being rapidly and completely metabolized to its parent compound, which is responsible for its antithyroid activity require a higher dose to have the same effect as methimazole Fewer gastrointestinal side effects – the prodrug reduced contact of methimazole on GI mucosa PO, with sustained-release formulation for teaching purposes only  Pituitary Thyroid reproductive endocrinology Pancreas for teaching purposes only  4 Drugs that influence glucose metabolism for teaching purposes only  1) Introduction Polyphagia What is the name of the disease characterized by Ps? Polydipsia DM Polyuria “Perte de poids” “Perda de peso” weight loss for teaching purposes only  1) Introduction www.greatpetcare.com/dog-health/diabetes-in-dogs/ https://rag-diabetes.org/global-diabetes-epidemic/ for teaching purposes only 1) Introduction a revolution in the treatment of diabetes mellitus Banting’s team extracted the active compound from pancreas and showed that it was able to control hyperglycemia in diabetic dogs and humans (1920s) in 1963 it was synthesized, as a large precursor, proinsulin for teaching purposes only 2) Insulin insulin is produced by beta cells of Islets of Langerhans (60-80% of the Islet) Insulin exists initially as preproinsulin, which is cleaved to proinsulin in the endoplasmic reticulum for teaching purposes only 2) Insulin Proinsulin is a large polypeptide consisting of an A and B chain and a connecting peptide amino acid sequence of insulin shows little species variation human differs from porcine by a single amino acid dog insulin is identical to porcine insulin myendoconsult.com for teaching purposes only  2) Insulin insulin is released from beta cells by exocytosis regulation by glucose Initiate with ATP-dependent K channels closure, which leads to depolarization of the beta cells and influx of calcium (voltage-gated calcium channels) ↑ Ca2+ triggers pulsatile secretion of insulin Diabetes: islet function and insulin secretion abnormal for teaching purposes only  2) Insulin Mechanism of action insulin binds to insulin receptor, which has tyrosine kinase activity autophosphorylation – phosphorylated Tyr residues serve as docking sites for downstream effects intracellular signaling cascade initiates e.g. formation of GLUT-4 (glucose transporter) and its translocation to allow glucose entry myendoconsult.com for teaching purposes only  apenas fins pedagógicos 2) Insulin No oral forms. Why? insulin cannot be administered orally because it is a peptide and would be broken down in the intestine  2) Insulin for teaching purposes only Insulin Approved for cats and dogs using appropriate syringes – parenteral Depending on the action profiles, insulin can be: fast: lispro, aspart, regular insulins with a quick onset of action and short duration Used for diabetic ketoacidosis – complicated intermediate: NPH (neutral protamine Hagedorn), Lente (Vetsulin, of porcine origin) – uncomplicated diabetes long-acting: glargine, detemir, protamine zin and pork zinc with longer duration; for uncomplicated diabetes In general, increasing the duration of insulin action decreases the onset of action and the potency of the insulin and increases the variability in the duration of action adcesconnect.org 2) Insulin Riviere, 2018 Strenght – capacity of insulin to lower blood glucose concentrations for teaching purposes only  apenas fins pedagógicos 2) Insulin Martini-Johnson, 2021 there are solutions (IM, IV, SC) and suspensions (just SC) Insulin is measured in International units (IU) 1 IU is defined as biological equivalent of 34.7 µg of pure crystalline insulin, corresponding to the amount of insulin required to reduce the blood glucose concentration of a fasting rabbit by 45 mg/dl Preparations: 40 IU/mL for vet (facilitate accurate dosing) and 100 IU/mL (may require dilution) for human use  2) Insulin Insulin is administered using specialized insulin syringes or injection devices (‘insulin pen’) that are calibrated in international units rather than volume (mL) Each syringe is designed for use with a different insulin preparation Right syringe holds 1 ml of insulin containing 100 IU Left syringe holds 1 ml of insulin containing 40 IU e.g. 4 IU 40 UI 100 UI  AAHA, 2022 for teaching purposes only A novel once-weekly insulin therapy maintained a similar level of diabetic control as compared with traditional BID insulin injections in a small population of dogs under research, could be the future  2) Insulin A lot of individual responses to insulin – “fine-tuning” with blood glucose measurements at frequent intervals – do a glucose curve The general rule of thumb is that the insulin dose should be between 0.5 and 1.0 U/kg once or twice daily (dog and cats) for teaching purposes only 2) Insulin Insulin short-acting usually injected by IV, IM and SC intermediate and long-acting: SC Clinical indications: diabetes mellitus in cats and dogs: maintain blood glucose concentrations in a normal to mild hyperglycemic for most of the day (90-270 mg/dl) and avoid too low nadir (90-160 mg/dl) fast –acting used for complicated diabetes (low CRI or IM); rapid onset and peak 1-4h after Tx ketosis in cattle, in particular in the first week of lactation and non-responding to glucose or corticosteroid Adverse effects: hypoglycemia (high dose and/or inadequate food intake) – confusion, nervousness, hyperexcitability, convulsions – treat with glucose or dextrose solutions glucagon can be used for insulin-induced hypoglycemia when dextrose is unavailable for teaching purposes only  for teaching purposes only 2) Insulin preferred site: flank, side of chest, place with loose skin Martini-Johnson, 2021  for teaching purposes only 3) Oral hypoglycemic agents Sulfonylureas glipizide is the most used in vet stimulate pancreas to secrete insulin: inhibit ATP-dependent K channels → depolarization → release of insulin Peak insulin after glipizide achieved after 15-30 minutes Given PO, in 5 or 10 mg tablets Clinical indications: antidiabetic in cats (2.5 – 5 mg BID) only work if beta cells still functional moderate to weak effectiveness Adverse effects: hypoglycemia (serious hypoglycemias are rare)  for teaching purposes only 3) Oral hypoglycemic agents Metformim oral antihyperglycemic used mostly for humans (T2DM) reduce hepatic glucose output and improve peripheral sensitivity to insulin - thus reduce blood glucose do not cause hypoglemia but only moderate effects in animals (cats) Acarbose: alfa glucosidase inhibitor (alfa amylase and saccharidases inhibitor) – acarbose delays and reduces hyperglycemia postprandial side effects – GI – diarrhea, flatulence, abdominal pain together with insulin and oral antihyperglycemic agents can help reduce doses of insulin, while keeping effectivenes 3) Oral hypoglycemic agents glucagon-like peptide 1 (GLP-1) augments insulin secretion after food intake inhibits glucagon release and gastric emptying Several new drugs are being based on agonits for GLP- 1 receptors, being now used to treat T2DM; SC Ozempic - Semaglutide for teaching purposes only  3) Oral hypoglycemic agents Velagliflozin - Senvelgo 15 mg/ml oral solution for cats Mechanism of action: highly selective inhibitor of the sodium-glucose co-transporter 2 (SGLT-2), mainly in the kidney inhibiting this glucose transporter in the kidney leads ↑ glucose elimination in the urine, thus ↓ blood glucose Mechanism of action of Senvelgo  3) Oral hypoglycemic agents Velagliflozin - Senvelgo 15 mg/ml oral solution for cats Mechanism of action: highly selective inhibitor of the sodium-glucose co-transporter 2 (SGLT-2), mainly in the kidney inhibiting this glucose transporter in the kidney leads ↑ glucose elimination in the urine, thus ↓ blood glucose USES: For the reduction of hyperglycaemia in cats with non-insulin-dependent diabetes mellitus PO, 1 mg/kg, SID Adverse events: GI effects (D, V), PU and PD, weight loss, dehydration; UTI may occur 4) Hyperglicemic agents Hyperglicemic agents diazoxide – inhibits insulin secretion octreotide: somatostatin analogue PO – tablets (BID) Clinical indications: Management of hyperinsulin-associated hypoglycemia (insulinoma) - dogs Adverse effects: anorexia, vomits, diarrhoea apenas fins pedagógicos  https://www.aaha.org/resources/2018-aaha-diabetes-management-guideline-for-dogs-and- cats/ for teaching purposes only  3 Adrenal Adrenal for teaching purposes only  1) Adrenal gland – function Adrenocorticotropin (ACTH), released from hypophysis plays a crucial role in stimulating the secretion of glucocorticoids, mineralocorticoids, and adrenal androgens from the adrenal cortex Limited therapeutic role Synthethic prepations of ACTH is in diagnosis of primary adrenal hypofunction – hypoadrenocorticism (ACTH stimulation test) for teaching purposes only  2) Drugs for the adrenal gland Animals can develop deficiency in the production/secretion of mineralocorticoids and/or glucocorticoides (cortisol) hipoadrenocorticism (Addison's Disease) - Mostly in young to middle- wellnessvet.com.hk aged dogs, females Clinical signs: hypotension, dehydration, hypoglycemia, hyponatremia (decreased sodium), azotemia, and hyperkalemia ( ↑ potassium) teaching purposes only  2) Drugs for the adrenal gland Treatment for mineralocorticoid deficiency: Deoxycorticosteron Pivalate (DOCP), mimics the effects of aldosterone – Zycortal, Pecorten-V injectable suspension with prolongued release Frequency of treatment (≈25d) depend on the serum Na+/K+ ratio (blood monitoring 10d after starting treatment apenas fins pedagógicos  2) Drugs for the adrenal gland Treatment for mineralocorticoid deficiency: Fludrocortisone – PO, BID; mineralocorticoid and also glucocorticoid activity USE: Treatment of hypoadrenocorticism (usually when dexocycortone not available) Adverse effects of mineralocorticoid replacement therapy: not commom, but hypokalemia, hypernatremia, muscle weakness, and hypertension may be present Dexamethasone or prednisone – replaces/provides glucocorticoid activity, may complement mineracorticoid deficiency in the situations with both the corticoid def. apenas fins pedagógicos 2) Drugs for the adrenal gland Hyperadrenocorticism (Cushing's) The primary cause (dogs, horses) is the excess production of ACTH (e.g. pituitary tumor) and/or cortisol (consequence); Cushing's disease The goal is to reduce the production of glucocorticoids (e.g. cortisol) by the adrenal mitotane e trilostane the most used Ketoconazole and L-Deprenyl may also be used, but less and with less efficacy Adrenolytic drugs pdsa.org.uk for teaching purposes only  2) Drugs for the adrenal gland Treatment of Hyperadrenocorticism Mitotane Trilostane 4α,5α-Epoxy-17β-hydroxy-3- oxoandrostane-2α-carbonitrile also known as 1-(o-chlorophenyl)-1-(p- chlorophenyl)-2,2-dichlorethane; o,p’/4-DDD for teaching purposes only 2) Drugs for the adrenal gland Treatment of Hyperadrenocorticism Mitotane Trilostane leads to relative destruction of zonae supression of adrenal cortex by reversibly inhibit fasciculata and reticularis (mechanism enzymatic conversion of steroids, blocking synthesis unclear) – Adrenal cytotoxic of adrenal steroids (as cortisol) Adrestan, Trilotab, vetoryl (vet forms) Clinical indications: hyperadrenocorticism in dog: 30–50 Clinical indications: mg/kg p.o. (with/after food) q24h to effect hyperadrenocorticism in dog, cat and horses; (generally 3–10 days), then 50 mg/kg PO effective q7–14 days; in cat efficacy is variable 2-10 mg/kg in dogs, SID also indicated for some adrenal carcinomas 0.5-12 mg/kg, q12-24h in cats goal: reduce ACTH Side effects: GI problems, CNS depression, mild liver damage, milg hypoglycemia Side effects: well tolerated, mild GI effects (V, D); lethargy; adrenal glands increase in size for teaching purposes only  References Riviere, J. E., & Papich, M. G. (Eds.). (2018). Veterinary pharmacology and therapeutics. John Wiley & Sons. Ritter, J. M., Flower, R., Henderson, G., Loke, Y. K., MacEwan, D., & Rang, H. P. (2020).Rang and Dale's Pharmacology. Philadelphia, PA: Elsevier. Lüllmann, H., Mohr, K., Hein, L., & Bieger, D. (2018). Color atlas of pharmacology. New York: ThiemeTillement, J. P. Allerton, F. (2020). BSAVA: Small Animal Formulary (Ed. 10). British Small Animal Veterinary Association Ross, M. H. & Pawlina, W. (2011). Histology: a text and atlas: with correlated cell and molecular biology, 6th edition. Lippincott Williams & Wilkins. Scott-Moncrieff, J. C. (2012). Thyroid disorders in the geriatric veterinary patient. Veterinary Clinics: Small Animal Practice, 42(4), 707-725. Gerhardt, P., Begall, S., Frädrich, C., Renko, K., Hildebrandt, T. B., Holtze, S.,... & Henning, Y. (2023). Comparative analysis of thyroid hormone systems in rodents with subterranean lifestyle. Scientific Reports, 13(1), 3122.