Endocrine Pharmacology I PDF

Endocrine Pharmacology Nuno Coelho Pharmacology and therapeutics II 3rd year – Master Degree in Veterinary Medicine for teaching purposes only  TABLE OF CONTENTS...

Endocrine Pharmacology Nuno Coelho Pharmacology and therapeutics II 3rd year – Master Degree in Veterinary Medicine for teaching purposes only  TABLE OF CONTENTS Hypothalamic and Thyroid pituitary hormones 3 Pharmacology of thyroid 1 and related agents Pharmacology of 4 glucose dynamic Reproductive Drugs for diabetes and related 2 pharmacology Drugs used to assist Adrenal reproductive functions 5 Pharmacology of adrenal gland (male and female)  1) ENDOCRINE SYSTEM Pituitary Thyroid reproductive endocrinology Pancreas for teaching purposes only  1 Hypothalamus and pituitary axis for teaching purposes only ENDOCRINE SYSTEM Endrocrine system is controlled by the brain Nerve cells of the hypothalamus synthesize and release messenger substances to regulate: hormones secretion and/or release from adenohypophysis (anterior pituirary) axonal processes of hypothalamic neurons project to the neurohypophysis (posterior pituitary), with ADH and oxytocin stored and released on demand for teaching purposes only  ENDOCRINE SYSTEM EFFECTS vascular and neuronal relationships between the hypothalamus, the hypophysis (adeno- and neuro-) and the main portal vessels for teaching purposes only ENDOCRINE SYSTEM for teaching purposes only ENDOCRINE SYSTEM Hypothalamic releasing hormones GnRH, gonadotropin releasing hormone (RH): stimulates release of FSH (follicle stimulating hormone) and LH (luteinizing hormone) TRH, thyrotropin-RH: stimulates the release of TSH (thyroid- stimulating hormone - thyrotropin) CRH, corticotropin RH: stimulates the release of ACTH (adrenocorticotropic hormone - corticotropin) GHRH, growth hormone RH, somatorelin: stimulates the release of GH (growth hormone or STH, somatotropic hormone) GHRIH; a somatostatin; inhibits release of GH (and also other peptide hormones including insulin, glucagon, and gastrin) for teaching purposes only  GH-related pharmacology Somatostatin, Growth-Hormone release inhibiting hormone GHRIH Function: inhibits the release of GH and TSH from the anterior Ritter, 2020 pituitary, and insulin and glucagon from the pancreas also decreases release of several GI hormones, and reduces gastric acid and pancreatic secretion Relevance in pharmacology? Analogues of somatostatin Octreotide (sandostatin, injectable SC, BID or TID), analogue of somatostin Used in acromegaly (a condition with oversecretion of GH) and also gastrinoma, pancreatic beta cell (endocrine) tumors, and glucagonoma in the dog - inhibits the release of several hormones in these conditions (gastrin, insulin, glucagon); also in cats (less used) Pegvisomat (GH receptor antagonist): also used in acromegaly for teaching purposes only  GH-related pharmacology Chronic overgrowth of connective tissue and bone - Acromegaly Ritter, 2020 Fracassi, 2014; https://www.sciencedirect.com/science/article/abs/pii/S1090023314002603 for teaching purposes only  GH-related pharmacology Somatotropin aka Growth-Hormone Function: stimulate normal growth and interferes in metabolic processes (as glucose-related ones) Clinical uses: Voorbij, 2015 pituitary dwarfism in dogs with bovine, porcine (SC, 3x/week, 4-6w) or human GH effect: increase in BW and weight of organs, increased skin thickness and serum IGF-1 levels; diabetes as adverse effect productive purposes: bov GH has been used in some countries in cattle to improve feed efficiency, with ↑ protein ↓ fat contents of meat (desirable carcass) increases milk production and alters milk composition in cows (not allowed in EU) for teaching purposes only Ritter, 2020  2 Reproductive pharmacology 2.1) Introduction brain (hypothalamus) regulates overall reproduction in animals via the synthesis and release of peptide hormones hormones are released from hypothalamic neurons in the region of the median eminence, and they reach the anterior pituitary through the hypothalamic– adenohypophyseal portal system GnRH will stimulate the release of hormones from the anterior pituitary: FSH, LH and prolactin FSH and LH will stimulate the secretion of gonadal steroids – estrogens and progesterone LH and FSH also regulate testosterone production and spermatogenesis in the male reproductive system for teaching purposes only  2.1) Introduction Estrous cycles: Proestrus Folicular phase; estrogen Estrus predominance Metestrus Luteal phase; progesterone Diestrus predominance The onset and maintenance of cyclicity are coordinated by a complex set of negative and positive feedback mechanisms therapeutic administration of natural or synthetic hormones have been used in the control and synchronization of estrous cycles for breeding purposes for teaching purposes only 2.1) Introduction Main events and hormones associated with the parturition important for the pharmacology, most of them are “therapeutic targets” for teaching purposes only 2.1) Introduction for teaching purposes only 2.2) GnRH, gonadorelin and gonadotropins GnRH – stimulate the release of gonadotropins In normal situations, GnRH has a very short life (2-4 min) and is released in pulses (intermittently) GnRH production is regulated by feedback negative GnRH stimulates the synthesis and release of gonadotropins by binding to GnRH receptor for teaching purposes only Shaw, 20210 2.2) GnRH, gonadorelin and gonadotropins 1) Pulsatile or episodic administration of GnRH stimulates the secretion of gonadotropins and forms the basis of infertility therapy and ovulation induction by increasing gonadal stimulation one of the principal clinical uses of GnRH is the induction of ovulation or follicular luteinization for teaching purposes only 2.2) GnRH, gonadorelin and gonadotropins 2) continuous administration of GnRH leads to desensitization and down-regulation of GnRH receptors on pituitary gonadotropes suppression of gonadotropin secretion and forms the basis for the clinical use of long-acting GnRH analogs to cause medical castration the other principal clinical use of GnRH is suppression of gonadotropin secretion (medical castration) for teaching purposes only 2.2) GnRH, gonadorelin and gonadotropins gonadorelin - synthetic GnRH buserelin (veterelin) - clinical GnRH analogs synthetic GnRH long-acting GnRH analog - agonist (e.g., deslorelin) for teaching purposes only 2.2) GnRH, gonadorelin and gonadotropins gonadorelin (gonavet, gonestin, ovarelin, cystorelin) synthetic preparation of GnRH used in animals that fail to ovulate or develop follicular cysts; injectable bovine, swines, equines (females) Deslorelin (suprelorin) SC implant (ovuplant) or injectable (sucromate) for horses and dogs Continuous exposure leads to desensitization and down-regulation of GnRH receptors (which can be positive if you want to limit estrus for teaching purposes only 2.2) GnRH, gonadorelin and gonadotropins Ovulation induction Clinical - gonadorelin induce ovulation at breeding time in dogs and horses; part of a “Ovsynch protocol” uses of in horses, deslorelin may be preferable, because of its long-lasting formulation, as mares have a prolonged LH surge (24-36h), GnRHs - induce estrus in dogs with prolonged anestrus (pulse-dosing) Cystic ovaries therapy (cattle and camelids) - drug of choice for ovarian folicular cysts (follicle that persist and don’t ovulate); 100 µg GnRH leads to luteinization of the cyst and estrus in 18-23d estrus synchronization: with PGF2a, in specific protocols (e.g. OvSynch) Timed embryo transfer protocols Estrus termination: in induced ovulators and in ferrets Used to identify intact from spayed or neutered animals lowering libido in stallions (gonadorelin) induction of temporary infertility – inhibit cyclicity (male cats and dogs) – deslolerin implants for teaching purposes only  for teaching purposes only G1 and G2 – GnRH (given on Day O and day 9 of a specific protocol, that also includes PGF2α (day 7) for estrus synchronization 2.2) GnRH, gonadorelin and gonadotropins for teaching purposes only 2.2) GnRH, gonadorelin and gonadotropins gonadotropins: FSH, LH and equine chorionic gonadotropin (eCG or pregnant mare serum gonadotropin – PMSG); primates: human chorionic gonadotropin (hCG) therapeutic uses in vet promoting male and female fertility preparations available: hCG, eCG and FSH (Follitropin-V) treating cryptorchidism for teaching purposes only 2.2) GnRH, gonadorelin and gonadotropins hCG (chorulon): possess LH-like activity, function as a substitute for LH to promote follicle maturation, ovulation and CL formation; 1 injection is enough for most of the reproductive issues; prolonged use: loss of efficacy Clinical uses in domestic animals (mostly used in bovines, equines and dogs) cases of repeated failure of conception in cows and heifers Induction of ovulation (prolonged pro-estrus and anestrus, mares and bitches for infertility: used in mares for hypogonadism due to pituitary hypofunction cystic ovaries in cows and heifers (luteinizing cysts) deficiency in libido in male dogs and stallions (impotence); cryptorquidism can be combined with eCG in pigs (PG600, Gestavet) – promote follicle development and induce and synchronize estrous in female pigs 2.2) GnRH, gonadorelin and gonadotropins Clinical used, for fertility problems, in domestic animals eCG: gonadotropic activity is mainly FSH-like; FSH: Folltropin V (porcine FSH), Ovagen ↑ follicule growth and also induce ovulation or (ovine FSH), Pluset (FSH+LH) luteinization (has some LH-like activity) single injection is enough; long lasting effects (like hCG) used to develop multiple follicles in donor stimulate folicular ovarian growth in cattle for ovulation (superovulation) and anestrous sheep or goaat oocyte collection used with hCG to induce ovulation and used for production of multiple embryos for CL formation embryo transfer procedures eCG + hCG induce fertile estrus in dogs for teaching purposes only 2.3) Prolactin and oxytocin Professor keep saying new and strange name of drugs Hormones related with lactation? for teaching purposes only  for teaching purposes only 2.3) Prolactin and oxytocin Prolactin stimulates lactation during postpartum period act via prolactin receptor – growth and differentiation of the ductal and lobuloalveolar epithelium NO prolactin – no lactation Prolactin is regulated (negatively) by dopamine (through dopamine recpetor D2 on lactrotopes) dopamine agonists or antagonists are expected to affect prolactin release cabergoline (galastop, kaberstop, finilac, veylactin), used in oral solution for cats and dogs Mec: inhibition of prolactin by D2 agonism metoclopramide (dopamine antagonist): USE: induce a transient increase in prolactin; but resolution of pseudopregnancy in the bitch not many data about the effect in milk Supression of lactation – cats and dogs production treatment of galactostasis in lactating bitches induce abortion in bitches and queens  2.3) Prolactin and oxytocin Oxytocin secreted normally when stimulated by teat suckling and fetal feet touching pelvix, vagina effect on uterus: increase frequency and force of uterine (myometrial smooth muscle) contraction effect on mammary gland: milk letdown (ejection) by contraction of myoepithelial cells Oxytocin - acts via G protein-coupled membrane receptors upon activation lead to generation of IP3 from phosphoinositide hydrolysis IP3 mobilizes intracellular Ca2+: depolarization–contraction of smooth muscle Adverse effects: uncommon, but repeated doses can lead to painful contractions or uterine rupture and fetal death for teaching purposes only  2.3) Prolactin and oxytocin induction of labor – small, large and exotic animals to promote parturition and uterum involution and emptying; IM or IM Clinical uses of oxytocin milk letdown – spray intranasal, 5-10 min before nursing; lack (Facilpart, Partovet, oxoject) of data in some species Persistent postmating endometritis – aids myometrial contractions to clear the uterus of debris after mating Inhibition of cyclicity– in mares during early diestrus disrupts luteolytic event, preventing cyclicity for teaching purposes only 2.3) Prolactin and oxytocin for teaching purposes only  2.4) Prostaglandin analogs PGF2a (prostaglandin): dinoprost (Dinolytic, enzaprost, lutalyse) and cloprostenol (Pgf vexy forte); luteolytic agent, used in small and large animals Adverse effects: increased smooth muscle tone – diarrhea, abdominal discomfort, bronchoconstriction, and increase in blood pressure; Induction of abortion may cause retained placenta Don’t give to pregnant animals (unless abortion is intended); shouldn’t be handled by pregnant women for teaching purposes only  2.4) Prostaglandin analogs PGF2a (prostaglandin) – luteolytic agent; IM injection Estrous synchronization: Dinoprost (PGF2α) and its analogs, by causing premature luteolysis and hastening the onset of estrus induce abortion and parturition in the bitch, cow, mare, pig; high doses required in early pregnancy are associated with side effects, Clinical uses including emesis, diarrhea, and cramping facilitate placenta delivery (uterine contractions) in the cow terminate diestrus in mare to facilitate rapid breeding used in uterine infections (pyometra) via luteolytic and ecbolic effects (uteral contractions) for teaching purposes only 2.5) Steroid hormones Steroid hormones: estrogens, progesterones, androgens regulate or induce estrous cycles Mechanism of action of steroid hormones (in general) steroid hormones cross easily membranes bind to intracellular steroid receptors (ER, PR, AR, etc) hormone-receptor complex interacts directly and specifically with sites on DNA – hormone response elements (HRE) act as transcription factor to activate or inhibit gene expression of the genes → mRNA → proteins that change a cell function for teaching purposes only  2.5) Steroid hormones Steroid hormones: estrogens, progesterones - regulate or induce cycles 1) Estrogens: estradiol, mestranol, dietilstilbestrol estradiol is active by PO administration, but low bioavailability – extensive first pass metabolism – injectable preferable Formulations used semisynthetic derivatives (ethinyl estradiol) or synthetic estrogens (mestranol) or nonsteroidal derivatives (diethylstilbosterol, DES) Clinical use: hypogonadism contraception/ elective pregnancy termination persistent vaginitis in prepubertally spayed bitches - diethylstilbosterol benign prostatic hyperplasia/ carcinoma of prostate (canine) urinary incontinence (increase urethral tone, reducing urine leakage) adverse effects: bone marrow suppression, risk of pyometra, tendon laxity, ventral alopecia Not widely used in vet, particulary in food animals (concerns of residues in meat for teaching purposes only  2.5) Steroid hormones 2) Progestins (synthetic forms of progesterone): the drugs with “gest” low bioavailability – extensive first pass metabolism – injectable preferable Synthetic progestins altrenogest (Suifertil, Virbagest, Regumate®), megestrol acetate (MGA), medroxyprogesterone acetate are widely used in vet adverse effects and precautions: Contraindications for the use of progestins can be a history of endometritis or pyometra; humans should ear gloves (possible absorption through skin) for teaching purposes only  for teaching purposes only 2.5) Steroid hormones Progestin – Altrenogest synthetic, orally active progestin indicated for controlling the estrous cycle of the mare and pig Indications: suppress estrus in mares (to go for a more predictable occurrence of estrus - PO for 15d (enhanced with co-administration with estrogen advance the first ovulation of the breeding season control equine estrous cycle synchronization of estrus in gilt prevention of pregnancy loss in mares (in cases of hypoluteodism, for instance Few adverse or side effects, but potential fetal or neonatal abnormalities, and slight delays in parturition  apenas fins pedagógicos 2.5) Steroid hormones Megestrol Acetate Pilusoft, megecat, piludog, pilucat synthetic progesterone - progestin USO: in bitches and queens for prevention or interruption of heat/estrus (tablet); also used to treat pseudopregnancy Used in males for satyriasis and behavioral problems (urine-spraying of cats) for teaching purposes only  apenas fins pedagógicos 2.5) Steroid hormones Medroxyprogesterone acetate Supprestral (Injectable), Perlutex (Tablets), ovigest (vaginal sponge) USE: Prevention and interruption of estrus (bitches,cats) Induction and synchronization of sheep estrus Adverse effects: pyometra, behavioural changes, increased appetite for teaching purposes only 2.5) Steroid hormones CIDR – progesterone-containing controlled internal drug release intravaginal device intravaginal progesterone-releasing devices are marketed for cattle, sheep, goat; 0 days withdrawal time milk and meat USE: synchronization of estrus, to improve timing and efficiency of breeding programs It releases progesterone during the 7-day treatment period for teaching purposes only  2.5) Steroid hormones Inhibitor of progesterone – aglepristone (Alizin) Action: Progesterone receptor blockage leads to elimination of progesterone support for up to 7 days; mifepristone is also a progesterone blocker Use: Termination of pregnancy throughout pregnancy (in dogs until 45th day, 2 SC injection in 2 consecutive days Treatment of pyometra in dogs, although recurrence is not unusual especially in older bitches Induction of parturition in cats and dogs Treat progesterone-induced acromegaly in dogs and progesterone-induced fibroadenomatous mammary hyperplasia in cats for teaching purposes only 2.6) testosterone Testosterone is secreted by Leydig cells of testes (obeying to LH) Several analogs of testosterone that possess greater anabolic (protein building) than androgenic (male sexual) effects have been synthesized: anabolic steroids nandrolone, stanazolol, oxymethalone equine medicine to increase athletic performance (tightly regulated) for teaching purposes only 2.6) testosterone Benign prostatic hypertrophy: most common prostatic disorder in intact male – results from androgenic stimulation clinical signs can go from being absent to hematúria, hemospermia, pollakiuria finasteride, a 5a-reductase inhibitor, that blocks conversion of testosterone to 5-αdihydrotestosterone finasteride induces prostatic involution by apoptosis in dog PO, daily, for 16weeks – effective in reducing hypertrophy side effect: impotence for teaching purposes only 2.7) Parturition reasons for inducing parturition enhancing the ability of managers to attend parturition attempting to save either the neonate or dam in cases of severe illness synchronize parturition for production purposes in cattle: dexamethasone or flumethasone IM is very effective, calves born 24-72h after also with PGF2a or cloprostenol (similar results) In mare is more complicated (higher complication rates) - combination of prostaglandin E and sequential doses of 15 IU oxytocin for teaching purposes only PGF2a also used in other animals  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 Shaw, R. W., Luesley, D., & Monga, A. K. (2010). Gynaecology E-Book: Expert Consult: Online and Print. Elsevier Health Sciences. Voorbij, A. M. W. Y. (2015). Shedding light on canine pituitary dwarfism. Utrecht University.