PHARMA-P2-1.pdf

VEM 022 PHARMACOLOGY - Evenly distributed, even the CNS BECAUSE: they are protected by the plasma membrane (highly lipophilic) I. ENDOCRINE SYSTEM Part 1...

VEM 022 PHARMACOLOGY - Evenly distributed, even the CNS BECAUSE: they are protected by the plasma membrane (highly lipophilic) I. ENDOCRINE SYSTEM Part 1 - Much longer t1/2 (hours to day) HORMONES Natural secretion of endocrine glands can exert powerful effects on other cells/tissues. Compounds that produce hormone-like effects have important therapeutic uses for the treatment of endocrine hypofunction. Compounds that inhibit the hormone synthesis or blocking receptors can be used for the treatment of endocrine hyperfunction. MOA: Affects signal transduction through 1 of 4 major mechanisms: a. GTP-binding proteins: Hormones bind to cell surface receptors, turning on G-proteins that relay signals inside the cell. b. Tyrosine kinase: Hormones activate these receptors, which then tag proteins inside the cell to start signaling. o Receptors with tyrosine kinase activity. o Cytosolic tyrosine kinase: these are helpers inside the cell that get activated by surface receptors and tag other proteins c. Guanylyl cyclase: An enzyme that makes a molecule called cGMP, which helps regulate various cell activities. d. Intracellular receptors: Hormones enter the cell and bind to receptors that then directly affect the cell's DNA to control gene expression Pharmacokinetics: PEPTIDES & PROTEINS - Destroyed in the Gl. - Good parenteral absorption - Even distribution, no BBB crossing, rapidly metabolize in kidney and liver, effect last hours GLYCOPROTEINS - Destroyed in the Gl. - Good parenteral absorption - Even distribution, no BBB crossing, slowly metabolize in kidney and liver, effect last hours to a day STEROIDS AND THYROID HORMONES - Well absorbed in the gut (BUT only thyroid and synthetic steroids are effective orally) COMMON ENDOCRINE DISORDERS rapid heartbeat due to an overactive ANTERIOR PITUITARY DISORDER metabolism. HORMONES: ACTH,GH, TSH, FSH, LH - Seen in cats caused by adenocarcinoma and the Hypopituitarism-aka pituitary dwarfism prognosis in these animals is usually poor. Acquired growth hormone deficiency Neoplasia: tumors in the pituitary gland: -Thus, antithyroid agents are only recommended for either cancerous or benign. cats Hypersecretion of pituitary hormones PARATHYROID - Acromegaly: results from excess of GH. HORMONE: Parathyroid hormone: regulating calcium and phosphate balance in the body. - Cushing's syndrome - (hyperadrenocorticism) -Hypoparathyroidism: Hypocalcemia-low K in the - Results from excess of ACTH blood; characterized by neuromuscular - Galactorrhea - result from excess of dysfunction (tetany and paresis), bradycardia, prolactin and convulsions - Hyperparathyroidism: Hypercalcemia -High K in POSTERIOR PITUITARY the blood; which has renal, skeletal, GI, and HORMONES: ADH and OXYTOCIN neurological ramifications - Diabetes insipidus: characterized by ADRENAL excessive thirst and the excretion of large volumes of dilute urine. HORMONES: - Result from vasopressin deficiency or Cortisol: regulate metabolism, manage stress, vasopressin receptor abnormality. control inflammation, and maintain blood glucose - Vasopressin or also known as levels. Antidiuretic hormone (ADH): low Aldosterone: regulates sodium and potassium levels ADH causes excess urine. in the blood and helps control blood pressure. Hypoadrenocorticism (Addison's disease) - Result of primary insufficiency, usually due to autoimmune disorder - Secondary insufficiency, due to a decrease in ACTH secretion, can occur as well. Hyperadrenocorticism (Cushing's disease) - Caused by overproduction of ACTH - Neoplasm of adrenal cortex can be a cause as well Pheochromocytoma: THYROID - A type of tumor in adrenal gland causes HORMONES: excessive production of catecholamines, Thyroxine (T4) & Triiodothyronine (T3): resulting in hypertension. Regulate metabolism and energy production. Calcitonin: Regulates calcium levels in the PANCREAS blood. Hormones: - Decreases extracellular fluid (ECF): Insulin: regulates blood glucose levels promotes deposition of calcium in the Hyperglycemia: Elevated blood glucose levels; bones common diabetes mellitus caused by - Hypothyroidism: a condition where the insufficient insulin production. thyroid gland does not produce enough - symptoms include increased thirst, thyroid hormones (T3 and T4); causes frequent urination, fatigue, blurred fatigue, weight gain, and constipation due to vision, slow wound healing, and a slowed metabolism unexplained weight loss. Hypoglycemia: Low blood glucose levels; - Seen in dogs and horses overmedication insulin. - Tx: thyroid hormone - symptoms include shakiness, sweating, - Overzealous tx can cause confusion, rapid heartbeat, intense hyperthyroidism hunger, irritability, headache, and in -Hyperthyroidism: characterized by excessive severe cases, loss of consciousness. production of thyroid hormones, commonly due to benign thyroid gland hyperplasia or adenomas (benign tumors): causes symptoms such as weight loss, increased appetite, and GONADAL DYSFUNCTION Tx: Sometribove (Posilac R) - is used in cattle to promote milk production. Hypogonadism: deficiencies in hormones such Adverse: as LH, FSH, testosterone (in males),and - Injection site irritation, swelling, and lameness estrogen/progesterone (in females),leading to - Anorexia reduced reproductive function. - weight loss - Ovarian cystic disorders: hormonal imbalances including elevated estrogen - Mastitis and androgens, as well as imbalances - Reduced reproduction performance in LH and FSH, leading to the formation of ovarian cysts and associated B. CORTICOTROPIN, CORTICOSTEROIDS, AND symptoms. INHIBITORS GENERAL CONSIDERATIONS “HORMONES AND AGENTS: AFFECTING HOMEOSTATIC ORGAN: Adrenal Cortex ENDOCRINE FUNCTION” Corticosteroid pathway: The release of adrenal corticosteroids is controlled by a pathway that includes the CNS. Stimuli: trauma, chemicals, diurnal rhythms, and stress, can cause the hypothalamus to release corticotropin-releasing hormone (CRH). Endogenous glucocorticoids: cortisol, corticosterone Endogenous mineralocorticoids: - Deoxycorticosterone: stim at adrenal cortex by ACTH stimulation - Aldosterone: secretion stim by high Angiotensin, ACTH, or K concentrations - Negative feedback (means regulating the secretion of corticosteroids when it is elevated) pathway A. GROWTH HORMONE maintains homeostasis. Release in the pituitary gland Prolactin and placental lactogen resemblance Hormone Function in structure. Corticotropin- Stimulates the anterior pituitary gland Stimulated by-GH-stimulating hormone Releasing Hormone to release adrenocorticotropic hormone (ACTH) in response to stress (GHRH) from the Hypothalamus gland (CRH) or other stimuli. &ghrelin produced by the stomach. Inhibited by-somatostatin Adrenocorticotropic Stimulates the adrenal cortex to Sometribove: a synthetic GH, used for cows’ Hormone (ACTH) produce and release corticosteroids growth & milk production. including glucocorticoids and mineralocorticoids MOA: Cortisol Regulates metabolism by increasing glucose availability, suppressing GH activates Janus kinase JAK2- signal inflammation, and modulating immune transduction and activation of transcription responses. Critical for stress (STAT) pathway: leads to an increase in management and homeostasis. transcription and protein synthesis. insulin-like growth factor-1 (IGF- 1, Corticosterone Similar to cortisol. it helps regulate somatomedins): from the liver, which in turn metabolism and immune responses. Its role is more prominent in some animals participates in some of the effects of GH (e.g., but contributes to stress responses in growth, cartilage, protein metabolism). humans. PE: Growth of all tissues Deaxycorticosterone Regulates electrolyte balance by promoting sodium retention and increases uptake of amino acids into cells and potassium excretion in the kidneys. promotes lipolysis promotes the breakdown Helps maintain blood pressure and of stored fat into fatty acids and glycerol, aiding fluid balance. in fat metabolism and energy production. Aldosterone Regulates sodium and potassium levels by increasing sodium reabsorption and potassium excretion in the kidneys. Essential for controlling blood pressure and fluid balance.  b. Cardiovascular effects Corticosteroid pathway: CRH > ACTH > Adrenal Increase vasomotor and myocardial cortex>Corticosteroids> negative feedback contraction Increase epinephrine synthesis Increase expression of alpha-adrenergic ACTH receptor in smooth muscles, beta Synthetic ACTH [ACTH (1-24)] adrenergic receptors in myocardium possesses the biological activity of Facilitate the angiotensin system by ACTH and is identical for all species. increasing expression of Tx: diagnostic tool to distinguish types angiotensinogen, angiotensin converting enzyme(ACE), and angiotensin ll Primary adrenal insufficiency - IM receptors. administration of ACTH produces little The increased ACE breaks down or no increase in cortisol secretion bradykinin: a peptide that causes because of the underlying adrenal vasodilation and increased capillary cortical dysfunction. permeability. Thus, decreases capillary Secondary adrenal insufficiency - (i.e., permeability (decongestion), anterior pituitary dysfunction). This is due to anterior pituitary dysfunction. ACTH administration may or may not cause a significant increase in cortisol levels depending on the health of the adrenal cortex; if the cortex is atrophied, the response to ACTH will be diminished. CORTICOSTEROIDS Glucocorticoids Effects: Liver glycogen increase, gluconeogenesis, lipolysis, lipid redistribution c. Respiratory effects - The increased gluconeogenesis can lead to hyperglycemia and Cause bronchodilation by increasing liver glycogen synthesis: expression of β2-receptor. Hyperglycemia>insulin Decrease retention of mast cells, Thus, it must not be prescribed to decrease autacoids histamine and patients with diabetes. bradykinin. Does not promote glycogenolysis Thus, induce decongestion in the airway. (breaking down of glucose to glycogen) d. Skeletal muscle effects of glucocorticoid. Increases protein breakdown Physiologic doses: maintain skeletal muscle function. a. CNS effects. Deficiency: Weakness if due to Glucocorticoids may stimulate the CNS, hypoglycemia and poor circulation leading to euphoria. Long-term at high dose = muscle wasting CNS depression is associated with the due to muscle protein breakdown deficiency (hypoadrenocorticism). e. Effects on blood cells and lymphoid tissue However, the mechanisms underlying CNS effects Increase the number of circulatory of glucocorticoids are not well understood. erythrocytes, neutrophils, monocytes, and platelets, while decreasing the number of circulatory lymphocytes, eosinophils, and basophils.  Decrease the size of lymph nodes and thymus. - Polycythemia: results from decreased phagocytosis of Mineralocorticoids erythrocytes that are old and worn- out. Thus, resulting in an increase of DEOXYCORTICOSTERONE, ALDOSTERONE RBC. Increase reabsorption of sodium and - Neutrophilia: results from increased bicarbonate in exchange for excretion of entry of neutrophils into the potassium, proton, and chloride in the renal circulation, combined with tubule and, to a lesser extent, in the Gl tract. decreased removal of cells from the - Hypernatremia: circulation. The function of ▪ Elevated sodium levels in the neutrophils, however, is suppressed. blood. - Eosinopenia, basophilia, ▪ increased blood pressure. lymphocytopenia: result from redistribution of these cells to - Hypokalemia: systems other than blood ▪ Low potassium levels in the - Apoptosis of lymphocytes is blood. induced ▪ Decrease excitability of nerves - Production of Interleukins by and skeletal muscle and smooth macrophage, and T-lymphocyte muscle. inhibition; suppression of adaptive ▪ increases excitability of cardiac immune cells & macrophages. muscle. f. Immunological effects MOA: Too little or too much can increase susceptibility to infection. Alter mrna synthesis: Aldosterone Can treat lesions (urticaria: humoral increases the mRNA synthesis of Na+ immunity, rejection of transplants: channels, K+channels, and H+-ATPase (in cellular immunity) the apical side) reabsorption and Na+, K+- ATPase, and HCO- 3-Cl- antiporter Decrease cytokine production *excretion* in the distal renal tubule and Involution of lymph nodes, thymus, and intestine. spleen occurs. - Decrease bradykinin, ace, g. Anti-inflammatory and anti-allergic effects gluconeogenesis, cytokines, Suppress inflammatory processes by the cyclooxygenase (reduces the suppression of immune responses. production of protein related to Leukocyte migration and function inflammation) suppressed due to decreased expression of - Increase MRNA synthesis of Na chemoattractant factors and adhesion channels, K channels, H atpase. factors. Synthesis of prostaglandins and CORTICOID leukotriene (eicosanoids) is suppressed as Pharmacokinetics: a result of inhibition of PLA2. can be administered orally thus gut Plasma and lysosomal membranes are absorption is good, mucous membranes, stable resulting in decreased arachidonic and skin acid. Conjugates: kidney excretion Fibroblast, collagen synthesis, tissue repair are reduced in inflamed areas Preparation can be classified as Short, Hair and skin growth inhibited. intermediate,long acting. Preparations ▪ Osteoporosis: is due to decreased ▪ Injectable, Oral: Intermediate, Short/long calcium absorption from the GI tract acting via Topical use to treat pruritus and and reabsorption from the kidneys. inflammation associated with allergy. The slight decrease in plasma Ca2+ concentration, sends a signal to the Therapeutic Uses parathyroid gland to increase ▪ Glucocorticoids parathyroid hormone o Pruritus, inflammation, secretion,which promotes bone Hypersensitivity and shock, allergy resorption. Also,glucocorticoids in cats inhibit bone formation by decreasing o Induce parturition osteoblast activity o Isoflurane-can treat ketosis in cattle ▪ Edema ▪ Ketosis: in cattle is a ▪ Congestive heart failure in cats. metabolic disorder caused by an energy deficit, leading ▪ Thrombosis: due to increase in platelets in to the accumulation of the blood, hepatotoxicity, gi ketone bodies in the blood. ulceration,DM,abortion in late preg,laminitis Symptoms include reduced Contraindications appetite, weight loss, decreased milk production, -Infection, DM, Corneal ulcer, cardiac disorder, and a sweet or acetone-like burns, pregnancy odor on the breath or in the milk. ▪ Mineralocorticoids ADRENAL STEROID INHIBITORS (Mitotane, - Aldosterone: is not available as a Ketoconazole, Trilostane, Selegiline) pharmacologic agent because of its short duration of action, MITOTANE particularly when it is Related to DDT administered orally. (dichlorodiphenyltrichloroethane) insecticide - Deoxycorticosterone and Cytotoxic to zonae fasciculata and reticularis fludrocortisone-replacement of the adrenal cortex. therapy for hypoadrenocorticism Can't secrete aldosterone because it does (Addison’s disease). not affect Zona glomerulosa that secretes aldosterone. Administration Rx: Cushing's, adrenal adenoma and carcinoma ▪ Oral, IV,IM,Topical - PO bid dose for 10-14 days, then once a - Alternate day helps reduce week inhibition of ACTH secretion. Adverse: Attributable to reduced corticosteroid - The natural products secretion, hepatotoxicity. Recommended to (hydrocortisone, receive glucocorticoid supplementation deoxycorticosterone) should not - Animals may show lethargy, ataxia, be administered orally, because weakness, anorexia, vomiting, or they are quickly metabolized diarrhea, attributable to lowered by the liver via enterohepatic corticosteroid secretion. circulation. - Adverse effects ▪ latrogenic hypoadrenocorticism-can be prevented easily ▪ Toxicity effects: - decrease wound healing, increase susceptibility to infection, fluid and KETOCONAZOLE electrolyte imbalance, myopathy, Rx: - Cushing's resistant to mitotane - Palliative tx for large invasive tumors cannot be surgically removed - Tx to dogs that have cushing's diseases that are resistant to mitotane. MOA: Inhibits cytochrome p450 enzymes that II. Endocrine Pharmacology Part 2 involved in steroid synthesis GONADOTROPINS - Steroid synthesis inhibition is reversible - Found in milk Follicle-stimulating hormone (FSH) - Hepatic metabolism, excreted via bile Adverse: git signs, hepatotoxicity, reproductive produced and secreted by the gonadotrope disturbance of the pituitary gland Warning: can inhibit metabolism of other drugs, do In males: not use in cats - FSH: increases the diameter of the seminiferous tubules and promotes TRILOSTANE spermatogenesis - Synthetic steroid analog. Compounded in the - LH: increases testosterone synthesis pharmacy. from Leydig cells. MOA: competitive inhibitor fo 3-beta steroid In females: hydroxysteroid dehydrogenase = > inhibits - FSH: stimulates graafian follicle corticosteroid synthesis development and estrogen synthesis Rx: Cushings in dogs - LH: ovulation and luteinization Pkntcs: MOA - all receptors are coupled to G, inc. - PO erratic absorption (because of high lipid cyclic AMP formation solubility) with peak levels occurring within -Gonadorelin: 2 hours - presence of food in the gut to stimulate bile - Analog of GnRH flow should increase absorption - Induced LH for treating follicular - Liver metabolism, conjugation, excreted into cysts in cows urine and feces Human chorionic gonadotropin Adverse: (HCG)has LH-like activity: - lethargy, anorexia, vomiting, ele imbalance, - Females: induce ovulation and treat diarrhea. persistent infertility Contra-indication: pregnant (Inhibits - Males: Treats infertility, increasing progesterone. Estrogen androgens unaffected) libido and sperm count SELEGILINE Equine chorionic gonadotropin (ECG)has MOA: Inhibits ACTH secretion by increasing FSH-like activity: dopamine concentration around corticotropic of - Treats estrus and infertility the anterior pituitary. Pkntcs: Increasing of dopamine concentration by - - Metabolized in liver and kidney Inhibit dopamine metabolism by the metabolism by proteases monoamine oxidase B(MOA-B) Adverse: Rx: pituitary-dependent Cushing’s in dogs - anaphylactic shock (underassessment), canine cognitive dysfunction - Leuprolide: syndrome - GnRH analog. - Partial agonists inhibit hyperactivity of gonadotropins. Pharmacokinetics: absorbed rapidly, liver - Rx: control adrenocortical disease metabolism, urine excretion in ferrets SEX STEROIDS Adverse: - Adverse effects include vomiting and ESTROGENS AND ANTI ESTROGENS diarrhea; CNS disturbances manifested by - Synthesis and secretion: Endogenous restlessness, repetitive movements, or estrogen from ovaries, testicles, adrenal lethargy; and salivation and anorexia. cortex, placenta. Diminished hearing/deafness, pruritus, Preparation: licking, shivers/ trembles/shakes have also - Steroidal: Estradiol, Estrone, Estriol been reported. Selegiline has the potential - Estradiol is available as estradiol to be abused by human cypionate injectable or estradiol and estradiol benzoate ear implants for beef cattle  - Nonsteroidal: Zeranol, mycotoxin, growth PROGESTINS promotant Sources: Pharmacologic effects: Corpus Luteum (CL): Progestins are Estrogens stimulate and maintain the produced by the corpus luteum in the reproductive tract and cause hyperemia, ovaries of mares and ewes. hypertrophy, and edema during estrus. Placenta: During pregnancy, the placenta They cause cervical dilation. also secretes progestins in mares and They stimulate growth of the mammary ewes. glands. Adrenal Cortex: The adrenal cortex They increase ossification of epiphyseal produces progestins such as progesterone, lines to limit bone growth, particularly in which plays a role in various bodily women. functions. They increase sexual receptivity. Pharmacologic effects: They have protein anabolic effects (i.e., they stimulate protein synthesis). Glandular growth after priming with They antagonize androgen effects by estrogen blocking androgen receptors. Desensitize myometrium to oxytocin: They can induce growth promotion possibly They make the uterine muscle by increasing GH secretion, expression of (myometrium) less responsive to GH receptors, insulin-like growth factors oxytocin, reducing uterine contractions secretion. and facilitating pregnancy maintenance. Anabolic effects: promote tissue Rx: growth and protein synthesis. Associated with OVH: urinary MOA incontinence, vaginitis, dermatitis. Phenylpropanolamine, choice tx Progestins bind to progesterone receptors Relax cervix and caudal repro tract -when? in target tissues, influencing gene = parturition induction or abortion expression and cellular activity. This action Sometimes induce estrus in anestrous regulates reproductive processes and animals other physiological functions. Persistent CL in cows Rx Tx of pyometra, mummified fetus (pgf is preferred) Altrenogest - synchronize or suppress Prostatic hyperplasia: It involves the non- estrus cancerous enlargement of the prostate Melengestrol gland. - cattle feed additives. - Estrogens can be used as - Suppress estrus. androgen receptor antagonists. However, finasteride, an Implantation failure and habitual abortion androgen inhibitor, is preferred Megestrol acetate - contraceptive in to estrogens for this use. bitches Mismating therapy in dogs - Decrease Medroxyprogesterone acetate - control implantation. Again, pgf2 preferred for this. aggressiveness and inappropriate urination Growth promotion in ruminants or spraying Progesterone combined with an estrogen: Pkntcs: increase sexual receptivity - Absorbed slowly. Accumulates in adipose. Melengestrol and progesterone: growth Urine and bile excretion promotants Adverse: Pkntcs progesterone not for PO - Vaginal and rectal prolapse, abortion, 90% bound by plasma proteins follicular cysts, bone fracture (how?), Adverse aplastic anemia Endometrial hyperplasia endometritis, - CI-pregnancy pyometra, DM, inhibition of ACTH - Anti-estrogen (estrogen receptor antagonist) - Tamoxifen: canine mammary gland tumors (adverse: pyometra, nausea, vomiting)  ANTIANDROGENS: FINASTERIDE ANDROGENS Pharmacologic effects: inhibit the formation of 5 alpha dihydrotestosterone Synthesis and Secretion Rx: benign prostatic hyperplasia Testis: Androgens, primarily testosterone, Pkntcs: no info are produced in the testes, which are the Adverse: teratogen- can cause abnormality main site of androgen production in males. to the embryo. Adrenal Cortex: Androgens are also synthesized in the adrenal cortex, though at lower levels compared to the testes. 5-alpha Dihydrotestosterone (DHT): This is a potent androgen derived from testosterone through the action of the enzyme 5-alpha reductase. DHT plays a critical role in the development of male secondary sexual characteristics and certain conditions. Preparation: Esters: These include testosterone esters (e.g., testosterone enanthate, testosterone cypionate) used for hormone replacement therapy and other medical purposes. Boldenone: An anabolic steroid used primarily in veterinary medicine for growth promotion and to improve muscle mass. Stanozolol: An anabolic steroid with applications in veterinary medicine for growth promotion and muscle buildup. Danazol: A synthetic androgen with partial agonistic activity at androgen receptors, used for various conditions including as an adjunct to glucocorticoids. Pharmacologic effects: Masculinizing: development of accessory sex organs, etc., spermatogenesis, libido Anabolic effects, erythropoiesis, inhibit gonadotropin secretion Danazol: synthetic partial androgen receptor agonist Rx Impotency, infertility, uti, dermatitis, teaser animal Stanozolol and boldenone: growth promotion, muscle buildup, anemia, crf, arthritis Trenbolone and testosterone: Implants for growth promotion Danazol: adjunctive to glucocorticoids Pkntcs -90% bound by plasma proteins Refer to the book Adverse effects: Infertility or oligospermia, masculinization, hepatotoxicity DIHYDROTACHYSTEROL It is a vit d2 analog. ·Rx: hypocal secondary to hypopth or severe renal disease ·MOA: ·^ synth ca-binding proteins. How does this work? ·^Ca influx via-- ·Pkntcs: ·With food.Bile-dissolve DHT ·Vit D-binding globulin ·Hydroxylated to 25-hydroxy DHT. ·T1/2 is 8days in humans. Overdose is a prob. CALCITRIOL (1,25 (OH)2 D3). Is the most potent vitamin D3 metabolite. ·Tx. Hypocal secondary to hypopth or renal disease.(Other:idiopathic seborrhea because ^differentiation) ·Pkntcs. ·PO.Bile?. ·UNLIKE DHT, more rapid onset and shorter t1/2.Duration of action: ·Adverse  ·Hypercal. Nephrocalcinosis. But adverse effects are shorter than that of DHT. EPO Promotes erythropoiesis ·Chemistry. ·Pfx:^diff and prolif of red cell precursors ·MOA: activate EPO receptors and stimulate Janus kinase cascade ·Tx:Anemia associated with crf ·Pkntcs: Correction of hematocrit may take 2-8weeks to occur ·Adverse: May induce antibodies to EPO therapy.