ENDOCRINE DRUGS HYPOTHALAMIC AND PITUITARY HORMONES Menotropins Hypothalamic Hormones Growth hormone - Rapid increase in plasma GH levels releasing - Used to determine cause of GH deficiency hormone (GHRH) Somatostatin - Inhibits release of GH, thyrotropin, glucagon, (SRIH)/ insulin and gastrin somatotropin - Octreotide: acromegaly, carcinoid, release inhibiting gastrinoma, glucagonoma (longer acting) hormone Thyrotropin - Stimulates release of thyrotropin from releasing anterior pituitary hormone (TRH)/ - Increase prolactin production protirelin - No effect on GH or ACTH - Diagnostic testing of thyroid dysfunction Corticotropin - Stimulates secretion of both ACTH and beta releasing endorphin hormone (CRH) - Diagnose abnormalities of ACTH secretion (if outside pituitary, CRH will not lead to increase 41aa peptide in ACTH) Gonadotropin - Pulsatile doses: Stimulate gonadotropin treatmen t of releasing release, used in diagnosis and treatment hormone (GnRH) hypogonadal states - Steady doses: inhibit gonadotropin release, used for patients with prostatic carcinoma, decapeptide gonadal steroid sensitive tumors, endometriosis or precocious puberty - Leuprolide: GnRH agonist - Ganirelix and Cetrorelix : GnRH antagonists (prevent premature surge of LH during controlled ovarian hyperstimulation) Prolactin - Dopamine: physiologic inhibitor of prolactin Inhibiting release Hormone (PIH, - Bromocriptine(Cabergoline, Bromocriptine(Cabergoline, Pergolide): dopamine) effective in reducing prolactin secretion, prolactinomas(central prolactinomas(central dopaminergic effects) Anterior Pituitary Hormones Growth Hormone - Somatropin, Somatrem: GH analogs, used (GH) in treatment of GH deficiency in children and adults (Turner’s syndrome, chronic renal failure, failure to thrive, AIDS AIDS associated wasting) Thyroid stimulating - Increase iodine uptake and production of hormone (TSH) thyroid hormones - Diagnose primary from secondary hypothyroidism Adrenocorticotopin - Formed from pro-opiomelanocortin Hormone (ACTH) - Source of melanocyte stimulating hormone, beta endorphin, met encephalin - Cosyntropin: Cosyntropin: used to diagnose patients with abnormal corticosteroid production Follicle Stimulating - Glycoprotein that stimulates Hormone (FSH) gametogenesis and follicle development in women and spermatogenesis in men - Urofollitropin, follitropin alpha: used to treat infertility Leutinizing - Acts in concert with FSH to regulate gonadal Hormone (LH) steroid production, follicular development and ovulation - LH regulates testosterone production - hCG: treatment of hypogonadism in men and women, controlled ovarian
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Prolactin
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hyperstimulation and assisted reproductive technology programs human menopausal gonadotropins mixture of LH and FSH purified from urine of postmenopausal women used in combination with hCG in treatment of hypogonadal states glycoprotein responsible for lactation not used in therapy
Posterior Pituitary Hormones Oxytocin - nonapeptide synthesized in paraventricular nuclei of hypothalamus - Effective stimulator of uterine contraction - Induce and reinforce labor Vasopressin - Acts on V2 receptors, increases synthesis of (Antidiuretic water channels Hormone) - Increase water permeability in collecting tubules - Smooth muscle contraction (V1 (V1 effect) effect) - Desmopressin: selective V2 agonist, used in the treatment of pituitary diabetes insipidus
ENDOCRINE DRUGS CORTICOSTEROIDS AND ANTAGONISTS Glucocorticoids Metabolic effects Stimulate - Blood sugar rises gluconeogenesis - Muscle protein catabolism - Insulin secretion stimulated Lipolysis and - Fat deposition in face (moon facies) lipogenesis - Fat deposition in shoulders and back (buffalo hump) Catabolic effects Muscle protein - Lymphoid, CT, fat, skin undergo wasting catabolism - Osteoporosis in bone - Growth inhibited in children Immunosuppressive effects -Inhibit cell mediated immunologic functions -Actively lymphotoxic -Important in treatment of hematologic cancers -Delay rejection reactions in patients with organ transplants Anti-inflammatory effects -increase neutrophils, inhibit production of leukotri enes and prostaglandins -decrease lymphocytes, eosinophils, basophils, monocytes -inhibit migration of leukocytes Other effects -large doses: stimulate gastric acid secretion and decrease resistance to ulcer formation Important Glucocorticoids Cortisol - Major natural glucocorticoid - Physiologic secretion regulated by ACTH - Secretion varies during the day (circadian rhythm) (Peaks in morning, troughs in midnight) - 95% bound to CBG in plasma - Small but significant salt-retaining (mineralocorticoid) effect, responsible for HPN in patients with cortisol secreting tumor Synthetic Glucocorticoids Prednisone Longer halflife Prednisolone Longer duration of action Dexamethasone Reduced salt-retaining effect Triamcinolone Better penetration of lipid barriers (topical) Special Glucocorticoids Beclomethasone - Readily penetrate the airway mucosa - Short halflife after entering blood (less systemic Budesonide effect) Clinical Uses -chronic adrenal cortical insufficiency (Addison’s disease) -acute adrenal insufficiency with life threatening shock, infection or trauma -congenital adrenal hyperplasia -inflammatory or immunologic disorders -in combination with other antiemetics t o prevent chemotherapy induced nausea and vomiting Betamethasone: given to pregnant women in premature labor to hasten fetal lung maturation Toxicity: -adrenal suppression (suppress ACTH secretion) -metabolic effects : growth inhibition, muscle wasting, osteoporosis -salt retention, psychosis -to avoid toxicity: taper slowly to prevent adrenal insufficiency, “stress doses”
MINERALOCORTICOIDS Aldosterone Other mineralocorticoids -
Major natural mineralocorticoid in humans Short halflife and little glucocorticoid activity Same MOA as glucocorticoids Deoxycorticosterone (naturally occurring precursor of aldosterone) Fludrocortisone – significant glucocorticoid activity, favored for replacement therapy after adrenalectomy and other diseases, severe adrenal insufficiency
Corticosteroid Antagonists Receptor Antagonists Spironolactone, - Aldosterone antagonists Eplerenone Mifepristone - Inhibitor at glucocorticoid receptors as well as RU 486 progesterone receptors - Used in the treatment of Cushing’s syndrome Synthesis Inhibitors – treatment of adrenal cancer when surgical therapy is impractical/unsuccessful Aminoglutethimide - Blocks the conversion of cholesterol to pregnenolone - Inhibits synthesis of all hormonally active steroids Metyrapone - Inhibits normal synthesis of cortisol, not cortisol precursors - Diagnostic tests of adrenal function Ketoconazole - Inhibits cyp450 necessary for synthesis of steroids - Used in adrenal carcinoma, hirsutism, breast, prostate CA - Reduce unregulated overproduction of corticosteroids in adrenal tumors
ENDOCRINE DRUGS GONADAL HORMONES & INHIBITORS OVARIAN HORMONES ESTROGENS - Major ovarian estrogen in women: estradiol - Responsible for the growth of genital structures, secondary sexual characteristics, growth spurt during puberty - Modifies serum proteins - Reduces bone resorption - Enhances coagulability of blood - Increases plasma triglyceride levels while reducing LDL cholesterol Clinical Uses - Treatment of hypogonadism in young females - HRT in women with estrogen deficiency (premature ovarian failure, menopause, surgical removal of ovaries) - Prevent bone loss and osteoporosis Toxicity -premature closure of epiphyses of long bones, short stature (hypogonadal girls) -increase risk of endometrial cancer (HRT) – ameliorated with progestin combination -small increase in breast cancer and stroke (postmenopausal women) – not ameliorated with progestin combination -dose dependent toxicity: nausea, breast tenderness, increased risk of migraine headache, thromboembolic events, gall bladder disease, hypertriglyceridemia, hypertension PROGESTINS -major progestin in humans: progesterone -induces secretory changes in endometrium, -required for maintenance of pregnancy -carbohydrate metabolism, stimulate deposition of fat -high doses: suppress gonadotropin secretion, cause anovulation in women Older drugs: L-norgestrel, norethindrone – more androgenic Newer: norgestimate, desogestrel - less androgenic Synthetic progestins: improved oral bioavailability but do not support pregnancy Clinical Use: -used as contraceptives -prevent estrogen-induced endometrial cancer: in combination with estrogen -assisted reproductive technology Toxicity: -low toxicity -increase BP, decrease HDLs -reversible decrease in bone density and delayed resumption of ovulation after termination of therapy HORMONAL CONTRACEPTIVES -combination of estrogen and progestin, or progestin alone -inhibition of ovulation (primary action) -Progestin-only: do not always inhibit ovulation, may act to decrease likelihood of fertilization and implantation (mucus glands, endometrium) - ethinyl estradiol (estrogenic part of most OCPs) Clinical Uses -combination: used in young women with primary hypogonadism after their growth has been achieved to prevent estrogen deficiency - acne, hirsutism, dysmenorrhea, endometriosis - reduced risk of : ovarian cysts, ovarian and endometrial CA, benign breast disease, pelvic inflammatory disease -lower incidence of : ectopic pregnancy, IDA, RA Toxicity: -thromboembolism (estrogen effect on blood coagulation) -breast cancer
-nausea, breast tenderness, headache (estrogen effect), skin pigmentation, depression SERMs -mixed estrogen agonists Tamoxifen, - Treatment of hormone-responsive breast CA Toremifene - Decrease rate of recurrence of CA - Antagonist to prevent receptor activation by endogenous estrogens - Reduce incidence of breast cancer in high risk - Agonist at endometrial receptors – hyperplasia, increase risk of endometrial CA - prevent osteoporosis in women (agonist effect) - Hot flushes (antagonist effect), increase risk of venous thrombosis (agonist effect) Raloxifene - Prevention of osteoporosis in postmenopausal women, partial agonist effect on bone - Antagonist effects on breast tissue - No estrogenic effects on endometrial tissue - AE: hot flushes (antagonist effect) and increased risk of venous thrombosis (agonist effect) ESTROGEN AND PROGESTERONE AGONISTS, ANTAGONISTS, SYNTHESIS INHIBITORS Clomiphene - Induce ovulation in anovulatory women who wish to become pregnant - Nonsteroidal, tissue selective - Selectively block estrogen receptors in pituitary (reduce negative feedback, increase FSH/LH output) DES - Nonsteroidal, estrogen agonist - Associated with infertility, ectopic pregnancy and vaginal adenocarcinoma (in daughters) Mifepristone - Orally active, steroid antagonist of progesterone and (RU 486) glucocorticoids - Abortifacient in early pregnancy (49 days up to last LMP) - Postcoital contraceptive Danazol - Weak partial agonist (progestin, androgen, glucocorticoid receptors) - Inhibits p450 enzymes involved in gonadal synthesis - Treatment of endometriosis and fibrocystic disease of breast Aromatase - Anastrozole, Letrozole: nonsteroidal inhibitors of inhibitors aromatase (required for estrogen synthesis) - Useful in treatment of breast CA ANDROGENS TESTOSTERONE -synthesized from progesterone and DHEA -partly bound to SHBG in plasma -active hormone: dihydrotestosterone (in prostate) -Oxandrolone, Stanozolol: increased ratio of anabolic-androgenic action -enter cells and bind to receptors, hormone-receptor complex enters nucleus and modulates expression of target genes -necessary for normal development of male fetus -major changes in male at puberty, maintain secondary characteristics, fertility and libido, male pattern baldness -anabolic action : increased muscle size and streng th, increase red blood cell production -reduced excretion of urea nitrogen, nitrogen balance becomes more positive -helps maintain normal bone density Clinical Use -replacement therapy in hypogonadism - stimulate RBC production in anemias -promote weight gain in patients with wasting syndromes (AIDS)
-increase muscle bulk and strength (athletes) Toxicity -virilization in women (hirsutism, enlarged clitoris, deep voice) -menstrual irregularity -virilization of fetus’s external genitalia (if pregnant) -feminization in men (gynecomastia, testicular shrinkage, infertility) due to feedback inhibition -hostility, aggression (high doses) -cholestatic jaundice, elevation of liver enzyme, hepatocellular ca ANTI ANDROGENS -mode of therapy for both benign and malignant prostate disease, precocious puberty, hair loss and hirsutism Receptor inhibitors Flutamide - nonsteroidal competitive antagonists at androgen receptors - Decrease action of endogenous androgens in patients with prostate carcinoma Spironolactone - K sparing, also inhibits androgen receptors, treatment for hirsutism Gonadotropin-Releasing Hormone Analogs Leuprolide - Reduction of gonadotropins (esp LH) reduce production of testosterone - Used in prostatic carcinomas 5 alpha reductase inhibitors -conversion to DHT by 5 alpha reductase (prostate cells and hair follicles) Finasteride - Treatment of benign prostatic hyperplasia - Prevent hair loss in men (lower dose) - Less likely to cause impotence, infertility and loss of libido Combined Hormonal Contraceptives -antiandrogenic effect when used in women with hirsutism -estrogen acts in liver to increase SHBG, reduced concentration of free androgen in blood Inhibitors of Steroid Synthesis Ketoconazole - Antifungal, inhibits gonadal and adrenal steroid synthesis - Used in patients with steroid responsive metastatic tumors Spironolactone - Antiandrogen effect due to reduction of 17 alpha reductase
ENDOCRINE DRUGS PANCREATIC HORMONES, ANTIDIABETIC AGENTS, HYPERGLYCEMIC DRUGS INSULIN -synthesized as prohormone proinsulin -cleavage of proinsulin : 51 peptide insulin + 31 aa residual C protein Targets of Insulin Action Liver - increase storage of glucose and glyc ogen in liver - insert GLUT2 transport molecules - increased synthesis of pyruvate kinase, phosphofructokinase and glucokinase - decrease protein catabolism Muscle - glycogen synthesis and protein synthesis - insert GLUT4 transport molecules Adipose - facilitates triglyceride storage - activate plasma lipoprotein lipase - increase glucose transport via GLUT4 - reduce intracellular lipolysis Insulin Preparations -all insulin preparations contain zinc (influence rate of release of active hormone and duration of action) Ultra rapid and - recombinant human insulin (transposition of very short action lysine and proline) – dissolve more rapidly - suitable for use immediately before meals Insulin Lispro - increase in dose only increases intensity, not duration of effect Rapid onset and - used intravenously in emergencies or Short action subcutaneously in ordinary maintenance regimens Crystalline zinc - primary rapid onset agent before Lispro Regular Insulin (required administration 1 hour or more before each meal) Intermediate - given by SQ injection, not suitable for IV use onset and action - NPH: preferred when mixing intermediateonset with regular insulin NPH insulin - Lente insulin can retard onset of action of (isophane insulin regular insulin suspension) Lente suspension Slow onset and - Usually given in the morning only or in morning long action and evening - Maintenance or basal levels for 12-24h Ultralente insulin - Insulin glargine: ultra long acting preparation, provides peakless basal insulin level that last s >24 hours - Protamine zinc insulin: no longer available Hazards of Insulin Use Hypoglycemia : excessive insulin effect May result in brain damage o o Prompt administration of glucose (candy/sugar) Prompt administration of glucagon o o Most susceptible to detrimental effect: Advanced renal disease Elderly or <7 years old Immunologic toxic effects : development of antibodies
ORAL ANTIDIABETIC DRUGS Insulin Secretagogues - Stimulate release of endogenous insulin - not effective in patients who lack functional beta cells Sulfonylureas: close K channels in pancreatic B cell membrane, depolarization triggers insulin release nd 2 generation (Glyburide, More potent, used more commonly Glipizide, Glimepiride) Glyburide/Glipizide: greater potency Older agents: Tolbutamide, Chlorpropamide: long duration of action Chlorpropamide -drugs that compete for protein binding may enhance these effects Meglitinides: Repaglinide -newer insulin secretagogue -rapid onset and short duration of action -controlling postprandial glucose concentrations Nateglinide -D phenylalanine derivative -newest insulin secretagogue -help restore immediate insulin release in response to a glucose load -isolated postprandial hyperglycemia -given just before meals Toxicity: adverse effects relatively uncommon hypoglycemia (overdosage), rash (occasional), allergy Glyburide/Glipizide: hypoglycemia more common Biguanides -poorly understood mechanism -effects don’t rely on functional islet cells -DO NOT cause hypoglycemia Metformin - Inhibits vit B12 absorption - Reduced hepatic gluconeogenesis - Reduced glucose absorption formGIT - Reduced plasma glucagon levels - Stimulation of glycolysis in peripheral tissue Toxicity: -gastrointestinal distress (most common) - can cause lactic acidosis especially in tissue anoxia Thiazolidinediones -increase target tissue sensitivity to insulin -stimulate the PPAR-y receptor (regulate genes encoding proteins involving carbohydrate and lipid metabolism) -increase glucose uptake in muscle and adipose -inhibit hepatic gluconeogenesis -reduce both fasting and postprandial hyperglycemia Troglitazone - First introduced - Removed due to hepatotoxicity Rosiglitazone - Less risk of serious liver dysfunction Pioglitazone Toxicity: -edema, mild anemia -hypoglycemia is rare if used alone -Pioglitazone/ Troglitazone: induce p450 (3A4 isozyme) Alpha glucosidase inhibitors -alpha glucosidase is an enzyme necessary for conversion of complex starches to monosaccharides -slowed absorption, postprandial hyperglycemia is reduced -lack effect on FBS -Acarbose, Miglitol Toxicity: -flatulence, diarrhea, abdominal pain (increased fermentation of unabsorbed carbohydrate) -hypoglycemia – give GLUCOSE, not sucrose (delayed absorption)
TREATMENT OF DIABETES MELLITUS Diagnosis More than 1 FBS >140mg/dL Type 1 Diabetes Type 2 Diabetes Onset during childhood Progressive disorder, usually adult Autoimmune reaction – Increasing insulin resistance and destruction of pancreatic cells diminished insulin secretory capacity Frequently associated with obesity More common than Type 1 -
Long acting drugs (sulfonylureas, metformin, thiazolinediones) control BOTH fasting and post prandial glucose levels Short acting drugs (repaglinide, a-glucosidase inhibitors, regular insulin, insulin lispro) primarily target Postprandial glucose levels
HYPERGLYCEMIC DRUGS Glucagon (IM/IV) Product of A cells of pancrease Acts on G protein coupled receptors, increase cAMP Increases in heart rate, force of co ntraction Increase hepatic glycogenolysis and gluconeogenesis Relaxation of smooth muscle (marked in the gut) Treatment of severe hypoglycemia, hyperglycemic action requires intact hepatic glycogen stores Valuable for Xray studies of bowel or abdomen (temporary reduction of motility is necessary) Most effective method for stimulating heart in B blocker overdose (increase cAMP without requiring access to B receptors)
ENDOCRINE DRUGS THYROID AND ANTITHYROID DRUGS
ENDOCRINE DRUGS DRUGS THAT AFFECT BONE MINERAL HOMEOSTASIS
Thyroid Hormones -much of the circulating T3 is formed by the deiodination of T4 in tissues -tyhroxine binding globulin: synthesized by liver, transport T3 and T4 in the blood
ENDOGENOUS SUBSTANCES PTH - 84 amino acid peptide - Increases blood calcium and decreases phosphorus by increasing net bone resorption Vitamin D - Derivative of 7-dehydrocholesterol - Active : 25-hydroxyvitamin D or calcifediol (liver) - Active: 1, 25 dihydroxyvitamin D or calcitriol (kidney) - Increased intestinal Ca and phosphorus absorption - 24,25 dihydroxyvitamin D or secalcifediol : may increase bone formation Calcitonin - Peptide hormone - Decrease bone resorption, decrease serum Ca and phosphate - For acute reduction of serum calcium (Paget’s disease, hypercalcemia) - Salmon calcitonin: longer halflife and greater potency Estrogens - Prevent or delay bone loss in postmenopausal women - Inhibition of PTH stimulated bone resorption Gllucocorticoids - Chronic systemic use: common cause of osteoporosis - Useful in intermediate term treatment of hypercalcemia
Mechanisms of Action of T4 and T3 -T3 is 10x more potent than T4 -Effects of Thyroid Hormone Synthetic - Liothyronine: faster acting, shorter halflife levothyroxine (T4) - Levothyroxine : form of choice for most cases Liothyronine (T3) ANTITHYROID DRUGS Thioamides - Block iodination of tyrosine residues of thyroglobulin Propylthiouracil - Block coupling of DIT and MIT Methimazole - Block synthesis of thyroid hormone, slow onset (3-4 weeks for full effect) - Oral route - Effective in uncomplicated hyperthyroidism High dose PTU - Inhibits conversion of T4 to T3 (potent) - PTU less likely to cross placenta and enter milk Toxicity: Skin rash (common) Severe immune reactions – vasculitis, hypoprothrombinemia, agranulocytosis (rare) -effects usually reversible Iodide Salts and - Inhibit iodination of tyrosine in thyroid gland Iodine - Inhibit thyroid hormone release - Decrease size and vascularity of hyperplastic thyroid gland - Onset occurs rapidly (2-7 days) - Used in thyroid storm, severe thyrotoxicosis, prepare for surgical resection of hyperactive thyroid - Forms: Lugol’s solution (Iodine and Potassium Iodide) and saturated solution of KI - Short term administration of iodide for pregnant prior to surgery Radioactive - Contentrated in thyroid gland Iodine (I131) - Permanent cure for thyrotoxicosis without surgery - Permanent reduction of thyroid activity - Should NOT be used in pregnant or nursing women Iodinated - Ipodate: suppress the conversion of T4 to T3 via 5 Radiocontrast deiodinase Media - fast onset of antithyroid therapy - Useful for rapidly reducing T3 concentration in thyrotoxicosis (reduce intensity of thyroid storm) Other drugs - B blockers - Propranolol : inhibits 5 deiodinase (T4 to T3 conversion) - Control the tachycardia and other cardiac abnormalities
EXOGENOUS AGENTS Bisphosphonates -short chain, organic, polyphosphate compounds that reduce both resorption and formation of bone by action on basic hydroxyapatite crystal structure -calcium absorption on GIT -direct effects on osteoclasts -chronic therapy: slow progress of postmenopausal osteoporosis a nd reduce fractures -low bioavailability Older drugs - Bone mineralization defects Etidronate, Pamidronate - Lose effectiveness over 12months Alendronate, Risedronate - Fewer bone problems - Effective for at least 5 years - Used commonly for treatment of osteoporosis (postmenopausal or glucocorticoid induced) and Paget’s disease Alendronate - Further increases bone mass in menopausal patients when used with HRT Adverse Effects: -esophageal ulcer Fluoride - Chronic exposure, may increase bone synthesis - Reduce dental caries - No reduction in fractures Acute toxicity: Usually caused by ingestion of rat poison (GI/neurologic symptoms) Chronic toxicity: fluorosis, ectopic bone formation and exostoses (bumps on bones) OTHER DRUGS WITH EFFECT ON CALCIUM AND BONE Plicamycin - Antibiotic used to reduce serum calcium and bone resorption in Paget’s disease and hypercalcemia (Mithramycin) - Serious toxicity (thrombocytopenia, hemorrhage, hepatic and renal damage) - Short term treatment of serious hypercalcemia Thiazide diuretics, Loop diuretics: increase urine Ca Furosemide Thiazides: decrease urine Ca
