Steroidal Drugs II Androgens Anabolics Corticosteroids ANDROGENS sex related traits ANABOLIC STEROIDS o a class of steroid hormones or drugs with profound effects on the development of male reproductive capacity and o same as above pharmacologically inseparable includes all androgens developed for human or veterinary use o refers to nitrogen retaining activity of androgens which is used medically to reverse protein loss associated with debilitating disease mass or abused by athletes to build muscle mass strength and increase aggressiveness to improve competitive athletic performance Endogenous Androgens o Testosterone T o 5 dihydrotestosterone DHT o Active Metabolites of T DHT Estradiol The more DHT the more estradiol because DHT is broken down to estradiol Testosterone Metabolic Enzymes o 5 reductase catalyzes irreversible biotransformation of T to DHT two isoforms type I II Type I Nongenital predominant in nongenital skin liver Type II Genital predominant in male urogenital tissues genital tissues of both sexes catalyzes irreversible biotransformation of T to estradiol found in many tissues especially liver fat tissues also hypothalamus Testosterone 3 Molecular Mechanisms of Action o Aromatase o Direct T binds to androgen receptor development of internal genitalia epididymis vas deferens seminal vesicles ejaculatory duct suppression of breast development descent of testicles increased skeletal muscle mass strength anabolic action stimulates release of erythropoietin by kidney to increase Hct conc probably effects on bone Ca retention increased bone density pubertal longitudinal growth marked increase in body wgt due to bone muscle actions Hb o Indirect DHT binds to androgen receptor development of external genitalia male urethra penis scrotum prostate gland male pseudohermaphrodites lack type II 5 reductase have normal T no DHT undeveloped external genitalia development of prostatic diseases in adults benign prostatic hypertrophy BPH and prostate cancer Type I reductase hair growth associated with puberty pubic axillary facial Type II development of male pattern baldness Type II Estradiol binds to estrogen receptor bone epiphyseal closure cessation of growth aromatase req d brain libido gonadal function breast gynecomastia Testosterone Target Tissues o Testes enlargement at puberty maintains spermatogenesis along with FSH o brain CNS libido via estradiol o sebacious glands growth secretion acne o skeletal muscle o hair follicles hair growth of puberty o hypothalamus pituitary negative feedback receptors o kidney o bone o larynx vocal chords deepening of voice Specific Therapeutic Agents Testosterone o Poor bioavailabity due to 1st pass effect cypionate or enanthate esters of T in oil i m 2 4 week dosing propionate ester 3 x weekly dosing o topical gel or ointment 10 absorbed daily administration eg Androgel hydroalcoholic gel stable blood levels o transdermal patchs Testoderm Androderm o implantable long acting pellets Testopel Implants Specific Therapeutic Agents 17 Alkyl Androgens o Better bioavailability but less androgenic than T o Hepatotoxicity jaundice 2 5 month onset hepatic adenocarcinoma 1 7 yr onset o Danazol major use tx of endometriosis Therapeutic Uses o Hypogonadism t1 2 15 hrs oral least androgenic weak progestin glucocorticoid neonatal microphallus cryptorchidism puberty gynecomastia eunuchoid long arms legs adult libido energy muscle mass o Anabolic Agents tx catabolic wasting states not always effective efficacy proven in tx of AIDS wasting with hypogonadism o Short stature o Angioneurotic edema only 17 alkyl androgens stimulates liver to synthesize C1 esterase inhibitor Undesired Effects Side Effects o Masculinization virilization growth retardation without pituitary insufficiency short term tx 6 mo to avoid epiphyseal closure especially women prepubertal children acne facial hair deepening of voice prolonged tx male pattern baldness xs body hair prominent muscles acne clitoral hypertrophy amenorrhea o Feminization esp gynecomastia most severe in children men with liver disease other uses tx of fibrocystic breast disease allergic or hematologic disorders hereditary angioneurotic edema due to aromatization of androgens to estrogens aromatization chemical change in the rings of the steroids not with 19 nortestosterone derivatives nandrolone or fluoxymesterone poor substrates for aromatase Undesired Effects Adverse Effects o Edema particularly high doses used in neoplastic diseases o Hepatotoxicity 17 alkyl androgens o Testicular atrophy infertility diminished spermatogenesis o Priapism or impotence gynecomastia o Stunting of growth in children o Increase risk of premature coronary artery disease due to LDL HDL o Increased aggressivensss roid rage Anabolic Steroid Misuse Abuse o To improve athletic conditioning performance o To improve self image of adolescent boys Androgen Suppression o Continuous GnRH agonist tx add flutamide initially tx advanced prostatic carcinoma o Inhibitors of androgen synthesis imidazole antifungals ketoconazole also inhibit cortisol synthesis hepatotoxic GI side effects short acting better agents available o 5 reductase inhibitors finesteride marketed as Proscar and Propecia steroid like inhibits type I II causes profound in DHT but not T or LH tx of BPH reduce prostate size urine flow male baldness alopecia propecia drug name alopecia what it treats Androgen Receptor Antagonists o Flutamide Eulexin Bicalutamide Casodex limited effectiveness alone LH causes T also block adrenal androgen actions not steroids used in conjunction with GnRH to tx metastatic prostate carcinoma efficacy similar to castration bicalutamide less hepatoxic once daily dosing flutamide used to tx hirsutism in women nilutamide newest same advantages as bicalutamide ADRENOCORTICOSTEROIDS o steroidal derivatives of endogenous adrenal hormones corticsol corticosterone aldosterone o Two types of activity Glucocorticoid metabolic prednisone Mineralocorticoid electrolyte regulating fludrocortisone o Clinical Uses Replacement therapy for deficiency states Antiinflammatory Immune suppression Addison s Disease chronic adrenal insufficiency o Muscle weakness fatigue weight loss anorexia o Hyperpigmentation o Hypoglycemia inability to maintain blood glucose during fasting o Sodium loss potassium retained hypotension o Minor stress or trauma can trigger acute adrenal insufficiency with shock death Adrenocorticosteroid Deficiency State Causes o Acute adrenal insufficiency