Steroids Flashcards
How does an inverse agonist work?
Reduces low level of gene transcription that would occur with the receptor in the ABSENCE OF LIGAND
Prevents agonist activity
There are multiple nuclear hormone receptors. Name some.
Androgen Receptor (AR) Estrogen Receptor (ERa, ER-b) Progesterone Receptor Glucocorticoid Receptor Mineralocorticoid Receptor
Vitamin D Receptor
Thyroid Receptor
Selective Receptor Modulators are Nuclear Hormone Receptor Ligands. Are they agonists or antagonists?
How do they manage coactivators and repressors?
What is their advantage?
They are agonists in some tissues and antagonists in other.
Promote receptor confirmation to be closely balanced between favoring activators and repressors so it doesnt lean one way or the other.
(depends on what regulator is present in higher concentration)
Advantage: has + effects in target tissue, and minimal SEs in non targets.
What are the effects of glucocorticoids (cortisol)?
- Metabolic
- Immune
- CNS
Metab: Gluconeogenesis, Lipolysis, Protein Catabolism (from sk. muscle)
Immune: Anti-inflam, Immunosuppresion
CNS: Arousal/Mood/Memory
Mineralcorticoids has a role in fluid e- regulation. What e-lytes and what organ?
Effect on BP/volume
Na+ and K+ regulation in kidney
Increase
What are the glucocorticoid agonists? antagonists? synthesis inhibitors
Agonists: Dexamethasone, Betamethasone, Triamcinolone; of course hydrocortisone, cortisone, methylprednisone
Antagonist: Mifeprostine
Syn Inhib: Ketoconazole, Aminogluthimide, Metyrapone
What are the mineralocorticoid agonists? antagonists? synthesis inhibitors
Agonists: Fludrocortisone, Aldosterone, Hydrocortisone
Antagonist: Spironolactone, Eplerenone
Syn Inhibs: Ketoconozole, Aminogluthemide, Metyrapone
What dose of glucocorticoid used to treat endocrine disorders? Non endocrine disorders?
Low for endocrine
High for non endocrine (suppress inflamm and immune responses)
What are the adverse effects of Glucos?
Worsen or mask bacterial or mycotic infections Elevate blood sugar n/v, dizziness, weight loss, ulcers growth retardation in children muscle wasting, osteoporosis, skin atrophy (cushings symptoms) Increased IOP, catarracts Na and fluid retention, loss of K CNS (euphoria, psychosis, depression) Cushings syndrome
Contraindication: Hypersensitivity, fungal or serious infection diabetes, osteoporosis, glaucoma, heart disease, ulcers, pyschosis
What is acute insufficiency? chronic? CAH?
Acute: Abrupt w/drawal of exog steroids, life threatening shock, infection, trauma
Chronic: Addison’s disease (primary autoimmune destruction of adrenal cortex); Hypopituitary (secondary);
Both of these require chronic replacement therapy
CAH: Suppresses ACTH stimulation
Treatment of Cushings
Decrease Cortisol Production:
- Ketaconazole: inhibits p450, antifungal - Aminiglutethimide - Metatyrapone
Gluco receptor antagonist:
-Mifepristone: comp inhib of GR, also a PR antagonist
Mineralcorticoid receptors are expressed where?
What are the endogenous agonists?
What has a similar potency at both MRs and GRs?
Kidney, heart, colo, CNS, brown adipose, and sweat glands
These receptors increases expression of ion pumps and channels reg Na and water transport
Endog Agonists
Aldosterone, Deoxycorticosterone
Cortisol
What is Fludrocortisone, therapeutic use, adverse effects?
Its a potent selective minerlocorticoid
Mineralocorticoid Agonist used for :
Replacement therapy for Addisons, usu given with hydrocortisone
CAH to provide neg fdbk on ACTH
Increase blood vol in orthohydrostic HTN
Adv Effects: HTN, edema, cardiac enlargement, hypokalemia
What is spironolactone, and eplerenone, what do they block?
What is its action in the kidney
What condition can it be used to treat?
They are mineralcorticoid antagonists that block action of aldosterone on MR
In kidney, its a K+ sparing diuretic tht decreases blood volume and pressure
Treats hyperaldosteronism which is due to a primary benign adenoma
Gonadal Sex Hormones
Androgens, Estrogens, Progestins
Androgens: Testosterone, DHT, Fluoxymesterone (synth anabolic steroid)
Estrogen: 17B Estradiol; Ethinyl Estradiol (synthetic)
Progestins: Progesterone, Norgestrel (synthetic, aka methocyprogesterone)
How does the Androgen Receptor work?
What are the agonists?
Antagonists?
AR homodimerizes upon ligand binding, translocates to nucleus, binds androgen response element, then transcription
Agonists: DHT 10x more potent than testosterone; Testosterone Testosterone Esters Fluoxymesterone, methyltestosterone
Antagonists (competitive) Flutamide Bicalutamide Nilutamide Test
What are the androgens used for?
Replacement therapy in men and menopausal women, delayed puberty, breast cancer, wasting, severe anemia
Androgen abuse is real…steroids!!!
How can be testosterone be administered for replacement therapy?
IM injection of T esters
Topical: transdermal patches, gels apply these daily
Buccal tablets
Implantable pellets
Oral…but large first pass metabolism. the synthetic agonists are given orally which are fluoxymesterone, methytestosterone
Androgen SEs?
Contraindications
Liver tox: effect on cholesterol and jaundice
High doses cause gynecomastia, testes shrinkage and infertility
Virilization in females
Edema
Acne
Contras:
Prostate/Breast Cancer
Pregnancy
Sever liver, kidney, or heart disease
Androgen Suppression
What are the synthesis inhibitors?
AR antagonists?
Syn Inhibitors: Finasteride
AR Antags: Flutamide
What is finasteride, what are its uses, SEs?
It is a 5a reductase inhibitor so it blocks testosterone from being converted to 5DHT. its is a comp inhib.
Dutestaride is the same thing with a longer half life
Uses: Oral, reduce sypmtoms of enlarged prostate, reduce urinary retention, prevent hair loss in men (at lower doses)
SEs: Does not interfere with testosterone, but may cause:
Loss of Libido
Infertility
Gynecomastia
What are the Androgen Rec Antagonists?
Flutamide, Bicalutamide
Flutamide and Bicalutamide are AR Antagonists. What are their uses and SEs?
Competitive inhibs taken orally
Used to treat prostate cancer which is an androgen sensitive disease and 2nd most common cause of cancer in men
SEs: Low T: Sexual dysfunction, muscle atrophy, osteoporosis, hot flashes, gynecomastia, anemia, fatigue, depression, cognitive dysfunction
Liver Toxicity
How is Prostate Cancer treated?
Treated with combination therapy
Treated with:
AR Antags
GnRH agonists and antagonists (suppress pituitary stim of adrogen production)
Estogen receptor agonists?
Antagonists?
SERMs?
Agonists: Estrogens, ethinyl estradiol
Antagonists: Fulvestrant
SERMs: Selective Estrogen Recep Modulators)
Tamoxifen, raloxifene
What are the therapeutic uses for estrogens?
Replacement therapy: Hypogonadism which can affect breast, period, height in girls
Menopause: Loss of ovarian function, relief of symptoms, osteoporisis
Regulation of reproductive functions
Oral contraceptives, dysmenorrhea, SUPPRESSION of lactation
Can be given orally, transdermally, intravag, parenteral
Adverse effects of estrogens that are mild/mod? Serious?
N/v GI issues
Breast tenderness
Breakthru bleeding
Feminization (males)
Serious: Thromboembolism High Trigs HTN Gallbladder disease Migraine Incr risk of Breast cancer Endometrial Hyperplasia/Uterine Cancer (opposed by progestins)
Contraindicated in pregnancy, estrogen dependent cancers, unDx’d abnormal vag bleeding, thrombotic disorders
What are the symptoms of menopause resulting from?
Decline in estrogen production by the ovaries
What is transdermal estradiol? what can it treat? Advantages?
Natural estrogen (17B estradiol)
Patch or topical
vaginal cream that treats dryness, burning, and itching,of vag area and urgency
Advantages: No first pass metabolism in liver, body exposed to less, so less SEs
SERM
Raloxifene
ER agonist in bone, ANTAGONIST IN BREAST
Protects against osteoporosis in postmenopausal women
Protects AGAINST breast cancer (unlike tamoxifen, no agonist effect on endometrial tissue)
SERM
Tamoxifen
Has an antagonist effect on breast, but agonist effect on uterus.
Used in estrogen receptor + breast cancer. improves survival and reduce recurrence in both pre and post menopause
ONLY USE FOR 5 YEARS
Use w/other treatments: chemo and mastectomy
SEs: Menopause symptoms, increase risk of endometrial (uterine) cancer
What is hormone therapy for estrogen + breast cancer?
Use aromatase inhibitors ANASTROZOLE, LETROZOLE, EXEMESTANE (irreversible inhibitor)
**first line hormonal treatment of post men at any stage
Or you can do an aromatase inhib alone or with 2-5 yrs of tamoxifen
SE: increased osteo, msk probs,
EXEMESTANE: risk of visual disturbances, diarrhea
LETROZOLE: risk of cardiac events
What is fulvestrant and what is it used for?
It is an ER ANTAGONIST used for estrogen + breast cancer
SEs: hotflash, HA, injection site reactions
Progestins are produced from what two sources?
Ovaries and Placenta
Reproductive Effects of Progesterone? Non Reproductive?
Hormone of preg, prepares uterus for implantation, thickens cervical mucus, stimulate development of breast lobules and alveoli, INHIBITS FSH secretion
Non Reproductive:
Metab: incr fat deposition, helps insulin
CNS: Thermogenic, converted to neurosteroids (anti-anxiety, enhance GABA)
Kidney: Potent MR ANTAGONIST so w/drawal causes Na retention
Progesterone Agonists:
Norgestrel, medroxyprogesterone
Progesterone Antagonists:
Mifepristone…also MR antagonist
What hormone upregulates PR expression?
Estrogen. Prog effects amplified in the presence of estrogen
What are the therapeutic uses for progestins?
Postmenopause replacement Contraception Endometrial cancer and hyperplasia Dysfunctional uterine bleeding Amenorrhea Often used with estrogens
Oral HRT (hormone replacement therapy) consists of what two hormones?
Estrogen and progestin therapy used by women with intact uterus
Progestin counteracts endometrial hyperplasia of uterus that is caused by unopposed estrogen
Prevents Estrogen stimulation of uterine cancer
Prempr
CEE or conjugated Equine Estrogen Medroxyprogesterone acetate (oral progestin)
Progestin SEs:
Weight Gain
Gyno effects (breakthru bleeding, spotting, amenorrhea)
Breast tenderness/Cancer
Depression
Teratogenic effects during first 4 mos of preggo
