Adrenal Corticosteroid Drugs (Konorev) Flashcards
Fludrocortisone is what type of drug?
Mineralocorticoid
Hydrocortisone, cortisone, prednisone, prednisolone, and methylprednisolone are what type of drugs?
Short-to-medium acting glucocorticoids (<12 hr)
Triamcinolone is what type of drug?
Intermediate acting glucocorticoid (12-36 hr)
Betametasone and dexametasone are what type of drugs?
Long acting (>36 hr) glucocorticoids
Aminoglutethimide, ketoconazole, metyrapone, and mitotane are what type of inhibitors?
Steroid synthesis inhibitors
Mifepristone is what type of drug?
Glucocorticoid antagonist
Spironolactone and eplerenone are what type of drugs?
Aldosterone antagonists
Mineralocorticoids are induced by __
Glucocorticoids are induced by __
Ang II and K+; regulate electrolyte, H2O balance and BP; Glomerulosa
ACTH; regulate metabolism and immunity; Fasciculata
This protein binds 90% of blood cortisol and 60% blood aldosterone. It is high during pregnancy, with estrogen administration, and in hyperthyroidism. It is low in liver disease
Transcortin or CBG
This enzyme converts cortisol —> cortisone
11 B-HSD2
This makes it mineralocorticoid responsive
These compounds inhibit 11 B-HSD type which results in excessive activation of MR mediated by cortisol. It can cause hypertension
Glycyrrhizin (active ingredient in licorice root extract)
Carbenoxolone (approved in UK to tx esophageal ulcers)
Inactivating mutations in ___ cause AME (Apparent Mineralocorticoid Excess) and presents as a form of severe juvenile HTN that is usuall transmitted as an autosomal recessive trait
11 B-HSD2
Target cell types of mineralocorticoids (Fludrocortisone)? Effect on gene expression in principal cells? Consequences?
Principal cells of collecting tubule and collecting duct
Increase ENaC on apical membrane, increase Na/K pump (basolateral)
Na retention, water retention, K loss
List the effect on gene expression for the following with mineralocorticoids:
NADPH reductase –> ____
Collagen, TGF-b–> ____
IL-6, cell adhesion molecules –> ____
PAI-1—> ____
Oxidative stress
Fibrosis, cell senescence
Inflammation
Inhibition of fibrinolysis, blood clotting
Aldosterone excess directly causes what in the heart and vasculature>
Cardiac fibrosis and hypertrophy
Vascular remodeling and inflammation
Use aldosterone antagonists in HTN and HF
Which glucocorticoids receptor isoform is prototypical? Which one does not bind ligands, is inactive, is induced by TNF-a, and may be responsible for glucocorticoid resistance?
GR-a
GR-B
Metabolic effects of glucocorticoids on carbohydrate metabolism?
- Increased gluconeogenesis (d/t increased PEP carboxykinase)
- Increase glucose output into circulation (d/t increase G-6-Pase)
- Increased glycogen synthesis (d/t increase glycogen synthase)
- Decreased glucose uptake by muscle and adipose tissues (d/t decreased expression of GLUT4)
- Development of hyperglycemia
Metabolic effects of glucocorticoids on lipid metabolism?
Increase lipolysis
Increase mobilization of free FA and glycerol into the gluconeogenic pathway
Increased lipgenesis
Net increase in fat deposition
Change in fat distribution –> increased fat accumulation in the upper body (shoulders, neck, rounded face), thinning arms and legs
Metabolic effects of glucocorticoids on protein metabolism?
Decreased AA uptake into cells
Decreased protein synthesis, - nitrogren balance
Mobilization of AAs into gluconeogenic pathway
Skeletal muscle: suppressed protein synthesis wil lead to development of myopathy and muscle wasting
The effects of glucocorticoids on the immune system and inflammation occurs due to transrepression of ___
NF-kB and AP-1 which leads too…
- decreased PLA2 and COX2 –> decreased production of PGs and LTs
- decreased production and increased apoptosis of immune cell types
- decreased production of cytokines (TNF-a, IL1, IFNy) and their receptors
- decreased expression of cell adhesion molecules
- decreased transmigration of neutrophils and macrophages from blood into tissues
What are some common clinical applications for adrenal corticosteroid drugs for endocrine conditions?
Acute and chronic adrenal insufficiency
Congential adrenal hyperplasia (21a-hydroxylase deficiency)
List some non-endocrine conditions for the use of adrenal corticosteroids
Immunosuppression–> following organ or HSC transplant; autoimmune disease; hematological disorders
Inflammatory and allergic conditions –> RA, IBD, asthma and COPD, allergic rhinits, skin diseases, hypersensitivity rxns
Adverse effects of mineralocorticoids?
Retention of Na and water, edema
HTN
Increased preload and cardiac enlargement, development of CHF
K loss and alkalosis (muscle spasms and tetany)
Adverse effects of glucocorticoids?
Suppressed ability to fight infx, opportunistic infx Hyperglycemia Skin: striae, easy bruising Muscle wasting, steroid myopathy HTN Steroid-induced glaucoma Cataracts Peptic ulcers Psych disorders Osteoporosis Retarded growth in children
Aminoglutethimide:
MOA?
Indications?
Side effects?
MOA: blocks conversion of cholesterol to pregnenolone; reduces production of all steroid hormones
Indications: adrenocortical cancer
Side effects: drowsiness, GI upset
Ketoconazole:
MOA?
Indications?
Side effects?
MOA: P450 inhibition, reduces synthesis of adrenal and sex hormones
Indications: antifungal drug, Cushing’s syndrome, suppresses androgenic hair loss, prostate CA
Side effects: hepatotoxicity, gynecomastia in males
Metyrapone:
MOA?
Indications?
Side effects?
MOA: Inhibition of steroid 11-hydroxylation; relatively selectively suppresses formation of cortisol and corticosterone
Indications: Cushings syndrome (can be used in pregnant women)
Side effects: accumulation of 11-deoxycortisol –> increased aldosterone –> Na and H2O retention
-accumulation of 11-deoxycortisol –> increased androgens –> hirsutism in women
GI upset and dizziness
Mitotane:
MOA?
Indications?
Side effects?
MOA: Na ionofore, Ca ionofore; Protein kinase C and AC inhibitor; Non-selective cytotoxic action on adrenal cortex
Indications: adrenal carcinoma
Side effects: depression, somnolence; GI upset; rashes
Mifepristone:
MOA?
Indications?
Side effects?
MOA: glucocorticoid receptor antagonist; stabilizes hsp90-GR complex in cytosol, prevents nuclear translocation of GR; Progesterone receptor antagonist
Indications: hypercortisolism in adult pts with endogenous Cushing’s syndrome; anti-progesterone action-used for medical termination of intrauterine pregnancy
Side effects: dizziness, GI upset, Fatigue
Spironolactone:
MOA?
Indications?
Side effects?
MOA: aldosterone receptor antagonist; also antagonist at androgen receptors
Indications: primary hyperaldosteronism; hirsutism in women; diuretic-used in tx of HF and HTN
Side effects: Hyper-K, gynecomastia and impotence in men, menstrual abnormalities in women
Eplerenone:
MOA?
Indications?
Side effects?
MOA: competitive antagonist of aldosterone at mineralocorticoid receptors; lower affinity for androgen receptors vs spironolactone
Indications: HTN; HF
Side effects: Hyper-K
