Adrenal Corticosteroids (Konorev) Flashcards
What are the 2 broad categories of adrenal corticosteroid drugs
- Mineralocorticoids
- Glucocorticoids
What is the one mineralocorticoid
Fludrocortisone
What are the short to medium acting <12 hours glucocorticoids
- Hydrocortisone
- Cortisone
- Prednisone
- Prednisoone
- Methyprednisolone
What is the intermediate acting 12-36 hours glucocorticoid
Triamcinolone
What are the Long acting >35 hour glucocorticoids
- Betametasone
- Dexametasone
What are the 3 categories of inhibitors of adrenal corticosteroid action?
- Steroid synthesis inhibitors
- Glucocorticoid antagonists
- Aldosterone antagonists
What are the steroid synthesis inhibitors
- Aminoglutethimide
- Ketoconazole
- Metyrapone
- Mitotane
What is the glucocorticoid antagonist
Mifepristone
What are the aldosterone antagonists?
- Spironolactone
- Eplerenone
What are mineralocorticoids induced by
-Ang II and K+
What do mineralocorticoids do
-regulate electrolytes and H2O balance and blood pressure
What are glucocorticoids induced by
ACTH
What do glucocorticoids do
regulate metabolism and immunity
What is the high affinity protein that binds cortisol and aldosterone
-Transcortin, or Corticosteroid Binding Globulin
What condition is Transcortin levels high?
Low?
- pregnancy, with estrogen administration and in hyperthyroidism
- Liver disease (cirrhosis)
What protein binds corticosteroids loosely which makes them basically free even when bound
albumin
When plasma cortisol exceeds _________, the binding capacity of transcortin is saturated, and concentration of free cortisol rises rapidly
20-30 ug/dL
Describe the role of the liver in pharmacokinetics of cortisol
- liver produces transcortin
- about 80% of cortisol is metabolized by the liver
- The half live of cortisol is normally about 60-90 min and is often increased in pts with liver diseases
Describe why cortisol does not have a big effect on mineralocorticoid receptor even though it is in higher concentration in blood and has same affinity for it as aldosterone?
-it is converted to cortisone by 11 B-HSD2 in renal tubular epithelium, salivary glands, sweat glands, and colon which is inactive
What happens when 11B-HSD2 is inhibited
excessive activation of MR by cortisol . . . leads to hypertension
What are the 2 things in the powerpoint that inhibit 11B-HSD2
- Glycyrrhizin (licorice root extract)
- Carbenoxolone (approved in UK to treat esophageal ulcers)
Describe what AME (apparent mineralocorticoid excess) is
- inactivating mutations in 11B-HSD2
- presents as a form of severe juvenile hypertension
- autosomal recessive
What cells do mineralocorticoids target
-Principal cells of collecting tubule and collecting duct
What is the effect of mineralocorticoids on gene expression in principal cells
- increase epithelial sodium channels on apical membrane (ENaC)
- increase Na/K pump (basolateral membrane)
What are the electrolyte consequences of mineralocorticoids
- Na and water retention
- K loss
What non epithelial cells do mineralocorticoids target
- Heart
- vasculature
What are the effects of gene expression on mineralocorticoids on non epithelial cell types
- NADPH reductase: oxidative stress
- Collagen, TGF-B: fibrosis, cell senescence
- IL-6, cell adhesion molecules: inflammation
- PAI-1: inhibition of fibrinolysis, blood clotting
Aldosterone excess (directly) causes what?
- cardiac fibrosis and hypertrophy
- Vascular remodeling and inflammation
-why we used aldosterone antagonists in hypertension and heart failure
Transactivation mechanism of Glucocorticoids
- GR-ligand complex bind to GRE in gene promoters to activate gene expression
- effects on carbohydrate, lipid, protein metabolism
Transexpression of Glucocorticoids
- GR-ligand complex binds to other transcription factor complexes to suppress their activation of gene transcription
- NF-kappaB, AP-1 transcription factors
- Antiinflammatory, immunosuppressive, anti growth effects
What is the prototypical (fully functional) isoform of glucocorticoid receptors?
Which one lack 35 aa at the C terminal and does not bind ligands and is inactive?
- alpha
- bets
What GR isoform is induced by TNF-alpha and may be responsible for glucocorticoid resistance?
beta
Describe the carbohydrate metabolism of glucocorticoids
- increase phosphoenolpyruvate carboxykinase —-> increased gluconeogenesis
- Increased G6P –> increased glucose output into circulation
- increase glycogen synthase so more glycogen synthesis
- decrease GLUT4 –> decreased glucose uptake by muscle and adipose tissues
- Hyperglycemia
Describe the lipid metabolism of glucocorticoids
- stimulation of hormone sensitive lipase in adipose tissue –>increase lypolysis
- increase mobilization of free fatty acid and glycerol into the gluconeogenic pathway
- increase insulin secretion: increasd lipogenesis
- Net increase in fat deposition
- change in fat distrubution
Describe the change in fat distribution caused by glucocorticoids
- Adipocyte sensitivity to insulin vs. glucocorticoids varies in differetn areas of the body
- Increased fat accumulation in upper body (shoulders, neck area, rounded face)
- thinning arms and legs
Describe the Protein metabolism of glucocorticoids
- Decreased amino acid uptake into cells
- Decreased protein synthesis, negative nitrogen balance
- mobilization of amino acids into the gluconeogenic pathway
- Skeletal muscle: suppressed protein synthesis will lead to the development of myopathy and muscle wasting
What are the effects of glucocorticoids on intermediary metabolism antagonize actions of insulin
- Changes in gene expression that favor lipid and protein breakdown to supply substrates for gluconeogenesis
- Direct interference with the insulin receptor signal transduction
What are the immune and inflammatory effects of glucocorticoids due to transrepression of NF-kappaB and AP-1
- decreased in phospholipase A2 and COX2 –> decreased prostaglandins and leukotrienes
- decrease production and increased apoptosis of immune cells
- decreased cytokines (TNF-alpha, IL-1, IFNgamma,
- decreased cell adhesion molecules
- decrease transmigration of neurtrophils and macrophages from blood into tissues
What are the consequences of the effects that glucocorticoids have on immune system
- decreased inflammation and its manifestations
- immune suppression
- decreased allergic/hypersensitivity reactions
What endocrine conditions can you use corticosteroids for replacement therapy?
- Acute and chronic adrenal insufficiency (e.g. Addison Disease): a combo of a glucocorticoid (hydrocortisone) and a mineralocorticoid (fludrocortisone)
- congenial adrenal hyperplasia (21a-hydroxylase deficiency)
What are the clinical applications of corticosteroid use for immunosuppression?
- following organ or hematopoietic stem cell transplantation
- Autoimmune disease (MS)
- Hematological cancers (leukemia)
use corticosteroids for what inflammatory and allergic conditions
- RA
- IBD
- Asthma and COPD
- Allergic rhinitis
- Skin diseases: inflammatory dermatoses (psoriasis)
- hypersensitivity reactions
Adverse effects of mineralocorticoids?
- Retention of sodium and water, edema
- HTN
- increased preload and cardiac enlargement, development of congestive heart failure
- K+ loss and alkalosis (muscle spasms and tetany)
Adverse effects of Glucocorticoids
- Suppressed ability to fight infections, development of opportunistic infections
- Hyperglycemia
- Striae and easy bruising
- muscle wasting, steroid myopathy
- HTN
- steroid induced glaucoma
- cataracts
- peptic ulcers
- psychiatric disorders: euphoria, mania, anxiety
- increased appetite and weight gain
- Osteoporosis
- retarded growth in children
Describe the dosing of coricosteroids
- use lowest dose for shortest duration possible: use intermediate or short acting vs. long acting
- Reduce distribution of drugs into systemic circulation: use topical, inhalation routes, etc
- Give single daily dose in morning
- Alternate day, short course, pulse therapy administration
- Dose tapering (to allow recovery of hypothalamic-pituitary-adrenal system)
What is a prodrug activated by esterases present in bronchial epithelial cells; systemically absorbed active drug is tightly bound to serum proteins
-Ciclesonide (Alvesco)
What are the patient populations in which systemic glucocorticoid administration is problematic?
- Immunocompromised
- Diabetics
- infections
- peptic ulcers
- Cardiovascular conditions: HTN, congestive heart failure, angina
- psychiatric conditions
- osteoporosis (post menopausal women)
- children
MOA of Aminoglutethimide
- Blocks conversion of cholesterol to pregnenolone
- reduces production of all steroid hormones
Indications for Aminoglutethimide
- Was used for breast cancer treatment
- ADRENOCORTICAL cancer
Side effects of Aminoglutethimide
- Drowsiness
- GI upset
MOA of Ketoconazole
- P450 inhibition
- Reduces synthesis of adrenal sex hormones
Indications for Ketoconazole
- Antifungal druge
- Cushing’s syndrome
- Suppresses androgenic hair loss
- Prostate cancer
Side effects of Ketoconazole
- Hepatotoxicity
- Gynecomastia in males
MOA of Metyrapone
- Inhibition of steroid 11-Hyroxylation
- Relatively selectively suppresses formation of cortisol and corticosterone
Indications for Metyrapone
-Cushing’s syndrome (only drug for this indiciation used in PREGNANCY)
Side effects of Metyraone
- Accumulationg of 11-Deoxycortisol
- increased aldosterone–> Na and water retention
- increased androgen -> hirsutism in women
- GI upset
- Dizziness
MOA of Mitotane
- Na and Ca ionofore
- protein kinase C and adenylyl cyclase inhibitor
- non selective cytotoxic action on adrenal cortex
indications for Mitotane
Adrenal Carcinoma
Side effects of Mitotane
- Depression, somnolence
- GI upset
- Rashes
MOA of mifepristone
- Glucocorticoid receptor antagonist
- Stabilizes hsp90-GR complex in cytosol so prevents nuclear translocation of GR
- Progesterone receptor antagonist
inidications for Mifepristone
- hypercortisolism in adult patients with endogenous Cushing’s syndrome
- Anti-progesterone action: used for medical termination of intrauterine pregnancy
Side effects of mifepristone
- Dizziness
- GI upset
- Fatigue
MOA of Spironolactone
- Aldosterone receptor antagonist
- Also an antagonist of androgen receptors
indications of Spironolactone
- Primary Hyperaldosteronism
- Hirsutism in women
- Diuretic - used in treatment of HF and HTN
Side effects of Spironolactone
- Hyperkalemia
- Gynecomastia and impotence in men
- menstrual abnormalities in women
MOA of Eplerenone
- A competitive antagonist of aldosterone at mineralocorticoid receptors
- Lower affinity for androgen receptors vs. Spironolactone
indications for Eplerenone
- HTN
- HF (reduces cardiac remodeling and increases survival in HF patients in recent clinical trials
side effects of Eplerenone
-hyperkalemia
What 3 glucocorticoids do not have any mineralcorticoid receptor action so could be used to treat apparent juvenile hypertension because they will negatively feedback to hypothalamus and ultimately decrease production of cortisol?
- Triamcinolone
- Dexamethosone
- Betamethosone
Describe the relationship b/t ketoconazole and Atorvastatin?
- ketoconazole inhibits CYP 34A which metabolizes Atorvastatin
- so half life is increased and you get liver damage and skeletal muscle damage . .Rhabdo and acute renal failure
