Konorev DSA: Corticosteroids Flashcards
What is the Mineralocorticoid we have to know?
Fludrocortisone
What are the glucocorticoids?
- Hydrocortisone
- Cortisone
- Prednisone
- Prednisolone
- methypredisolone (those are short acting)
- Tramcinolone is intermediate acting
- Betametasone and Dexametasone are long acting
What are the Steroid synthesis inhibitors?
- Aminoglutethimide
- Ketoconazole
- Metyrapone
- Mitotane
What is the Glucocorticoid antagonist?
Mifepristone?
Aldosterone antagonists
- Spironolactone
- Eplerenone
What are Mineralocorticoids induced by and what do they regulate?
- induced by Ang II and K+
- regulate electrolyte, H2O balance and blood pressure
Glucocorticoids induction and what they regulate?
- induced by ACTH
- Regulate metabolism and immunity
What are weak androgens converted to?
- potent androgens in males
- estrogens in females
What carries steroid hormones?
Transcortin
- high in preggo
- low in liver disease
What is the role of the liver in pharmacokinetics or cortisol?
- produces transcortin
- about 80% of cortisol is metabolized by the liver
When is the half-life of cortisol increased?
- patients with liver diseases
- hypothyroid patients
MOA of adrenal corticosteroids
- nuclear receptors
- gene expression after lag period
- -effects can last even after the agonist is gone
What are the target cells for Mineralocorticoids?
- principal cells of collecting tubule and collecting duct
- other epithelial cells involved in electrolyte transport
What are the effects of activation of mineralocorticoid receptor in principal cells of collecting tubule and collecting duct?
- increased eptihelial sodium channel (ENaC)
- increased Na+/K+ pump
- Retention of water and sodium, loss of potassium
Direct effects of mineralocorticoids on cardiovascular system
- NADPH reductase—> oxidative stress
- Collagen, TGFB –> fibrosis, cell senescence
- IL-6, cell adhesion molecules —> inflammation
- PAI-1–> inhibition of fibrinolysis, blood clotting
What does aldosterone excess directly cause?
- cardiac fibrosis and hypertrophy
- vascular remodeling and inflammation
What is the transactivation mechansim of glucocorticoid effects?
-GR-ligand complex binds to GRE in gene promoters to activate gene expression
What is the transrepression mechanism of glucocorticoid effects?
-GR-ligand complex binds to other transcriptionfactor complexes to suppress their activation of gene transcription
What are glucocorticoid receptor isoforms?
- encoded by the same gene
- products of the alternative splicing
- GRalpha is a protoypcal isoform
- GRbeta lack 35 aa at C terminal- does not bind ligands and is inactive
What is GRbeta induced by?
- TNF-alpha
- May be responsible for glucocorticoid resistance
What binds a mineralocorticoid receptor (MR) with equal affinity as cortisol?
aldosterone
What does 11B-HSD (hydroxysteroid dehydrogenase) type 2 do?
- converts cortisol into inactive at MR cortisone
- makes tissues mineralocorticoid responsive for some reason
What is the result of decreased activity of 11B-HSD type 2?
excessive activation of MR mediated by cortisol
-causes hypertension and edema
What is that weird thing from candy that will decrease 11B-HSD type 2?
Glycyrrhizin
-because of this, it may cause hypertension
What do glucocorticoids do to carbohydrate metabolism?
- increased gluconeogenesis (increased PEP carboxykinase)
- increased glucose output into circulation (glucose-6-Phosphatase)
- increased glycogen synthesis
- decreased glucose uptake by muscle and adipose tissues (GLUT4)
glucocorticoid effect on lipid metabolism
- promote stimulation of hormone-sensitive lipase in adipose tissue–> increase lipolysis
- incraese mobilization of FFA and glycerol into the gluconeogenic pathway
- increase insulin secretion–> increased lipogenesis
- Net increase in fat deposition
- Change in fat distribution (shoulders neck face)
glucocorticoid effect on protein metabolism
- decreased aa uptake into cells
- decreased ptn synth, negative nitrogen balance
- mobilization of aas into the gluconeogenic pathway
- skeletal muscle: suppressed protein synthesis will lead to the development of myopathy and muscle wasting
What do the effects of glucorticoids on metabolism do to the actions of insulin?
ANTAGONIZE THEM!
What do glucocorticoids do to the immune system?
suppresses it
glucocorticoid effect on the cardiovascular system?
- increased E and NE
- increased HR and CO
- elevated BP
glucocorticoid effect on GI system?
- decreased gastro-protective prostaglandins
- decreased immune response against H. pylori
- increase in gastric acid and pepsin secretion
effect on CNS
- insomnia
- irritability
- euphoria followed by depression
- decreased sexual libido in males
effect on bone growth
- dereased blast activity
- increased clast activity
- growth retardation in children
- osteoporosis, bone fractures
- decreased intestinal and renal Ca2+ absorption
effect on skin
- low collagen
- low fibroblast proliferation
- low would healing, increased bruising
- fragile and thin skin with stretch marks called striae
Common clinical indication of adrenal corticosteroid drugs
- replacement therapy
- immunosupression
- inflammatory and allergic conditions
Adverse effects of Mineralocorticoids (Fludrocortisone)
- retention of sodium and water, edema
- HTN
- increased preload and cardiac enlargement, development of congestive heart failure
- K+ loss and alkalosis
Adverse effects of Glucocorticoids
-can’t fight infections
-hyperglycemia
-striae, easy bruising
-muscle wasting
-HTN
-glaucoma
-cataracts
peptic ulcers
-psych disorders: euphoria, mania, anxiety
-Increased appetite and weight gain
-Osteoporosis
-retarded growth in children
Dosing of adrenal corticosteroid drugs
- use lowest dose for the shortest duration possible depending on the condition
- reduce distribution of drugs into systemic circulation
- give single daily doses in the morning
- alternate day, short-course, pulse therapy administration
- dose tapering
What are some patient populations in which systemic glucocorticoids administration is problematic?
- IC patients (AIDS)
- Diabetics
- Infections
- pt’s w/ ulcers
- pts w/ CV conditions
- psych conditions
- osteoporosis
- children
What are the inhibitors of adrenal corticosteroid action?
- aminoglutethimide
- ketoconazole
- metyrapone
- mitotane
- mifepristone
- spironolatctone
- eplerenone
MOA of aminoglutethimide?
- blocks the conversion of cholesterol to pregnenolone
- reduces production of all steroid hormones
Indications for aminoglutethimide?
- was used for breast cancer
- adrenocortical cancer
side effects of aminoglutethimide?
- drowsiness
- GI upset
MOA of Ketoconazole
- P450 inhibition
- reduces synthesis of adrenal and sex hormones
Indications of Ketoconazole
- anitfungal drug
- cushing’s syndrome
- suppresses androgenic hair loss
- prostate cancer
side effects of Ketoconazole
- Hepatotoxicity
- Gynecomastia in males
MOA of Metyrapone
- inhibition of steroid 11-hydroxylation
- relatively selectively suppresses formation of cortisol and corticosterone
indications of metyrapone
- cushings syndrome
* the only drug for this indication that can be used in pregnant women**
side effects of metyrapone
- accumulation of 11-deoxycortisol… increased aldosterone…. Na+ and H2O retention
- same thing…. increased androgens…. hirsutism in women
- GI upset
- Dizziness
MOA of Mitotane
- Na+ ionofore, Ca2+ ionofore
- Protein kinase C and adenylys cyclase inhibitor
- non-selective cytotoxic action on adrenal cortex
Indications for Mitotane
-Adrenal Carcinoma
Side effects of Mitotane
- depression, somnoloence
- GI upset (diarrhea, nausea, vomiting
- rashes
MOA of Mifepristone
- glucocorticoid receptor antagonist
- stabilizes hsp90-GR complex in cytosol, prevents nuclear translocation of GR
- Progesterone receptor antagonist
Indication of 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 (anorexia, nausea, vomiting)
- Fatigue
Spironolactone MOA
- Aldosterone receptor antagonist
- also an antagonist at androgen receptors
Indications for 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
Eplerenone MOA
- competitive antagonist of aldosterone at mineralocorticoid receptors
- lower affinity for androgen receptors vs. spironolactone
Indication of Eplerenone
- HTN
- Heart failure
Side effects of Eplerenone
-Hyperkalemia
