EXAM #5: ADRENAL AGENTS Flashcards
What hormone is released from the hypothalamus in the HPA axis?
Corticotropin-releasing hormone (CRH)
How does CRH act on in the Anterior Pituitary?
Receptors on the corticotropic cells of the Anterior Pituitary
What is the outcome of CRH activation of the Anterior Pituitary?
ACTH secretion
Where does ACTH exert its action?
ACTH activates receptors on the ADRENAL CORTEX
What happens when ACTH stimulates the adrenal cortex?
1) Increased steroidogenic enzyme expression
2) Stimulation of cortisol and adrenal androgens
What receptors does cortisol bind and activate?
Mineralcorticoid
Glucocorticoid
What happens with activation of the mineralcorticoid and glucocorticoid receptors?
1) Cortisol binds in cytosol
2) Receptors translocate to nucleus to DECREASE gene expression
What is the role of 11B-HSD2?
- Enzyme in minerocorticoid sensitive tissues
- Converts active Cortisol to INACTIVE Cortisone
Elevated levels of Cortisol can overwhelm this enzyme and cause adverse effects
What are the major adverse effects seen with elevated Cortisol levels?
1) Salt/water retention
2) Hypokalemia
3) HTN
What is the role of 11B-HSD1?
Activation of Cortisone to Cortisol
What is the benchmark corticosteroid drug? What is the anti-inflammatory to salt-retaining ratio?
Hydrocortisone
1:1
What is the relative duration of action of Prednisone? What is the anti-inflammatory to salt-retaining ratio?
- Intermediate duration of action
- 4:0.8 ratio
What is the relative duration of action of Dexamethasone? What is the anti-inflammatory to salt-retaining ratio?
- Long duration of action
- 30:0
What is the relative duration of action of Fludrocortisone? What is the anti-inflammatory to salt-retaining ratio?
Mineralcorticoid with 10:125 ratio
Which corticosteroids are prodrugs? How are they activated?
Cortisone and prednisone
*Activated by 11B-HSD1
What is Primary Adrenal Insufficiency or “Addison’s Disease?”
Autoimmune or tuberculoid induced destruction of the adrenal cortex leading to deficiency in cortisol, aldosterone, and androgens
What are the symptoms of Primary Adrenal Insufficiency?
Hypotension
Hyponatremia
Hyperkalemia
Hypoglycemia
How is Primary Adrenal Insufficiency treated?
1) Oral cortisol and liberal Na+ intake
2) Fludrocortisone (mineralcorticoid)
What is Secondary Adrenal Insufficiency?
1) Pituitary disease with a decrease in ACTH production and thus, cortisol
2) Hypothalamic disease with decrease in CRH
- Less ACTH
- Less Cortisol
*Note that because aldosterone is controlled by ACE II, people with secondary pituitary DO NOT have elevated aldosterone
How is Secondary Adrenal Insufficiency treated?
Cortisol
What is Cushing’s Disease?
Corticosteroid excess
When is Cushing’s Syndrome commonly seen?
Iatrogenic chronic glucocorticoid therapy
Also seen with:
1) Pituitary tumor and increased ACTH
2) Ectopic ACTH tumor
3) Adrenal tumor
What are the characteristic features of Cushing’s Syndrome?
- Moon-face
- Buffalo hump
- Increased abdominal fat
- Muscle wasting
- Osteoporosis
- Easy bruising
What is the utility of high dose dexamethasone suppression test?
Determining the etiology of Cushing’s Syndrome
What happens with the high-dose dexamethasone test with pituitary hypersecretion of ACTH?
50% reduction in cortisol (b/c of some negative feedback)
What happens with the high-dose dexamethasone test with adrenal adenoma?
No reduction in cortisol
- CRH and ACTH down
What happens with the high-dose dexamethasone test ectoptic ACTH production?
No reduction in cortisol
- CRH down but ACTH up
What drugs are used to treat Cushing’s Disease?
Ketoconazole
Metyrapone
Mifepristone
What is the MOA of Ketoconazole to treat Cushing’s Disease?
Antifungal that inhibits 17a-hydroxylase
What toxicity is assocaited with Ketoconazole?
Liver toxicity
What is the MOA of Metyrapone to treat Cushing’s Disease?
Inhibits 11B-hydroxylase
What is Metyrapone commonly used for aside from treating Cushing’s Disease?
Diagnostic agent to evaluate ACTH production
What is the MOA of Mifepristone?
Glucocorticoid receptor antagonist
What is the indication for Mifepristone?
1) Inoperable ectopic ACTH production
2) Adrenal carcinoma
What are low doses of Mifepristone used for?
Termination of pregnancy
What is the clinical utility for inhaled corticosteroids?
1) First-line in patients with persistent asthma
2) B2 agonists more than twice a week= indication to start inhaled corticosteroid
What is the effect of corticosteroids in the treatment of asthma in patients using B2 agonist on a frequent basis?
1) Corticosteroids increase B2 receptor production
2) Counter-acts receptor desensitization
What are the mechanisms of corticosteroids to treat asthma?
1) Reduced proliferation and hypertrophy of airway smooth muscle
2) Prevents leakage of vascular endothelium
3) Reduce adhesion of molecules in airway epithelial cells
4) Increased epithelial integrity
What are the beneficial effects of B2 agonists with corticosteroid use?
1) Increased nuclear translocation of GRs
2) Increased binding of GR to GREs on genes
What is advair?
- Salmeterol= B2 agonist
- Fluticasone= glucocorticoid
What are the adverse systemic effects of inhaled glucocorticoids?
Impaired growth in children
What are the adverse local effects of inhaled glucocorticoids?
1) Dysphonia
2) Oropharyngeal candidiasis
3) Cough
What is the biggest long-term adverse effect of glucocorticoid administration and HPA axis suppression?
Inability to make cortisol in a time of stress–>hypotension
What secretes the steroid hormones?
Adrenal CORTEX
What are the steroid hormones secreted by the adrenal cortex referred to as?
Corticosteroids
What are the three classes of corticosteroids?
1) Glucocorticoids
2) Mineralcorticoids
3) Androgens
What is the primary glucocorticoid?
Cortisol
What is the primary mineralcorticoid?
Aldosterone
What is the effect of Aldosterone on Na+ and K+?
- Increases Na+ absorption
- Causes K+ EXCRETION
What are the two enzymes involved in the synthesis of the glucocorticoids that are drug targets
1) 17-a hydroxylase
2) 11-B hydroxylase
Why is the rapid cessation of glucocorticoids dangerous?
1) Cortisol exerts a negative feedback on the hyothalamus and anterior pituitary
2) Synthesis of CRH and ACTH is inhibited with cortisol administration
Thus, rapid cessation would lead to dangerous HYPOCORTISOLISM
