Pharmacology: Corticosteroids and Mineralocorticoids Flashcards
What are the 3 categories of steroid hormones secreted by the adrenal gland?
- Adrogenic/estrogenic steroids
- Glucocorticoids
- Mineralocorticoids
(2 & 3 are considered corticosteroids)
What are important regulators of the reproductive system?
Androgenic/estrogenic steroids
What mediates intermediary metabolism and immune function?
Glucocorticoids
What is the most important glucocorticoid?
Cortisol
What has salt-retaining activities?
Mineralocorticoids
What is the most important mineralocorticoid?
Aldosterone
The classical model (free hormone hypothesis) that dominates endocrinology states that the MOA of steroids (including adrenal steroids) is what?
- Passively diffuse across plasma membrane
- Bind an intracellular receptor which links to a heat-shock protein
- Translocates into cell nucleus (where response elements on numerous DNA are located)
What 2 things can the response elements on numerous DNA do?
Stimulate or inhibit the transcription of various genes
What are 3 examples of endogenous glucocorticoids?
- Cortisol
- Corticosterone
- Cortisone
Cortisol accounts for what % of all glucocorticoid activity and is therefore the most important?
95%
What are 3 examples of synthetic glucocorticoids?
- Fludrocortisone
- Dexamethasone
- Betamethasone
What are clinical uses of glucocorticoids? (4)
- Adrenal insufficiencies (Addison’s)
- Anti-inflammatory effects (Rheumatoid arthritis, asthma)
- Depression of immune response (anti-cancer regimens and transplantation)
- Lipolysis
What does treatment for Chronic Addison’s Disease consist of?
20-30mg of hydrocortisone daily
What does therapy of 20-30mg of hydrocortisone daily for Chronic Addison’s disease require supplementation with?
Salt-retaining hormone like fludrocortisone
Why are long-acting synthetic glucocorticoids (like betamethasone) not suitable for treatment of Addison’s disease?
They are devoid of salt-retaining activity
True or False: Acute adrenoinsufficiency can be fatal?
TRUE
What is acute adrenoinsufficiency characterized by?
Abdominal pain, fatigue, darkening of skin, confusion, or coma
For adrenoinsufficiency, what does therapy include?
Large doses (100mg) of hydrocortisone intitially and then the dose is tapered down once patient is stabilized)
What else is an important part of therapy for adrenoinsufficiency?
Maintenance of fluid and electrolyte balance
When is a salt-retaining hormone added to the regimen for adrenoinsufficiency?
Once the dose of hydrocortisone has been lowered to 50mg/dL
What are 3 early events in the inflammation response?
Increased thromboxanes, prostaglandings, and leukotrienes
Increased thromboxanes, prostaglandings, and leukotrienes mediate the early steps of inflammation including what 3 things?
- Platelet aggregation
- Vascular permeability
- Vasoconstriction
What blocks inflammatory pathways?
Glucocorticoids
What regimens are glucocorticoids often used in?
Anti-cancer (ex. MOPP- Prednisone)
Due to the blocking of inflammatory pathways by glucocorticoids, it makes them useful for what?
Anti-asthma and anti-inflammatory
What are 3 treatment options for treatment of Cushing Syndrome?
- Surgical removal of ACTH-producing pituitary tumor
- Irradiation of pituitary tumor
- Removal of one or both adrenal glands
What is done pharmacologically for treatment of Cushing Syndrome after adrenalectomy (adrenocortical hypo/hyper function)?
Large doses of cortisol (300mg) are required initially, then the dose is tapered down
What is required if the adrenal glands are removed?
Long-term GC hormone replacement
Why are corticosteroids effecting in the setting of transplant rejection?
It is due to their ability to suppress antigens expression from transplant graft and interference with the sensitization of cytotoxic T lymphocytes
Glucocorticoids are useful for the treatment of what type of skin diseases?
Inflammatory (psoriasis)
-Synthetic topical non-absorbable glucocorticoids
Why is the use of glucocorticoids hampered in treating things like arthritis and asthma?
Adverse effects (osteoporosis)
What do long-term glucocorticoids inhibit?
ACTH from the pituitary
What type of effect does ACTH have on the adrenal cortex?
Trophic
What will happen if exogenous GCs are withdrawn abruptly?
The patient will have chronic adrenal insufficiency
How can you avoid chronic adrenal insufficiency due to the abrupt removal of GCs?
Taper GCs over months
What are 5 toxicities associated with glucocorticoids?
- Iatrogenic Cushing’s Syndrome caused by prolonged use of synthetic glucocorticoids
- Osteoporosis
- Impaired wound healing
- Multiple disorders for energy storage and possible development of type II DM
- Redistribution of fat from periphery to trunk
In cases of Cushing’s disease, production of GCs can be stopped by what 3 drugs?
Enzyme inhibitors: Mitotane, Metyrapone, or Ketoconazole
Trilostane is only for animals
At higher doses, what drug blocks the GC intracellular receptor?
Mifepristone (RU-486)
What are the 3 mineralocorticoids?
Aldosterone, Deoxycorticosterone, and Fludrocortisone
What is a synthetic glucocorticoid and is the most commonly prescribed salt-retaining hormone?
Fludrocortison
What has a similar pharmacology to aldosterone, but is less important pharmacologically?
Deoxycorticosterone
What is the most important mineralocorticoid in humans?
Aldosterone
What 2 pathways regulate Aldosterone?
ACTH and the renin-angiotensin pathways
What is used both for diagnosis and treatment of aldosteronism that is a mineralocorticoid receptor antagonist?
Spironolactone
What receptors does spironolactone inhibit and what a possible AE of this?
Androgen and progesterone receptors- It can cause gynecomastia in men
What is a more selective mineralocorticoid receptor antagonist and it inidcated for patients with heart failure?
Eplerenone
What needs to be monitored with eplerenone?
Potassium levels
What is an endogenous precursor of aldosterone and is normally secreted in far lower amounts than aldosterone?
Deoxycorticosterone (DOC)
What controls the release of DOC?
ACTH- This is unlike aldosterone
What is fludrocortisone?
A potent synthetic steroid with both glucocorticoid and mineralocorticoid activity
True or False: Fludrocortisone has a much lower first-pass effect than aldosterone?
TRUE
What must be monitored with fludrocortisone?
Blood pressure and serum potassium
What are 2 pathophysiologic functions of corticosteroids?
- Anti-inflammation
2. Immunosuppressant
What are 3 general clinical uses of corticosteroids?
- Adrenoinsufficiency
- Adreno hypo and hyperfunction
- Diagnosis
What are 3 general; toxicities and C/I of corticosteroids?
- Osteoporosis
- Na+ retention
- Type II DM
What is a clinical term denoting a number of enzyme inherited deficiencies in the adrenal cortex?
Congenital adrenal hyperplasia
What is the result of congential adrenal hyperplasia?
Increased androgen production by the fetal adrenal and ends with masculinizing the fetus
For females what is the specific affects of congential adrenal hyperplasia?
Hirsuitism and virilization
What is the most common deficiency with congential adrenal hyperplasia?
Steroid 21-hydroxylase
What does a deficiency of steroid 21-hydroxylase cause?
The adrenal is unable to metabolize aldosterone or cortisol forcing steroid precursors of these into the androgen-producing pathway
An infant with congential adrenal hyperplasia initially has symptoms to what?
Those of acute adrenal insufficiency
How should infants with congential adrenal hyperplasia be treated?
Adminitraction of hydrocortisone accompanied by correct of fluid and electrolyte imbalance (similar to acute adrenal insufficiency)
Once an infant with congential adrenal hyperplasia is stabilized, what kind of hydrocortisone is used?
ORAL
Why must the dose of oral hydrocortisone be adjusted in congential adrenal hyperplasia?
To allow proper growth and bone maturation
What can used to suppress ACTH without increasing growth inhibition in congenital adrenal hyperplasia?
Prednisone
What should be administered orally with added salt to maintain normal BP, renin activity, and electrolytes for congential adrenal hyperplasia?
Fludrocortisone
What is used to diagnose Cushing syndrome and in the differential diagnosis of depression (about 30%)?
Dexamethasone suppression test
What is the general procedure of the dexamethasone suprression test?
1mg of dexamethasone is administered at night and cortisol levels are measured the next morning
In a normal individual, what are the cortisol concentrations in the AM after administration of 1mg dexamethasone, in a Cushing’s Syndrome Patient?
Normal: Under 3mch/dL
Cushing Syndrome: Over 5mch/dL
What can make the results of the dexamethasone suppression test inaccurate?
Depression, anxiety, alcoholism, and/or concurrent illness
How do you distinguish between pseudo-Cushing’s syndrome and bonafide Cushing’s Syndrome?
Combine test of dexamathasone and CRH
-Small dose of dexamthasone is administered every 6 hours for 2 days, followed with a standard CRH test
What is seen with distinguished Cushing’s syndrome after dexamethaosne suppression test and CRH?
Plasma cortisol concentration greater than 1.4mg/dL measured 15 minutes after cortisol administration
What is done do distinguish between Cushing’s disease and steroid-producing tumors of the adrenal gland or in an ectopic ACTH sundrome?
- 5 mg oral dexamthasone is administered every 6 hours for 2 days, followed by oral 2mg every 6 hours for 2 days
- 50% decrease in urine cortisol levels distinguishes Cushing’s disease
Why do glucocorticoids cause osteoporosis?
GCs inhibit vitamin-D mediated calcium absorption (secondary hyperparathyroidism develops) and they also inhibit osteoblast function
What is a potent synthetic steroid with both glucocorticoid and mineralocorticoid activity?
Fludrocortisone
What is very effective in treating adrenocortical insufficiency associated with mineralocorticoid deficiency?
Fludrocortisone as low as 0.1mg dose 7 times per week
Anti-inflammatory and anti-growth adverse effects don’t occur at such low doses
