Pharmacology: Steroids II Flashcards
What are the distinct domains of steroid receptors?
C-terminally located ligand binding domain
H Domain
Centrally positioned DNA binding domain
N-terminally located MOD/IMM Domain
What are characteristics of steroid hormones?
Small and Lipophilic
- can traverse plasma membrane without channels or carrier proteins
What is the difference between cortisol and cortisone?
Cortisol (active) = binds to Mineralicorticoid R and Glucocorticoid R
Cortisone (inactive) = binds to neither receptor
**Injections of cortisone allows for extended release of cortisol due to active enzymes
How do glucocorticoids act as anti-inflammatory agents?
- Increase transcription of anti-inflammatory genes
- Decrease transcription of inflammatory genes
Cytokines
Chemokines
Adhesion molecules
Inflammatory enzyme
- Decrease mRNA stability of other inflammatory genes
TNF-a
IL-6
GM-CSF
COX-2
What are the therapeutic uses of adrenal steroids?
Replacement Therapy:
Addison’s
Congenital Adrenal Hyperplasia
Anti-inflammatory:
arthritis, rheumatic carditis,
inflammation of eye, skin, bowel, etc
Cancer Chemotherapy
Allergy
Asthma
Fetal lung syndrome
Immunosuppression:
Transplantation
Autoimmune disease
Cerebral edema
And then some…
What enzyme activates cortisone and prednisone?
11ß-dehydrogenase
Inactive = 11b-carbonyl
Active = 11b-hydroxyl
What are the toxicities associtaetd with adrenal steroids?
Pituitary -adrenal suppression
Hypokalemic, alkalosis, edema
Hyperglycemia (DM)
Increased susceptibility of infxn
Inhibited wound healing
Myopathy
Behavioral disturbances
Peptic ulceration
Cataracts
Growth arrest in children
Osteoporosis
Various other Cushingoid effeccts
What can happen if someone doesn’t taper off of their prednisone/steroid?
They can get cardiovascular collapse
–> steroids suppres adrenal gland, so when they stop prednisone, the adrenals are still suppressed
–> when they are put under a stressor before the adrenals are working again, they go into cardiovascular collapse
How do glucocorticoids cause osteoporosis?
Inhibit osteoblastic activity
Activate osteoclastic activity
What are the 5 parameters that can be modulated in order to choose the correct glucocorticoid?
Affinity
Specificity
Bioavailability
Solubility
Metabolism
What affects the bioavilability of glucocorticoids?
Binding to CBG
–> more CBG binding = less bioavailability
Why would you want to change the metabolism of glucocorticoids?
Inhaled steroids should be rapidly metabolized so that they are not systemically available b/c they are taken daily
Budesonide and Beclomethasone have highest first past metabolism
What are different approaches to therapy? (there are 4)
**1. Replacement (Addison's, adrenalectomy):** Low dose (in the morning)
2. Suppression (congenital adrenal hyperplasia):
Low dose twice (or more) a day to trick pituitary to believing cortisol is being made
3. Induction (giant cell arteritis; acute phase nephrotic syndrome):
High dose daily for immune suppression
**4. Maintenance (rheumatoid arthritis):** Alternate day (if possible) to minimize immunosuppression and other side effects
What are the glucocorticoid antagonists available?
Mifepristone
Spironolactone
Eplerenone
What is Mifepristone?
Glucocorticoid antagonist used to treat hyperglycemia in Cushing’s syndrome patients with diabetes whoa re not candidates for surgery
