Adrenal Corticosteroids (Konorev) Flashcards
1
Q
What are the 2 broad categories of adrenal corticosteroid drugs
A
- Mineralocorticoids
- Glucocorticoids
2
Q
What is the one mineralocorticoid
A
Fludrocortisone
3
Q
What are the short to medium acting <12 hours glucocorticoids
A
- Hydrocortisone
- Cortisone
- Prednisone
- Prednisoone
- Methyprednisolone
4
Q
What is the intermediate acting 12-36 hours glucocorticoid
A
Triamcinolone
5
Q
What are the Long acting >35 hour glucocorticoids
A
- Betametasone
- Dexametasone
6
Q
What are the 3 categories of inhibitors of adrenal corticosteroid action?
A
- Steroid synthesis inhibitors
- Glucocorticoid antagonists
- Aldosterone antagonists
7
Q
What are the steroid synthesis inhibitors
A
- Aminoglutethimide
- Ketoconazole
- Metyrapone
- Mitotane
8
Q
What is the glucocorticoid antagonist
A
Mifepristone
9
Q
What are the aldosterone antagonists?
A
- Spironolactone
- Eplerenone
10
Q
What are mineralocorticoids induced by
A
-Ang II and K+
11
Q
What do mineralocorticoids do
A
-regulate electrolytes and H2O balance and blood pressure
12
Q
What are glucocorticoids induced by
A
ACTH
13
Q
What do glucocorticoids do
A
regulate metabolism and immunity
14
Q
What is the high affinity protein that binds cortisol and aldosterone
A
-Transcortin, or Corticosteroid Binding Globulin
15
Q
What condition is Transcortin levels high?
Low?
A
- pregnancy, with estrogen administration and in hyperthyroidism
- Liver disease (cirrhosis)
16
Q
What protein binds corticosteroids loosely which makes them basically free even when bound
A
albumin
17
Q
When plasma cortisol exceeds _________, the binding capacity of transcortin is saturated, and concentration of free cortisol rises rapidly
A
20-30 ug/dL
18
Q
Describe the role of the liver in pharmacokinetics of cortisol
A
- 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
19
Q
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?
A
-it is converted to cortisone by 11 B-HSD2 in renal tubular epithelium, salivary glands, sweat glands, and colon which is inactive
20
Q
What happens when 11B-HSD2 is inhibited
A
excessive activation of MR by cortisol . . . leads to hypertension
21
Q
What are the 2 things in the powerpoint that inhibit 11B-HSD2
A
- Glycyrrhizin (licorice root extract)
- Carbenoxolone (approved in UK to treat esophageal ulcers)
22
Q
Describe what AME (apparent mineralocorticoid excess) is
A
- inactivating mutations in 11B-HSD2
- presents as a form of severe juvenile hypertension
- autosomal recessive
23
Q
What cells do mineralocorticoids target
A
-Principal cells of collecting tubule and collecting duct
24
Q
What is the effect of mineralocorticoids on gene expression in principal cells
A
- increase epithelial sodium channels on apical membrane (ENaC)
- increase Na/K pump (basolateral membrane)
25
What are the electrolyte consequences of mineralocorticoids
- Na and water retention
| - K loss
26
What non epithelial cells do mineralocorticoids target
- Heart
| - vasculature
27
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
28
Aldosterone excess (directly) causes what?
- cardiac fibrosis and hypertrophy
- Vascular remodeling and inflammation
-why we used aldosterone antagonists in hypertension and heart failure
29
Transactivation mechanism of Glucocorticoids
- GR-ligand complex bind to GRE in gene promoters to activate gene expression
- effects on carbohydrate, lipid, protein metabolism
30
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
31
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
32
What GR isoform is induced by TNF-alpha and may be responsible for glucocorticoid resistance?
beta
33
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
34
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
35
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
36
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
37
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
38
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
39
What are the consequences of the effects that glucocorticoids have on immune system
- decreased inflammation and its manifestations
- immune suppression
- decreased allergic/hypersensitivity reactions
40
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)
41
What are the clinical applications of corticosteroid use for immunosuppression?
- following organ or hematopoietic stem cell transplantation
- Autoimmune disease (MS)
- Hematological cancers (leukemia)
42
use corticosteroids for what inflammatory and allergic conditions
- RA
- IBD
- Asthma and COPD
- Allergic rhinitis
- Skin diseases: inflammatory dermatoses (psoriasis)
- hypersensitivity reactions
43
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)
44
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
45
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)
46
What is a prodrug activated by esterases present in bronchial epithelial cells; systemically absorbed active drug is tightly bound to serum proteins
-Ciclesonide (Alvesco)
47
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
48
MOA of Aminoglutethimide
- Blocks conversion of cholesterol to pregnenolone
| - reduces production of all steroid hormones
49
Indications for Aminoglutethimide
- Was used for breast cancer treatment
| - ADRENOCORTICAL cancer
50
Side effects of Aminoglutethimide
- Drowsiness
| - GI upset
51
MOA of Ketoconazole
- P450 inhibition
| - Reduces synthesis of adrenal sex hormones
52
Indications for Ketoconazole
- Antifungal druge
- Cushing's syndrome
- Suppresses androgenic hair loss
- Prostate cancer
53
Side effects of Ketoconazole
- Hepatotoxicity
| - Gynecomastia in males
54
MOA of Metyrapone
- Inhibition of steroid 11-Hyroxylation
| - Relatively selectively suppresses formation of cortisol and corticosterone
55
Indications for Metyrapone
-Cushing's syndrome (only drug for this indiciation used in PREGNANCY)
56
Side effects of Metyraone
- Accumulationg of 11-Deoxycortisol
- increased aldosterone--> Na and water retention
- increased androgen -> hirsutism in women
- GI upset
- Dizziness
57
MOA of Mitotane
- Na and Ca ionofore
- protein kinase C and adenylyl cyclase inhibitor
- non selective cytotoxic action on adrenal cortex
58
indications for Mitotane
Adrenal Carcinoma
59
Side effects of Mitotane
- Depression, somnolence
- GI upset
- Rashes
60
MOA of mifepristone
- Glucocorticoid receptor antagonist
- Stabilizes hsp90-GR complex in cytosol so prevents nuclear translocation of GR
- Progesterone receptor antagonist
61
inidications for Mifepristone
- hypercortisolism in adult patients with endogenous Cushing's syndrome
- Anti-progesterone action: used for medical termination of intrauterine pregnancy
62
Side effects of mifepristone
- Dizziness
- GI upset
- Fatigue
63
MOA of Spironolactone
- Aldosterone receptor antagonist
| - Also an antagonist of androgen receptors
64
indications of Spironolactone
- Primary Hyperaldosteronism
- Hirsutism in women
- Diuretic - used in treatment of HF and HTN
65
Side effects of Spironolactone
- Hyperkalemia
- Gynecomastia and impotence in men
- menstrual abnormalities in women
66
MOA of Eplerenone
- A competitive antagonist of aldosterone at mineralocorticoid receptors
- Lower affinity for androgen receptors vs. Spironolactone
67
indications for Eplerenone
- HTN
| - HF (reduces cardiac remodeling and increases survival in HF patients in recent clinical trials
68
side effects of Eplerenone
-hyperkalemia
69
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
70
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
