03 Adrenal Steroids Flashcards
Are steroids stored for later use?
No, they are synthesized when needed
Rate of secretion = rate of synthesis
Where is aldosterone synthesized?
Zone glomerulosa
Synthesized from cholesterol
Where is cortisol synthesized?
Zona fasciculata and reticularis
Synthesized from cholesterol
What controls the synthesis of cortisol?
Adrenocorticotropic Hormone (ACTH)
What controls the synthesis of aldosterone?
Angiotensin II and plasma K+
Are steroids free in plasma?
No, 90% bound in plasma to corticosteroid binding globulin (CBG) and Albumin
How are steroids inactivated?
Steroids are inactivated in the liver by making it more polar for urine excretion
- Reduction of A ring
- Sulfate conjugation
- Glucuronide conjugation
How does a corticosteroid produce an effect?
- Binds to cytosolic steroid receptor
- Translocated to nucleus
- Stimulates transcription of mRNA
- Stimulates mRNA directed protein synthesis
- Proteins mediate glucocorticoid effect
What mediates carbohydrate and protein metabolism?
Mediated by glucocorticoid receptor
Enhances liver gluconeogenesis from protein and stimulates AA mobilization from muscle, skin, etc.
- Increased plasma glucose and liver glycogen
- Increased urinary Nitrogen excretion
- Reduces peripheral glucose utilization
How is lipid metabolized?
There is a redistribution of body fat
Stimulates release of fatty acids from adipose tissue
How are minerals and electrolytes metabolized?
Mediated by mineralocorticoid receptor in kidney bound by cortisol and aldosterone
- Increased Na+ reabsorption
- Increased K+ and H+ excretion
- Hypertension
What is the effect of corticosteroids on the immune system’s ability to traffic cells?
Reduced access of cells to target tissue
- Lymphocytopenia and monocytopenia –redistribution of cells out of vascular space
- Prevent neutrophil adherence to endothelium
- Inhibit action of chemotactic factors
What is the effect of corticosteroids on macrophages and lymphocytes?
Macrophage:
- inhibit Ag processing
- inhibit binding to Fc receptor
- inhibit synthesis and release of IL-1
T-lymphocytes:
- interfere with macrophage Ag processing
- interfere with lymphokine action
- absence of IL-1 prevents activation
- reduces IL-2 synthesis
What is the anti-inflammatory activity of corticosteroids?
a. Inhibits signs and symptoms of inflammation by inhibiting immune system.
b. Inhibits arachidonic acid release so synthesis of prostaglandins and leukotrienes is reduced.
c. Inhibits induction of cyclooxygenase-2 by cytokines.
d. Decrease capillary permeability
In most cases is steroid use curative?
Use is not etiological or curative in most cases. Palliative or symptomatic therapy.
Why shouldn’t you abruptly discontinue corticosteroid therapy?
With prolonged use of steroids, the adrenal gland atrophies. If abruptly discontinue steroid therapy, will result in acute adrenal insufficiency of both mineralocorticoid and glucocorticoid steroids.
No mineralocorticoid activity = increased excretion of Na+ and H2O and decreased K+ excretion = hypertension and hyperkalemia.
What can be used for adrenal insufficiency?
Glucocorticoids for replacement therapy
Use Cortisol or Prednisone because both have glucocorticoid AND mineralocorticoid functions
If needed to treat an inflammation or autoimmune disease, what would you use?
Need glucocorticoid activity for the anti-inflammatory effects BUT want little to no mineralocorticoid activity because Na+ retention and K+ excretion would result in hypertension and hypokalemia.
What is a common problem due to steroid use?
Infection due to immune suppress
Contraindication during existing infection, esp. tuberculosis
Cortisol: glucocorticoid/mineralocorticoid/both?
Anti-inflam: 1
Na+ retention: 1
Both
Prednisolone: glucocorticoid/mineralocorticoid/both?
Anti-inflam: 3
Na+ retention: 0.8
Both
Dexamethasone: glucocorticoid/mineralocorticoid/both?
Anti-inflam: 20
Na+ retention: 0
Glucocorticoid
Fludrocortisone: glucocorticoid/mineralocorticoid/both?
Anti-inflam: 12
Na+ retention: 100
Both
Aldosterone: glucocorticoid/mineralocorticoid/both?
Anti-inflam: 0.2
Na+ retention: 250
Mineralocorticocid
What happens with prolonged steroid therapy?
Suppression of pituitary-adrenal function
1) Related to dose and duration of therapy (Large doses for period longer than 2 weeks).
2) May last for periods longer than 12 mo.
3) Reduce dosage slowly.
What are the characteristics of Cushing’s Syndrome?
1) Moon face and Buffalo hump.
2) Poor wound healing.
3) Thin skin.
4) Hypertension.
5) Thin extremities.
6) Striae.
Metyrapone
Steroid Synthesis Inhibitor
a. Blocks 11-beta hydroxylation so synthesis is stopped at 11- desoxycortisol.
b. 11-Desoxycortisol does not inhibit ACTH release so plasma ACTH levels increase.
c. ACTH stimulates synthesis and excretion of 17-hydroxycorticoids as 11-desoxycortisol.
d. Used as diagnostic test.
What drug blocks 11-beta hydroxylation?
Metyrapone
Steroid synthesis inhibitor
What drug allows the accumulation of ACTH to stimulate the synthesis and excretion of 11-desoxycortisol?
Metyrapone
Steroid synthesis inhibitor
Used as a diagnostic test
Mifeprisone
Adrenal Steroid Antagonist
Competitive antagonist at progesterone and glucocorticoid receptor
Progesterone– Termination of pregnancy
Glucocorticoid– Treat Cushing Disease
What drug is used as a competitive antagonist of the progesterone receptor resulting in pregnancy termination?
Mifeprisone
What drug treats Cushing’s Disease because it is a competitive antagonist of the glucocorticoid receptor?
Mifeprisone
Spironolactone and Eplerenone
Adrenal Steroid Antagonist
a. Competitive antagonists at mineralocorticoid receptor
b. Diuretics
c. Treat Hypertension
d. Cardiac hypertrophy and heart failure
What drugs are competitive antagonists at the mineralocorticoid receptor?
Spironolactone and Eplerenone
What drugs are competitive antagonists at the mineralocorticoid receptor and used as a diuretic?
Spironolactone and Eplerenone
Drospirenone–antagonizes the salt retaining effects of estrogen
What drugs are competitive antagonists at the mineralocorticoid receptor and used to treat hypertension?
Spironolactone and Eplerenone
What drugs are competitive antagonists at the mineralocorticoid receptor and used to treat cardiac hypertrophy and heart failure?
Spironolactone and Eplerenone
Drospirenone
Adrenal Steroid Agonist and Antagonist
a. Progesterone receptor agonist
1. Used with estrogen to suppress ovulation
2. Used with estrogen as hormone replacement therapy in post-menopausal women
b. Mineralocorticoid receptor antagonist
1. Diuretic
2. Antagonizes the salt retaining effects of estrogen
c. Androgen receptor antagonist
What drug is a progesterone receptor agonist and used with estrogen to suppress ovulation?
Drospirenone
Used with estrogen as hormone replacement therapy in post-menopausal women
What drug is an androgen receptor antagonist?
Drospirenone
