Adrenal Steroids Flashcards
How does the rate of secretion of steroids relate to the rate of synthesis
steroids are not stored. They are synthesized when they are needed. Therefore the rate of secretion is equal to the rate of synthesis
Describe the creation of aldosterone including where does it take place
- Aldosterone is created in the zona glomerulosa of the adrenal gland
- cholesterol → pregnenolone → desoxycorticosterone →aldosterone
Describe the production of cortisol including where it takes place
It takes place in the Zona fasciculata and reticularis
cholesterol → pregnenolone → desoxycortisol→ cortisol
What is the synthesis of cortisol controlled by
ACTH:Adrenocorticotropic hormone
What is the synthesis of Aldosterone controlled by
Angiotensin II and plasma K
Describe how adrenergic steroids are found
90% are bound to plasma proteins or albumin
How are adrenergic steroids inactivated and where
they are inactivated in the liver by
- Reduction of A ring
- sulfate conjugation
- Glucuronide conjugation
What adrenergic steroid structure would increase glucocorticoid activity and reduce mineralo- corticoid activity.
A 1,2-double bond and 16- substitution
What structures on an adrenergic steroid are necessary for function
Structures necessary for activity include 4,5-double bond, 3-ketone, 11-hydroxyl, 17-hydroxyl, 21-hydroxyl
Describe the mechanism of action of glucocorticoids
- glucocorticoid (that is probably bound to plasma protein or albumin) bind to a cytosolic steroid receptor
- translocated to the nucleus
- Stimulates transcription of mRNA
- stimulates mRNA directed protein synthesis
- proteins mediate glucocorticoid effect
describe the physiological effects of the glucocorticoids on Carbohydrate and protein metabolism
- Mediated by Glucocorticoid receptor
- Enhances liver gluconeogenesis from protein
- Stimulates amino acid mobilization (skeletal muscle, skin, etc.)
- Increases plasma glucose (bc GCs decrease uptake of glucose into tissues which increase plasma concentrations of glucose and liver concentration of glycogen)
- Increases liver glycogen
- Increases urinary nitrogen excretion
- Reduces peripheral glucose utilization
describe the physiological effects of the glucocorticoids on Lipid metabolism
- redistribution of fat (moon face, buffalo hump)
- stimulates release of fatty acids from adipose tissue
describe the physiological effects of the glucocorticoids on Mineral and electrolyte metabolism
- mediated mineralocorticoid receptor in kidney
- Cortisol = Aldosterone»_space; Cortisone meaning that cortisol and aldosterone have equal affinity to the glucocorticoid receptor, but most cortisol is converted to cortisone via the enzyme 11B-hydroxysteroid dehydrogenase and cortisone does not bind to the mineralocorticoid receptor
- therefore aldosterone is primarily responsible for the mineralocorticoid receptor mediated effects
The Mineralocorticoid receptor induces it effects via transcriptional activation. What are these effects
- increased Na reabsorption
- increased K and H ion excretion
- Responsible for cardiovascular effects - hypertension
Effects of adrenal steroids on the CNS
-sleepiness, lability of mood
Effects of adrenal steroid on immune system
specifically discuss how they impact cell traffic or accumulation
General
-Mediated through NFkB pathway. Steroids decrease amount of inflammatory cells at the inflammatory site
-steroids reduce access of cells to target tissues
1. Lymphocytopenia and monocytopenia - redistribution of
cells out of vascular space
2. Prevent neutrophil adherence to endothelium
3. Inhibit action of chemotactic factors
What immune cells do steroids change function in
- Macrophages
- B Lymphocytes (although nothing specific in notes about how)
- T Lymphocytes
How do steroids influence macrophage function
a) Inhibits antigen processing
b) Inhibit binding to Fc receptors
c) Inhibit synthesis and release of IL-1
how do steroids influence T-lymphocyte function
a) Interfere with macrophage antigen processing
b) Interfere with actions of lymphokines - IL-2, macrophage migration inhibitory factor, macrophage aggregating factor, monocyte chemotactic factor and lymphotoxin
c) Absence of IL-1 prevents activation
d) Reduces IL-2 synthesis
Describe the relationship between IkBa and NFkB and Glucocorticoids
when NFkB is bound to IkBa it is inactive. When the immune system is stimulated it causes IkBa to dissociate from NFkB and that is how it allows NFkB to cause its downstream transcriptive effect.
BUT GCs bind to their receptor and then translocate to the nucleus and upregulates transcription of IFkB which binds to NFkB inhibiting the immune response
Describe how glucocorticoids have an anti-inflammatory effect
-Inhibits signs and symptoms of inflammation by inhibiting
immune system
-Inhibits arachidonic acid release so synthesis of prostaglandins and leukotrienes is reduced.
-Inhibits induction of cyclooxygenase-2 by cytokines. (remember COX2 is primarily associated w inflammation and it converts AA to prostaglandins
What are the 4 therapeutic principles of steroid therapy
-Therapeutic dose is variable and may change with therapy. (necessary dose may change as therapy progresses) Reevaluate frequently.
-therapy has lethal potential.
A single dose is usually without harmful effects. Prolonged
- Use is not etiological or curative in most cases. Palliative or symptomatic therapy.
- Abrupt discontinuation may be life-threatening due to adrenal -insufficiency. (bc it takes the anterior pituitary gland to begin making ACTH again, and it takes even longer for the adrenal gland to recognize that ACTH fully and begin producing cortisol again after taking cortisol for a while)
What is the major use of glucocorticoid therapy
replacement therapy for adrenal insufficiency
Uses of Adrenocortical Steroids
a. Adrenal insufficiency - steroid replacement therapy
b. Rheumatoid arthritis - use only in progressive disease in combination with salicylates, gold salts, and physical therapy.
c. Osteoarthritis - given into joint for acute inflammation.
d. Allergic diseases - hay fever, serum sickness, drug reaction, anaphylaxis, bronchial asthma.
e. Inflammatory diseases of eye, ear, skin, etc. Used locally. (bc you only want glucocorticoid activity not mineralocorticoid, so you use it locally to try to acheive this)
f. Cerebral edema.
g. Shock - questionable value.
h. Miscellaneous - organ transplantation, thrombocytopenia, liver diseases, collagen diseases, renal diseases, etc.
