Antiinflammatory Steroids Flashcards
Drug list
Aldosterone
Cortisol
Prednisolone
Dexamethasone
Fludrocortisone
Mineralocorticoid role?
water, electrolyte balance
Glucocorticoid role?
Primary effects on carbohydrate and protein metabolism ***Antiinflammatory effects
Corticosteroid comparisons
Everything is compared to cortisol.
Cortisol and Cortison have shortest DOA.
Betamethasone and Dexamethasone have longest DOA.
** Fludrocortisone is the mineralocorticoid of choice for replacement therapy.
Regulation of synthesis of CORTISOL
Stimuli (NT) >>
Hypothalamus to release CRH (via neurons)
>> Anterior pituitary to release ACTH (via blood)
>> Adrenal cortex: stimulates cholesterol and increased synthesis and release of CORTISOL
Cortisol >> negative feedback IMMUNE SYS (cytokines stimulate CRH and ACTH), negative feedback on CRH and ACTH)
Diurnal Variation
Cortisol
Hi in morning
Lo in evening
NOTE: very small relative aldosterone levels
Actions of Glucocorticoids
Maintains blood glucose
- increase liver synthesis
- increase protein breakdown (donate carbons)
Actions of Glucocorticoids
Lipid metabolism
- permissive effects to facilitate other hormones (epi, growth hormone)
- increase free fatty acids
Actions of Glucocorticoids
CV Adverse effects
- HTN with prolonged high levels (more than Na retention)
Skeletal Muscle Adverse effects
- muscle wasting, especially in the limbs (fast-twitch go first)
Actions of Glucocorticoids
CNS
- excess or insufficiency, mood alterations, insomnia, euphoria, restlessness, increased motor activity OR anxiety, depression, psychosis
What is the major use for Glucocorticoids?
Antiinflammatory action (occurs at higher doses)
STEROIDS DO NOT PREVENT OR SUPPRESS THE UNDERLYING DISEASE PROCESS THAT RESULTs IN INFLAMMATION but they can suppress the inflammation associated with multiple inciting events.
*but can be life saving!!
Glucocorticoid Anti-inflammatory MOA
Alter immune responses of lymphocytes
Alter cytokine release and synthesis- macrophages and monocytes
Decrease production of prostglandin/leukotriene products
Where are the nuclear receptors for glucocorticoids?
Class 1 NR = CYTOPLASM
Class 2 NR = NUCLEUS
What is the MOA for glucocorticoids?
The GC receptor resides in the cytosol and has Zn finger binding domains.
Induces expression of new proteins
- lipocortin
- IkB
Transpression: alters interactions with other proteins and transcription factors . . . INHIBITS PROTEIN expression.
Why does the mineralocorticoid receptor bind cortisol with high affinity?
There is an enzyme that inactivates cortisol to cortisone to prevent excessive stimulation of the MC receptor.
Note: aldosterone does NOT stimulate the GC receptor
How does licorice cause HTN?
Licorice inhibits 11-beta HSD2, which is the enzyme that prevents cortisol from stimulating MC receptors too much.
How does Cortisol regulate stress?
Cortisol-ACTS as a BRAKE ON THE IMMUNE SYSTEM
Helps to protect against life threatening consequences of a full blown inflammatory response in stress.
**recall the relase of inflammatory cytokines
What should you do when a patient on replacement cortisol is under stress?
give EXTRA cortisol
What are four ways to inhibit inflammatory events via the GC receptor?
Key: the antiinflammatory effects and the immunosuppressive effects of GCs are linked
How does cortisol inhibit the Arachidonic acid pathway?
- Induces synthesis of Annexin 1.
- Annexin inhibits phospholipase A2
Recall . . . PLA2 promotes synthesis of arachadonic acid which makes prostaglandins and leukotrienes.
Where do steroids work on the AA pathway?
high up
How to GCs affect the cyclooxygenase pathway?
Cox 2 is the isoenzyme that is induced under inflammatory conditions.
Glucocorticoids inhibit the synthesis of Cox-2 such that prostaglandin metabolite production is decreased.
What are the effects of GCs on components of the immune response?
EVERYTHING goes DOWN.
What does TNF alpha do?
**central **role in inducing inflammation.
Produced by: macrophages, lymphocytes, NK cells
*Increases *
- epithelial permeability
- proteinases
- chemokines
- IFN gamma
- NFkB
