Corticosteroids Flashcards
What is the endogenous control mechanism of corticosteroids?
HPA axis
Where are corticosteroids produced?
The adrenal cortex produces corticosteroids.
Mineralocorticoids- aldosterone (ZG)
Glucocorticoids- cortisol and corticosterone (ZF and ZR)
Synthesised from cholesterol.
What is the structure of glucocorticoids?
It is a four ring 21 carbon basic structure.
It must have a double bond at C4-5 and a ketone at C3 to be active.
What are the pharmacokinetics of Corticosteroids?
90% PPB to albumin and corticotrophin binding globulin.
CBG high affinity but low capacity.
Metabolism occurs in liver and it is excreted in the urine.
There are pro-drugs- cortisone and prednisone.
What are the mechanisms of action of corticosteroids?
1) cross the cell by diffusion
2) bind to the cytosolic receptor
3) steroid complex translocates to the nucleus
4) increases or decreases mRNA transcription
5) up/down regulation of genes
What are 2 examples of proteins induced by corticosteroids?
1) Angiotensin converting enzyme (drives RAAS)
2) B2-adrenoreceptor (bronchodilation- B2 agonist) It enhances action and is an anti-inflammatory
Also induce mineralocorticoids
What are 3 proteins that are inhibited by cortiosteroids?
Cytokines
Cyclo-oxygenase
Collagenase
What are the four actions that glucocorticoids have?
1) metabolic effects
2) systemic effects
3) anti-inflammatory effects
4) immune suppressive effects
What effects do glucocorticoids have on metabolism?
Mainly on carbohydrate and proteins.
1) inc. gluconeogenesis
2) inhibit utilisation of glucose= hyperglycaemia
3) protein breakdown and reduced synthesis
4) negative calcium balance
5) redistribution of fat.
What are the systemic effects of glucocorticoids?
1) elevation of liver enzymes
2) induction of parturition
3) alteration of CNS function (behaviour)
4) mineralocorticoid activity
When do glucocorticoids have an inflammatory effect and what is there effect?
Only at pharmacological concentrations.
Act on early and late inflammation stages, affect all inflammatory reactions, decrease vasodilation and fluid exudation.
What is the inflammatory effect on cells?
decrease T helper cells, decrease leukocytes, decrease macrophages, increase fibroblasts, decrease osteoblasts and increase osteoclasts. (not all are good!)
What is there effect on inflammatory mediators?
Inhibit COX, inhibit PLA2 by inducing lipocortin (higher up in pathway), decrease inflammatory cytokines and decrease histamine release.
What effects do glucocorticoids have on the immune system?
At low doses: cellular response inhibited e.g. lymphocytes, eosinophils, monocytes and basophils. Increase in neutrophils.
At high doses the humoral response is inhibited.
What are three examples of short acting glucocorticoids?
Prednisolone, prednisone and methylprednisolone (pro-drug).
<24hrs
What are examples of long acting glucocorticoids?
Dexamethasone, Betamethasone, Triamcinolone >24hrs
What formulations are glucocorticoids available in?
Water soluble salts- IV e.g. Dexamethasone
Insoluble esters- acetate for s/c, i/m or orally.
How can glucocorticoids be used topically?
On the eyes, ears and skin. Opthalmic preparations can cause adrenal suppression as they are highly lipid soluble and get into the systemic circulation.
What are the 5 clinical uses of glucocorticoids?
Inflammatory disease- acute and chronic (osteoarthritis).
Immune-mediated disease (high to low dose)
Shock (prevent degranulation)
Cerebral oedema
Neoplasia (2ndary problems e.g. hypercalcaemia)
What are Methylprednisolone acetate and Triamcinolone used for?
Intra-articular steroids.
1) maintained for 39d 2)no alteration on bone remodelling but undetectable after 2 weeks.
What is Addison’s Disease and what are the presenting signs?
Deficiency of adrenocortical steroid production, both glucocorticoid and mineralocorticoid deficiency. Present collapsed, bradycardic (would expect tachycardia-WARNING!), hyperkalaemic, hyponatraemic and dehydrated. (aldosterone deficiency).
What are the two treatments for Addison’s disease?
Acutely with hydrocortisone and long term with fludrocortisone.
DOCP- US, more long term than fludrocortisone
