Corticosteroids Flashcards
Regulation of endogenous cortisol production
Hypothalamus produce corticotropin releasing hormones (CRH) stimulates anterior pituitary to produce adrenocorticotropin hormones (ACTH) stimulates adrenal cortex to produce glucocorticoids (cortisol) and mineralcorticoids (androgens)
physiological role of cortisol (hydrocortisone)
metabolic effects:
- increase gluconeogenesis, reduce glucose peripheral uptake = increase blood glucose level
- increase glycogen deposition
- increase lipolysis and lipogenesis (break down of lipids = increase net fat deposition)
- has some androgen effects (increase NA reabsorption and water retention and increase excretion of K+ and protons)
catabolic effects:
- protein break down in muscle, skin, bones and tissue
- ca lost and nitrogen lost
cortisol has a negative feedback mechanism to regulate its production by reducing ACTH release
nuclear receptor mechanism of action of corticosteroids
glucocorticoid receptors are nuclear receptors they have a ligand binding domain, a DNA binding domain that will be revealed when cortisol binds to the glucocorticoid receptor and a transcription activating domain.
corticosteroids binds to ligand binding domain at the GR alpha region (active) > form homodimer > translocate into nucleus of cells > binds to GRE glucocorticoids response element within promoter region and regulate gene expression/repression
genomic actions of corticosteroids
dimer transactivation and trans repression
monomer binding to a co-activator for transactivation, binding to a co-repressor for trans repression
monomer tethering to another transcription factor for transactivation and trans repression
anti inflammatory effects of corticosteroids
Transrepression:
pro inflammatory cytokines (IL-1beta, IL-6 and YNF-alpha) stimulates the adrenal cortex to produce more cortisol inflammatory enzymes: COX2, phospholipase A2, LOX
receptors (T-cell receptors)
Transactivation:
phospholipase A2 inhibitor
cytokines antagonist
anti-inflammatory biological outcomes by steroids
- decrease in immune cells via apoptosis of T cells, B cells, basophils, eosinophils
- increase macrophage production to phagocytoes bacteria to reduce inflammatory signs
- decrease lymphoid content of the lymph nodes
- circulating neutrophils increase due to its resistance against corticosteroids and extravasion
- decrease in delayed in Type 4 hypersensitivity reaction for organ transplant
commonly used corticosteroids
hydrocortisone
prednisones/prednisolones
methylprednisolones/triamcinolone
bexamethasone/dexamethasones
PK/PD properties of commonly used corticosteroids
hydrocortisone
duration of action- 8-12hrs
GC effects- 1
MC effects - 1
prednisones/prednisolones
duration of action- 12-36hrs
GC effects- 4/5
MC effects - 0.3
methylprednisolones/triamcinolone
duration of action- 12-36hrs
GC effects- 5
MC effects - 0
bexamethasone/dexmethasones
duration of action- 24-72hrs
GC effects- 25-40 /30
MC effects - 0
Adverse side effects of corticosteroids
endocrine/metabolic effects:
- hyperglycemia (due to increase in glucose level)
- moon face, buffalo hump and truncal obesity
- increased appetite and weight gained
- muscle wastage, skin thinning and bruising, delayed wound healing
- mineralcorticoid effects only applicable for hydrocortisones, predisones and predisolones
musculoskeletal: osteoporosis and myopathy
eye: gluacoma
GI tract: peptic ulcer
immune system: immunodeficiency
nervous system: depression, psychosis, euphoria,
corticosteroids cannot be withdrawn suddenly as it will lead to withdrawal symptoms such as headache, lethargic, reduce dose gradually
Dosage forms of corticosteroids
systemic taken orally but can be given as topical medication (ie: cream, lotion) to reduce the chance of adverse side effects on the GIT, can be given as a steroid inhaler or a nasal spray and ophthalmic medication
