corticosteroids Flashcards
what are corticosteroids used as a treatment for?
treatments for inflammatory and autoimmune diseases
what drug mimics cortisol?
synthetic prednisone
at what time of day are our cortisol levels highest?
morning
what does too high/too low levels of cortisol cause?
immune activity to go down
what processes does cortisol play a role in?
o Fluid loss – ADH o Infection – immune reaction o Tissue damage – inflammation o Metabolic disturbance – insulin o Neural disturbance – neurochemical
what are the main side effects of corticosteroids?
- Glycosuria
- Hypertension
- Glaucoma
- Osteoperosis
- Juvenile growth retardation
what are other side effects of corticosteroids?
oedema, weight gain, myopathy, hyperlipidaemia, thrombosis, GI bleeding, peptic ulcers, pancreatitis etc
what is cushings syndrome?
excess cortisol in the body
what are the main effects of cushings syndrome?
upper body obesity with thin arms and legs; red, round face; high blood sugar; high blood pressure; vertigo; blurry vision; acne; female balding; water retention etc
what does a lack of cortisol in the body cause?
Addisons disease
what 2 main cells are involved in osteoperosis?
osteoclasts
osteoblasts
what effect do corticosteroids have on osteoblasts and osteoclasts?
Corticosteroids decrease osteoblast function and increase osteoclast function
what causes avascular necrosis?
Due to loss of blood vessels going to that part of the bone
what organs and metabolic pathways do glucocorticoids have an effect on?
immune system cardiovasculatue carbohydrate metabolism kidney skeletal system CNS lipid metabolism
where is the human glucocorticoid receptor?
found in the cytoplasm and nucleus of most body cells
what are the two main forms of the glucocorticoid receptor?
o Alpha – binds steroid (777aa)
o Beta – doesn’t bind steroid (742aa)
what type of receptor is the glucocorticoid receptor?
dominant negative repressor
how and why does high levels of GCR affect the steroid action?
When there’s lots of the beta form of the receptor it blocks the potential sites of binding DNA so it’s harder for the steroids to have their effect
what form of the GCR is high in steroid resistant rheumatoid arthritis?
B form
what are the 2 activities of GCR activities?
genomic
non-genomic
what are the genomic actions of GCR?
o Transactivation of gene transcription by direct interaction with DNA
o Transrepression by interaction with other proteins in cytoplasm or nucleus
what are the non-genomic actions of GCR?
o Interaction of GC with cytoplasmic GR
o Interaction of GC with plasma membrane GR
o Interaction of GC with membranes
explain the mechanism of glucocorticoid action
- Steroid is lipophilic – can get through plasma membranes
- Binds with the glucocorticoid receptor
- Goes to the nucleus and bind DNA to have their effects
- Transactivational effects are what cause the side effects
explain the normal action of TNF-a
- TNF-a activates cells - pro-inflammatory molecule
- TNF binds to its receptor - activates transcription factors NFkB, STTA, CREB and AP1
- This complex moves to the nucleus - has pro-inflammatory effects here
explain the GR trans-repressive action
if you have corticosteroids, they bind to receptor/transcription factor complex
• Heat shock proteins dissociates
• Receptor dimerises and cross-couples with transcription factors like NFkB
• NFkB can’t have its proper effect on transcription of genes wipes out transcriptional effects of TNFa
what are the 3 main non-genomic effects of glucocorticoid?
membrane GR
cytosolic GR signalling
intercalation in membrane
why do we need membrane GR?
to sample medium around the cell and signal to the inside of the cell when steroid is coming
what is the effect of glucocorticoid being intercalated in membranes? how can this be used clinically?
Steroid can link in with the membrane cholesterol and make the membrane more sticky and less fluid so membrane receptors can’t interact – cell function drops off.
o Useful in traumatic brain injury to protect the brain
