72 - Iatrogenic Complications of Steroid Treatments Flashcards
Diurnal pattern of cortisol
Three peaks at breakfast, lunch and dinner (opposes the action of insulin).
Between 10pm and 2am is a trough of lowest concentration.
What causes the pigmentation of the skin in Addison’s disease?
Melanocortin release
How does cortisol deficiency present?
Cortisol deficiency presents with weakness, fatigue,
anorexia, nausea, vomiting, hypotension and hypoglycaemia.
Symptoms of primary adrenal hypofunction
In primary adrenal hypofunction, cortisol deficiency is
combined with mineralocorticoid deficiency to cause
hyperkalaemia and hyponatraemia, acidosis and
dehydration
Administration of cortisol replacement therapy
1
2
3
1) Divide dose to mimic the physiological time-course
2) Extra doses for infections and periods of stress
3) Add fludrocortisone if needed
Side effects of cortisone replacement therapy
None, if managed correctly
Some iatrogenic complications of glucocorticoid therapy 1 2 3 4 5 6
1) Cushingoid syndrome
2) Adrenal suppression
3) Immunosuppression (reactivation of latent
tuberculosis)
4) Peptic ulcers
5) Osteoporosis
6) Inhibition of linear growth in children
Two things suppressed by cortisol
Immune system and adrenal gland
Effect of excessive cortisol
1-5
1) Weight gain
2) Wasting of muscle, skin and bone
3) Hyperglycaemia (muscle amino acid for gluconeogenesis)
4) Hypertension (from salt retention)
5) Inhibition of linear growth
Why doesn’t cortisone stimulate aldosterone receptors?
Equal affinity for mineralocorticoid receptors as aldosterone.
Normally, kidney converts cortisol to cortisone (inactive), preventing stimulation of aldosterone receptors by cortisol.
Liver reconstructs cortisol from cortisone.
Cortisol half life
Short half life of cortisol (60-90 minutes).
Longer half life of reconstructed cortisol (reconstructed by liver)
Relative affinity of dexamethasone and cortisone for cortisol receptor
Dexamethasone has 75 times the affinity.
Aldosterone replacement hormone
Fludrocortisone.
Mineralocorticoid-selective exogenous steroid.
How can cortisol stimulate aldosterone receptors in kidney?
Equal affinity for mineralocorticoid receptors as aldosterone.
Normally, kidney converts cortisol to cortisone (inactive), preventing stimulation of aldosterone receptors by cortisol.
Liver reconstructs cortisol from cortisone.
If there is too much cortisol, it overwhelms the ability of the kidneys to convert cortisol, and stimulates aldosterone receptors.
Dissociated selectivity of steroids
Better at either doing:
Transactivation (activation of gene transcription via GREs)
or
Transrepression (reduction of gene transcription via inhibition of AP-1 and NFkB).
Gross morphological effect of long-term glucocorticoid therapy on adrenal glands
Atrophy (as not being stimulated by ACTH for a long time).
Strategies for minimising adrenal suppression with steroid therapy 1 a, b, c 2 3 4
1) Allow for ACTH secretion if possible
- Avoid long-lasting drugs
- Alternate day dosing
- Morning dosing
2) Minimise systemic absorption of steroids
3) Inhaled or topical (but note: still absorbed!)
4) Third generation glucocorticoid drugs
Example of a third-generation glucocotricoid
Ciclesonide
Ciclesonide
1-4
Third-generation glucocorticoid
Reduced systemic effects after inhalation because:
1) Pro-drug, activated in lungs (not in mouth or larynx)
2) Lipophilic: retained in tissue
3) Low oral bioavailability (hepatic first pass)
4) Highly protein bound in plasma
Relationship between glucocorticoids and peptic ulcers
1
2
3
1) Causal role is debatable
2) Mostly occur in patients who are also taking NSADS, which are implicated in stomach ulcers.
3) Could be a synergistic effect
Effect of higher doses of glucocorticoids on bones
Osteoclast precursor has RANK (a receptor for RANKL).
OPG is a soluble RANK, which mops up RANKL.
These oppose each other in osteoclast activation.
Glucocorticoids decrease OPG, increase RANKL, leading to more osteoclasts, leading to increased bone resorption.
Effect of inhaled glucocorticoids on bone density
Increases risk of fracture, but not hugely.
Effect of inhaled glucocorticoids on childhood growth
Untreated asthma reduces growth, so can increase hight in severe asthmatics, as reduces effect of illness.
Glucocorticoids can decrease growth, but not to the point that it would offset the effect of untreated asthma.
