Drugs Corticosteroids Flashcards
what does cortisol regulate
carbohydrate metabolism and thus is a glucocorticoid
what does aldosterone regulate?
regulates fluid and electrolytes
mineralcorticoid
what regulates the zona glomerulosa
outermost zone
regulated by ANG II and extracellular K+
what regulates the zona fasciculata and zona reticularis?
ACTH (Corticotropin)
what type of receptor does ACTH interact with
GPCR –> Gs and enzyme adenylyl cylase –> cAMP
Cyclic AMP stimulates a cascade of reactions leading to activation of transcription factors that enhance the transcription of steroidogenic enzymes and the synthesis of corticosteroids. A key element in this response is the mobilization of cholesterol, the precursor for steroid synthesis.
what causes the release of ACTH
CRH
AVP in stress response
what fact must be critically assessed when the dose and duration of glucocorticoid therapy are being considered
therapeutic use of glucocorticoids at high doses and/or for prolonged periods leads to suppression of the HPA axis
what can override the normal negative feedback control mechanisms of the HPA axis
stressful stimuli
Examples of stress signals include injury, hemorrhage, severe infection, major surgery, hypoglycemia, cold, pain, and fear.
hyperkalemia, hypotension, decreased renal Na+ reabsorption, decreased cardiac function, and cardiovascular collapse, decreased work capacity, hypoglycemia, depression/psychosis.
primary adrenocortical insufficiency
what are two main causes of secondary adrenocortical insufficiency
pituitary hypothalamic insufficiency (low or absent CRH and/or ACTH) or iatrogenic due to prolonged glucocorticoid treatment
how do glucocorticoids affect the actions of epinephrine on lipolysis
Administration of a small dose of a glucocorticoid markedly potentiates the lipolytic action of epinephrine.
where are the corticosteroid receptors and what is the signalling pathway when a corticosteroid binds
Steroid hormone receptors are located in the cytoplasm of cells (they are soluble, mobile proteins; not membrane-associated). The receptors are associated in a complex with a number of other proteins (heat shock proteins; hsp); these proteins dissociate from the receptor upon binding of the steroid. The activated receptor moves to the nucleus of the cell where it binds to specific sequences of DNA termed glucocorticoid-responsive elements (GREs).
Receptor binding at the GRE site can either activate or inhibit transcription of specific genes.
Cortisol and aldosterone both bind to the mineralcorticoid receptor with equal affinity …. what factors contribute to mineralocorticoid specificity ?
Tissue specific localization of receptor
-MR receptor is only in kidney, colon, salivary glands, sweat glands, hippocampus
Enzymatic protection against glucocorticoid excess
-An enzyme is expressed in mineralocorticoid-responsive tissues (11β-hydroxysteroid dehydrogenase) that metabolizes cortisol to the inactive compound cortisone.
Differential binding of GR and MR to nuclear transcription factors (AP-1)
what are the affects of corticosteroids on glucose uptake/blood glucose levels, protein, lipolysis, gluconeogenesis
- decrease peripheral glucose uptake (“anti-insulin effect”).
- stimulate protein breakdown and lipolysis, which provides amino acids and glycerol for conversion to glucose.
- stimulate gluconeogenesis in liver (from AA and glycerol); glucose is deposited in liver as glycogen.
- net effect is to elevate blood glucose levels. Glucocorticoids can worsen control with diabetes and precipitate hyperglycemia in other patients.
- These peripheral effects are associated with a number of catabolic actions, including atrophy of lymphoid tissue, decreased muscle mass, negative nitrogen balance, and thinning of the skin.
what effect do corticosteroids have on lipid metabolism
- Corticosteroids cause a dramatic redistribution of body fat with increased fat in the back of the neck, “buffalo hump”, and face, “moon facies”, coupled with a loss of fat in the extremities.
- Have a “permissive effect”, i.e., facilitate lipid breakdown stimulated by growth hormone and catecholamines with a resultant increase in free fatty acids.
aldosterone excess
causes elevated Na+ expansion of extracellular fluid volume, hypokalemia, and alkalosis and chronic excess causes hypertension.
aldosterone deficiency findings
deficiency leads to Na+ wasting, contraction of extracellular fluid volume, hyponatremia, hyperkalemia, and acidosis; and if chronic, hypotension and vascular collapse.
what is the role of glucocorticoids on Ca
play a permissive role in the excretion of free water, interfere with Ca2+ uptake in the gut, increase Ca2+ excretion by the kidney, and decrease total body Ca2+ stores.
glucocorticoids effects on vascular wall
AND overall effect of corticosteroids on vascular reactivity
Corticosteroids enhance vascular reactivity to other vasoactive substances.
Glucocorticoids increase expression of adrenergic receptors in the vascular wall.
what happens to muscles with adrenocortical insufficiency
diminished work capacity is a prominent sign of adrenocortical insufficiency.
- Chronic glucocorticoid excess causes skeletal muscle wasting.
what are the effects of glucocorticoids on formed elements of blood
The administration of glucocorticoids leads to a decreased number of circulating lymphocytes, eosinophils, monocytes, and basophils. This effect is due to redistribution of cells away from the periphery and into lymphoid tissue rather than from increased destruction.
In contrast, glucocorticoids increase circulating PMN leukocytes, RBCs, and platelets.
what are the anti-inflammatory and immunosuppressive actions of Corticosteroids
- Corticosteroids profoundly alter the immune responses of lymphocytes and can prevent or suppress inflammation in response to any number of inciting stimuli (radiant, mechanical, chemical, infectious, and immunological).
- Glucocorticoids inhibit the production and release of many different cytokines that normally would stimulate the proliferation and function of B and T lymphocytes. Glucocorticoids suppress interferon, GM-CSF, interleukins, tumor necrosis factor, prostaglandins and leukotrienes.
how are the HPA axis and the immune system interlinked
The HPA axis and the immune system are capable of bidirectional interactions during the stress response. Several cytokines, e.g., IL-1, stimulate release of CRH and ACTH. This centrally mediated feedback by the immune system stimulates glucocorticoid release which inhibits the immune/inflammatory response and helps “protect” the organism from the potentially life-threatening consequences of a full-blown inflammatory reaction.
what occurs with lack of glucocorticoid feedback
leads to elevated ACTH, which stimulates hyperplasia of the adrenal cortex
what can occur with prolonged glucocorticoid treatment….
Secondary adrenocortical insufficiency
adrenal atrophy and low levels of circulating glucocorticoids
low or absent CRH and/or ACTH
why can most corticosteroids be given orally
In general, steroids are lipophilic; i.e., they can readily diffuse across cellular membranes, and thus, can be widely distributed into tissue compartments and intracellularly.
