Konorev: Adrenal Corticosteroids Flashcards
Mineralocorticoids
- induced by Ang II and K+
- regulate electrolyte, water balance and BP
- apprently come from aldosterone… (from CYP11B2)
Glucocorticoids
- induced by ACTH
- regulate metabolism and immunity
- come from cortisol (CYP11B1 and 17)
Weak androgens
- converted into potent adrogens in males
- converted into estrogens in females
- come from DHEA (CYP17)
What is the protein carrier for the steroid hormones?
- Transcortin… or corticosteroid binding globulin (CBG)
- high during preggo, with Est administration, and in hyperthyroidism
- low in liver disease (cirrhosis)
After 90% of steroids are bound to transcortin, what is the rest bound to?
-albumin (low affinity, high capacity
What is the main carrier for synthetic corticosteroid (CS) drugs?
albumin
When is transcortin capacity saturated?
when plasma cortisol exceeds 20-30 ug/dL
-concentration of free cortisol rises rapidly
What is the role of liver in pharmacokinetics of cortisol?
- produces transcortin
- 80% of cortisol is metabolized by liver
- 1/2 life of cortisol is normally about 60-90 min and is often increased in patients with liver diseases
In general, what does the steroid hormone do to the nuclear receptor?
-makes hsp90 go away so it can bind to and activate DNA
What 2 things bind an MR with equal affinity?
-aldosterone and cortisol
how much cortisol and aldosterone is made each day?
- cortisol= 10 mg/day
- aldosterone= 0.125 mg/day
What enzyme changes Cortisol to cortisone?
11 B-HDS2 11B-dehydrogenase
- changes an HO to just O (ketone… “one”
- cortisone is inactive
What enzyme changes cortisone to cortisol?
11 B-HSD1 11-ketoreductase
-turns the ketone back into an alcohol (“ol”)
What happens at the MR (mineralocorticoid receptor) with cortisol
- 11B-HSD 2 converts it into cortisone
- cortisone can’t bind the MR
- so, now it renders that tissue responsive to mineralocorticoids (aldosterone!)
What tissues does that thing with cortisole happen at?
- renal tubular epithelium
- salivary glands
- sweat glands
- colon eptithelium
So, what will inhibition of 11B-HSD type 2 result in?
- excessive activation of the MR mediated by cortisol
- increased activation of MR by cortisol to cause hypertension
What two things will inhibit 11B-HSD 2?
- Glycyrrhizin (licorice root)
- Carbenoxolone (approved in UK to treat esophageal ulcers)
What is it called when there are inactivating mutations in 11B-HSD2?
- AME
- apparent mineralocorticoid excess
- presents as a form of severe juvenile htn that is usually transmitted as an auto recessive trait
What is the mineralocorticoid we have to know?
Fludrocortisone
What are the short to medium-acting glucocorticoids?
- hydrocortisone (cortisol)
- cortisone
- prednisone
- prednisolone
- methprednisolone
Intermediate -acting glucocorticoid
-triamcinolone
Long acting glucocorticoid
- betametasone
- dexametasone
What is released from the kidney in response to decreased blood volume?
-renin
What does renin do?
-turns angiotensinogen into Ang I
Where does Ang I go?
to the lungs
-ACE turns it into Ang II
What are the effects of Ang II?
- vasoconstriction of arterioles
- adrenal cortex
What does the adrenal cortex secrete then?
aldosterone
What does aldosterone do?
-in kidneys, increases Na+ and water reabsorption and increased secretion of K+ and H+ into urine
What specific cells are targeted by aldosterone?
-principal cells of collecting tubule and collecting duct
aldosterone’s effect on gene expression in principal cells?
- high epithelial sodium channel (apical membrane)- ENaC
- high Na+/K+ pump (basolateral membrane)
What are the overall consequences of aldosteron then?
- Na+ retention
- Water retention
- K+ loss
What non-epithelial tissues do mineralocorticoids target?
- heart
- vasculature
What are aldosterone’s effects on gene expression in non-epithelial tissues?
- NADPH reductase…. oxidative stress
- Collagen, TGF B…. fibrosis, cell senescence
- IL-6, cell adhesion molecules…. inflammation
- PAI-1…. inhibition of fibrinolysis, blood clotting
What does aldosterone excess directly cause?
- cardiac fibrosis and hypertophy
- vascular remodeling and inflammation
When should we use aldosterone antagonists?
in hypertension and heart failure
In the cell, what is the end result of glucocorticoids?
receptor dimer bound to a promoter region of one of the responsive Genes
-remember that it dimerizes before entering the nucleus
What is the transactivation mechanism?
- GR-ligand complex binds to GRE in gene promoters to activate gene expression
- effects on carb, lipid, and ptn metabolism
What is transrepression?
- GR-ligand complex binds to other transcription factor complexes to suppress their activation of gene transcription
- NFKB, AP-1 tf’s
- antiinflammatory, immunosuppressive, anti-growth effects
What % of genes in a human genome are regulated by glucocorticoids?
10-20%
What are glucocorticoid receptor isoforms?
- encoded by same gene
- products of alt splicing
- GRa is prototypical (functional) isoform
- GRb lacks 35 aa at C-terminal… does not bind ligands and is inactive
Glucocorticoids effects on carbohydrate metabolism
- increased PEP carboxykinase… increased gluconeogenesis
- increased G6Pase…increased glc output into circulation
- increased glycogen synthase… incrased glycogen synthesis
- decreased expression of GLUT4… decrased glc uptake by muscle and adipose tissues
- development of hyperglycemia
Glucocorticoids effects on lipid metabolism
- promote stimulation of HSL in adipose tissue… increased lipolysis
- increase mobilization of FFA and glycerol into gluconeogenic pathway
- increase insulin secretion… increased lipogenesis
- Net incrase in fat deposition
- change in fat distribution (shoulders, neck, rounded face): bc that’s where the adipocyte sensitivity to glucocorticoids is the greatest
Glucocorticoids effect on protein metabolism
- decreased aa uptake into cells
- decreased ptn synthesis, negative nitrogen balance
- mobilization of aa’s into the gluconeogenic pathway
- suppressed ptn synth will lead to development of myopathy and muscle wasting
What does the effect of glucocorticoids on intermediary metabolism do to the actions of insulin?
antagonizes them
- changes in gene expression that favor lipid and ptn breakdown to supply substrates for gluconeogensis
- direct interference with the insulin receptor signal transduction
Effects of glucocorticoids on immune system and inflammation.
suppresses everything
Common clinical applications of adrenal corticosteroids
- Endocrine conditions: replacement therapy
- acute and chronic adrenal insufficiency: a combo of glucocorticoid and mineralocorticoid is used
- congenital adrenal hyperplasia
- Non-endocrine conditions:
- immunosuppression
- inflammatory and allergic conditions
adverse effects of mineralocorticoids
- retention of sodium and water, edema
- htn
- increased preload and cardiac enlargement… development of congestive heart failure
- K+ loss and alkalosis (muscular spasms and tetany)
- wherever Na+ goes, K+ will usually go the opposite
adverse effects of Glucocorticoids
- suppressed ability to fight infections, development of opportunistic infections
- hyperglycemia
- skin: striae, easy bruising
- muscle wasting, steroid myopathy
- Hypertension
- steroid-induced glaucoma
- Cataracts
- peptic ulcers
- psych disorders
- osteoporosis
- retarded growth in children
Dosing of corticosteroids
- use lowest dose for the shortest duration possible depending on the condition
- use intermediate or short-acting vs. long-acting drugs
- reduce distribution of drugs into systemic circulation
How would we go about reducing distribution of drugs into systemic circulation?
- use topical, inhalational routes, etc…
- Ciclesonide, a prodrug activated by esterases present in bronchial epithelial cells; systemically absorbed active drug tightly bound to serum proteins
How else should we dose Corticosteroids?
- give single daily doses in the morning
- alternate day, short-course, pulse therapy administration
- dose tapering (to allow the recovery of hypothalamic-pituitary-adrenal system
- rate of taper depends on severity of illness, duration of steroid therapy and maintenance dosage
Which patient populations have problems with glucocorticoids?
- IC patients
- diabetics
- infections
- peptic ulcer
- CV conditions
- psych conditions
- osteoporosis
- children
