Konorev: Adrenal Corticosteroids Flashcards
1
Q
Mineralocorticoids
A
- induced by Ang II and K+
- regulate electrolyte, water balance and BP
- apprently come from aldosterone… (from CYP11B2)
2
Q
Glucocorticoids
A
- induced by ACTH
- regulate metabolism and immunity
- come from cortisol (CYP11B1 and 17)
3
Q
Weak androgens
A
- converted into potent adrogens in males
- converted into estrogens in females
- come from DHEA (CYP17)
4
Q
What is the protein carrier for the steroid hormones?
A
- Transcortin… or corticosteroid binding globulin (CBG)
- high during preggo, with Est administration, and in hyperthyroidism
- low in liver disease (cirrhosis)
5
Q
After 90% of steroids are bound to transcortin, what is the rest bound to?
A
-albumin (low affinity, high capacity
6
Q
What is the main carrier for synthetic corticosteroid (CS) drugs?
A
albumin
7
Q
When is transcortin capacity saturated?
A
when plasma cortisol exceeds 20-30 ug/dL
-concentration of free cortisol rises rapidly
8
Q
What is the role of liver in pharmacokinetics of cortisol?
A
- 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
9
Q
In general, what does the steroid hormone do to the nuclear receptor?
A
-makes hsp90 go away so it can bind to and activate DNA
10
Q
What 2 things bind an MR with equal affinity?
A
-aldosterone and cortisol
11
Q
how much cortisol and aldosterone is made each day?
A
- cortisol= 10 mg/day
- aldosterone= 0.125 mg/day
12
Q
What enzyme changes Cortisol to cortisone?
A
11 B-HDS2 11B-dehydrogenase
- changes an HO to just O (ketone… “one”
- cortisone is inactive
13
Q
What enzyme changes cortisone to cortisol?
A
11 B-HSD1 11-ketoreductase
-turns the ketone back into an alcohol (“ol”)
14
Q
What happens at the MR (mineralocorticoid receptor) with cortisol
A
- 11B-HSD 2 converts it into cortisone
- cortisone can’t bind the MR
- so, now it renders that tissue responsive to mineralocorticoids (aldosterone!)
15
Q
What tissues does that thing with cortisole happen at?
A
- renal tubular epithelium
- salivary glands
- sweat glands
- colon eptithelium
16
Q
So, what will inhibition of 11B-HSD type 2 result in?
A
- excessive activation of the MR mediated by cortisol
- increased activation of MR by cortisol to cause hypertension
17
Q
What two things will inhibit 11B-HSD 2?
A
- Glycyrrhizin (licorice root)
- Carbenoxolone (approved in UK to treat esophageal ulcers)
18
Q
What is it called when there are inactivating mutations in 11B-HSD2?
A
- AME
- apparent mineralocorticoid excess
- presents as a form of severe juvenile htn that is usually transmitted as an auto recessive trait
19
Q
What is the mineralocorticoid we have to know?
A
Fludrocortisone
20
Q
What are the short to medium-acting glucocorticoids?
A
- hydrocortisone (cortisol)
- cortisone
- prednisone
- prednisolone
- methprednisolone
21
Q
Intermediate -acting glucocorticoid
A
-triamcinolone
22
Q
Long acting glucocorticoid
A
- betametasone
- dexametasone
23
Q
What is released from the kidney in response to decreased blood volume?
A
-renin
24
Q
What does renin do?
A
-turns angiotensinogen into Ang I
25
Where does Ang I go?
to the lungs
| -ACE turns it into Ang II
26
What are the effects of Ang II?
- vasoconstriction of arterioles
| - adrenal cortex
27
What does the adrenal cortex secrete then?
aldosterone
28
What does aldosterone do?
-in kidneys, increases Na+ and water reabsorption and increased secretion of K+ and H+ into urine
29
What specific cells are targeted by aldosterone?
-principal cells of collecting tubule and collecting duct
30
aldosterone's effect on gene expression in principal cells?
- high epithelial sodium channel (apical membrane)- ENaC
| - high Na+/K+ pump (basolateral membrane)
31
What are the overall consequences of aldosteron then?
- Na+ retention
- Water retention
- K+ loss
32
What non-epithelial tissues do mineralocorticoids target?
- heart
| - vasculature
33
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
34
What does aldosterone excess directly cause?
- cardiac fibrosis and hypertophy
| - vascular remodeling and inflammation
35
When should we use aldosterone antagonists?
in hypertension and heart failure
36
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
37
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
38
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
39
What % of genes in a human genome are regulated by glucocorticoids?
10-20%
40
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
41
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
42
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
43
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
44
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
45
Effects of glucocorticoids on immune system and inflammation.
suppresses everything
46
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
47
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
48
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
49
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
50
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
51
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
52
Which patient populations have problems with glucocorticoids?
- IC patients
- diabetics
- infections
- peptic ulcer
- CV conditions
- psych conditions
- osteoporosis
- children
