therapeutic use of adrenal steroids

Question 1

what section of the adrenal cortex produces cortisol *

Answer 1

zona fasciculata

Question 2

what region of the adrenal cortex produces aldosterone *

Answer 2

zona glomerulosa

Question 3

what section of the adrenal cortex produces androgens and oestrogens *

Answer 3

zona reticularis

(but main source is the gonads)

Question 4

briefly summarise the control of production of cortisol *

Answer 4

it is under the control of ACTH - which is under a -ve feedback mechanism

cortisol also produced in respose to stress, especially in response to illness

Question 5

briefly summarise the control of aldosterone production *

Answer 5

NOT ACTH

angiotensinogen is produced in the liver, renin (enzyme) from the kidney acts on angiotensiongen to produce ANG1, ACE acts on ANG1 to make ANG2

ANG 2 acts on adrenal gland - stimulating production of aldosterone

Question 6

what are the stimuli for aldosterone production *

Answer 6

low renal perfusion pressure because of haemorrhage for eg - this stims ANG 2 production

ANG 2 causes vasoconstriction to raise the BP and stimulates aldosterone which casues Na and water retention - increaseing blood vol

hyperkalaemia and hyponatraemia also stimulate aldosterone production, becasue aldosterone corrects these

B1 adrenoceptor stimulation

Question 7

describe the principle biological action of cortisol *

Answer 7

essential for life

if you have illness, need cortisol otherwise become very unwell

Question 8

describ the principle biological action of aldosterone *

Answer 8

promotes Na retention and K excretion

Question 9

what are the 2 receptors for corticosteroids *

Answer 9

glucocorticoid receptors (GR) and mineralocorticoid receptors (MR)

Question 10

summarise glucocorticoid receptors *

Answer 10

wide distribution

selective for glucocorticoids (ie cortisol)

low affinity for cortisol

Question 11

describe muscarinic receptors *

Answer 11

discrete distribution (just in kidney)

do not distinguish between aldosterone and cortisol - not selective

high affinity for cortisol

Question 12

how are the MR protected from cortisol *

Answer 12

in the kidneys and sweat glands 11B-hydroxysteroid dehydrogenase 2 converts cortisol into cortisone (inactive), which cant bind to MR

if cortisol binds to MR - acts like aldosterone

Question 13

why is hypokalaemia a symptom of cushings *

Answer 13

when there is a high level of cortisol, there is not enough 11BHSD to convert it all to cortisone

so some cortisol acts on MR and has mineralocorticoid effects = K excretion = hypokalaemia

Question 14

describe hydrocortisone including receptor sensitivity *

Answer 14

glucocorticoid with mineralocorticoid activity at high doses - like cortisol it can overwhelm 11BHSD

Question 15

describe prednisolone including receptor sensitivity *

Answer 15

glucocorticoid with weak mineralocorticoid activity

immunosuppressant - asthma, and rheumatoid arthritis

Question 16

describe dexamethasone and its receptor selectivity *

Answer 16

synthetic glucocorticoid with no mineralocorticoid activity

used to see if you can switch off cortisol production

Question 17

describe fludrocortisone and its receptor sensitivity *

Answer 17

aldosterone analogue (aldosterone receptor agonist) - bind to MR

used as an aldosterone substitute

aldosterone is not used because it is not effective when given by mouth

Question 18

what hormones do you need to replace for Addison’s, and what drugs would you use*

Answer 18

cortisol and aldosterone

hydrocortisone/prednisolone for cortisol

fludrocortisone for aldosterone

Question 19

structural differences between the corticosteroid drugs *

Answer 19

very small structual difference but they have different properties

Question 20

describe the routes of admin for the drugs to treat addisons *

Answer 20

If pt enters hospital verry unwell give drugs parentally, usually IV but can be IM - gets large dose into systemic circulation quickly. also give IV saline (0.9% NaCl) to make salts replete because been losing salt

when you discharge - give oral medication: hydrocortisone/prednisolone/dexamethasone for cortisol replacement, fludrocortisone for aldosterone replacement

Question 21

describe the distribution of corticosteroid drugs *

Answer 21

bind to plasma proteins (cortisol bionding globulin and albumin) like circulating cortisol does - because they are synthetic glucocorticoids

approx 90-95% of hydrocortisone is protein bound

the free steroid penentrates all compartments of the body

dexamethasone and fludrocortisone only bind weakly to albumin

Question 22

describe the duration of action of corrticosteroid drugs and what this means for the administration *

Answer 22

hydrocortisone - duration 8hrs - so need to give at different times through the day, more in the morning to mimic the diurnal cycle

prednisolone - duration 12 hrs - only give in the morning as it wears off through the day it mimics the biological levels

dexamethasone - 40hrs - useful for the suppression test

Question 23

describe corticosteroid replacement therapy for adrenocortical failure - Addison’s *

Answer 23

give IV 0.9% NaCl (saline)

treat with IV hydrocortisone (works accutely, high dose so works on MR and GR)

then treat with hydrocortisone/prednisolone and fludrocortisone orally

Question 24

describe how you would treat secondary adrenocortical failure - ACTH deficiency *

Answer 24

lack cortisol, aldosterone is normal (not under influence of ACTH)

treat with hydrocortisone/prednisolone

Question 25

describe how you would treat an acute Addisonian crisis *

Answer 25

iv 0.9% NaCl - rehydrate pt

high dose hydrocotisone- IV/IM every 6hours

5% dextrose if hypoglycaemic (because lack of cortisol)

dont need to give fludrocortisone because: it would take a few days for effects anyway, high dose of hydrocortisone has mineralocorticoid effects and normal saline restores sodium losses sufficiently

Question 26

what precurser do you measure to make diagnosis for 21- hydroxylase deficiency *

Answer 26

17a-hydroxyprrogesterone - it accumulates just before the enzyme block

Question 27

describe the treatment of congenital adrenal hyperplasia *

Answer 27

0.9% NaCl - restore Na levels and excrete K

objectives of the therapy:

• replace cortisol with dexamethasone (give big dose at night in attemot to suppress the morning rise in ACTH because it is a long lasting drug) or prednisolone/hydrocortisone
• suppress ACTH and so adrenal androgen production
• replace aldosterone in salt wasting forms - fludrocortisone

monitor therapy and work out dose by monitoring 17OH progesterone - if glucocorticoid replacement is too high = cushings, if too low = ACTH high = more androgens = hirsutism

may need reconstructive surgery becuase of high androgens

Question 28

what is the problem of people with Addison’s during stress *

Answer 28

cortisol levels normally rise by 10x during stress/illness but wouldnt if you take a constant dose

so when ill need to double dose of corticosteroids

if going into surgery need to have hydrocortisone IM before, during and after op until healthy and eating again at 6-8hr intervals

Question 29

how can you identify a person with adrenocortical failure *

Answer 29

they should have a steroid alert card/MedicAlert bracelet/necklace so that the paramedic would know to give cortisol if in an accident

Question 30

describe spirinolactone *

Answer 30

it is an MR antagonist

Question 31

describe ketoconazole *

Answer 31

it inhibits the cytochrome P450 enzymes

Question 32

what are the receptors for adrenal androgens

Answer 32

adrenal androgens are often metabolised to testosterone in the peripheral tissues and exert their action via androgen receptors

Question 33

metabolism of the corticosteroid drugs *

Answer 33

mainly in the liver

main step is reduction of the A ring

hydrocortisone and fludrocortisone have half life - 1.5 hrs

Question 34

what could the effect be of taking long term corticosteroid treatment for chronic inflammation *

Answer 34

it may cause adrenal insufficiency - so these patients would need to take exogenous corticosteroids for surgery

Question 35

what hormone replacement would be needed for someone having a trans-sphenoidal pit surgery *

Answer 35

surgery damage the acth cells so need to replace the hormones

give IV/IM hydrocortisone pre surgery and until eating/drinking again - higher than normal dose ie 20 10 10 rather than 10 5 5 because the body would normally produce more cortisol under stress

dont need fludrocortisone becasue aldosterone is not affected by acth

Question 36

what is the protocol of giving steroids to people after pit surgery when they go home *

Answer 36

a 9am cortisol of more than 350 in the morning of day 5 can go home without steroids

less than 300 give them steroids - wait for 6 weeks then give another dynamic test - insulin tolerance give them hypoglycaemic massive stress to pit - acth secrete so cortisol, should go over 500 best way to check pit acth. Want blood glucose to be 2.2 or lower - then measure the hormones. Can also measure growth hormone from this, should rise to 5 at least. If you have ischemic heart disease or epilepsy you shouldn’t do this, or if the morning cortisol is less than 100 - probably have a deficiency so don’t want to push it. Glucagon stress test - rise in GH and cortisol for someone who can’t have insulin one

Question 37

why wont a pt with cortisol replacement get symptoms of cushing’s *

Answer 37

because they are not takong excess - they are taking a physiological dose