Adrenal Glands & Corticosteroids as Potential Drug Targets

Question 1

What is cortisol?

Answer 1

Cortisol (glucocorticoids):
• Stress Response
• Raises Blood Sugar
• Protein/Fat Metabolism

Question 2

What is aldosterone?

Answer 2

(mineralocorticoids):
• Increases serum [Na+]
• Raises blood pressure

Question 3

What are androgen precursors?

Answer 3

• Maturation, Development

Question 4

How many adrenal glands are there?

Answer 4

Two - sit on top of kidney

Question 5

What are the three parts of the adrenal gland?

Answer 5

Capsule (keeps everything in). adrenal cortex (produces steroids), medulla (catecholamines)

Question 6

Zona glomerulosa contains:

Answer 6

Mineralocorticoids (aldosterone)

Question 7

Zona fasciculata contains

Answer 7

Glucocorticoid (cortisol)

Question 8

Zona reticularis contains:

Answer 8

• Adrenal androgens

- Androstenediones

Question 9

What is steroidogenesis?

Answer 9

Synthesis of steroids in adrenal cortex (they are not stored but synthesised on demand

• Synthesised from cholesterol (primary molecule, precursor)

Question 10

What is the rate limiting step in steroidogenesis?

Answer 10

• Rate limiting step is cholesterol to pregnenolone. The enzyme for cholesterol to pregnenolone (PS) is regulated by adrenocorticotropic hormone (ACTH)
• Cyclo-pentanoperhydrophenanthrene nucleus (17C atoms)

Question 11

Physiological Actions of Glucocorticoids (GCs)?

Answer 11

o Metabolic effects
o Anti-inflammatory
o Immunosuppressive

Question 12

Physiological Actions of Mineralocorticoids (MCs)?

Answer 12

o Water & Electrolyte Balance

Question 13

Physiological Actions of Adrenal Androgens

Answer 13

o Maturation & Development

Question 14

Control of Glucocorticoid Release:

Answer 14

• Stress activates hypothalamus via sensory receptors
• Once activated hypothalamus releases CRH stimulating releasing ACTH from pituitary gland, activates adrenal gland which releases cortisol which reduces inflammations, sensitises blood vessels etc.
• Once cortisol reaches threshold, ACTH production stops via negative feedback loop.

Question 15

Mechanism of Action – Mineralocorticoids:

Answer 15

• MC receptors have a limited tissue distribution
• MCs cause Na + -uptake leading to fluid resorption, and K+ loss
• Spironolactone acts as competitive inhibitor of MC receptors: diuretic & antihypertensive
• Aldosterone release partly triggered by angiotensin 2 -aldosterone promotes salt retention which increases blood pressure.

Question 16

Mechanism of Action – (steroids) Overview

Answer 16

• Corticosteroid binding globulin (transcortin) binds 90% of cortisol and 60% of aldosterone.
• Transcortin (endogenous cortisol binding protein) does not bind synthetic steroids.
• Albumin binds synthetic and natural steroids
• Actions of steroids involve changes in gene transcription & translation
• Altering the synthesis of specific proteins

Question 17

Chemical modification of steroids influences the pharmacokinetics: Give examples.

Answer 17

1) Varying duration of actions/ half life:

o Short-acting, t1/2 8-12h (e.g. hydrocortisone, fludrocortisone)

o Intermediate, t1/2 12-36h (e.g. prednisolone)

o Long-acting, t1/2 36-72h (dexamethasone, betamethasone)

Question 18

Chemical modification of steroids influences the selectivity: Give examples

Answer 18

(2) Different split of activities/potencies
(GC = glucocorticoids, MC =mineralocorticoid)

o Mixed GC/MC activity – e.g. prednisolone, (prednisone)

o Pure GC – e.g.
dexamethasone, betamethasone, beclomethasone,

o Mainly MC – e.g. fludrocortisone

Question 19

What is adrenal gland insufficiency known as?

Answer 19

Addison’s Disease

- Can’t make own endogenous hormones

Question 20

Addisons disease symptoms?

Answer 20

Appetite loss
Discolouration of skin
Dehydration 
Increased thirst
Salt cravings
Oligomenorrhoea 
No energy or motivation 
Sore/painful muscles/joints.

Question 21

Treatment of Addison’s disease?

Answer 21

• Hydrocortisone (GC) with or without fludrocortisone (MC)

* Limited side-effects as plasma levels mimic natural situation

Question 22

What is Congenital Adrenal Hyperplasia?

Answer 22

Hyperfunction.

• Fault in steroidogenesis pathway
• Over-production of androgens
• Limited / no cortisol negative feedback
• ACTH output is raised

Question 23

How is Congenital Adrenal Hyperplasia controlled?

Answer 23

• Synthetic steroids are used to recover the missing feedback e.g. dexamethasone, betamethasone have few side effects as plasma levels mimic natural situation

Question 24

How do steroids work as anti inflammatory immunosuppressants?

Answer 24

o Reduce mediators of inflammation and immune responses inc. prostaglandin, cytokines, NO, IgG, etc
o Applications: asthma, eczema, arthritis, psoriasis, allergic rashes, itching …. .etc
o Agents: hydrocortisone, prednisolone, beclomethasone, dexamethasone, budesonide, etc

Question 25

Side effects and problems of steroids?

Answer 25

Inappropriate metabolic influences:

• Excessive glucocorticoid administration/use:
  (a) Drug-Induced Cushing’s syndrome
  (b) Osteoporosis
• Increased risk of infection - A common unwanted side of inhaled GCs.. ..reduced by using a spacer device - or by rinsing the mouth after inhaler use.
• Oral thrush

Question 26

What is aminoglutethimide and what is it used for?

Answer 26

Aminoglutethimide, Inhibition of Steroid Synthesis; - Treatment of Hyperfunction targeting steroidogenesis

o	Inhibits several enzymes inc. pregnenolone synthase; 21-, 11β- and 18-hydroxylase; aromatase (oestrogen production from testosterone) 
o	Reduces steroid output
o	Uses: 
o	Cushing's syndrome
o	Postmenopausal breast cancer*
o	Prostate cancer*

Question 27

Selective inhibition for treatment of hyperfunction?

Answer 27

Metyrapone (Metopirone)
o Inhibits 11 b-hydroxylase
o Reduces GC, MC synthesis

Uses:
o Cushing’s syndrome
o Hyperaldosteronism
o Side effect – hirsutism in women because of excess androgens

Question 28

How to test for pituitary function?

Answer 28

Metyrapone (Metopirone) 
   - GC will also    
   - negative feedback drive and
   -  ACTH 
Used to test anterior pituitary function

Question 29

How to test for adrenal insufficiency?

Answer 29

ACTH mimetic;
Tetracosatide / Synacthen

• Synthetic peptide & ACTH analogue
• Stimulates synthesis and release of adrenal hormones
• Used to diagnose adrenal cortical insufficiency