Adrenal Glands & Corticosteroids as Potential Drug Targets Flashcards
What is cortisol?
Cortisol (glucocorticoids):
• Stress Response
• Raises Blood Sugar
• Protein/Fat Metabolism
What is aldosterone?
(mineralocorticoids):
• Increases serum [Na+]
• Raises blood pressure
What are androgen precursors?
• Maturation, Development
How many adrenal glands are there?
Two - sit on top of kidney
What are the three parts of the adrenal gland?
Capsule (keeps everything in). adrenal cortex (produces steroids), medulla (catecholamines)
Zona glomerulosa contains:
Mineralocorticoids (aldosterone)
Zona fasciculata contains
Glucocorticoid (cortisol)
Zona reticularis contains:
- Adrenal androgens
- Androstenediones
What is steroidogenesis?
Synthesis of steroids in adrenal cortex (they are not stored but synthesised on demand
• Synthesised from cholesterol (primary molecule, precursor)
What is the rate limiting step in steroidogenesis?
- 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)
Physiological Actions of Glucocorticoids (GCs)?
o Metabolic effects
o Anti-inflammatory
o Immunosuppressive
Physiological Actions of Mineralocorticoids (MCs)?
o Water & Electrolyte Balance
Physiological Actions of Adrenal Androgens
o Maturation & Development
Control of Glucocorticoid Release:
- 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.
Mechanism of Action – Mineralocorticoids:
- 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.
Mechanism of Action – (steroids) Overview
- 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
Chemical modification of steroids influences the pharmacokinetics: Give examples.
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)
Chemical modification of steroids influences the selectivity: Give examples
(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
What is adrenal gland insufficiency known as?
Addison’s Disease
- Can’t make own endogenous hormones
Addisons disease symptoms?
Appetite loss Discolouration of skin Dehydration Increased thirst Salt cravings Oligomenorrhoea No energy or motivation Sore/painful muscles/joints.
Treatment of Addison’s disease?
- Hydrocortisone (GC) with or without fludrocortisone (MC)
* Limited side-effects as plasma levels mimic natural situation
What is Congenital Adrenal Hyperplasia?
Hyperfunction.
- Fault in steroidogenesis pathway
- Over-production of androgens
- Limited / no cortisol negative feedback
- ACTH output is raised
How is Congenital Adrenal Hyperplasia controlled?
• Synthetic steroids are used to recover the missing feedback e.g. dexamethasone, betamethasone have few side effects as plasma levels mimic natural situation
How do steroids work as anti inflammatory immunosuppressants?
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
Side effects and problems of steroids?
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
What is aminoglutethimide and what is it used for?
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*
Selective inhibition for treatment of hyperfunction?
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
How to test for pituitary function?
Metyrapone (Metopirone) - GC will also - negative feedback drive and - ACTH Used to test anterior pituitary function
How to test for adrenal insufficiency?
ACTH mimetic;
Tetracosatide / Synacthen
- Synthetic peptide & ACTH analogue
- Stimulates synthesis and release of adrenal hormones
- Used to diagnose adrenal cortical insufficiency
