Adrenal Glands and Corticosteroids as potential drug targets Flashcards
Where do the adrenal glands sit?
On top of the kidney
What 3 parts are the adrenal glands separated into?
Capsule, cortex and medulla
The cortex is further divided into 3 sections, what are they?
Zona Glomerulosa
Zona Fasciculata
Zona Reticularis
- they all produce different hormones
What hormone does the Zona Glomerulosa produce?
Mineralcorticoids –> Aldosterone
What hormone does the Zona fasciculata produce?
Glucocorticoid –> Cortisol
What hormone does the Zona Reticularis produce?
“Adrenal androgens”, “Androstenediones”
* adrenal androgens go on to producing testosterone
What makes up corticosteroids?
Glucocorticoids and mineralcorticoids
What sort of cells does the medulla have?
electrically active cells
In what way are steroids made?
On demand - not exocytosed across cell membrane
What are steroids synthesised from?
Cholesterol (precursor)
Where does steroidogenesis take place?
in the adrenal cortex
What is the rate limiting step in steroidogenesis ?
cholesterol to pregnenolone
What enzyme catalyses the step from cholesterol to pregenolone?
PS
What regulates enzyme PS?
ACTH - stimulates induction of PS enzyme
What sort of corticoid is cortisol?
primary corticoid
What are the physiological actions of glucocorticoids? (3)
- metabolic effects (glucose like effect on the body)
- Anti-inflammatory
- Immunosuppressive
What are the physiological actions of mineralocorticoids on the body?
water and electrolyte balance
What are the physiological actions of adrenal androgens on the body?
maturation and development
What is transcortin?
Corticosteroid binding globulin
What does transcortin do?
Detects and binds 90% of cortisol and 60% of aldosterone when in circulation.
It does NOT bind synthetic steroids
What does albumin do?
Binds synthetic and natural steroids
What does stress lead the hypothalamus to do (and all following effects)
- hypothalamus becomes activated and releases CRH
- this stimulates the release of ACTH from the pituitary gland
- this then works on the adrenal glands and stimulates the release of cortisol, promoting a number of effects
What effects does cortisol have?
- lipolysis
- gluconeogenesis
- protein catabolism
- sensitising blood vessels
- reduce inflammation
What is the mechanism of action for mineralcorticoids?
They cause Na+ uptake, leading to fluid resorption and K+ loss
What does spironolactone act as in relation MCs?
Acts as a competitive inhibitor of MC receptors: diuretic and anti-hypertensive
How does the release of aldosterone lead to the increase of blood pressure?
Aldosterone release partly triggered by angiotensin 2 – aldosterone promotes salt retention which increases blood pressure
Name 2 short acting steroids
t1/2 8-12 hrs
- hydrocortisone
- fludrocortisone
Name an intermediate steroid?
t1/2 12-36 hrs
- prednisolone
Name 2 long acting steroids
t1/2 36-72 hrs
- dexamethasone
- betamethasone
What steroid has mixed GC/MC activity, and what part of the molecule is responsible for this? (Glucocorticoid receptor/Mineralcorticoid receptor)
prednisolone
-ring A double bond, ketone group and single bond of aromatic ring
What steroids have pure GC activity, nd what part of the molecule is responsible for this?
dexamethasone, betamethasone and beclomethasone
- OH bond
What steroid has mainly MC activity, nd what part of the molecule is responsible for this?
fludrocortisone
- CH3OH group
What is Addison’s disease?
It’s a long-term endocrine disorder in which the adrenal glands do not produce enough steroid hormones. - HYPOFUNCTION
Appetite loss, unintentional weight loss Discolouration of the skin Dehydration Increased thirst and need to urinate frequently Salt, soy sauce or liquorice cravings Oligomenorrhoea (irregular or infrequent periods) No energy or motivation (fatigue) Sore/painful, weak muscles and joints
What is used for the treatment of Addison’s?
Hydrocortisone (GC) with or without fludrocortsone (MC)
Has limited side effects as plasma levels mimic natural situation
What is Congenital Adrenal Hyperplasia?
HYPERFUNCTION - overproduction of androgens and underproduction of other hormones such as cortisol, so there is no negative feedback which can switch off physiological signals to produce hormones - therefore androgen is overproduced.
ACTH output is also raised
What is used in the treatment of Congenital Adrenal Hyperplasia?
Exogenous cortisol is used as a treatment - replaces cortisol and restores negative feedback loop to reduce production of androgen.
Synthetic steroids are used to recover the missing feedback e.g. dexamethasone, betamethasone have few side effects as plasma levels mimic natural situation
How can steroids act as anti-inflammatory immunosuppressants?
They reduce mediators of inflammation and immune responses including prostaglandin, cytokines, Nitric Oxide, Immunoglobulin G etc
In what conditions are steroids used as anti-inflammatory immunosuppressants?
Asthma Eczema Arthritis Psoriasis Allergic rashes Itching etc
What steroids can be used as anti-inflammatory immunosuppressants?
hydrocortisone,prednisolone, beclomethasone, dexamethasone, budesonide
What side effects and problems can arise from the use of steroids?
Excessive Glucocorticoid use can lead to:
- drug-induced Cushing’s Syndrome
- 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.
What are some symptoms of Cushing’s Syndrome?
Increased abdominal fat Red round “moon” face Hypertension Hyperglycaemia Vertigo Blurry vision Acne Female balding Water retention Menstrual irregularities Thin skin & bruising Poor wound healing Muscle wasting Osteoporosis Purple striae Hirsutism Depression Cognitive difficulties Emotional instability Sleep disorders Fatigue
What is Aminoglutethimide used for?
Used in the treatment of hyperfunction. It inhibits several enzymes including pregnenolone synthase (inhibits cholesterol to pregnenolone step) 21-, 11β- and 18-hydroxylase; aromatase (oestrogen production from testosterone).
Reduces steroid output.
Used in Cushing’s syndrome, Postmenopausal breast cancer and Prostate cancer
INHIBITION OF STEROID SYNTHESIS
What is Metyrapone used for?
SELECTIVE INHIBITION, in the treatment of hyperfunction.
Inhibits 11 b-hydroxylase and reduces GC, MC synthesis.
Used in Cushing’s syndrome and Hyperaldosteronism.
What is a side effect of Metyrapone?
hirsutism in women because of excess androgens
What is used to test for pituitary function?
Metyrapone.
It will decrease GC, decrease negative feedback drive and increase ACTH (Adrenocorticotropic hormone)
What is used to test for adrenal insufficiency?
Tetracosatide/synacthen.
ACTH mimetic:
- Synthetic peptide & ACTH analogue
- Stimulates synthesis and release of adrenal hormones
- Used to diagnose adrenal cortical insufficiency
