Adrenal Glands and Corticosteroids as potential drug targets

Question 1

Where do the adrenal glands sit?

Answer 1

On top of the kidney

Question 2

What 3 parts are the adrenal glands separated into?

Answer 2

Capsule, cortex and medulla

Question 3

The cortex is further divided into 3 sections, what are they?

Answer 3

Zona Glomerulosa
Zona Fasciculata
Zona Reticularis
- they all produce different hormones

Question 4

What hormone does the Zona Glomerulosa produce?

Answer 4

Mineralcorticoids –> Aldosterone

Question 5

What hormone does the Zona fasciculata produce?

Answer 5

Glucocorticoid –> Cortisol

Question 6

What hormone does the Zona Reticularis produce?

Answer 6

“Adrenal androgens”, “Androstenediones”

* adrenal androgens go on to producing testosterone

Question 7

What makes up corticosteroids?

Answer 7

Glucocorticoids and mineralcorticoids

Question 8

What sort of cells does the medulla have?

Answer 8

electrically active cells

Question 9

In what way are steroids made?

Answer 9

On demand - not exocytosed across cell membrane

Question 10

What are steroids synthesised from?

Answer 10

Cholesterol (precursor)

Question 11

Where does steroidogenesis take place?

Answer 11

in the adrenal cortex

Question 12

What is the rate limiting step in steroidogenesis ?

Answer 12

cholesterol to pregnenolone

Question 13

What enzyme catalyses the step from cholesterol to pregenolone?

Answer 13

PS

Question 14

What regulates enzyme PS?

Answer 14

ACTH - stimulates induction of PS enzyme

Question 15

What sort of corticoid is cortisol?

Answer 15

primary corticoid

Question 16

What are the physiological actions of glucocorticoids? (3)

Answer 16

• metabolic effects (glucose like effect on the body)
• Anti-inflammatory
• Immunosuppressive

Question 17

What are the physiological actions of mineralocorticoids on the body?

Answer 17

water and electrolyte balance

Question 18

What are the physiological actions of adrenal androgens on the body?

Answer 18

maturation and development

Question 19

What is transcortin?

Answer 19

Corticosteroid binding globulin

Question 20

What does transcortin do?

Answer 20

Detects and binds 90% of cortisol and 60% of aldosterone when in circulation.
It does NOT bind synthetic steroids

Question 21

What does albumin do?

Answer 21

Binds synthetic and natural steroids

Question 22

What does stress lead the hypothalamus to do (and all following effects)

Answer 22

• 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

Question 23

What effects does cortisol have?

Answer 23

• lipolysis
• gluconeogenesis
• protein catabolism
• sensitising blood vessels
• reduce inflammation

Question 24

What is the mechanism of action for mineralcorticoids?

Answer 24

They cause Na+ uptake, leading to fluid resorption and K+ loss

Question 25

What does spironolactone act as in relation MCs?

Answer 25

Acts as a competitive inhibitor of MC receptors: diuretic and anti-hypertensive

Question 26

How does the release of aldosterone lead to the increase of blood pressure?

Answer 26

Aldosterone release partly triggered by angiotensin 2 – aldosterone promotes salt retention which increases blood pressure

Question 27

Name 2 short acting steroids

Answer 27

t1/2 8-12 hrs - hydrocortisone - fludrocortisone

Question 28

Name an intermediate steroid?

Answer 28

t1/2 12-36 hrs | - prednisolone

Question 29

Name 2 long acting steroids

Answer 29

t1/2 36-72 hrs - dexamethasone - betamethasone

Question 30

What steroid has mixed GC/MC activity, and what part of the molecule is responsible for this? (Glucocorticoid receptor/Mineralcorticoid receptor)

Answer 30

prednisolone | -ring A double bond, ketone group and single bond of aromatic ring

Question 31

What steroids have pure GC activity, nd what part of the molecule is responsible for this?

Answer 31

dexamethasone, betamethasone and beclomethasone | - OH bond

Question 32

What steroid has mainly MC activity, nd what part of the molecule is responsible for this?

Answer 32

fludrocortisone | - CH3OH group

Question 33

What is Addison's disease?

Answer 33

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 ```

Question 34

What is used for the treatment of Addison's?

Answer 34

Hydrocortisone (GC) with or without fludrocortsone (MC) | Has limited side effects as plasma levels mimic natural situation

Question 35

What is Congenital Adrenal Hyperplasia?

Answer 35

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

Question 36

What is used in the treatment of Congenital Adrenal Hyperplasia?

Answer 36

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

Question 37

How can steroids act as anti-inflammatory immunosuppressants?

Answer 37

They reduce mediators of inflammation and immune responses including prostaglandin, cytokines, Nitric Oxide, Immunoglobulin G etc

Question 38

In what conditions are steroids used as anti-inflammatory immunosuppressants?

Answer 38

``` Asthma Eczema Arthritis Psoriasis Allergic rashes Itching etc ```

Question 39

What steroids can be used as anti-inflammatory immunosuppressants?

Answer 39

hydrocortisone, prednisolone, beclomethasone, dexamethasone, budesonide

Question 40

What side effects and problems can arise from the use of steroids?

Answer 40

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.

Question 41

What are some symptoms of Cushing's Syndrome?

Answer 41

``` 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 ```

Question 42

What is Aminoglutethimide used for?

Answer 42

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

Question 43

What is Metyrapone used for?

Answer 43

SELECTIVE INHIBITION, in the treatment of hyperfunction. Inhibits 11 b-hydroxylase and reduces GC, MC synthesis. Used in Cushing's syndrome and Hyperaldosteronism.

Question 44

What is a side effect of Metyrapone?

Answer 44

hirsutism in women because of excess androgens

Question 45

What is used to test for pituitary function?

Answer 45

Metyrapone. | It will decrease GC, decrease negative feedback drive and increase ACTH (Adrenocorticotropic hormone)

Question 46

What is used to test for adrenal insufficiency?

Answer 46

Tetracosatide/synacthen. ACTH mimetic: - Synthetic peptide & ACTH analogue - Stimulates synthesis and release of adrenal hormones - Used to diagnose adrenal cortical insufficiency