Corticosteroids

Question 1

Four main classes of steroids?

Answer 1

1. sex hormones
2. bile acids
3. vitamins
4. adrenocorticoids

Question 2

Where are adrenocorticoids formed?

Answer 2

in the adrenal cortex

Question 3

what do mineralocorticoid affect?

Answer 3

sodium and water retention

Question 4

What do glucocorticoids affect?

Answer 4

• glucose homeostasis

- and have anti-inflammatory activity

Question 5

how many rings in a steroid structure?

Answer 5

4 (A,B,C,D)

Question 6

what conformation are rings A,B and C of the glucocorticoid structure?

Answer 6

a chair conformation

Question 7

what are the ring junctions in a glucocorticoid structure?

Answer 7

trans (meaning hydrogens at ring junction are on opposite sides)

Question 8

how do glucocorticoids bind to receptors?

Answer 8

via the beta face

Question 9

what is the structure of the glucocorticoid?

Answer 9

1. at least one double bond in A-ring
2. has an OH at C-11, C-17 and C-21
3. has a ketone group at C-3 and C-20

Question 10

what is the starting material for steroid hormone synthesis?

Answer 10

cholesterol

Question 11

What two major classes of adrenocorticoids are released from the adrenal cortex into the circulatory system?

Answer 11

1. hydrocortisone

2. aldosterone

Question 12

Explain the feedback mechanism for the maintenance of adrenocorticoid levels?

Answer 12

1. adrenocorticoid levels low.
2. hypothalamus secretes corticotrophin-releasing factor (CRF) to the pituitary.
3. Adrenocorticotrophic hormone (ACTH) released from anterior pituitary
4. this stimulates adrenal cortex to release adrenocorticoids
5. adrenocorticoid levels become high
6. CRF secretion from hypothalamus is inhibited

Question 13

What are the pharmacological activities of glucocorticoids?

Answer 13

1. anti-inflammation
2. inhibit cytokines
3. inhibit mast cell release of autocoids

Question 14

where do steroids and drugs that mimic glucocorticoids act?

Answer 14

on gene’s

Question 15

Explain the gene activity of glucocorticoids?

Answer 15

1. steroid hormones enter cell by diffusion, as it’s lipophilic
2. they then combine with intracellular receptors (receptors are inactive and located in the cytoplasm)
3. this causes a conformational change exposing a DNA binding domain
4. receptor-steroid complex move to the nucleus and bind to steroid response elements in DNA
5. specific gene transcription is either switched on or off to alter mRNA levels and the rate of synthesis of mediator proteins

Question 16

How do glucocorticoids work as anti-inflammatory drugs?

Answer 16

• affect protein synthesis hence increasing lipocortin
• lipocortin inhibits phospholipase A2 hence cell membrane phospholipids can’t be converted to arachidonic acid, then no prostaglandin and thromboxane formation.
• they cause the infiltration of eosinophils and activate CysLT receptors and bronchoconstriction.

Question 17

how do glucocorticoids inhibit cytokines?

Answer 17

• they inhibit interleukin-1 (IL-1).
• this inhibits proliferation of T and B lymphocytes, which are responsible for cytokines and antibodies production.
• hence resulting in immunosuppression.

Question 18

how do glucocorticoids inhibit mast cell release of autocoids?

Answer 18

• by inhibiting release of histamine and autocoids from mast cells
• autocoids have both vasoconstriction and vasodilating properties.

Question 19

What do glucocorticoid receptors consist of?

Answer 19

11 alpha-helices and 7 beta-strands with a unique binding site compared to other steroidal receptors.

Question 20

Why do glucocorticoid receptors have a strong binding affinity?

Answer 20

Because of hydrophobic and hydrophilic interactions

Question 21

Wha do the atoms of glucocorticoids interact with and by what type of bond?

Answer 21

• amino acids

- by Hbonds

Question 22

What type of bonds do receptors make with glucocorticoids?

Answer 22

• important ones are H-bonds

- these are at every hydrophilic groups on the glucocorticoid structure

Question 23

What 4 functional groups are essential for both mineralocorticoid and glucocorticoid activity?

Answer 23

1. pregnane skeleton
2. A-ring enone
3. 17beta-ketol side chain
4. C-21 hydroxy

Question 24

What structure increases anti-inflammatory and mineralocorticoid activity?

Answer 24

open circle

Question 25

What structure increases anti-inflammatory activity?

Answer 25

triangle and square

Question 26

what structure decreases mineralocorticoid activity?

Answer 26

closed circle and square

Question 27

where are drugs most commonly detoxified and metabolised?

Answer 27

liver and kidneys

Question 28

what happens during phase 1 of drug metabolism?

Answer 28

introduction of polar functional groups into molecules to be metabolised, providing a site for phase 2 metabolism.

Question 29

What happens during phase 2 of drug metabolism?

Answer 29

introduction of polar conjugates into the drug molecule, increasing its polarity, making it more readily excreted in urine.

Question 30

what type of philicity do drugs have from when absorbed to when excreted?

Answer 30

lipophilic when absorbed, hydrophilic when excreted.

Question 31

3 major metabolic reactions of glucocorticoids?

Answer 31

1. Ring A reduction 2. C-17 oxidation 3. C-11 keto-enol isomerisation

Question 32

what is used to esterify an hydroxyl group?

Answer 32

a carboxylic acid

Question 33

which carbon OH groups are easy to esterify?

Answer 33

C-21-OH and C-17-OH as they're the most accessible.

Question 34

which carbon OH groups aren't easily esterified and why?

Answer 34

C-11-OH as they're hindered by angular methyls so won't react with acids

Question 35

what effect does esterification have on the binding affinity and metabolism of steroids?

Answer 35

- C-21-OH of steroid must be free to form H-bonds with Arg-254. Esters are prodrugs, when metabolised become active form of drug (steroid) - esters prolong duration of C-17-OH oxidation (metabolism)

Question 36

how can you increase the LogP values of steroids?

Answer 36

by esterification with lipophilic acids

Question 37

what are the systemic glucocorticoids for asthma?

Answer 37

1. hydrocortisone 2. prednisolone 3. methylprednisolone

Question 38

what are inhaled glucocorticoids?

Answer 38

1. beclomethasone dipropionate 2. budesonide 3. ciclesonide 4. flunisolide 5. fluticasone propionate 6. mometasine fuorate 7. triamcinolone acetonide

Question 39

what is the effect of prodrugs on drug action?

Answer 39

increases duration of drug action`

Question 40

what is the effect of bulkier molecules on the hydrolysis of esters?

Answer 40

it slows down the process of hydrolysis