Corticosteroids Flashcards
Four main classes of steroids?
- sex hormones
- bile acids
- vitamins
- adrenocorticoids
Where are adrenocorticoids formed?
in the adrenal cortex
what do mineralocorticoid affect?
sodium and water retention
What do glucocorticoids affect?
- glucose homeostasis
- and have anti-inflammatory activity
how many rings in a steroid structure?
4 (A,B,C,D)
what conformation are rings A,B and C of the glucocorticoid structure?
a chair conformation
what are the ring junctions in a glucocorticoid structure?
trans (meaning hydrogens at ring junction are on opposite sides)
how do glucocorticoids bind to receptors?
via the beta face
what is the structure of the glucocorticoid?
- at least one double bond in A-ring
- has an OH at C-11, C-17 and C-21
- has a ketone group at C-3 and C-20
what is the starting material for steroid hormone synthesis?
cholesterol
What two major classes of adrenocorticoids are released from the adrenal cortex into the circulatory system?
- hydrocortisone
2. aldosterone
Explain the feedback mechanism for the maintenance of adrenocorticoid levels?
- adrenocorticoid levels low.
- hypothalamus secretes corticotrophin-releasing factor (CRF) to the pituitary.
- Adrenocorticotrophic hormone (ACTH) released from anterior pituitary
- this stimulates adrenal cortex to release adrenocorticoids
- adrenocorticoid levels become high
- CRF secretion from hypothalamus is inhibited
What are the pharmacological activities of glucocorticoids?
- anti-inflammation
- inhibit cytokines
- inhibit mast cell release of autocoids
where do steroids and drugs that mimic glucocorticoids act?
on gene’s
Explain the gene activity of glucocorticoids?
- steroid hormones enter cell by diffusion, as it’s lipophilic
- they then combine with intracellular receptors (receptors are inactive and located in the cytoplasm)
- this causes a conformational change exposing a DNA binding domain
- receptor-steroid complex move to the nucleus and bind to steroid response elements in DNA
- specific gene transcription is either switched on or off to alter mRNA levels and the rate of synthesis of mediator proteins
How do glucocorticoids work as anti-inflammatory drugs?
- 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.
how do glucocorticoids inhibit cytokines?
- 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.
how do glucocorticoids inhibit mast cell release of autocoids?
- by inhibiting release of histamine and autocoids from mast cells
- autocoids have both vasoconstriction and vasodilating properties.
What do glucocorticoid receptors consist of?
11 alpha-helices and 7 beta-strands with a unique binding site compared to other steroidal receptors.
Why do glucocorticoid receptors have a strong binding affinity?
Because of hydrophobic and hydrophilic interactions
Wha do the atoms of glucocorticoids interact with and by what type of bond?
- amino acids
- by Hbonds
What type of bonds do receptors make with glucocorticoids?
- important ones are H-bonds
- these are at every hydrophilic groups on the glucocorticoid structure
What 4 functional groups are essential for both mineralocorticoid and glucocorticoid activity?
- pregnane skeleton
- A-ring enone
- 17beta-ketol side chain
- C-21 hydroxy
What structure increases anti-inflammatory and mineralocorticoid activity?
open circle
What structure increases anti-inflammatory activity?
triangle and square
what structure decreases mineralocorticoid activity?
closed circle and square
where are drugs most commonly detoxified and metabolised?
liver and kidneys
what happens during phase 1 of drug metabolism?
introduction of polar functional groups into molecules to be metabolised, providing a site for phase 2 metabolism.
What happens during phase 2 of drug metabolism?
introduction of polar conjugates into the drug molecule, increasing its polarity, making it more readily excreted in urine.
what type of philicity do drugs have from when absorbed to when excreted?
lipophilic when absorbed, hydrophilic when excreted.
3 major metabolic reactions of glucocorticoids?
- Ring A reduction
- C-17 oxidation
- C-11 keto-enol isomerisation
what is used to esterify an hydroxyl group?
a carboxylic acid
which carbon OH groups are easy to esterify?
C-21-OH and C-17-OH as they’re the most accessible.
which carbon OH groups aren’t easily esterified and why?
C-11-OH as they’re hindered by angular methyls so won’t react with acids
what effect does esterification have on the binding affinity and metabolism of steroids?
- 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)
how can you increase the LogP values of steroids?
by esterification with lipophilic acids
what are the systemic glucocorticoids for asthma?
- hydrocortisone
- prednisolone
- methylprednisolone
what are inhaled glucocorticoids?
- beclomethasone dipropionate
- budesonide
- ciclesonide
- flunisolide
- fluticasone propionate
- mometasine fuorate
- triamcinolone acetonide
what is the effect of prodrugs on drug action?
increases duration of drug action`
what is the effect of bulkier molecules on the hydrolysis of esters?
it slows down the process of hydrolysis
