Steroidal Drugs Flashcards
What are THREE ways steroidal drugs may function as?
- STEROID RECEPTOR AGONISTS (majority)
- STEROID RECEPTOR ANTAGONISTS
- ENZYME INHIBITORS
Why is the development of synthetic steroids required? Provide a few issues linked to natural steroids
Due to issues with natural steroids
- RAPID METABOLISM, BIOCONVERSION AND ELIMINATION LEADING TO SHORT BIOLOGICAL LIFETIME
- LACK OF SPECIFICITY LEADING TO ADVERSE AFFECTS
What is the basic chemical structure of a steroidal drug?
Tetracyclic template (3 Hexagons and 1 Pentagon)
What is a substituent/atom group that projects
A) Upwards (top side) called?
B) Downwards (bottom side) called?
A)
- β SUBSTITUENT
B)
- α SUBSTITUENT
What are the FOUR main groups of steroidal drugs?
- Androgenic/anabolic drugs (testosterone)
- Estrogenic
- Progestogenic
- Adrenocortical
For testosterone;
A) Is it orally active or inactive
B) Provide THREE aims during design for synthetic testosterone?
C) How can chemical modifications alter the structure of a steroid in vivo?
D) What does introduction of small alkyl substituents do at C-17?
E) How can anabolic/androgenic ratio be improved? Provide FOUR ways
F) What chemical structures are essential for BA in the testosterone derivatives
A)
ORALLY INACTIVE due to rapid metabolism -
B)
- Introducing/Increasing oral activity
- Increasing potency of anabolic/androgenic bioactivity
- Increasing anabolic bioactivity coupled with removal or reduction in androgenic bioactivity
Anabolic: muscle building
Androgenic: increased sex male characteristics
C)
- Absorption
- Distribution
- Rate of metabolism
- Receptor interaction/fit
D)
- Introduces oral BA without altering anabolic/androgenic activity
- Also reduces metabolism of 17B-OH group
E)
- Removing C-19 methyl unit, add 10B-H atom
- Increase ring electron density –> unsaturated groups to ring A such as alkene
- Adding oxygen based groups into ring A
- Removing 4,5 alkene bind and add 5a-H atom
F)
- 17B-OH group
- High electron density in ring A
For estrogen;
A) What are the two structural requirements for agonist activity? How far do they have to be apart?
B) What does the introduction of 17 an alkyne group do?
C) What property makes it different from other steroids
D) Are natural analogs utilized clinically in preference to synthetic forms?
A)
- Phenol ring A and 17-hydroxyl with two H-bonding oxygens at 10-12 A distance apart
B)
- Increases oral bioactivity
C)
- Ionisable steroid –> different to other steroids
D)
- Natrual analogues are utilised clinically instead of synthetic forms
For Progesterone;
A) Orally active or inactive?
B) How is it administered?
C) What does adding a 17a alkynyl do?
D) What does adding a C-6A alkyl group enhance activity? Provide THREE ways
E) How to get decreased C-20 Keto metabolism and subsequently oral/long-acting forms?
A)
- ORALLY INACTIVE due to high metabolic instability
B)
- Parenterally via oil based depot preparations
C)
- Makes it orally active and lowers androgenic activity
D)
- Decreases metabolic reduction in ring A
- Preventing metabolic hydroxylation at C-6
- Increasing lipid solubility of steroid system
E)
- Introduction of 17a ester progesterones
For adrenocortical drugs (glucocorticoid and mineralocorticoid);
A) What makes it different from other steroids?
B) What are some disadvantages?
C) Why are synthetic modifications introduced into the glucocorticoids? Provide THREE reasons.
D) What does the prevention of ring A reduction at 3-keto and 4,5 C=C bond and subsequently reduced metabolism do?
E) What does the introduction of an additional C=C bond at C-1,2 do? For GC/MC activity?
F) What does the introduction of C-6 substituent do (eg ME, F)? For GC/MC activity?
G) What does the introduction of a 9a halogen (F or CL) do? For GC/MC activity
H) What does the introduction of a or B methyl at C-16 do? For GC/MC activity?
I) What does the introduction of a 16a hydroxyl(OH) group do for GC/MC activity? How to prevent metabolism of this?
A)
DISPLAYS ORAL BIOACTIVITY –> can be formulated as tablets, topical agents and parenterals
B)
- Needs high therapeutic dosages (due to rapid metabolism)
- Variety of side effects (mostly mineral corticoid)
C)
- Increase potency and duration of action
- Reduce mineralocorticoid side-effects
- Increase absorption/delivery at the site of action
D)
Increases GC/MC potency
E)
Increases potency and ring A metabolic stability
- Results in 4-5 fold increased in GC anti-inflammatory potency but importantly not increase in MC (adverse) bioactivity
F)
Reduction in metabolic 6-hydroxylation and increases GC potency
G)
Prevent oxidation of the 11B-OH group and increases GC/MC potency –> most significantly MC activity
H)
Decreases metabolism at C-17/20/21 oxygen-based groups. Boosts GC and significantly reduces MC activity.
I)
Significantly decreases MC activity
- To prevent the metabolism of the introduced 16a-OH group, an ester can be added
For steroidal ester prodrugs;
A) What three issues are they trying to overcome that is associated with steroidal drugs?
B) Can it improve drug delivery and range of available formulations?
C) Why is the addition of an ester group straightforward?
D) How are bio drugs transformed in vivo to the active steroid?
E) How is increased steroid aqueous solubility achieved?
A)
- LOW OR ABSENT ORAL ACTIVITY
- LOW DURATION OF ACTION
- LOW AQUEOUS SOLUBILITY
B)
Yes
C)
- Due to the presence of one or more steroidal HYDROXYL group
D)
- Enzymatic or chemical hydrolysis
E)
- via the introduction of H2O-soluble ester groups –> namely with succinate and phosphate ester salts
- THESE SUCCINATE AND PHOSPHATE ESTER SALTS ARE LOCATED AT C-21
- used in a variety of formulations such as eye,drop,injection,tablet
For steroidal ester prodrugs (pt 2);
A) What is fatty ester prodrugs used for?
B) What does ester group block the metabolism of?
C) Why are large and sterically hindered esters used in depot slow-release preparations
D) Why do fatty ester prodrugs undergo slow hydrolysis?
E) Formulation types?
A)
- enhance drug absorption and delivery for various dosage forms
- Used to further boost lipid solubility of steroids for better penetration and formulation compatability
B)
- blocks metabolism of the parenthydroxyl unit and any nearby groups (keto, OH)
C)
- Slowly hydrolyzed invivo
D)
- Low aqueous solubility with prolonged release of active steroid
E)
- Topicals, IM injection, Aerosol
