Corticosteroids are a cornerstone in the management of various inflammatory and immune-mediated diseases, including respiratory conditions like asthma and COPD. They are available in oral formulations for systemic effects and inhaled formulations designed to maximize local lung activity while minimizing systemic exposure. The therapeutic efficacy, potency, selectivity, and pharmacokinetic profiles of these agents are intrinsically linked to their chemical structures. For PharmD students, a robust understanding of the medicinal chemistry of oral and inhaled corticosteroids—including their core steroid nucleus, key functional groups, structure-activity relationships (SAR), and metabolic pathways—is essential for appreciating their design, clinical application, and side effect profiles. This MCQ quiz will explore these critical medicinal chemistry aspects.
1. The fundamental core chemical structure of all corticosteroids is based on the:
- A. Estrane nucleus (18 carbons)
- B. Androstane nucleus (19 carbons)
- C. Pregnane nucleus (21 carbons)
- D. Cholestane nucleus (27 carbons)
Answer: C. Pregnane nucleus (21 carbons)
2. For glucocorticoid activity, which of the following structural features is generally considered essential on the steroid A-ring?
- A. A hydroxyl group at C3
- B. A Δ4-3-keto moiety (a double bond between C4 and C5, and a ketone at C3)
- C. A saturated A-ring with a 3α-hydroxyl group
- D. A methyl group at C19
Answer: B. A Δ4-3-keto moiety (a double bond between C4 and C5, and a ketone at C3)
3. The presence of an 11β-hydroxyl group on the corticosteroid nucleus is crucial for:
- A. Mineralocorticoid activity only
- B. Glucocorticoid receptor binding and activity
- C. Increasing water solubility significantly
- D. Preventing all metabolism
Answer: B. Glucocorticoid receptor binding and activity
4. Prednisone is an orally administered corticosteroid that is a prodrug. It is metabolically converted to its active form, prednisolone, by which reaction?
- A. Hydrolysis of an ester group
- B. Reduction of the C3 ketone to a hydroxyl group
- C. Enzymatic reduction of the C11-ketone to an 11β-hydroxyl group by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)
- D. Acetylation at C21
Answer: C. Enzymatic reduction of the C11-ketone to an 11β-hydroxyl group by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)
5. The introduction of a double bond between C1 and C2 in the A-ring of hydrocortisone (to form prednisolone) or cortisone (to form prednisone) generally leads to:
- A. Decreased glucocorticoid activity and increased mineralocorticoid activity.
- B. Increased glucocorticoid activity and reduced mineralocorticoid activity compared to the parent compound.
- C. Complete loss of anti-inflammatory activity.
- D. Enhanced water solubility only.
Answer: B. Increased glucocorticoid activity and reduced mineralocorticoid activity compared to the parent compound.
6. Fluorination at the 9α-position of the steroid nucleus (e.g., in fludrocortisone, dexamethasone, fluticasone) typically:
- A. Decreases both glucocorticoid and mineralocorticoid activity.
- B. Markedly increases both glucocorticoid and mineralocorticoid activity (fludrocortisone) or primarily glucocorticoid when combined with other modifications.
- C. Increases water solubility only.
- D. Makes the compound orally inactive.
Answer: B. Markedly increases both glucocorticoid and mineralocorticoid activity (fludrocortisone) or primarily glucocorticoid when combined with other modifications.
7. To reduce mineralocorticoid activity (sodium-retaining effects) while maintaining or enhancing glucocorticoid activity, which structural modification is often made at C16?
- A. Introduction of a ketone group
- B. Introduction of a methyl group (α or β, e.g., dexamethasone, betamethasone) or a hydroxyl group (α, e.g., triamcinolone)
- C. Removal of the C21 hydroxyl group
- D. Saturation of the A-ring
Answer: B. Introduction of a methyl group (α or β, e.g., dexamethasone, betamethasone) or a hydroxyl group (α, e.g., triamcinolone)
8. Inhaled corticosteroids (ICS) are designed to maximize topical anti-inflammatory effects in the lungs and minimize systemic absorption/effects. This is often achieved by incorporating features that promote:
- A. High oral bioavailability and slow hepatic metabolism.
- B. High lipophilicity (for lung retention) and susceptibility to rapid first-pass hepatic metabolism to inactive metabolites if systemically absorbed.
- C. Low receptor binding affinity.
- D. Systemic distribution to all tissues.
Answer: B. High lipophilicity (for lung retention) and susceptibility to rapid first-pass hepatic metabolism to inactive metabolites if systemically absorbed.
9. Fluticasone propionate is a potent inhaled corticosteroid. The “propionate” refers to an ester group located at:
- A. C3
- B. C11
- C. C17α (as part of a carbothioate ester)
- D. C21
Answer: C. C17α (as part of a carbothioate ester) (Fluticasone has a C17α carbothioate, and the propionate ester can also be considered as part of this unique side chain. More commonly, ICS have C17 or C21 esters). Correction: Fluticasone propionate has a propionate ester at C17 formed from a carboxylic acid which is a thioester. The key is the C17 esterification for lipophilicity. More precise answer for propionate ester of fluticasone propionate: The propionate forms part of a S-fluoromethyl carbothioate ester at C17. Considering typical esterification sites on other ICS for clarity: Many ICS like beclomethasone dipropionate or flunisolide have ester groups at C17 and/or C21 to increase lipophilicity. Fluticasone propionate’s propionate is part of the C-17 α-hydroxyl derived carbothioate structure.
9. Fluticasone propionate is a potent inhaled corticosteroid. The esterification at C17 with a fluorinated carbothioate and propionate group significantly contributes to its:
- A. High water solubility.
- B. High lipophilicity, receptor affinity, and rapid hepatic inactivation.
- C. Low topical potency.
- D. Mineralocorticoid activity.
Answer: B. High lipophilicity, receptor affinity, and rapid hepatic inactivation.
10. Budesonide is an inhaled corticosteroid that is a mixture of two epimers (22R and 22S) due to the formation of an acetal (ketal) group. This acetal linkage involves the 16α,17α-hydroxyl groups and:
- A. Acetic acid
- B. Propionaldehyde
- C. n-Butyraldehyde
- D. Benzaldehyde
Answer: C. n-Butyraldehyde (specifically, it’s an acetal with the 16α-OH and 17α-OH).
11. Ciclesonide is an inhaled corticosteroid prodrug that is activated in the lungs by:
- A. CYP3A4 enzymes
- B. Esterases, which hydrolyze it to the active metabolite des-ciclesonide
- C. Glucuronosyltransferases
- D. Sulfotransferases
Answer: B. Esterases, which hydrolyze it to the active metabolite des-ciclesonide
12. The 17α-hydroxyl group and the 21-hydroxyl group on the corticosteroid side chain (at C17) are important because they:
- A. Decrease glucocorticoid activity.
- B. Are often sites for esterification or acetal formation to modify potency, lipophilicity, and duration of action (especially for topical/inhaled use).
- C. Are essential for mineralocorticoid activity only.
- D. Prevent binding to the glucocorticoid receptor.
Answer: B. Are often sites for esterification or acetal formation to modify potency, lipophilicity, and duration of action (especially for topical/inhaled use).
13. Mometasone furoate is a potent inhaled/topical corticosteroid. The “furoate” refers to an ester formed with furoic acid at which position?
- A. C3
- B. C11
- C. C17α
- D. C21
Answer: C. C17α
14. The primary mechanism by which corticosteroids exert their anti-inflammatory effects involves:
- A. Direct inhibition of cyclooxygenase enzymes.
- B. Binding to intracellular glucocorticoid receptors (GR), which then translocate to the nucleus to modulate gene expression (transactivation and transrepression).
- C. Antagonism of beta-2 adrenergic receptors.
- D. Direct stabilization of mast cell membranes.
Answer: B. Binding to intracellular glucocorticoid receptors (GR), which then translocate to the nucleus to modulate gene expression (transactivation and transrepression).
15. Hydrocortisone (cortisol) is the body’s natural glucocorticoid. Its structure contains:
- A. A 9α-fluoro group
- B. An 11β-hydroxyl group, a 17α-hydroxyl group, and a 21-hydroxyl group
- C. A C16-methyl group
- D. A C1-C2 double bond
Answer: B. An 11β-hydroxyl group, a 17α-hydroxyl group, and a 21-hydroxyl group
16. Beclomethasone dipropionate is an inhaled corticosteroid prodrug that is hydrolyzed to active beclomethasone-17-monopropionate and then to beclomethasone. The “dipropionate” indicates esterification at:
- A. C3 and C11
- B. C11 and C16
- C. C17 and C21
- D. C6 and C9
Answer: C. C17 and C21
17. The lipophilicity of inhaled corticosteroids is a key factor for their retention in lung tissue and duration of action. Which of the following modifications generally increases lipophilicity?
- A. Addition of multiple hydroxyl groups
- B. Esterification of hydroxyl groups with fatty acids or formation of acetals
- C. Conversion to a sodium phosphate salt
- D. Removal of all fluorine atoms
Answer: B. Esterification of hydroxyl groups with fatty acids or formation of acetals
18. Systemic absorption of inhaled corticosteroids can lead to side effects. Which ICS is known for its very high first-pass hepatic metabolism to inactive metabolites, thus minimizing systemic bioavailability?
- A. Hydrocortisone (oral)
- B. Prednisone
- C. Fluticasone propionate and Budesonide
- D. Dexamethasone
Answer: C. Fluticasone propionate and Budesonide
19. The C20-ketone and C21-hydroxyl group (dihydroxyacetone side chain at C17) are important for glucocorticoid activity. Reduction of the C20-ketone generally:
- A. Increases glucocorticoid activity
- B. Decreases or abolishes glucocorticoid activity
- C. Enhances mineralocorticoid activity
- D. Has no effect on activity
Answer: B. Decreases or abolishes glucocorticoid activity
20. Dexamethasone and Betamethasone are potent systemic glucocorticoids with minimal mineralocorticoid activity. They both possess a 9α-fluoro group and a methyl group at which position?
- A. C6α
- B. C11β
- C. C16 (dexamethasone is 16α-methyl, betamethasone is 16β-methyl)
- D. C21
Answer: C. C16 (dexamethasone is 16α-methyl, betamethasone is 16β-methyl)
21. The mineralocorticoid activity of corticosteroids (e.g., causing sodium/water retention) is primarily due to their ability to bind to and activate:
- A. Glucocorticoid receptors in the kidney
- B. Mineralocorticoid receptors in the distal tubules and collecting ducts
- C. Androgen receptors
- D. Beta-2 adrenergic receptors
Answer: B. Mineralocorticoid receptors in the distal tubules and collecting ducts
22. The conversion of cortisone to hydrocortisone (cortisol) in the body involves reduction of the C11-ketone to an 11β-hydroxyl by 11β-HSD1. This activation is important because:
- A. Cortisone itself is a potent mineralocorticoid.
- B. Cortisol (hydrocortisone) is the primary active endogenous glucocorticoid that binds effectively to the glucocorticoid receptor.
- C. Cortisone has a longer half-life.
- D. This conversion only occurs in the lungs.
Answer: B. Cortisol (hydrocortisone) is the primary active endogenous glucocorticoid that binds effectively to the glucocorticoid receptor.
23. Triamcinolone is a synthetic corticosteroid with a 9α-fluoro group and a 16α-hydroxyl group. The 16α-hydroxyl group primarily serves to:
- A. Greatly increase mineralocorticoid activity.
- B. Eliminate glucocorticoid activity.
- C. Reduce mineralocorticoid activity and can also influence potency and side effect profile (e.g., muscle wasting).
- D. Make the drug orally inactive.
Answer: C. Reduce mineralocorticoid activity and can also influence potency and side effect profile (e.g., muscle wasting).
24. What type of isomerism exists between dexamethasone (16α-methyl) and betamethasone (16β-methyl)?
- A. Geometric (cis-trans) isomers
- B. Enantiomers
- C. Diastereomers (epimers at C16)
- D. Tautomers
Answer: C. Diastereomers (epimers at C16)
25. From a medicinal chemistry perspective, the development of inhaled corticosteroids focused on maximizing local anti-inflammatory potency while minimizing systemic effects. This often involved creating compounds with:
- A. High oral bioavailability and low receptor affinity.
- B. High topical potency (high receptor affinity), good lung retention, and rapid systemic inactivation.
- C. Low lipophilicity and slow metabolism.
- D. Predominant mineralocorticoid activity.
Answer: B. High topical potency (high receptor affinity), good lung retention, and rapid systemic inactivation.
26. The ester or acetal groups in many inhaled corticosteroids (e.g., fluticasone propionate, budesonide) are susceptible to hydrolysis by which enzymes, often leading to activation (ciclesonide) or facilitating inactivation if systemically absorbed?
- A. Cytochrome P450 enzymes
- B. Esterases present in the lungs and other tissues
- C. Glucuronyltransferases
- D. Sulfotransferases
Answer: B. Esterases present in the lungs and other tissues
27. The anti-inflammatory action of glucocorticoids involves the inhibition of phospholipase A2 (indirectly, via lipocortin-1/annexin A1), which leads to reduced synthesis of:
- A. Only histamine
- B. Prostaglandins and leukotrienes (arachidonic acid metabolites)
- C. Only bradykinin
- D. Nitric oxide
Answer: B. Prostaglandins and leukotrienes (arachidonic acid metabolites)
28. Which structural feature is primarily responsible for the high glucocorticoid potency of fluticasone furoate compared to hydrocortisone?
- A. Absence of the 11β-hydroxyl group
- B. Multiple fluorine substitutions (e.g., 6α, 9α-difluoro) and specific esterification at C17
- C. A saturated A-ring
- D. A simple C21 acetate ester
Answer: B. Multiple fluorine substitutions (e.g., 6α, 9α-difluoro) and specific esterification at C17 (Fluticasone has 6α,9α-difluoro and a C17α carbothioate ester).
29. The presence of a 17α-hydroxyl group is common in many potent glucocorticoids. Its role is often to:
- A. Decrease binding to the glucocorticoid receptor.
- B. Enhance glucocorticoid activity and allow for esterification or acetal formation to modulate properties.
- C. Increase mineralocorticoid activity.
- D. Make the compound a prodrug.
Answer: B. Enhance glucocorticoid activity and allow for esterification or acetal formation to modulate properties.
30. The metabolism of the A-ring of corticosteroids (e.g., reduction of the C4-C5 double bond and C3-ketone) generally leads to:
- A. Increased anti-inflammatory activity
- B. Formation of more potent metabolites
- C. Inactivation of glucocorticoid activity and preparation for conjugation and excretion
- D. Conversion to mineralocorticoids
Answer: C. Inactivation of glucocorticoid activity and preparation for conjugation and excretion
31. The high lipophilicity imparted by C17/C21 esterification in ICS like fluticasone propionate or beclomethasone dipropionate contributes to:
- A. Rapid systemic absorption and distribution.
- B. Increased residence time in the lung tissue and binding to lung proteins/lipids, enhancing local effect.
- C. Decreased affinity for the glucocorticoid receptor.
- D. Exclusively renal excretion of the unchanged drug.
Answer: B. Increased residence time in the lung tissue and binding to lung proteins/lipids, enhancing local effect.
32. Ciclesonide is activated to des-ciclesonide in the lung. Des-ciclesonide has a higher affinity for the glucocorticoid receptor than ciclesonide itself. This is an example of:
- A. Metabolic inactivation
- B. A prodrug strategy to enhance local activity and reduce systemic effects
- C. A drug that bypasses receptor binding
- D. A drug that primarily acts as a mineralocorticoid
Answer: B. A prodrug strategy to enhance local activity and reduce systemic effects
33. Which of the following oral corticosteroids has the highest relative anti-inflammatory potency compared to hydrocortisone (potency=1)?
- A. Prednisone (potency ~4)
- B. Methylprednisolone (potency ~5)
- C. Dexamethasone (potency ~25-30)
- D. Cortisone (potency ~0.8)
Answer: C. Dexamethasone (potency ~25-30)
34. The “furoate” ester in mometasone furoate or fluticasone furoate is derived from:
- A. Formic acid
- B. Furoic acid (a furan derivative)
- C. Propionic acid
- D. Acetic acid
Answer: B. Furoic acid (a furan derivative)
35. From a medicinal chemistry standpoint, the ideal inhaled corticosteroid would have:
- A. High oral bioavailability and low topical potency.
- B. High topical (lung) potency, high receptor affinity, rapid systemic inactivation, and low oral bioavailability.
- C. Predominant mineralocorticoid activity.
- D. A very long systemic half-life.
Answer: B. High topical (lung) potency, high receptor affinity, rapid systemic inactivation, and low oral bioavailability.
36. The 21-hydroxyl group of corticosteroids can be esterified with various acids (e.g., acetate, phosphate, succinate). Phosphate or succinate esters are often used to:
- A. Decrease water solubility for oral tablets.
- B. Increase water solubility for parenteral (IV) formulations.
- C. Enhance lipophilicity for topical creams.
- D. Create long-acting depot injections.
Answer: B. Increase water solubility for parenteral (IV) formulations.
37. The difference in the C16 substituent between dexamethasone (16α-methyl) and betamethasone (16β-methyl) affects their:
- A. Primary mechanism of action.
- B. Relative glucocorticoid and mineralocorticoid potency (both are highly potent GCs with minimal MC activity, but subtle differences can exist).
- C. Route of administration (both are oral/parenteral/topical).
- D. Chemical classification (both are synthetic glucocorticoids).
Answer: B. Relative glucocorticoid and mineralocorticoid potency (both are highly potent GCs with minimal MC activity, but subtle differences can exist). (And potentially subtle PK differences).
38. Which structural feature is NOT typically found in orally active glucocorticoids like prednisone or methylprednisolone?
- A. A Δ4-3-keto moiety in the A-ring
- B. An 11β-hydroxyl group (or a group convertible to it)
- C. A large, highly lipophilic ester group at C17 or C21 designed for lung retention
- D. A 17α-hydroxyl group
Answer: C. A large, highly lipophilic ester group at C17 or C21 designed for lung retention (These are characteristic of ICS).
39. The binding of a corticosteroid to its intracellular glucocorticoid receptor initiates a cascade that involves:
- A. Direct opening of ion channels.
- B. Dissociation of heat shock proteins, receptor dimerization, translocation to the nucleus, and binding to glucocorticoid response elements (GREs) on DNA.
- C. Activation of adenylyl cyclase.
- D. Inhibition of phosphodiesterase.
Answer: B. Dissociation of heat shock proteins, receptor dimerization, translocation to the nucleus, and binding to glucocorticoid response elements (GREs) on DNA.
40. The “dipropionate” ester in beclomethasone dipropionate contributes to:
- A. Decreased lipophilicity and potency.
- B. Increased lipophilicity, enhanced lung retention, and potentially acts as a prodrug moiety.
- C. Only improved taste.
- D. High water solubility.
Answer: B. Increased lipophilicity, enhanced lung retention, and potentially acts as a prodrug moiety.
41. What is the significance of the 11β-HSD2 enzyme, predominantly found in mineralocorticoid target tissues like the kidney?
- A. It activates prednisone to prednisolone.
- B. It converts active cortisol (hydrocortisone) to inactive cortisone, thus protecting the mineralocorticoid receptor from illicit activation by cortisol.
- C. It metabolizes aldosterone to an inactive form.
- D. It activates inhaled corticosteroids in the lungs.
Answer: B. It converts active cortisol (hydrocortisone) to inactive cortisone, thus protecting the mineralocorticoid receptor from illicit activation by cortisol.
42. The chemical properties of inhaled corticosteroids, such as particle size and formulation, are critical for:
- A. Determining their systemic bioavailability only.
- B. Ensuring efficient delivery to and deposition in the lungs.
- C. Their interaction with CYP3A4.
- D. Their ability to cause oral candidiasis.
Answer: B. Ensuring efficient delivery to and deposition in the lungs.
43. The fluorination of corticosteroids at positions like 6α or 9α often leads to:
- A. Decreased receptor binding affinity.
- B. Enhanced anti-inflammatory potency by altering electronic properties and receptor binding.
- C. Increased water solubility.
- D. Rapid metabolic inactivation.
Answer: B. Enhanced anti-inflammatory potency by altering electronic properties and receptor binding.
44. Which of the following corticosteroids is endogenous (naturally produced by the adrenal cortex)?
- A. Dexamethasone
- B. Prednisolone
- C. Hydrocortisone (Cortisol)
- D. Fluticasone
Answer: C. Hydrocortisone (Cortisol)
45. The introduction of a 16α,17α-acetonide (ketal) structure, as seen in triamcinolone acetonide or flunisolide, is a medicinal chemistry strategy to:
- A. Decrease topical potency.
- B. Increase topical anti-inflammatory potency and lipophilicity for dermal or inhaled use.
- C. Improve oral bioavailability.
- D. Reduce all systemic side effects to zero.
Answer: B. Increase topical anti-inflammatory potency and lipophilicity for dermal or inhaled use.
46. From a SAR perspective, removal or modification of the C21-hydroxyl group in a corticosteroid generally:
- A. Enhances glucocorticoid activity significantly.
- B. Reduces or abolishes glucocorticoid activity unless other potentiation features are present.
- C. Increases mineralocorticoid activity only.
- D. Has no impact on activity.
Answer: B. Reduces or abolishes glucocorticoid activity unless other potentiation features are present. (The -CO-CH2OH side chain is important).
47. What is the primary reason for the extensive hepatic metabolism of systemically absorbed fluticasone propionate by CYP3A4?
- A. To convert it to a more potent active metabolite.
- B. To rapidly inactivate it, thereby minimizing systemic glucocorticoid side effects.
- C. To facilitate its renal excretion as an unchanged drug.
- D. This drug is not metabolized by CYP3A4.
Answer: B. To rapidly inactivate it, thereby minimizing systemic glucocorticoid side effects.
48. The glucocorticoid receptor belongs to which superfamily of receptors?
- A. Ligand-gated ion channels
- B. G-protein coupled receptors
- C. Nuclear hormone receptors
- D. Tyrosine kinase receptors
Answer: C. Nuclear hormone receptors
49. The “propionate” or “furoate” esters in inhaled corticosteroids are designed to be cleaved by esterases. This cleavage:
- A. Always leads to an inactive compound in the lung.
- B. Can release the active corticosteroid alcohol in the lung (for some prodrugs like ciclesonide) or are features of already active molecules designed for optimal PK/PD.
- C. Only occurs systemically after absorption.
- D. Makes the drug more water-soluble for nebulization.
Answer: B. Can release the active corticosteroid alcohol in the lung (for some prodrugs like ciclesonide) or are features of already active molecules designed for optimal PK/PD. (For fluticasone propionate/furoate, the ester is part of the active molecule, contributing to lipophilicity; for ciclesonide, ester cleavage activates it).
50. The medicinal chemistry goal of creating inhaled corticosteroids with high topical potency and low systemic activity is crucial for minimizing which type of adverse effects during chronic asthma/COPD treatment?
- A. Local side effects like thrush
- B. Systemic corticosteroid side effects like adrenal suppression, osteoporosis, and glucose intolerance
- C. Bronchoconstriction
- D. Tachycardia and tremor
Answer: B. Systemic corticosteroid side effects like adrenal suppression, osteoporosis, and glucose intolerance