MCQ Quiz: Medicinal Chemistry of Glycosides (Cardiac Glycosides)

Cardiac glycosides are a fascinating class of naturally derived compounds that have been used for centuries in the treatment of heart conditions. Their potent effects on myocardial contractility stem from their unique chemical structures, which consist of a steroidal aglycone linked to one or more sugar moieties. For PharmD students, a deep understanding of the medicinal chemistry of these glycosides—including their core structures, specific functional groups, structure-activity relationships (SAR), and how these chemical features influence their pharmacological actions and pharmacokinetic profiles—is essential for appreciating their therapeutic use and managing their narrow therapeutic index. This MCQ quiz will explore the intricate medicinal chemistry of cardiac glycosides.

1. The fundamental chemical structure of a cardiac glycoside consists of a steroid aglycone (genin) and what other component linked by a glycosidic bond?

• A. An amino acid
• B. A fatty acid chain
• C. One or more sugar moieties (glycone)
• D. A peptide chain

Answer: C. One or more sugar moieties (glycone)

2. The steroid aglycone of most clinically important cardiac glycosides (like digoxin) possesses which specific type of nucleus?

• A. Androstane
• B. Estrane
• C. Pregnane
• D. Cyclopentanoperhydrophenanthrene (gonane)

Answer: D. Cyclopentanoperhydrophenanthrene (gonane)

3. Which structural feature at position C17 of the steroid aglycone is essential for the cardiotonic activity of cardiac glycosides?

• A. A simple methyl group
• B. An α,β-unsaturated lactone ring (e.g., cardenolide) or a doubly unsaturated lactone (bufadienolide)
• C. A long alkyl chain
• D. A primary alcohol

Answer: B. An α,β-unsaturated lactone ring (e.g., cardenolide) or a doubly unsaturated lactone (bufadienolide)

4. The sugar moieties in cardiac glycosides are typically attached to which position on the steroid aglycone via a glycosidic linkage?

• A. C17 hydroxyl group
• B. C14 hydroxyl group
• C. C3 hydroxyl group
• D. C12 hydroxyl group

Answer: C. C3 hydroxyl group

5. The fusion of the C/D rings in the steroid nucleus of active cardiac glycosides is typically:

• A. Trans
• B. Cis
• C. Planar
• D. Aromatic

Answer: B. Cis (A/B and C/D are cis; B/C is trans, giving an overall U-shape)

6. Which hydroxyl group on the steroid nucleus of cardiac glycosides is crucial for activity and typically has a β-orientation?

• A. C3-OH (before glycosylation)
• B. C7-OH
• C. C11-OH
• D. C14-OH

Answer: D. C14-OH

7. Cardenolides, such as digoxin and digitoxin, possess which type of unsaturated lactone ring at C17?

• A. A five-membered α,β-unsaturated γ-lactone ring
• B. A six-membered α,β,γ,δ-doubly unsaturated δ-lactone ring
• C. A saturated six-membered lactone ring
• D. A four-membered β-lactone ring

Answer: A. A five-membered α,β-unsaturated γ-lactone ring

8. Bufadienolides, another class of cardiac glycosides (e.g., from toad venom), possess which type of lactone ring at C17?

• A. A five-membered α,β-unsaturated γ-lactone ring
• B. A six-membered doubly unsaturated (two double bonds) δ-lactone ring
• C. A saturated five-membered lactone ring
• D. An open-chain carboxylic acid

Answer: B. A six-membered doubly unsaturated (two double bonds) δ-lactone ring

9. The sugar most commonly found in digoxin is D-digitoxose. Digitoxose is a:

• A. Hexose with an aldehyde group
• B. Ketohexose
• C. 2,6-dideoxyhexose
• D. Pentose sugar

Answer: C. 2,6-dideoxyhexose

10. How do the sugar moieties generally influence the pharmacokinetic properties of cardiac glycosides?

• A. They significantly decrease water solubility and absorption.
• B. They increase lipophilicity and enhance CNS penetration.
• C. They affect water solubility, lipid solubility, absorption, protein binding, and duration of action.
• D. They have no impact on pharmacokinetics, only on potency.

Answer: C. They affect water solubility, lipid solubility, absorption, protein binding, and duration of action.

11. Digoxin differs structurally from digitoxin by the presence of an additional hydroxyl group at which position on the steroid nucleus?

• A. C3
• B. C5
• C. C12 (12β-OH)
• D. C16

Answer: C. C12 (12β-OH)

12. The presence of the C12-hydroxyl group in digoxin, compared to digitoxin, makes digoxin:

• A. More lipophilic and longer-acting
• B. More polar (hydrophilic) and generally shorter-acting with more renal excretion
• C. Less potent
• D. More susceptible to acid hydrolysis

Answer: B. More polar (hydrophilic) and shorter-acting with more renal excretion

13. The primary target enzyme inhibited by cardiac glycosides, leading to their positive inotropic effect, is:

• A. Adenylyl cyclase
• B. Phosphodiesterase-3
• C. Na+/K+-ATPase
• D. HMG-CoA reductase

Answer: C. Na+/K+-ATPase

14. From a structure-activity relationship (SAR) perspective, what is the significance of the α,β-unsaturation in the C17 lactone ring?

• A. It increases water solubility.
• B. It is believed to be critical for interaction with the Na+/K+-ATPase binding site, possibly via Michael addition or by conferring a specific conformation.
• C. It protects the steroid nucleus from metabolism.
• D. It facilitates glycosidic bond formation at C3.

Answer: B. It is believed to be critical for interaction with the Na+/K+-ATPase binding site, possibly via Michael addition or by conferring a specific conformation.

15. If the C17 lactone ring of a cardiac glycoside is saturated (double bond reduced), what is the general effect on its cardiotonic activity?

• A. Activity is significantly increased.
• B. Activity is greatly diminished or abolished.
• C. Oral bioavailability is improved.
• D. The drug becomes a negative inotrope.

Answer: B. Activity is greatly diminished or abolished.

16. Hydrolysis of the glycosidic bonds in cardiac glycosides (removing sugar units) leads to the formation of the:

• A. More potent hologlycoside
• B. Aglycone (or genin), which may retain some activity but has different PK properties
• C. Inactive lactone ring
• D. A simple steroid alcohol with no activity

Answer: B. Aglycone (or genin), which may retain some activity but has different PK properties

17. The overall “U” shape or bent conformation of the cardiac glycoside steroid nucleus, due to specific ring fusions (cis-A/B, trans-B/C, cis-C/D), is considered important for:

• A. Its taste
• B. Its ability to fit optimally into the binding site on Na+/K+-ATPase
• C. Its resistance to acid hydrolysis
• D. Its interaction with P-glycoprotein

Answer: B. Its ability to fit optimally into the binding site on Na+/K+-ATPase

18. Ouabain (G-strophanthin) is a cardiac glycoside that is more polar than digoxin due to:

• A. Fewer sugar moieties.
• B. A more lipophilic steroid nucleus.
• C. A greater number of hydroxyl groups on its steroid aglycone (at C1, C5, C11, C14, C19).
• D. The absence of a lactone ring.

Answer: C. A greater number of hydroxyl groups on its steroid aglycone (at C1, C5, C11, C14, C19).

19. The relatively low oral bioavailability of ouabain compared to digoxin is primarily due to its:

• A. High lipophilicity
• B. High polarity (hydrophilicity) leading to poor absorption
• C. Rapid first-pass metabolism
• D. Chemical instability in gastric acid

Answer: B. High polarity (hydrophilicity) leading to poor absorption

20. The sugar residues in cardiac glycosides are linked to the C3-OH via what type of glycosidic bond stereochemistry?

• A. α-glycosidic linkage
• B. β-glycosidic linkage
• C. Both α and β equally
• D. The linkage is not stereospecific.

Answer: B. β-glycosidic linkage

21. Which part of the cardiac glycoside molecule is thought to interact with the extracellular domain of the Na+/K+-ATPase α-subunit?

• A. Only the sugar moieties
• B. The steroid nucleus and the lactone ring
• C. The C3 hydroxyl group directly
• D. The angular methyl groups

Answer: B. The steroid nucleus and the lactone ring

22. Metabolic reduction of the C=C double bond in the lactone ring of digoxin leads to the formation of dihydrodigoxin, which is:

• A. More potent than digoxin
• B. Substantially less active or inactive
• C. A metabolite with a longer half-life
• D. The primary renally excreted form

Answer: B. Substantially less active or inactive

23. The presence of a 16-formyl group (as in gitoxin) or acetyl group on some cardiac glycoside sugar moieties can influence:

• A. The mechanism of Na+/K+-ATPase inhibition.
• B. The compound’s lipophilicity and pharmacokinetic profile.
• C. The stability of the steroid nucleus.
• D. The type of lactone ring present.

Answer: B. The compound’s lipophilicity and pharmacokinetic profile.

24. Medicinal chemistry efforts to improve the therapeutic index of cardiac glycosides have often involved:

• A. Making the molecule as lipophilic as possible.
• B. Modifying the sugar chain or steroid nucleus to alter pharmacokinetics or selectively reduce toxicity while retaining efficacy.
• C. Removing the lactone ring.
• D. Increasing the number of nitrate ester groups.

Answer: B. Modifying the sugar chain or steroid nucleus to alter pharmacokinetics or selectively reduce toxicity while retaining efficacy.

25. The interaction between cardiac glycosides and the Na+/K+-ATPase is specific to the enzyme being in which conformational state, often when it is phosphorylated?

• A. E1 conformation (high Na+ affinity, ATP-bound)
• B. E2-P conformation (high K+ affinity, phosphorylated)
• C. Dephosphorylated E2 state
• D. Any conformation with equal affinity

Answer: B. E2-P conformation (high K+ affinity, phosphorylated)

26. The term “genin” refers to:

• A. The sugar portion of a cardiac glycoside.
• B. The entire cardiac glycoside molecule.
• C. The steroid aglycone portion of a cardiac glycoside.
• D. The precursor molecule for steroid synthesis.

Answer: C. The steroid aglycone portion of a cardiac glycoside.

27. What structural feature is common to both cardenolides and bufadienolides?

• A. The same type of sugar moieties
• B. A steroid nucleus with a 14β-hydroxyl group and a C3-glycosidic linkage
• C. A five-membered lactone ring at C17
• D. Identical oral bioavailability

Answer: B. A steroid nucleus with a 14β-hydroxyl group and a C3-glycosidic linkage

28. The metabolism of digitoxin to digoxin (a minor pathway) involves which type of reaction on the steroid nucleus?

• A. Reduction
• B. Oxidation (hydroxylation at C12)
• C. Hydrolysis
• D. Glucuronidation

Answer: B. Oxidation (hydroxylation at C12)

29. The high degree of tissue binding (large Vd) of digoxin, particularly to skeletal muscle, means that:

• A. Serum concentrations rapidly equilibrate with tissue concentrations.
• B. Changes in muscle mass can affect the volume of distribution and potentially serum levels.
• C. It is rapidly cleared by hemodialysis in case of toxicity.
• D. It primarily acts on skeletal muscle Na+/K+-ATPase.

Answer: B. Changes in muscle mass can affect the volume of distribution and potentially serum levels.

30. The chemical stability of digoxin in acidic conditions (like stomach pH) can lead to:

• A. Enhancement of its activity.
• B. Hydrolysis of the glycosidic linkages, releasing sugars and the aglycone.
• C. Oxidation of the lactone ring.
• D. No significant degradation.

Answer: B. Hydrolysis of the glycosidic linkages, releasing sugars and the aglycone. (though absorption occurs before complete degradation).

31. The “digitalis” group of plants (e.g., Digitalis purpurea, Digitalis lanata) are the natural source of which important cardiac glycosides?

• A. Ouabain and strophanthin
• B. Digoxin, digitoxin, and lanatosides
• C. Scillaren A (a bufadienolide)
• D. Theophylline

Answer: B. Digoxin, digitoxin, and lanatosides

32. The difference in polarity between digoxin and digitoxin (digoxin being more polar) directly influences their:

• A. Primary mechanism of action.
• B. Route of elimination (digoxin more renal, digitoxin more hepatic/enterohepatic).
• C. Affinity for androgen receptors.
• D. Ability to cause visual disturbances.

Answer: B. Route of elimination (digoxin more renal, digitoxin more hepatic/enterohepatic).

33. From a medicinal chemistry standpoint, the narrow therapeutic index of cardiac glycosides means that:

• A. They are very safe drugs with minimal side effects.
• B. The dose required for therapeutic effect is very close to the dose that causes toxicity.
• C. They can be dosed once weekly.
• D. They are not effective at low doses.

Answer: B. The dose required for therapeutic effect is very close to the dose that causes toxicity.

34. The lactone ring oxygen atoms and the carbonyl group in cardiac glycosides are important for:

• A. Forming the glycosidic bond.
• B. Hydrogen bonding interactions or dipole interactions within the receptor binding site.
• C. Making the molecule highly lipophilic.
• D. Undergoing metabolic reduction.

Answer: B. Hydrogen bonding interactions or dipole interactions within the receptor binding site.

35. The structural requirements for cardiac glycoside activity are highly specific. Minor changes in stereochemistry or functional groups on the steroid nucleus can:

• A. Always lead to increased potency.
• B. Drastically alter or abolish pharmacological activity.
• C. Only affect the color of the compound.
• D. Make the compound orally inactive.

Answer: B. Drastically alter or abolish pharmacological activity.

36. Lanatoside C is a precursor glycoside found in Digitalis lanata. It can be hydrolyzed to yield:

• A. Ouabain
• B. Digoxin (plus glucose and an acetyl group on one of the digitoxose sugars)
• C. Digitoxin only
• D. Proscillaridin A

Answer: B. Digoxin (plus glucose and an acetyl group on one of the digitoxose sugars)

37. The C3-OH group on the steroid aglycone must have which stereochemistry for proper glycosidic linkage and activity?

• A. α (alpha) orientation
• B. β (beta) orientation
• C. The orientation is not critical.
• D. It is typically a ketone at C3.

Answer: B. β (beta) orientation

38. The development of digoxin-specific antibody fragments (DigiFab) for treating toxicity is an example of using what type of molecule as a therapeutic agent?

• A. A small synthetic organic molecule
• B. A protein (antibody fragment)
• C. A nucleic acid
• D. A polysaccharide

Answer: B. A protein (antibody fragment)

39. The binding affinity of cardiac glycosides to Na+/K+-ATPase can be modulated by:

• A. Only the number of sugar units.
• B. The specific structure of both the aglycone and the glycone portions, as well as extracellular K+ concentration.
• C. The ambient temperature.
• D. The patient’s blood type.

Answer: B. The specific structure of both the aglycone and the glycone portions, as well as extracellular K+ concentration.

40. The methyl groups at C10 and C13 of the steroid nucleus in cardiac glycosides are termed “angular” methyl groups. Their presence and orientation contribute to:

• A. The molecule’s acidity.
• B. The overall three-dimensional shape and rigidity of the steroid backbone.
• C. The site of glycosylation.
• D. The reactivity of the lactone ring.

Answer: B. The overall three-dimensional shape and rigidity of the steroid backbone.

41. What is the significance of the 2-deoxy nature of sugars like digitoxose in cardiac glycosides?

• A. It makes the glycosidic bond more resistant to acid hydrolysis.
• B. It increases the polarity of the sugar.
• C. It alters the sugar’s conformation and can influence the overall molecule’s lipophilicity and binding.
• D. It is required for interaction with P-glycoprotein.

Answer: C. It alters the sugar’s conformation and can influence the overall molecule’s lipophilicity and binding. (And generally increases lipophilicity compared to non-deoxy sugars).

42. If the C14-β-hydroxyl group of a cardiac glycoside is removed or epimerized to the α-configuration, the molecule typically:

• A. Becomes more potent.
• B. Loses most of its cardiotonic activity.
• C. Has an improved pharmacokinetic profile.
• D. Becomes orally bioavailable if it wasn’t before.

Answer: B. Loses most of its cardiotonic activity.

43. The interaction of the unsaturated lactone ring with the Na+/K+-ATPase is thought to be stabilized by:

• A. Covalent bond formation only.
• B. Multiple non-covalent interactions, including hydrogen bonds and van der Waals forces, possibly involving a nucleophilic attack in some theories.
• C. Ionic bonds with potassium ions.
• D. Its complete lack of interaction; only the steroid binds.

Answer: B. Multiple non-covalent interactions, including hydrogen bonds and van der Waals forces, possibly involving a nucleophilic attack in some theories.

44. The differences in the sugar chains between various cardiac glycosides (e.g., digoxin vs. lanatoside C) primarily affect:

• A. The intrinsic inhibitory potency at the Na+/K+-ATPase site.
• B. The pharmacokinetics (absorption, distribution, metabolism, excretion) more than the intrinsic potency.
• C. The mechanism of action entirely.
• D. The color of the resulting drug powder.

Answer: B. The pharmacokinetics (absorption, distribution, metabolism, excretion) more than the intrinsic potency. (The aglycone is the primary determinant of intrinsic potency).

45. From a medicinal chemistry perspective, the challenge with cardiac glycosides is their:

• A. Lack of potency
• B. Broad spectrum of activity beyond the heart
• C. Narrow therapeutic index and complex SAR
• D. Instability in all formulations

Answer: C. Narrow therapeutic index and complex SAR

46. Which statement best describes the general acid/base nature of cardiac glycosides like digoxin?

• A. They are strong acids.
• B. They are strong bases.
• C. They are essentially neutral compounds, though the steroid hydroxyls are very weakly acidic.
• D. They are zwitterionic.

Answer: C. They are essentially neutral compounds, though the steroid hydroxyls are very weakly acidic.

47. Efforts to synthesize simplified analogues of cardiac glycosides that retain inotropic activity but have a better safety profile have focused on:

• A. Mimicking only the sugar moieties.
• B. Identifying the minimal structural requirements of the aglycone (especially the lactone and steroid conformation) for Na+/K+-ATPase inhibition.
• C. Creating larger, more complex steroid structures.
• D. Developing purely peptide-based mimetics.

Answer: B. Identifying the minimal structural requirements of the aglycone (especially the lactone and steroid conformation) for Na+/K+-ATPase inhibition.

48. The presence of an acetyl group on one of the digitoxose sugars in lanatoside C, compared to digoxin (which lacks it after processing), affects its:

• A. Mechanism of action
• B. Polarity and pharmacokinetic properties (lanatoside C is more lipophilic than digoxin if considering the full trisaccharide)
• C. Binding site on the Na+/K+-ATPase
• D. Color and odor

Answer: B. Polarity and pharmacokinetic properties (Acetylation generally increases lipophilicity).

49. The extraction and purification of cardiac glycosides from plant material (like Digitalis leaves) is a complex process due to:

• A. Their extreme volatility.
• B. The presence of multiple closely related glycosides and the need to separate them.
• C. Their complete insolubility in all solvents.
• D. Their rapid degradation upon exposure to air.

Answer: B. The presence of multiple closely related glycosides and the need to separate them.

50. The C5 hydrogen in naturally occurring cardiac glycosides typically has which orientation relative to the A/B ring fusion?

• A. Always α (trans A/B fusion)
• B. Always β (cis A/B fusion)
• C. It can be either α or β with equal activity.
• D. There is no hydrogen at C5.

Answer: B. Always β (cis A/B fusion) (This, along with cis C/D and trans B/C, defines the characteristic shape).