Antiarrhythmic drugs are a diverse group of compounds designed to correct disturbances in cardiac rhythm by targeting the electrical properties of heart cells. Their chemical structures are intricately linked to their mechanisms of action, dictating how they interact with specific ion channels or receptors, their pharmacokinetic profiles, and their potential for adverse effects. For PharmD students, understanding the medicinal chemistry of antiarrhythmics—including their core scaffolds, structure-activity relationships (SAR), stereochemical considerations, and metabolic pathways—is crucial for appreciating their therapeutic applications, limitations, and the rationale behind the development of newer agents. This MCQ quiz will test your knowledge on these vital medicinal chemistry principles.
1. The Vaughan Williams classification of antiarrhythmic drugs is primarily based on their effect on cardiac action potentials. Class I drugs are known to block which ion channels?
- A. Potassium channels
- B. Calcium channels
- C. Sodium channels
- D. Chloride channels
Answer: C. Sodium channels
2. Quinidine, a Class Ia antiarrhythmic, is a cinchona alkaloid. Its structure consists of a quinoline ring system linked to a:
- A. Piperidine ring
- B. Quinuclidine ring system
- C. Benzothiazepine ring
- D. Dihydropyridine ring
Answer: B. Quinuclidine ring system
3. Procainamide (Class Ia) was developed as an analogue of procaine. The key structural modification from procaine to procainamide to improve its stability against plasma esterases was the replacement of the:
- A. Aromatic amino group with a nitro group
- B. Ester linkage with an amide linkage
- C. Tertiary amine with a primary amine
- D. Phenyl ring with a pyridine ring
Answer: B. Ester linkage with an amide linkage
4. Disopyramide (Class Ia) is characterized by a central phenylacetamide structure with a basic _________ ring, which contributes to its anticholinergic side effects.
- A. Imidazole
- B. Pyridine (specifically a 2-(diisopropylamino)ethyl side chain on a α-phenyl-2-pyridineacetamide structure)
- C. Piperazine
- D. Morpholine
Correction for Disopyramide’s structure: 4. Disopyramide (Class Ia) has an α-phenyl-α-(2-pyridyl)acetamide core. The basicity contributing to anticholinergic effects comes from its:
- A. Pyridine ring nitrogen
- B. N,N-diisopropylaminoethyl side chain
- C. Amide nitrogen
- D. Phenyl ring
Answer: B. N,N-diisopropylaminoethyl side chain (The tertiary amine is highly basic).
5. Lidocaine, a Class Ib antiarrhythmic, has an amide linkage. The presence of two methyl groups ortho to the amide nitrogen on the aromatic ring (xylidide structure) serves to:
- A. Increase its water solubility.
- B. Sterically hinder hydrolysis of the amide bond, increasing its stability and allowing for IV use.
- C. Enhance its binding to potassium channels.
- D. Make it orally active.
Answer: B. Sterically hinder hydrolysis of the amide bond, increasing its stability and allowing for IV use.
6. Mexiletine is an orally active Class Ib antiarrhythmic and a structural analogue of lidocaine. The key difference from lidocaine that confers oral activity is the replacement of the amide linkage with a(n):
- A. Ester linkage
- B. Ether linkage (and it’s a primary amine, not tertiary)
- C. Sulfonamide linkage
- D. Direct carbon-carbon bond
Answer: B. Ether linkage (and it’s a primary amine, not tertiary) (Mexiletine is an amine with an ether linkage in the side chain, making it more stable to first-pass metabolism than lidocaine’s amide).
7. Flecainide, a Class Ic antiarrhythmic, contains which highly electronegative functional groups that contribute to its potent sodium channel blockade?
- A. Multiple hydroxyl groups
- B. Two trifluoroethoxy groups on the benzamide ring
- C. A nitro group
- D. A sulfhydryl group
Answer: B. Two trifluoroethoxy groups on the benzamide ring
8. Propafenone (Class Ic) possesses a chiral center. It is typically marketed as a racemic mixture. In addition to its potent sodium channel blocking activity, propafenone also exhibits weak:
- A. Calcium channel blocking activity
- B. Beta-adrenergic blocking activity
- C. Potassium channel opening activity
- D. Muscarinic agonistic activity
Answer: B. Beta-adrenergic blocking activity (due to its aryl-oxy-propanolamine side chain).
9. The general pharmacophore for many Class II antiarrhythmics (beta-blockers) is an aryloxypropanolamine structure. The “propanolamine” part refers to:
- A. A three-carbon chain with an alcohol and an amine
- B. A propane ring with an amino group
- C. A propanamide structure
- D. A proprionic acid derivative
Answer: A. A three-carbon chain with an alcohol and an amine (-O-CH2-CH(OH)-CH2-NHR).
10. Sotalol is unique as it exhibits both Class II (beta-blocking) and Class III (potassium channel blocking) antiarrhythmic properties. Its Class III activity is primarily attributed to the presence of which group?
- A. The aryloxypropanolamine side chain
- B. A methanesulfonamide group (-NHSO2CH3) on the aniline ring
- C. An iodine atom
- D. A benzofuran ring
Answer: B. A methanesulfonamide group (-NHSO2CH3) on the aniline ring
11. Amiodarone, a Class III antiarrhythmic, is a highly lipophilic molecule containing two iodine atoms on which part of its structure?
- A. The benzofuran ring
- B. The diethylaminoethoxy side chain
- C. The benzoyl moiety attached to the benzofuran
- D. It does not contain iodine.
Answer: C. The benzoyl moiety attached to the benzofuran
12. The high lipophilicity and extensive tissue distribution of amiodarone contribute to its:
- A. Rapid onset of action and short half-life.
- B. Very long elimination half-life and large volume of distribution, requiring loading doses.
- C. Primary renal excretion as unchanged drug.
- D. Minimal drug interactions.
Answer: B. Very long elimination half-life and large volume of distribution, requiring loading doses.
13. Dofetilide and ibutilide are considered more “pure” Class III antiarrhythmics, primarily blocking the rapid component of the delayed rectifier potassium current (IKr). They belong to which chemical class?
- A. Benzofuran derivatives
- B. Methanesulfonanilide derivatives
- C. Phenothiazines
- D. Cinchona alkaloids
Answer: B. Methanesulfonanilide derivatives
14. Dronedarone was designed as an analogue of amiodarone to reduce toxicity. Key structural modifications include the removal of iodine atoms and the addition of a:
- A. Second benzofuran ring
- B. Methanesulfonyl group to increase water solubility and alter metabolism
- C. Nitro group
- D. Thienopyridine ring
Answer: B. Methanesulfonyl group to increase water solubility and alter metabolism
15. Verapamil, a Class IV antiarrhythmic, belongs to which chemical class?
- A. Benzothiazepine
- B. Dihydropyridine
- C. Phenylalkylamine
- D. Aryloxypropanolamine
Answer: C. Phenylalkylamine
16. Diltiazem, another Class IV antiarrhythmic, has a core __________ ring system.
- A. Phenylalkylamine
- B. Benzothiazepine
- C. Dihydropyridine
- D. Benzofuran
Answer: B. Benzothiazepine
17. The stereochemistry of verapamil is important for its activity. The (S)-enantiomer is:
- A. Less potent than the (R)-enantiomer as a calcium channel blocker.
- B. More potent than the (R)-enantiomer as a calcium channel blocker.
- C. Equipotent to the (R)-enantiomer.
- D. The primary active metabolite.
Answer: B. More potent than the (R)-enantiomer as a calcium channel blocker.
18. The cis-configuration of the substituents on the benzothiazepine ring of diltiazem is:
- A. Unimportant for its activity.
- B. Essential for its antiarrhythmic activity.
- C. Important only for its solubility.
- D. Responsible for its Class III effects.
Answer: B. Essential for its antiarrhythmic activity.
19. Adenosine, used for acute termination of SVT, is chemically a(n):
- A. Synthetic peptide
- B. Endogenous purine ribonucleoside (adenine + ribose)
- C. Catecholamine
- D. Organic nitrate
Answer: B. Endogenous purine ribonucleoside (adenine + ribose)
20. The basic amino group present in many Class I and Class III antiarrhythmics is important because at physiological pH, it is largely protonated, allowing for:
- A. Increased lipophilicity and CNS penetration.
- B. Ionic interactions with negatively charged residues in ion channel binding sites.
- C. Resistance to metabolic degradation.
- D. Direct activation of beta-receptors.
Answer: B. Ionic interactions with negatively charged residues in ion channel binding sites.
21. The presence of an aromatic ring is a common structural feature in many Class I antiarrhythmics. This group often participates in what type of interaction with the sodium channel?
- A. Covalent bonding
- B. Hydrogen bonding primarily
- C. Hydrophobic and/or pi-stacking interactions
- D. Metal chelation
Answer: C. Hydrophobic and/or pi-stacking interactions
22. Many antiarrhythmic drugs are weak bases. Their degree of ionization, and thus absorption and distribution, can be influenced by:
- A. Only their molecular weight
- B. The pH of the environment and their pKa value
- C. Only their route of administration
- D. The presence of iodine in their structure
Answer: B. The pH of the environment and their pKa value
23. N-acetylation is a key metabolic pathway for which Class Ia antiarrhythmic, leading to an active metabolite (NAPA) with predominantly Class III activity?
- A. Quinidine
- B. Procainamide
- C. Disopyramide
- D. Lidocaine
Answer: B. Procainamide
24. The metabolism of lidocaine to monoethylglycinexylidide (MEGX) and glycinexylidide (GX) involves:
- A. Hydrolysis of the amide bond as the primary step.
- B. N-dealkylation of the tertiary amine.
- C. Aromatic hydroxylation only.
- D. Glucuronidation as the first step.
Answer: B. N-dealkylation of the tertiary amine.
25. Amiodarone’s extensive metabolism is primarily mediated by which CYP enzyme, leading to its active metabolite, desethylamiodarone?
- A. CYP2D6
- B. CYP2C19
- C. CYP3A4 (and to a lesser extent CYP2C8)
- D. CYP1A2
Answer: C. CYP3A4 (and to a lesser extent CYP2C8)
26. The methanesulfonamide group in Class III drugs like sotalol and dofetilide is thought to be crucial for their:
- A. Beta-blocking activity
- B. Potassium channel (IKr) blocking activity
- C. Sodium channel blocking activity
- D. Oral bioavailability
Answer: B. Potassium channel (IKr) blocking activity
27. The design of dronedarone from amiodarone by removing iodine atoms aimed to:
- A. Increase its lipophilicity.
- B. Reduce thyroid-related adverse effects and potentially alter its pharmacokinetic profile.
- C. Enhance its Class I activity.
- D. Make it suitable for IV administration only.
Answer: B. Reduce thyroid-related adverse effects and potentially alter its pharmacokinetic profile.
28. The structure of adenosine includes a ribose sugar and an adenine base. Its rapid inactivation in the blood is due to cellular uptake and enzymatic degradation by:
- A. Cytochrome P450 enzymes
- B. Esterases
- C. Adenosine deaminase (to inosine) and adenosine kinase
- D. Glucuronyltransferases
Answer: C. Adenosine deaminase (to inosine) and adenosine kinase
29. The positive charge on the quaternary ammonium group of some antiarrhythmics (e.g., bretylium, an older Class III agent) would make them:
- A. Highly lipophilic and well-absorbed orally.
- B. Permanently charged, poorly absorbed orally, and primarily active via extracellular mechanisms or specific transporters.
- C. Prone to rapid metabolism.
- D. Effective sodium channel blockers.
Answer: B. Permanently charged, poorly absorbed orally, and primarily active via extracellular mechanisms or specific transporters.
30. What structural feature of digoxin (a cardiac glycoside with antiarrhythmic properties) makes it a substrate for the P-glycoprotein efflux pump?
- A. Its overall steroidal structure and specific sugar moieties contribute to P-gp recognition.
- B. The unsaturated lactone ring.
- C. The C14 hydroxyl group.
- D. It is not a P-gp substrate.
Answer: A. Its overall steroidal structure and specific sugar moieties contribute to P-gp recognition.
31. Class Ib antiarrhythmics like lidocaine exhibit greater binding to sodium channels that are in which states, making them more effective in ischemic tissue?
- A. Resting state only
- B. Activated (open) and inactivated states, which are more prevalent in rapidly firing or depolarized ischemic cells
- C. Only the closed state at hyperpolarized potentials
- D. They do not show state-dependent binding.
Answer: B. Activated (open) and inactivated states, which are more prevalent in rapidly firing or depolarized ischemic cells
32. The anticholinergic effects of disopyramide are attributed to its structural resemblance, particularly its basic side chain, to:
- A. Beta-blockers
- B. Muscarinic antagonists like atropine
- C. Calcium channel blockers
- D. Digitalis glycosides
Answer: B. Muscarinic antagonists like atropine
33. The presence of a chiral center in propafenone leads to enantiomers. (S)-propafenone and (R)-propafenone exhibit:
- A. Identical pharmacological activity and metabolism.
- B. Differences in Na+ channel blocking potency and beta-blocking activity, as well as metabolism.
- C. Only differences in solubility.
- D. Only (S)-propafenone being active.
Answer: B. Differences in Na+ channel blocking potency and beta-blocking activity, as well as metabolism.
34. The aryl-oxy-propanolamine moiety is characteristic of beta-blockers. The oxygen atom in this moiety is important for:
- A. Direct sodium channel blockade.
- B. Ether linkage and proper spatial arrangement for receptor binding.
- C. Forming a reactive metabolite.
- D. Undergoing rapid hydrolysis.
Answer: B. Ether linkage and proper spatial arrangement for receptor binding.
35. In amiodarone, the two iodine atoms contribute significantly to its:
- A. Water solubility.
- B. High lipophilicity and unique pharmacokinetic/pharmacodynamic profile, including thyroid effects.
- C. Rapid renal excretion.
- D. Lack of protein binding.
Answer: B. High lipophilicity and unique pharmacokinetic/pharmacodynamic profile, including thyroid effects.
36. The chemical stability of adenosine in IV solution is relatively good, but its pharmacological effect is terminated rapidly in vivo due to:
- A. Spontaneous hydrolysis
- B. Efficient cellular uptake and enzymatic degradation
- C. Binding to plasma proteins
- D. Photodegradation
Answer: B. Efficient cellular uptake and enzymatic degradation
37. What is the difference in the state of the nitrogen atom in lidocaine (tertiary amine) versus mexiletine (primary amine) at physiological pH?
- A. Lidocaine’s nitrogen is uncharged; mexiletine’s is charged.
- B. Both are predominantly protonated (charged), but their pKa values and lipophilicity of the free base will differ.
- C. Mexiletine’s nitrogen is uncharged; lidocaine’s is charged.
- D. Both are predominantly uncharged.
Answer: B. Both are predominantly protonated (charged), but their pKa values and lipophilicity of the free base will differ.
38. The benzofuran ring system is a core structural component of which Class III antiarrhythmics?
- A. Sotalol and Dofetilide
- B. Amiodarone and Dronedarone
- C. Quinidine and Procainamide
- D. Lidocaine and Mexiletine
Answer: B. Amiodarone and Dronedarone
39. Medicinal chemistry strategies to reduce the toxicity of amiodarone, leading to dronedarone, involved:
- A. Adding more iodine atoms.
- B. Removing iodine (de-iodination) and incorporating a methanesulfonyl group to reduce lipophilicity and alter PK/PD.
- C. Converting the benzofuran to a quinoline.
- D. Increasing the size of the N-alkyl substituent.
Answer: B. Removing iodine (de-iodination) and incorporating a methanesulfonyl group to reduce lipophilicity and alter PK/PD.
40. The ability of Class Ia drugs like quinidine to also block potassium channels contributes to their effect of:
- A. Shortening the action potential duration.
- B. Prolonging the action potential duration and the QT interval.
- C. Causing beta-blockade.
- D. Only affecting Phase 0 of the action potential.
Answer: B. Prolonging the action potential duration and the QT interval.
41. The chemical structure of sotalol contains a chiral center. The beta-blocking activity resides primarily in which enantiomer?
- A. (R)-sotalol
- B. (L)-sotalol
- C. Both are equipotent beta-blockers.
- D. The racemic mixture is required for beta-blockade.
Answer: B. (L)-sotalol (The Class III K+ channel blocking activity is present in both enantiomers).
42. From a medicinal chemistry perspective, the “use-dependence” of Class Ic drugs suggests their binding site on the sodium channel is more accessible when the channel is:
- A. In the resting state.
- B. In the open or inactivated state, which occurs more frequently at higher heart rates.
- C. Blocked by calcium ions.
- D. Phosphorylated.
Answer: B. In the open or inactivated state, which occurs more frequently at higher heart rates.
43. The positive charge on ionized basic antiarrhythmics (e.g., lidocaine, quinidine at physiological pH) is thought to facilitate their interaction with the sodium channel by:
- A. Allowing them to pass through the lipid membrane more easily.
- B. Interacting with negatively charged amino acid residues within the channel pore or binding site.
- C. Directly chelating calcium ions.
- D. Covalently binding to the channel protein.
Answer: B. Interacting with negatively charged amino acid residues within the channel pore or binding site.
44. The relatively high incidence of CNS side effects with lidocaine is related to its:
- A. Poor lipid solubility.
- B. Ability to cross the blood-brain barrier due to sufficient lipophilicity of the uncharged form.
- C. Primary renal excretion.
- D. Lack of metabolism.
Answer: B. Ability to cross the blood-brain barrier due to sufficient lipophilicity of the uncharged form.
45. The structural basis for the selectivity of non-dihydropyridine calcium channel blockers (verapamil, diltiazem) for cardiac L-type calcium channels over vascular L-type channels (compared to dihydropyridines) relates to:
- A. Their much smaller molecular size.
- B. Different binding sites and/or state-dependent interactions with the cardiac calcium channels.
- C. Their inability to cross cell membranes.
- D. Their rapid metabolism in vascular tissue.
Answer: B. Different binding sites and/or state-dependent interactions with the cardiac calcium channels.
46. Many Class I antiarrhythmics contain an amide or ester linkage. Which is generally more susceptible to rapid in vivo hydrolysis by esterases?
- A. Amide linkage
- B. Ester linkage
- C. Both are equally stable.
- D. Neither is susceptible to hydrolysis.
Answer: B. Ester linkage (e.g., procaine vs. procainamide).
47. The piperidine ring in flecainide is a basic moiety. This part of the molecule is important for:
- A. Its interaction with potassium channels.
- B. Its overall physicochemical properties (e.g., pKa, salt formation) and interaction with the sodium channel.
- C. Its metabolism by CYP2D6.
- D. Its conversion to an active metabolite.
Answer: B. Its overall physicochemical properties (e.g., pKa, salt formation) and interaction with the sodium channel.
48. The design of “soft drugs” in medicinal chemistry aims to create compounds that:
- A. Are very hard and crystalline.
- B. Exert their therapeutic effect and are then rapidly metabolized to inactive, non-toxic products in a predictable manner.
- C. Have very long half-lives.
- D. Are universally effective for all patients.
Answer: B. Exert their therapeutic effect and are then rapidly metabolized to inactive, non-toxic products in a predictable manner. (Esmolol is an example of a soft drug concept).
49. The presence of the methanesulfonamido group (-NHSO2CH3) in many Class III agents like sotalol, dofetilide, and ibutilide is a key pharmacophore for:
- A. Beta-adrenergic blockade
- B. IKr potassium channel blockade
- C. Sodium channel blockade
- D. Calcium channel blockade
Answer: B. IKr potassium channel blockade
50. The molecular structure of adenosine allows it to activate specific G-protein coupled purinergic receptors (A1 receptors) on AV nodal cells. This receptor activation leads to:
- A. Increased cAMP and calcium influx.
- B. Activation of an outward potassium current (IK,Ado) and inhibition of adenylyl cyclase, causing hyperpolarization and slowed conduction.
- C. Direct blockade of sodium channels.
- D. Inhibition of Na+/K+-ATPase.
Answer: B. Activation of an outward potassium current (IK,Ado) and inhibition of adenylyl cyclase, causing hyperpolarization and slowed conduction.