The safe and effective use of digoxin and other antiarrhythmic drugs is critically dependent on a thorough understanding of their pharmacokinetic properties. These properties—Absorption, Distribution, Metabolism, and Excretion (ADME)—dictate dosing regimens, influence the onset and duration of action, predict the potential for drug interactions, and determine the need for therapeutic drug monitoring and dose adjustments in specific patient populations (e.g., renal or hepatic impairment). For PharmD students, mastering the pharmacokinetics of these often narrow-therapeutic-index agents is essential for optimizing therapy and minimizing adverse events. This MCQ quiz will test your knowledge on the key pharmacokinetic characteristics of digoxin and various classes of antiarrhythmic drugs.
1. Digoxin, a cardiac glycoside, is primarily eliminated from the body via:
- A. Hepatic metabolism by CYP3A4
- B. Renal excretion, largely as unchanged drug
- C. Biliary excretion and enterohepatic recirculation
- D. Pulmonary exhalation
Answer: B. Renal excretion, largely as unchanged drug
2. The oral bioavailability of digoxin can be variable and is notably affected by its interaction with which intestinal efflux transporter?
- A. Organic Anion Transporter (OAT1)
- B. P-glycoprotein (P-gp / MDR1)
- C. Organic Cation Transporter (OCT2)
- D. Multidrug Resistance-associated Protein 2 (MRP2)
Answer: B. P-glycoprotein (P-gp / MDR1)
3. Digoxin has a large volume of distribution (Vd), indicating that it:
- A. Is primarily confined to the plasma compartment.
- B. Distributes extensively into tissues (e.g., skeletal muscle, heart).
- C. Is highly bound to plasma proteins.
- D. Has a very short elimination half-life.
Answer: B. Distributes extensively into tissues (e.g., skeletal muscle, heart).
4. Quinidine, a Class Ia antiarrhythmic, is primarily metabolized by which cytochrome P450 enzyme?
- A. CYP2D6
- B. CYP2C9
- C. CYP3A4
- D. CYP1A2
Answer: C. CYP3A4
5. Procainamide (Class Ia) is metabolized in the liver by acetylation to an active metabolite with Class III antiarrhythmic properties. This metabolite is:
- A. Lidocaine
- B. N-acetylprocainamide (NAPA)
- C. Disopyramide
- D. Quinidine gluconate
Answer: B. N-acetylprocainamide (NAPA)
6. Both procainamide and its active metabolite, NAPA, are primarily eliminated by:
- A. Biliary excretion
- B. Hepatic metabolism only
- C. Renal excretion
- D. Pulmonary exhalation
Answer: C. Renal excretion
7. Lidocaine (Class Ib) is not effective when administered orally due to:
- A. Poor absorption from the GI tract
- B. Extensive first-pass hepatic metabolism
- C. Chemical instability in gastric acid
- D. Rapid renal excretion of the oral form
Answer: B. Extensive first-pass hepatic metabolism
8. Mexiletine is an oral Class Ib antiarrhythmic that is structurally similar to lidocaine. Unlike lidocaine, it:
- A. Is administered intravenously only.
- B. Has good oral bioavailability and is used for chronic ventricular arrhythmias.
- C. Is primarily eliminated unchanged by the kidneys.
- D. Does not undergo hepatic metabolism.
Answer: B. Has good oral bioavailability and is used for chronic ventricular arrhythmias.
9. Flecainide (Class Ic) is metabolized by which polymorphic cytochrome P450 enzyme, leading to potential variability in plasma concentrations?
- A. CYP3A4
- B. CYP2C19
- C. CYP2D6
- D. CYP1A2
Answer: C. CYP2D6
10. Propafenone (Class Ic) undergoes extensive first-pass metabolism, and its pharmacokinetics can be non-linear. It is primarily metabolized by:
- A. Renal hydrolysis
- B. CYP2D6, with contributions from CYP1A2 and CYP3A4
- C. Glucuronidation only
- D. Acetylation in the liver
Answer: B. CYP2D6, with contributions from CYP1A2 and CYP3A4
11. Which of the following beta-blockers (Class II) is highly lipophilic, undergoes extensive hepatic metabolism, and has significant CNS penetration?
- A. Atenolol
- B. Nadolol
- C. Propranolol
- D. Sotalol
Answer: C. Propranolol
12. Atenolol, a cardioselective beta-blocker, is primarily eliminated by:
- A. Hepatic metabolism via CYP2D6
- B. Renal excretion as unchanged drug
- C. Biliary excretion
- D. Hydrolysis by plasma esterases
Answer: B. Renal excretion as unchanged drug
13. Esmolol is an intravenous beta-blocker with an ultra-short duration of action due to its rapid metabolism by:
- A. Cytochrome P450 enzymes in the liver
- B. Esterases in red blood cells
- C. Renal tubular secretion
- D. Acetylation in the plasma
Answer: B. Esterases in red blood cells
14. Amiodarone (Class III) has a very complex pharmacokinetic profile characterized by:
- A. A small volume of distribution and short half-life.
- B. High water solubility and rapid renal excretion.
- C. High lipophilicity, very large volume of distribution, extensive tissue accumulation, and an extremely long elimination half-life.
- D. Complete lack of metabolism.
Answer: C. High lipophilicity, very large volume of distribution, extensive tissue accumulation, and an extremely long elimination half-life.
15. Amiodarone is a potent inhibitor of several CYP450 enzymes (e.g., CYP2C9, CYP2D6, CYP3A4) and P-glycoprotein. This leads to a high potential for:
- A. Decreased efficacy of concomitantly administered drugs.
- B. Numerous significant drug-drug interactions, often requiring dose adjustments of other drugs.
- C. No significant drug interactions.
- D. Rapid induction of its own metabolism.
Answer: B. Numerous significant drug-drug interactions, often requiring dose adjustments of other drugs.
16. Sotalol (Class III) is unique because it is a non-selective beta-blocker that also has K+ channel blocking properties. Its primary route of elimination is:
- A. Hepatic metabolism
- B. Renal excretion as unchanged drug
- C. Biliary excretion
- D. Metabolism by plasma esterases
Answer: B. Renal excretion as unchanged drug
17. Dofetilide (Class III) is primarily eliminated via active tubular secretion in the kidneys by which transporter, making it susceptible to interactions with inhibitors of this transporter?
- A. P-glycoprotein (P-gp)
- B. Organic Cation Transporter 2 (OCT2)
- C. Organic Anion Transporter 1 (OAT1)
- D. Bile Salt Export Pump (BSEP)
Answer: B. Organic Cation Transporter 2 (OCT2)
18. Dronedarone, a Class III antiarrhythmic and structural analogue of amiodarone, is a substrate and inhibitor of:
- A. Only renal organic cation transporters
- B. CYP3A4 and P-glycoprotein
- C. UGT1A1 only
- D. Aldehyde dehydrogenase
Answer: B. CYP3A4 and P-glycoprotein
19. Verapamil and diltiazem (Class IV non-dihydropyridine calcium channel blockers) undergo extensive:
- A. Renal excretion as unchanged drugs.
- B. First-pass hepatic metabolism, primarily by CYP3A4, often forming active metabolites.
- C. Hydrolysis by plasma esterases.
- D. No significant metabolism.
Answer: B. First-pass hepatic metabolism, primarily by CYP3A4, often forming active metabolites.
20. Adenosine is administered intravenously for acute termination of SVTs. Its therapeutic effect is very short-lived due to:
- A. An extremely rapid uptake into cells (e.g., erythrocytes, endothelial cells) and metabolism by adenosine deaminase.
- B. High plasma protein binding.
- C. Slow renal excretion.
- D. Enterohepatic recirculation.
Answer: A. An extremely rapid uptake into cells (e.g., erythrocytes, endothelial cells) and metabolism by adenosine deaminase.
21. Therapeutic Drug Monitoring (TDM) is most clinically useful for digoxin because of its:
- A. Wide therapeutic index and predictable dose-response.
- B. Narrow therapeutic index and high interpatient pharmacokinetic variability.
- C. Lack of serious adverse effects.
- D. Short half-life requiring frequent dosing.
Answer: B. Narrow therapeutic index and high interpatient pharmacokinetic variability.
22. When should serum digoxin levels generally be drawn to assess steady-state concentrations for therapeutic monitoring?
- A. 1-2 hours after an oral dose (peak concentration)
- B. Just before the next scheduled dose (trough concentration), and at least 6-8 hours after the last dose to allow for tissue distribution
- C. At any random time during the day
- D. Only when the patient is experiencing toxicity
Answer: B. Just before the next scheduled dose (trough concentration), and at least 6-8 hours after the last dose to allow for tissue distribution
23. The elimination half-life of a drug is the time required for:
- A. The drug to be completely absorbed.
- B. The plasma drug concentration to decrease by 50%.
- C. The drug to reach its peak effect.
- D. The drug to be fully metabolized in the liver.
Answer: B. The plasma drug concentration to decrease by 50%.
24. Renal impairment significantly affects the pharmacokinetics and requires dose adjustment for which of the following antiarrhythmics?
- A. Lidocaine
- B. Propranolol
- C. Digoxin, Sotalol, Dofetilide
- D. Amiodarone (primary elimination is not renal, but caution in severe renal disease)
Answer: C. Digoxin, Sotalol, Dofetilide
25. Which pharmacokinetic parameter primarily determines the dosing interval of a drug?
- A. Volume of distribution (Vd)
- B. Elimination half-life (t1/2)
- C. Peak plasma concentration (Cmax)
- D. Oral bioavailability (F)
Answer: B. Elimination half-life (t1/2)
26. P-glycoprotein (P-gp) is an efflux transporter that can affect the absorption and distribution of many drugs, including digoxin and dronedarone. P-gp inhibitors can:
- A. Decrease the bioavailability and tissue penetration of P-gp substrates.
- B. Increase the bioavailability and tissue penetration (or decrease efflux) of P-gp substrates.
- C. Have no effect on drugs that are P-gp substrates.
- D. Only affect the renal excretion of drugs.
Answer: B. Increase the bioavailability and tissue penetration (or decrease efflux) of P-gp substrates.
27. Hepatic impairment is most likely to significantly alter the pharmacokinetics of antiarrhythmic drugs that undergo:
- A. Primarily renal excretion as unchanged drug (e.g., sotalol, atenolol)
- B. Extensive hepatic metabolism (e.g., lidocaine, propranolol, verapamil, amiodarone)
- C. Hydrolysis by plasma esterases (e.g., esmolol)
- D. No metabolism
Answer: B. Extensive hepatic metabolism (e.g., lidocaine, propranolol, verapamil, amiodarone)
28. The loading dose of an antiarrhythmic drug like amiodarone or digoxin is given to:
- A. Minimize the risk of adverse effects.
- B. Rapidly achieve therapeutic concentrations in the plasma and tissues, especially for drugs with large volumes of distribution and long half-lives.
- C. Assess the patient’s tolerance to the drug.
- D. Bypass first-pass metabolism.
Answer: B. Rapidly achieve therapeutic concentrations in the plasma and tissues, especially for drugs with large volumes of distribution and long half-lives.
29. Which Class Ib antiarrhythmic is often used for ventricular arrhythmias and has a relatively narrow therapeutic window, necessitating monitoring for CNS toxicity (e.g., dizziness, paresthesias, seizures)?
- A. Quinidine
- B. Lidocaine (and its oral analog mexiletine)
- C. Amiodarone
- D. Sotalol
Answer: B. Lidocaine (and its oral analog mexiletine)
30. Propafenone exhibits non-linear pharmacokinetics at higher doses, meaning that:
- A. A proportional increase in dose leads to a proportional increase in plasma concentration.
- B. A proportional increase in dose leads to a less-than-proportional increase in plasma concentration.
- C. A proportional increase in dose leads to a greater-than-proportional increase in plasma concentration due to saturation of metabolism.
- D. Its half-life decreases with increasing doses.
Answer: C. A proportional increase in dose leads to a greater-than-proportional increase in plasma concentration due to saturation of metabolism.
31. The elimination of dofetilide is highly dependent on renal tubular secretion. Co-administration with drugs that inhibit its renal secretion (e.g., cimetidine, trimethoprim) can lead to:
- A. Decreased dofetilide levels and reduced efficacy.
- B. Increased dofetilide levels and increased risk of Torsades de Pointes.
- C. No significant change in dofetilide levels.
- D. Accelerated metabolism of dofetilide.
Answer: B. Increased dofetilide levels and increased risk of Torsades de Pointes.
32. Why is therapeutic drug monitoring less commonly performed for beta-blockers (Class II) compared to digoxin or Class I antiarrhythmics?
- A. Beta-blockers have a very wide therapeutic index.
- B. Their clinical effects (e.g., heart rate, blood pressure) and tolerance are often more easily monitored than serum drug concentrations, and a good concentration-response relationship is not always established for all effects.
- C. They are not metabolized.
- D. They have no significant drug interactions.
Answer: B. Their clinical effects (e.g., heart rate, blood pressure) and tolerance are often more easily monitored than serum drug concentrations, and a good concentration-response relationship is not always established for all effects.
33. Amiodarone’s very long half-life means that:
- A. Steady-state concentrations are reached within a few days.
- B. It takes a very long time (months) to reach steady-state and for the drug to be eliminated from the body after discontinuation.
- C. Dose adjustments can be made daily with immediate effect.
- D. It is primarily cleared by hemodialysis.
Answer: B. It takes a very long time (months) to reach steady-state and for the drug to be eliminated from the body after discontinuation.
34. Which of the following pharmacokinetic processes is most likely to be impaired in an elderly patient, potentially affecting the dosing of many antiarrhythmics?
- A. Increased hepatic blood flow
- B. Reduced renal function (glomerular filtration rate)
- C. Increased first-pass metabolism
- D. Faster drug absorption
Answer: B. Reduced renal function (glomerular filtration rate)
35. The pharmacokinetics of digoxin are significantly altered by thyroid status. In hyperthyroidism, digoxin clearance may be _________, requiring potentially _________ doses.
- A. Decreased; lower
- B. Increased; higher
- C. Unchanged; standard
- D. Increased; lower
Answer: B. Increased; higher
36. The bioavailability of oral procainamide is generally good, but it has a relatively short half-life. To maintain therapeutic concentrations, it often requires:
- A. Once-daily dosing
- B. Frequent dosing (e.g., every 3-6 hours) or use of sustained-release formulations
- C. Intravenous administration only
- D. Co-administration with a CYP inhibitor
Answer: B. Frequent dosing (e.g., every 3-6 hours) or use of sustained-release formulations
37. Which pharmacokinetic property of amiodarone contributes to its potential for causing corneal microdeposits?
- A. Its rapid renal excretion
- B. Its secretion into tears and lipophilic nature leading to accumulation in the cornea
- C. Its low volume of distribution
- D. Its lack of tissue binding
Answer: B. Its secretion into tears and lipophilic nature leading to accumulation in the cornea
38. The primary active metabolite of propafenone, 5-hydroxypropafenone, also possesses:
- A. Significant Class III antiarrhythmic activity.
- B. Beta-blocking activity, similar to the parent drug.
- C. No pharmacological activity.
- D. Pure potassium channel blocking effects.
Answer: B. Beta-blocking activity, similar to the parent drug. (It also has Na+ channel blocking activity).
39. For drugs like lidocaine with a high hepatic extraction ratio and extensive first-pass metabolism, oral bioavailability is typically:
- A. Very high (>90%)
- B. Very low (<10-30%)
- C. Moderate (50-70%)
- D. 100%
Answer: B. Very low (<10-30%)
40. The pharmacokinetics of sotalol are relatively simple because it:
- A. Undergoes extensive hepatic metabolism by multiple CYP enzymes.
- B. Is not significantly metabolized and is excreted almost entirely unchanged by the kidneys.
- C. Is a prodrug requiring complex activation steps.
- D. Has very high plasma protein binding.
Answer: B. Is not significantly metabolized and is excreted almost entirely unchanged by the kidneys.
41. A patient with heart failure may have altered pharmacokinetics for some antiarrhythmics (e.g., lidocaine, procainamide) due to:
- A. Increased hepatic blood flow and enhanced metabolism.
- B. Reduced hepatic blood flow (decreasing clearance of high-extraction drugs) and/or reduced renal perfusion.
- C. Increased volume of distribution for all drugs.
- D. Faster drug absorption from the GI tract.
Answer: B. Reduced hepatic blood flow (decreasing clearance of high-extraction drugs) and/or reduced renal perfusion.
42. The time to reach steady-state plasma concentration for a drug is primarily determined by its:
- A. Route of administration
- B. Elimination half-life (approximately 4-5 half-lives)
- C. Peak plasma concentration
- D. Degree of ionization
Answer: B. Elimination half-life (approximately 4-5 half-lives)
43. Therapeutic drug monitoring for procainamide should ideally include measurement of:
- A. Only procainamide levels
- B. Only NAPA levels
- C. Both procainamide and NAPA levels, as NAPA is active and renally cleared
- D. Serum potassium levels as a surrogate
Answer: C. Both procainamide and NAPA levels, as NAPA is active and renally cleared
44. Which Class III antiarrhythmic is administered as a short IV infusion for chemical cardioversion of atrial fibrillation or atrial flutter?
- A. Amiodarone (can be used, but often for rhythm/rate control or more resistant AF)
- B. Sotalol
- C. Dofetilide (oral)
- D. Ibutilide
Answer: D. Ibutilide
45. The pharmacokinetic profile of dronedarone was designed to be different from amiodarone, specifically to:
- A. Increase its half-life and tissue accumulation.
- B. Reduce its lipophilicity and shorten its half-life, potentially leading to fewer long-term tissue accumulation-related side effects.
- C. Eliminate its metabolism by CYP3A4.
- D. Make it primarily renally excreted.
Answer: B. Reduce its lipophilicity and shorten its half-life, potentially leading to fewer long-term tissue accumulation-related side effects.
46. Verapamil and diltiazem are inhibitors of CYP3A4 and P-glycoprotein. This means they can:
- A. Decrease the levels of co-administered drugs that are substrates of CYP3A4 or P-gp.
- B. Increase the levels of co-administered drugs that are substrates of CYP3A4 or P-gp.
- C. Only induce the metabolism of other drugs.
- D. Have no significant impact on other drugs’ pharmacokinetics.
Answer: B. Increase the levels of co-administered drugs that are substrates of CYP3A4 or P-gp.
47. The concept of “pharmacokinetic tolerance” or “metabolic tolerance” for an antiarrhythmic would imply that with chronic use:
- A. The drug’s receptor becomes less sensitive.
- B. The drug induces its own metabolism, leading to lower plasma concentrations over time with the same dose.
- C. The drug’s absorption increases over time.
- D. The drug’s renal excretion is inhibited.
Answer: B. The drug induces its own metabolism, leading to lower plasma concentrations over time with the same dose.
48. For an antiarrhythmic drug that is a weak base (e.g., quinidine), changes in urinary pH can affect its renal excretion. Alkalinization of urine would generally:
- A. Increase its ionization and decrease its reabsorption, leading to increased renal excretion.
- B. Decrease its ionization and increase its reabsorption, leading to decreased renal excretion.
- C. Have no effect on its renal excretion.
- D. Convert it to an inactive metabolite in the urine.
Answer: B. Decrease its ionization and increase its reabsorption, leading to decreased renal excretion. (Weak base: more ionized in acidic urine, less reabsorbed; less ionized in alkaline urine, more reabsorbed).
49. The extensive tissue binding of amiodarone contributes to its:
- A. Need for a loading dose to rapidly saturate tissue binding sites and achieve therapeutic plasma concentrations.
- B. Very small volume of distribution.
- C. Rapid elimination from the body.
- D. Minimal risk of drug interactions.
Answer: A. Need for a loading dose to rapidly saturate tissue binding sites and achieve therapeutic plasma concentrations.
50. Understanding the pharmacokinetics of an antiarrhythmic drug is crucial for designing a dosing regimen that achieves and maintains plasma concentrations within the:
- A. Toxic range.
- B. Subtherapeutic range.
- C. Therapeutic range, balancing efficacy and toxicity.
- D. Range that ensures complete protein binding.
Answer: C. Therapeutic range, balancing efficacy and toxicity.