Examkin

Question

Difficulty: EasyPharmacokinetic and Pharmacodynamic Principles

A 62-year-old man comes to the clinic due to a 2-day history of severe muscle aches and dark urine. He has a history of hyperlipidemia and hypertension, for which he takes stable doses of simvastatin and amlodipine. One week ago, he was diagnosed with community-acquired pneumonia and was prescribed a 7-day course of clarithromycin. Laboratory studies today show a serum creatine kinase level of 12,000 U/L. Which of the following pharmacokinetic mechanisms best explains this patient's current presentation?

  1. Inhibition of hepatic cytochrome P450 enzymesAnswer
  2. B
    Induction of hepatic cytochrome P450 enzymes
  3. C
    Decreased renal excretion of the lipid-lowering agent
  4. D
    Displacement of the lipid-lowering agent from plasma albumin
  5. E
    Synergistic pharmacodynamic toxicity at the skeletal muscle level

Answer

The correct answer is the inhibition of hepatic cytochrome P450 enzymes.
The patient's presentation of muscle aches, dark urine, and elevated creatine kinase following the addition of a macrolide antibiotic to a statin regimen is classic for statin-induced rhabdomyolysis. This occurs due to a pharmacokinetic drug-drug interaction. Simvastatin is heavily dependent on hepatic cytochrome P450 3A4 (CYP3A4) for its metabolism and clearance. Clarithromycin is a potent inhibitor of CYP3A4. When the two are co-administered, clarithromycin inhibits the metabolism of simvastatin, causing a significant increase in serum statin concentrations and leading to dose-dependent adverse effects like myopathy and rhabdomyolysis.

Step-by-Step Solution

1
Identify the primary clinical presentation.
The patient has severe muscle aches, dark urine, and markedly elevated creatine kinase, indicating rhabdomyolysis.
Recognizing the adverse event is required to trace back the etiology.
2
Identify the patient's medications and recent changes.
The patient is on a stable dose of simvastatin but recently started clarithromycin for pneumonia.
Adverse events following a new prescription are highly suspicious for drug-drug interactions.
3
Determine the pharmacokinetic relationship between the drugs.
Clarithromycin is a potent macrolide inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme. Simvastatin is extensively metabolized by CYP3A4.
Understanding the metabolic pathways explains why drug levels changed.
4
Conclude the mechanism of toxicity.
The inhibition of CYP3A4 by clarithromycin decreased the hepatic clearance of simvastatin, leading to toxic systemic levels and subsequent rhabdomyolysis.
This directly answers the question about the pharmacokinetic mechanism.

Key Concept

Pharmacokinetic drug-drug interactions via cytochrome P450 (CYP3A4) enzyme inhibition
Rate this question

Topics

Pharmacokinetic and Pharmacodynamic Principles

More questions from this topic