A 47-year-old man comes to the office due to worsening muscle weakness and dark urine for the past several days. Two weeks ago, the patient was evaluated for dyspepsia and found to have Helicobacter pylori infection; he was started on treatment and has had partial symptom improvement. Medical history includes hypertension and hyperlipidemia, for which he takes amlodipine and simvastatin. Temperature is 37.1 C (98.8 F), blood pressure is 130/80 mm Hg, and pulse is 74/min. Physical examination shows diffuse muscle tenderness. Laboratory evaluation reveals elevated blood urea nitrogen and serum creatinine levels. Urine microscopy shows no red or white blood cells. Which of the following medications most likely precipitated this patient's current condition?

Question

A 47-year-old man comes to the office due to worsening muscle weakness and dark urine for the past several days.  Two weeks ago, the patient was evaluated for dyspepsia and found to have Helicobacter pylori infection; he was started on treatment and has had partial symptom improvement.  Medical history includes hypertension and hyperlipidemia, for which he takes amlodipine and simvastatin.  Temperature is 37.1 C (98.8 F), blood pressure is 130/80 mm Hg, and pulse is 74/min.  Physical examination shows diffuse muscle tenderness.  Laboratory evaluation reveals elevated blood urea nitrogen and serum creatinine levels.  Urine microscopy shows no red or white blood cells.  Which of the following medications most likely precipitated this patient's current condition?

Quizplus · Accepted Answer

11ec160b_3c2a_9e9a_9249_adb84c279e3e_MD0001_00 This patient has muscle tenderness and weakness. The dark urine suggests myoglobinuria due to myocyte necrosis. In the context of ongoing statin therapy for hyperlipidemia, this presentation likely represents statin myopathy. Statin myopathy is due, likely at least in part, to decreased myocyte production of coenzyme Q10 (ubiquinone). Serum muscle breakdown markers (eg, creatine kinase) are often elevated, and severe cases may lead to rhabdomyolysis with subsequent acute kidney injury (eg, elevated BUN and creatinine). Statin myopathy is most common in the initial weeks or months of therapy. However, it can occasionally occur later, and can be acutely triggered by medications that increase circulating statin levels. This patient's myopathy is most likely related to the initiation of clarithromycin as part of a multidrug regimen for Helicobacter pylori. Statins, primarily simvastatin, lovastatin, and atorvastatin, are metabolized by CYP3A4. This enzyme can be inhibited by macrolide antibiotics (eg, erythromycin, clarithromycin), leading to increased statin drug levels and subsequent statin myopathy. (Azithromycin does not significantly inhibit CYP3A4.) Other significant CYP3A4 inhibitors that can induce statin myopathy include ketoconazole, non-dihydropyridine calcium channel blockers (eg, diltiazem), amiodarone, and protease inhibitors (eg, ritonavir). Because pravastatin is not primarily metabolized by CYP3A4, patients who must take a CYP3A4 inhibitor may benefit from switching to this drug. (Choice A) Amoxicillin does not inhibit CYP3A4 or increase circulating simvastatin levels. Penicillin antibiotics generally have only minor effects on the cytochrome P-450 system. (Choice B) Bismuth subsalicylate can cause black stools due to the formation of bismuth sulfate in the gastrointestinal tract. However, this medication does not cause myopathy or myoglobinuria. Excessive intake of bismuth can cause motor weakness, but this is due primarily to neural rather than muscle toxicity. (Choice C) Polyvalent cations (eg, calcium, iron) can form insoluble chelate complexes with certain antibiotics (eg, tetracyclines, fluoroquinolones) and other drugs (eg, levothyroxine, levodopa), leading to decreased drug absorption. Simvastatin does not form chelate complexes, and decreased absorption would lower, not increase, the risk for myopathy. (Choice E) Both metronidazole and simvastatin carry a small risk for peripheral neuropathy. In some patients, the effect can be additive and lead to numbness, pain, and paresthesia in the hands and feet. However, this neuropathy would not cause muscle tenderness or myoglobinuria. Educational objective: Statins, primarily simvastatin, lovastatin, and atorvastatin, are metabolized by CYP3A4. Drugs that inhibit this enzyme (eg, macrolide antibiotics, ketoconazole, non-dihydropyridine calcium channel blockers, amiodarone) can cause increased statin drug levels and lead to statin myopathy. __________ References: Clinical guidance for managing statin and antimicrobial drug-drug interactions. (http://www.ncbi.nlm.nih.gov/pubmed/28990114)

A 47-Year-Old Man Comes to the Office Due to Worsening