A 55-year-old man comes to the physician with acute-onset muscle pain. His other medical problems include hypertension, hyperlipidemia, and a myocardial infarction 2 months ago. His medications include metoprolol, lisinopril, aspirin, and simvastatin. His blood pressure is 130/80 mm Hg and pulse is 60/min. Examination shows no muscle weakness. There is no hepatosplenomegaly. No skin rash is present. Liver function tests show slightly increased aspartate aminotransferase and alanine aminotransferase. The serum creatine kinase level is elevated. The physician suspects a drug-induced reaction. Which of the following is the most likely mechanism of action for this drug?

Question

A 55-year-old man comes to the physician with acute-onset muscle pain.  His other medical problems include hypertension, hyperlipidemia, and a myocardial infarction 2 months ago.  His medications include metoprolol, lisinopril, aspirin, and simvastatin.  His blood pressure is 130/80 mm Hg and pulse is 60/min.  Examination shows no muscle weakness.  There is no hepatosplenomegaly.  No skin rash is present.  Liver function tests show slightly increased aspartate aminotransferase and alanine aminotransferase.  The serum creatine kinase level is elevated.  The physician suspects a drug-induced reaction.  Which of the following is the most likely mechanism of action for this drug?

Quizplus · Accepted Answer

Statins inhibit HMG-CoA reductase, a rate-limiting enzyme in the intracellular biosynthesis of cholesterol that converts HMG-CoA to mevalonate. The decreased hepatic cholesterol activates cellular signals that increase the number of LDL receptors on liver cell membranes. These LDL receptors remove circulating LDL and deliver it to the cell's interior, where it is digested. The net effect is reduced serum LDL with minimal change in liver LDL. However, a minority of patients can develop hepatic dysfunction as a result. Statin-induced myalgias can occur in 2%-10% of patients, but significant myositis with elevated creatine kinase is uncommon. Myalgias tend to present as symmetrical proximal muscle weakness or tenderness. Statins decrease coenzyme Q10 synthesis, which is involved in muscle cell energy production and possibly contributes to statin-induced myopathy. (Choice A) Immune-mediated reactions are responsible for a variety of drug-induced conditions such as membranous glomerulonephritis induced by captopril. However, they are not involved in statin myopathy. (Choice B) Cell surface receptor blockage is the primary action of many cardiovascular drugs (eg, beta blockers, alpha blockers, calcium channel blockers). This action is also responsible for some of the noncardiac adverse effects seen with nonselective beta blockers (eg, bronchospasm). Statins actually increase the number of LDL cell surface receptors. (Choice C) Angiotensin-converting-enzyme (ACE) inhibitors (eg, lisinopril) are a type of extracellular enzyme blocker. Inhibition of ACE also increases the levels of bradykinin, which is thought to be responsible for the cough and angioedema seen with their use. (Choice E) Damage of membrane-bound lipids usually takes place through peroxidation from free radicals. However, it is not thought to be the mechanism for statin-induced myopathy. Educational objective: Statins inhibit intracellular HMG-CoA reductase enzyme, prevent conversion of HMG CoA to mevalonic acid, and increase the number of cell membrane LDL receptors. Statins also decrease coenzyme Q10 synthesis, which is involved in muscle cell energy production and possibly contributes to statin-induced myopathy. References: Statin-induced myopathies. (http://www.ncbi.nlm.nih.gov/pubmed/22001973)

A 55-Year-Old Man Comes to the Physician with Acute-Onset Muscle