A 34-year-old man is found to have dyslipidemia. His other medical problems include a myocardial infarction 1 week ago. His father died of myocardial infarction at the age of 48 years. Several other family members have had myocardial infarctions and hypertension. The patient smoked cigarettes and drank alcohol occasionally but quit after his myocardial infarction. He is started on simvastatin and cholestyramine. Which of the following best describes the independent effects of simvastatin and cholestyramine, respectively, on hepatic cholesterol synthesis?

Question

A 34-year-old man is found to have dyslipidemia.  His other medical problems include a myocardial infarction 1 week ago.  His father died of myocardial infarction at the age of 48 years.  Several other family members have had myocardial infarctions and hypertension.  The patient smoked cigarettes and drank alcohol occasionally but quit after his myocardial infarction.  He is started on simvastatin and cholestyramine.  Which of the following best describes the independent effects of simvastatin and cholestyramine, respectively, on hepatic cholesterol synthesis?

Quizplus · Accepted Answer

11ec160b_3bce_c261_9249_f1555365e7ff_MD0001_00 Bile acids are synthesized in the liver from cholesterol catabolism. Bile enters the duodenum through gallbladder contraction. Bile acids are primarily absorbed in the terminal ileum, with the small amount that remains unabsorbed being excreted in the stool (this amount is matched by bile acid synthesis). Statins are the first-line therapy for most patients with hypercholesterolemia. These drugs competitively inhibit HMG CoA reductase, the enzyme responsible for the conversion of HMG CoA to mevalonate (ie, the rate-limiting step in hepatic cholesterol synthesis). This inhibition decreases hepatic cholesterol synthesis. The resulting upregulation of LDL receptors causes increased uptake of LDL from the circulation. Statins are very effective in reducing LDL cholesterol. Statins' effects on triglyceride and HDL levels are comparatively modest. Bile acid-binding resins (ie, bile acid sequestrants) work by binding bile acids in the gastrointestinal tract, thereby interfering with the enterohepatic circulation of bile acids and causing increased bile acid excretion. This results in hepatic synthesis of new bile acids, a process that consumes liver cholesterol stores. Hepatic uptake of LDL from the circulation is increased for continued bile acid synthesis. Bile acid production and secretion are increased by 10-fold due to this interruption of the enterohepatic circulation of bile acids. Hepatic cholesterol reduction is an activating factor for HMG CoA reductase and subsequently results in increased hepatic cholesterol synthesis. This effect can be blocked with the addition of a statin drug to the treatment regimen, leading to a greater reduction in LDL levels than with use of either drug alone (synergistic action). Educational objective: Simvastatin decreases hepatic cholesterol production, while cholestyramine increases hepatic cholesterol and bile acid synthesis. Combination therapy results in a synergistic reduction in plasma LDL level. __________ References: Overview of pharmacologic therapy for the treatment of dyslipidemia. (http://www.ncbi.nlm.nih.gov/pubmed/14613353)

A 34-Year-Old Man Is Found to Have Dyslipidemia