Statins
Statins
Statins or cholesterol synthesis inhibitors such as atorvastatin, simvastatin, and pravastatin are the drugs of first choice for lowering LDL. They lower LDL more effectively than other currently available agents, and they reduce the risk of cardiovascular diseases.
As inhibitors of hepatic hydroxymethylglutarylco-enzyme A-reductase (HMG-CoA reductase), the enzyme catalyzing the rate-limiting step in hepatic cholesterol synthesis, statins decrease synthesis of cholesterol by the liver, which results in two important effects: the up-regulation of LDL receptors by hepatocytes (mediated via SREBP) and consequent increased removal of apoE and apoB-containing lipoproteins from the circulation, and a reduction in the synthesis and secretion of lipoproteins from the liver. The net effect of statin therapy is lowering the plasma cholesterol concentrations with 25-45% and the triglycerides with 10-30%. The reduction of the latter is dependent on the baseline triglyceride level (the higher the baseline level, the greater the reduction) and the dose of the statin (the higher the dose, the greater the reduction).
Cardiovascular disease risk reduction with a statin appears to occur as a result of several related changes, including restoration of endothelial function, reduction in inflammation, and stabilization of vulnerable plaque. The time course for these antiatherosclerotic effects of statins ranges from days to years (see graphic below). Within weeks to months after beginning statin therapy, endothelial function of coronary arteries is restored. Concurrent with this or following by just a few months is a reduction in inflammatory markers, such as high-sensitivity C-reactive protein. These effects appear to coincide with the reduction in ischemic events demonstrated after about 18 months of statin therapy. After several years of therapy, fatal and nonfatal myocardial infarction rates begin to decline in statin-treated patients, and after 5 years of therapy, significant reductions have been documented. These changes coincide somewhat with stabilization of vulnerable atherosclerotic plaque during which the lipid-rich core of plaque is replaced with connective tissue and matrix.
Statins are considered as safe. 95% of patients can tolerate them well. Common side effects include headache, upset stomach, fatigue, flu-like symptoms, and myalgia. One or both liver transaminases may be elevated to >3 times the upper limit of normal.
Statins have the following effect on lipid levels in the plasma:
When statin monotherapy is not enough to bring a patient's LDL cholesterol level to goal, the best approach may be to:
Extra info: Increasing the dose of the statin is preferred since it has beneficial effects on morbidity and mortality. Second choice is the addition of e.g. ezetimibe, a cholesterol absorption blocker.
Which statement is correct concerning the cytochrome P450 enzyme 3A4?
Extra info: A drug that binds strongly to CYP3A4 is a potentially interacting medication with statins that also depend on that enzyme. For example, cyclosporine, macrolide antibiotics, azole antifungal agents, protease inhibitors, amiodarone and calcium channel blockers (diltiazem) all bind to CYP3A4 with greater affinity than that of statins and can thus inhibit the metabolism of those statins. The lipid-soluble statins that depend on CYP3A4-mediated metabolism tend to bind relatively weakly to the isoenzyme. Therefo
Pravastatin undergoes all of the following processes EXCEPT
Extra info: Pravastatin is one of the exceptions amongst the statins regarding metabolisation by the CYP P450 pathway. This drug does not depend on this enzyme complex.
