ant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
MECHANISM OF ACTION
Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and simvastatin exhibit synergistic mechanisms that reduce elevated serum total-C, LDL-C, Apo B, TG, and non-HDL-C concentrations and increase serum HDL-C concentrations through inhibition of cholesterol absorption and synthesis. The effects of combined therapy with ezetimibe and HMG-CoA reductase inhibitors ('statins') result in greater LDL reductions and therapeutic benefit than either ezetimibe or statin monotherapy. When used in combination with 10—80 mg of either simvastatin, combined use with ezetimibe achieved LDL-reductions of approximately > 51% compared to 36% with simvastatin monotherapy.
•Ezetimibe: Ezetimibe has a mechanism of action that is unique compared to other available antilipemic agents. Ezetimibe lowers serum cholesterol concentrations by selectively inhibiting the absorption of cholesterol and related phytosterols by the small intestine. Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Ezetimibe localizes and appears to act at the brush border of the small intestine. It inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in the blood clearance of cholesterol. With ongoing therapy, the overall effects of ezetimibe monotherapy are to reduce total cholesterol (13%), LDL-cholesterol (18%), and Apo-B (16%) in patients with hypercholesterolemia. Ezetimibe also reduces plasma concentrations of the noncholesterol sterols (sitosterol and campesterol). In a 2 week study of 18 hypercholesterolemic patients, ezetimibe has been reported to inhibit intestinal cholesterol absorption by 54% relative to placebo. In humans, the effects of ezetimibe to reduce triglycerides (TG) (8%) or to lower HDL-cholesterol (1%) are less prominent than the LDL-lowering effects; ezetimibe therapy usually increases HDL-C levels. In animal models (rodents), ezetimibe reduces the cholesterol content in chylomicrons without affecting the triglyceride content. In rodents, ezetimibe has no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins (A, D, and E), and does not impair adrenocortical steroid hormone production.
•Simvastatin: Like lovastatin, simvastatin is a prodrug with little or no inherent activity. The 6-membered lactone ring is hydrolyzed in vivo to generate mevinolinic acid. Mevinolinic acid, one of simvastatin's several active metabolites, is structurally similar to HMG-CoA (hydroxymethylglutaryl CoA). Once hydrolyzed, simvastatin competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme. Interference with the activity of this enzyme reduces the quantity of meva lonic acid, a precursor of cholesterol. This process occurs within the hepatocyte and is one of two mechanisms that generate cholesterol. Cholesterol can also be taken up from LDL by endocytosis. Since de novo synthesis of cholesterol is impaired by simvastatin, chol |
