ATC Group: C10B Lipid modifying agents, combinations

Combination of two drugs, a dihydropyridine calcium channel blocker, amlodipine, and an HMG-CoA reductase inhibitor, atorvastatin. The amlodipine component of CADUET inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. The atorvastatin component of CADUET is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol.

Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and atorvastatin are two lipid-lowering compounds with complementary mechanisms of action. Ezetimibe/atorvastatin combination reduces elevated total cholesterol (total-C), LDL-C, apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and increases high-density lipoprotein cholesterol (HDL-C) through dual inhibition of cholesterol absorption and synthesis.

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase. Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL. Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (Angiotensin Converting Enzyme ACE). Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity and reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein-kinin systems (and thus also activation of the prostaglandin system).

Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity (by inhibition of the negative feedback of renin release) and reduced secretion of aldosterone. Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.

Pravastatin and fenofibrate, which have different modes of action, show additive effects in terms of reduction of serum lipid. Pravastatin is more effective in reducing LDL-C and total cholesterol but presents only modest effects on TG and HDL-C while fenofibrate is very effective in decreasing TG and increasing HDL-C, but with few effects on LDL-C. Additionally, fibrates have the properties to modify the size and density of LDL-C particles to make them less atherogenic.

Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Ezetimibe and simvastatin are two lipid-lowering compounds with complementary mechanisms of action. Ezetimibe/simvastatin combination reduces elevated total cholesterol (total-C), LDL-C, apolipoprotein B (Apo B), triglycerides (TG), and non-high-density lipoprotein cholesterol (non-HDL-C), and increases high-density lipoprotein cholesterol (HDL-C) through dual inhibition of cholesterol absorption and synthesis.

The effects of simvastatin and fenofibrate are complementary. Simvastatin has a potent activity in inhibiting HMG-CoA reductase, an enzyme that catalyses the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthesis of cholesterol. Fenofibrate is a fibric acid derivative whose lipid modifying effects reported in humans are mediated via activation of Peroxisome Proliferator Activated Receptor type alpha (PPARα). Through activation of PPARα, fenofibrate activates lipoprotein lipase production and reduces production of apoprotein CIII.