Tukon Mechanism of Action

Category: Atorvastatin: Atorvastatin calcium is a synthetic lipid-lowering agent.
Amlodipine: Amlodipine is a dihydropyridine calcium antagonist with long duration of action, used for treatment of hypertension and angina pectoris.
Pharmacology: Atorvastatin: Atorvastatin is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of sterols, including cholesterol. Atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL. It also reduces LDL production, number of LDL particles and LDL-C in some patients with homozygous familial hypercholesterolemia (FH). The drug reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hyperlipidemia, and mixed dyslipidemia. It also reduces VLDL-C and TG and produces increases in HDL-C and apolipoprotein-A1.
Amlodipine: Amlodipine inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. It binds to both dihydropyridine and nondihydropyridine binding sites and inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
Pharmacokinetics: Atorvastatin: Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1-2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorvastatin is approximately 14% and the systemic availability of HMG-CoA reductase inhibitor activity is approximately 30%. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, LDL-C reduction is similar whether atorvastatin is given with or without food.
Distribution: Atorvastatin is ≥98% bound to plasma proteins. Based on observations in rats, atorvastatin is likely to be secreted inhuman milk.
Metabolism: Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Excretion: Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life is approximately 14 hours, with the half-life of inhibitor activity for HMG-CoA reductase being 20-30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration. In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased.
Amlodipine: Amlodipine is well absorbed after oral doses with peak blood concentration occurring after 6-12 hours. The bioavailability varies but is usually about 60-65% . Amlodipine is reported to be about 97.5% bound to plasma proteins. It has a prolonged terminal elimination half-life of 35-50 hours and steady-state plasma concentrations are not achieved until after 7-8 days of use. Amlodipine is extensively metabolized in the liver; metabolites are mostly excreted in urine together with less than 10% of a dose as unchanged drug.