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Pharmacodynamics

Ezetimibe

Ezetimibe works to selectively inhibit cholesterol and phytosterol absorption in the body’s intestines. This drug appears to work at the brush border of the small intestine inhibiting cholesterol absorption which then leads to a decrease in cholesterol delivery to the liver. This is different from other cholesterol-reducing compounds because it does not directly inhibit cholesterol synthesis in the liver. (https://www.drugbank.ca/drugs/DB00973) By inhibiting the absorption of cholesterol, ezetimibe decreases the cholesterol levels in the blood. (https://pubchem.ncbi.nlm.nih.gov/compound/Ezetimibe#section=Experimental-Properties) Ezetimibe specifically targets the sterol transporter, Niemann-Pick C1-Like1 (NPC1L1) which controls cholesterol uptake at the jejunal enterocyte brush border.

Simvastatin

Simvastatin interferes in the production of cholesterol. To produce cholesterol, Acetyl CoA is converted into HMG-CoA, which is then converted into mevalonate. Mevalonate is then converted into isopentenyl pyrophosphate (IPP), IPP is converted into squalene, and then finally squalene is converted into cholesterol. Simvastatin reduces the conversion of HMG-CoA to mevalonate, therefore lowering cholesterol levels. Simvastatin targets HMG-CoA reductase which is the enzyme responsible for said conversion. With the synthesis of cholesterol being divided into 5 major steps, this inability to convert targets only the second step in cholesterol synthesis.

Mechanism of Action

Ezetimibe

When administered, the drug is inactive until it is absorbed. Upon absorption ezetimibe is conjugated to active phenolic glucuronide where it is metabolized within the small intestine and liver. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021445s019lbl.pdf

Simvastatin

When the drug is administered it is initially inactive. It must be hydrolyzed in order to become active. Once hydrolyzed, simvastatin reduces the amount of mevalonic acid in the blood by competing for HMG-CoA reductase with HMG-CoA.

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