antihyperlipoproteinemics and inhibitors of cholesterol biosynthesis

CBDA final

what are the four types of cholesterol in the blood

cholesterol

cholesterol esters

triglycerides

phospholipids

what is hyperlipidemia

an excess of plasma concentration of one or more types of lipids

what is hyperlipoproteinemia

excess plasma concentration of lipoproteins used to transport lipids in the blood — associated with atherosclerotic lesions and coronary heart disease

what are the different lipoproteins

chylomicrons

VLDL

IDL

LDL

HDL

what are chylomicrons

lipoprotein assembled in the wall of the small intestine

carries lipids from the GI to the tissues

what is LDL

lipoprotein that transports lipids from the liver to the tissues

what is HDL

lipoprotein that transports lipids from the tissues to the liver

what structures are involved in cholesterol biosynthesis

acetyl CoA → HMG-CoA → mevalonic acid → lanosterol → cholesterol

what is the key intermediate in the conversion of HMG-CoA to mevalonic acid by HMG-CoA reductase

head group — rest of the molecule is just a carrier

what was mevastatin isolated from

two species of penicillium

what was mevastatin’s affinity for HMG-CoA reductase compared to HMG-CoA

10,000 times greater

what was lovastatin isolated from

monascus ruber and aspergillus terreus

what are the key features of lovastatin

lactone system — must be opened by hydrolysis for activity, has critical stereochemistry

what is unique about simvastatin

contains additional side chain methyl group → increase in logP → increased CNS penetration

what is unique about pravastatin

lactone ring is already open (does not require activation)

heptanoic acid derivative

improved water solubility

reduced CNS penetration and side effects

how many stereocenters were in the original statins (meva, lova)

8

what is unique about fluvastatin

only has 2 stereocenters

lactone already open

why was cerivastatin pulled from the market in 2001

100 deaths

rhabdomyolysis

describe the metabolism of statins

extensive first-pass metabolism

aromatic hydroxylation is primary route

how are statins primarily eliminated

through feces

how do bile sequestering agents work

sequester bile in GI tract and excreted out

how do bile acid sequestering agents trap bile acids

exchange chloride ions for bile acids

what is a major side effect of bile acid sequestering agents

constipation