Lecture 9: Atherosclerosis (Stains and Fibrates) Flashcards
What is lipid transport throughout the body mediated by?
lipoprotein complexes
HDL (high density lipoprotein)
LDL (low density lipoprotein)
VLDL (very low density lipoprotein)
What are lipoproteins?
packages of lipids (triglycerides, cholesterol) surrounded by apolipoproteins and phospholipids
categorized according to size and presence of specific apolipoproteins
an inappropriate balance of lipoproteins (too much LDL, VLDL, too little HDL) is a risk factor for serious diseases
What are the risks of lipid imbalance?
high levels of total cholesterol (especially LDL-C) are linked to adverse cardiovascular events
this is attributed to the formation of atherosclerotic plaques
rupture of atherosclerotic plaques followed by occlusion of vessels in the heart or brain is the leading cause of death in North America
What is atherosclerosis?
fatty deposits that occlude blood vessels, that form over time as cholesterol accumulates in the plaque
accumulation of cholesterol occurs over time in transformed macrophages (FOAM CELLS) that have invaded the endothelial wall of a blood vessel
macrophages have mechanisms for uptake of LDL, VLDL (via the LDL-receptor, ApoE receptor), leading to cholesterol accumulation
there are also mechanisms for cholesterol efflux and transport away, mediated by HDL
HDL is good, LDL is not good; the overall approach of therapies is to reduce circulating LDL-C
thinning/rupture of the cap exposes pro-thrombotic factors that can lead to formation of thrombi and total vessel occlusion
What is the overall effectiveness of statins?
in patients with cardiovascular risk, statins significantly reduce the incidence of cardiovascular evets, and all cause mortality
effectiveness is seen in most patient subgroups
How do statins work?
VLDL, LDL formation is primarily regulated in the liver
apolipoproteins (e.g., B-100) are packaged with cholesterol, triglycerides, etc.
cholesterol that is packaged can be dietary/extrinsic (taken up via the LDL receptor), OR synthesized in the liver hepatocyte
key enzyme is HMG-CoA reductase
What is the mevalonate pathway?
mevalonate pathway is the pathway for cholesterol synthesis in the liver
HMG-CoA reductase is the rate-limiting enzyme in the pathway and is targeted by statins (HMG-CoA reductase inhibitors)
HMG-CoA reductase is an ENZYME - it catalyzes formation of mevalonic acid from HMG-CoA
HMG-CoA is a transmembrane protein, primarily residing in the ER membrane
What downstream effects does the inhibition of HMG-CoA produce?
inhibition of HMG-CoA reductase has several downstream consequences that may reduce circulating LDL-C
reduction of cholesterol pool in hepatocytes leads to decreased formation in sensed by a sterol receptor in hepatocytes
this leads to increased expression of LDL receptors on the hepatocyte
more LDL is scavenged from the blood, leading to a reduction in circulating LDL
What does it mean that statins are “high-extraction” drugs?
statins are “high extraction” drugs that are rapidly absorbed and processed by first-pass metabolism
this is not a bad thing in terms of their mechanism of action, because the primary target organ is the liver
some of these are administered as prodrugs (like lovastatin in the image); some are administered in their active form
usually taken shortly before bed, because most cholesterol synthesis takes place during sleep
What is the formula for extraction ratio?
extraction ratio = clearance (liver)/blood flow
What does extraction ratio mean?
high amounts of the drug are cleared/processed by the liver
for an oral drug this means - LOW bioavailability
low extraction ratio means: when the drug is delivered to the liver, most of it passes through unprocessed
for an oral drug this means - HIGH bioavailability
What are fibrates?
a second class of drugs that is used to trate dyslipidemias is fibrates
drug to remember in this class: fenofibrate
fibrates are thought to target a family of receptors called PPARs (peroxisome proliferator-activated receptor), PPARalpha
these receptors are intracellular receptors, that act as transcription factors (bind DNA) and influence transcription of target genes
What is PPARalpha?
PPARs bind to their endogenous ligand or drug (Fibrates are agonists of the receptor)
receptors than migrate to the nucleus, heterodimerize with RXR (retinoic acid receptors), and influence transcription of target genes
What are the important outcomes of fibrates?
increased expression of lipoproetin lipase - leads to increased breakdown of triglycerides in VLDLs, and uptake of fatty acids as fuel in peripheral tissues
other important reported effects are: increased LDL uptake in the liver, reduced VLDL production in the liver
generally not considered to have nearly as strong evidence for effectiveness at statins
