module 12 Flashcards
what fraction of deaths are caused by CHD?
1/3 in canada
what is cholesterol essential for ?
precursor for steroid hormones and bile acids
cell membranes
what % of cholesterol is synthesized by the liver?
80
what is the purpose of lipoproteins?
transport cholesterol and triglycerides in the plasma (blood) - because they have a phosholipid surrounding, it allows them to be soluble in the blood
have embedded proteins (apolipoproteins) - allow recognition by cells which may bind and take up lipoproteins, activate enzymes that metabolize lipoproteins, increase the structural stability of lipoproteins
what do A-I lipoproteins do
transport cholesterol from non hepatic tissue back to the liver
what do B-100 apolipoproteins do?
transport cholesterol to non hepatic tissue
what are the characteristics of VLDLs
deliver triglyercides from the liver to adipose tissue + muscle
have triglyceride rich core and account for almost all of triglyceride content in blood
controversial but suggestions that high levels contribute to atherosclerosis
what are the characteristics of LDLs
-deliver cholesterol to non hepatic tissue
-cholesterol rich core (60-70% amount in blood)
-high LDL levels are correlated to CHD
-reducing these levels can even reverse atheroscler
what are the characteristics of HDLs?
-delivers from non hepatic back to liver (removal of cholesterol from blood)
-cholesterol is their main core (20-30% of blood cholesterol)
how does aterosclerossis occur?
- damage in the endothelium - substances travelling in the blood such as cholesterol, fat and waste accumulate inside the damaged area
- chemcial reactions occuring within the build up of material causes cholesterol molecules to oxidize - this initiaties an inflammatory response
- endothelial cells then release chemicals that signal a call for help - monocytes recruit at the damaged site and then are converted into macrophages that eat and digest the cholesterol molecules
- as a result, macrophages change into foam cells that accumulate as plaque
- smooth muscle cells also multiply and move to the surface of the plaque (fibrous cap covering the plaque) - this made errode and turn into a blood clot
what is the framingham risk score used for and include?
includes gender, age, total blood cholesterol, smoking, HDL cholesterol and systolic
used to estimate patients risk for cardiovascular disease in 10 years
what does the framingham score underestimate?
shown to underestimate risk in youth, women and patients with metabolic syndrome
what is metabolic syndrome?
3+ of the following
1.central obesity
2. elevated triglycerides
3. low HDL
4. hyperglycemia
5. hypertension
why is metabolic syndrome significant?
causes an increased risk of coronary heart disease AND type 2 diabetes
1/4 canadians have metabolic syndrome
what are the first lines of treatment for LDL cholesterol
diet - less cholesterol & fat + more fibre
weight control
exercise
smoking
what are the 5 different classes of drugs for elevated blood lipids
- statins
- nicotinic acid
- bile acid sequestrants
- cholesterol absorption inhibitors
- fibrates
how does the liver make cholesterol?
-occurs in the mevalonic acid pathway
-acetyl CoA is converted to 3 hydroxy-3-methylglutaryl CoA
-HMG CoA is then enzymatically converted to mevalonic acid by the enzyme HMG CoA reductase
-after several other enzymatic steps, cholesterol is formed
-conversion of HMG CoA into mevalonic acid is the rate limiting step in cholesterol synthesis
when is cholesterol synthesis greatest?
at night
how do statins work?
-decrease hepatic synthesis of cholesterol by inhibiting the enzyme HMG CoA reductase (rate limiting step)
-this causes an upregulation of hepatic LDL receptors (because there is less cholesterol), allowing the liver to remove more cholesterol from the blood
-net effect is a decrease in LDL cholesterol levels in the blood
what are the benefits of statins
-lower LDL cholesterol
-increase HDL cholesterol
-lower triglyercides
what are the highest prescribed statins?
atorvastatin and rosuvastation
what are the characteristics of statins?
-low oral bioavail (large fraction is extracted by liver)
-distrubtion to liver, spleen, adrenal, skeletal
-metabolized by CYP3A4
-predominantly eliminated in the feces and some renal excretion
why must there be caution when prescribing rosuvastatin to asian patients?
plasma concentrations are 2x higher
adverse effects of statins
-myopathy
-rhabdomyolysis
-hepatoxicity
-DONT USE WHEN PREGNANT as choelsterol is significant in hormone production
what is the mechanism of nicotinic acid?
-inhibits hepatic synthesis/secretion of VLDL
-since LDL is a by product of VLDL, it also decreases LDl
-increases levels HDL
what are the side effects of nicotinic acid?
-facial flushing
-hepatoxicity
-hyperglycemia
-skin rash
-increase uric acid levels
what are bile acids?
- negative charged molecules produced in liver from CYP cholesterol metabolism
-bile acids undergo enterhepatic recycling and 95% are reabsorbed
what are bile acid sequestrants?
-large positive molecules
-function by binding bile acids in the intestine and preventing their reabsorption
-since 95% of bile acids are reabsorped and sequestrants prevent this, there is an increased demand for the liver to produce more (LDL is required)
-this results in an increased uptake of cholesterol from the blood into the liver, causing a decrease in plama LDL cholesterol levels
what the adverse effects of bile acid sequestrants?
- they are not absorbed in the body, therefore there are no systemic effects
-constipation and bloating
-since they are designed to bind to negatively charged molecules, they may decrease absorption of some drugs such as thiazide, diuretics, digoxin, warfarin and certain antibiotics
what are cholesterol absorption inhibitors?
-transport protein called NPC1L is responsible for the intestinal uptake up cholesterol - ezetimibe is an inhibitor which has shown to decrease absoprtion by 54% and lower LDL by 15-20%
-decreased absoprtion leads to increase in hepatic cholesterol synthesis
-this is usually an ajunctive therapy along with a statin
what is vytorin?
contains a statin with ezetimibe
reduces LDL cholesterol by 60%
characteristics of fibrates and how they work
-most effective class of drugs for lowering plasma triglyeride levels
-increase HDL cholesterol
-no effect on LDL cholesterol levels
-act by binding to and activating a receptor in the liver called PRAR-a causing multiple effects:
1. increased synthesis of the lipoprotein lipase (enhances the clearnace of triglyceride rich lipoproteins)
2. decreased apolipoprotein C III production (this is an inhibitor of lipoprotein lipase, decrease allowed for increased lipoprotein lipase activity) 3. increased apolipoprotein AI and AII levels (this is responsible for the increased HDL levels)
adeverse effects of fibrates?
-increased risk for gallstones
-myopathy
-hepatoxicity
