module 12

Question 1

what fraction of deaths are caused by CHD?

Answer 1

1/3 in canada

Question 2

what is cholesterol essential for ?

Answer 2

precursor for steroid hormones and bile acids
cell membranes

Question 3

what % of cholesterol is synthesized by the liver?

Answer 3

80

Question 4

what is the purpose of lipoproteins?

Answer 4

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

Question 5

what do A-I lipoproteins do

Answer 5

transport cholesterol from non hepatic tissue back to the liver

Question 6

what do B-100 apolipoproteins do?

Answer 6

transport cholesterol to non hepatic tissue

Question 7

what are the characteristics of VLDLs

Answer 7

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

Question 8

what are the characteristics of LDLs

Answer 8

-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

Question 9

what are the characteristics of HDLs?

Answer 9

-delivers from non hepatic back to liver (removal of cholesterol from blood)

-cholesterol is their main core (20-30% of blood cholesterol)

Question 10

how does aterosclerossis occur?

Answer 10

1. damage in the endothelium - substances travelling in the blood such as cholesterol, fat and waste accumulate inside the damaged area
2. chemcial reactions occuring within the build up of material causes cholesterol molecules to oxidize - this initiaties an inflammatory response
3. 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
4. as a result, macrophages change into foam cells that accumulate as plaque
5. 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

Question 11

what is the framingham risk score used for and include?

Answer 11

includes gender, age, total blood cholesterol, smoking, HDL cholesterol and systolic

used to estimate patients risk for cardiovascular disease in 10 years

Question 12

what does the framingham score underestimate?

Answer 12

shown to underestimate risk in youth, women and patients with metabolic syndrome

Question 13

what is metabolic syndrome?

Answer 13

3+ of the following

1.central obesity
2. elevated triglycerides
3. low HDL
4. hyperglycemia
5. hypertension

Question 14

why is metabolic syndrome significant?

Answer 14

causes an increased risk of coronary heart disease AND type 2 diabetes

1/4 canadians have metabolic syndrome

Question 15

what are the first lines of treatment for LDL cholesterol

Answer 15

diet - less cholesterol & fat + more fibre
weight control
exercise
smoking

Question 16

what are the 5 different classes of drugs for elevated blood lipids

Answer 16

1. statins
2. nicotinic acid
3. bile acid sequestrants
4. cholesterol absorption inhibitors
5. fibrates

Question 17

how does the liver make cholesterol?

Answer 17

-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

Question 18

when is cholesterol synthesis greatest?

Answer 18

at night

Question 19

how do statins work?

Answer 19

-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

Question 20

what are the benefits of statins

Answer 20

-lower LDL cholesterol
-increase HDL cholesterol
-lower triglyercides

Question 21

what are the highest prescribed statins?

Answer 21

atorvastatin and rosuvastation

Question 22

what are the characteristics of statins?

Answer 22

-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

Question 23

why must there be caution when prescribing rosuvastatin to asian patients?

Answer 23

plasma concentrations are 2x higher

Question 24

adverse effects of statins

Answer 24

-myopathy
-rhabdomyolysis
-hepatoxicity
-DONT USE WHEN PREGNANT as choelsterol is significant in hormone production

Question 25

what is the mechanism of nicotinic acid?

Answer 25

-inhibits hepatic synthesis/secretion of VLDL -since LDL is a by product of VLDL, it also decreases LDl -increases levels HDL

Question 26

what are the side effects of nicotinic acid?

Answer 26

-facial flushing -hepatoxicity -hyperglycemia -skin rash -increase uric acid levels

Question 27

what are bile acids?

Answer 27

- negative charged molecules produced in liver from CYP cholesterol metabolism -bile acids undergo enterhepatic recycling and 95% are reabsorbed

Question 28

what are bile acid sequestrants?

Answer 28

-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

Question 29

what the adverse effects of bile acid sequestrants?

Answer 29

- 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

Question 30

what are cholesterol absorption inhibitors?

Answer 30

-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

Question 31

what is vytorin?

Answer 31

contains a statin with ezetimibe reduces LDL cholesterol by 60%

Question 32

characteristics of fibrates and how they work

Answer 32

-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)

Question 33

adeverse effects of fibrates?

Answer 33

-increased risk for gallstones -myopathy -hepatoxicity