Module 12 - Part 2 Flashcards
What is the first line of treatment for elevated LDL cholesterol?
Primary treatment is lifestyle changes including diet modification, weight exercise plans and change in smoking status
What are the benefits of CV exercise?
Decreasing LDL cholesterol, elevating HDL cholesterol and decreasing insulin resistance and BP
How does smoking affect cholesterol levels.
Decreases HDL and increases LDL
When is drug treatment for cholesterol levels initiated?
When target cholesterol levels are not achieved by lifestyle changes
What are the different classes of drugs used to treat elevated blood lipids?
1 - Statins 2 - Bile acid sequestrants 3 - Nicotinic acid 4 - Cholesterol absorption inhibitors 5 - Fibric acid derivates (Fibrates)
Hepatic cholesterol synthesis occurs in what pathway?
Mevalonic acid pathway
Describe the important parts of the mevalonic acid pathway.
Acetyl-CoA –> HMG CoA - HMG CoA reductase -> mevalonic acid –> several other steps –> cholesterol
What is the rate limiting step in cholesterol synthesis?
Conversion of HMG-CoA into mevalonic acid by HMG-CoA reductase
What is the mechanism of action of statins?
Statins decrease hepatic synthesis of cholesterol by inhibiting HMG-CoA reductase
This causes upregulation of hepatic LDL receptors –> more cholesterol removed from the blood –> decrease in LDL cholesterol levels in the blood
What are the physiological benefits of statins use?
1 - Decreased LDL cholesterol
2 - Increased HDL cholesterol
3 - Decreased triglycerides in the blood
What is primary prevention aimed at?
Aimed at preventing the development of CV disease
Multiple recent studies have shown that statins decrease the incidence of _______ events even in low risk patients with no history of ____.
coronary
CHD
What does secondary prevention aim to do?
Prevent the recurrence of CV events
These are among the highest prescribed drugs in the world.
In fact, _________ (_______) is the highest prescribed drug in Canada and the US, while ________ (______) is the 4th highest prescribed drug in Canada.
Statins
Atorvastatin (Lipitor) - highest prescribed
Rosuvastatin (Crestor) - 4th highest in Canada
Atorvastatin (Lipitor)
- ____ oral bioavailability
- _____ fraction of absorbed dose is extracted by the liver
- Distribution is primarily to the ______, but also to the ________, _______ _______ and ________ _______
- Metabolized by ___ ____
- Predominantly eliminated in the _____, with minimal ______ excretion
- LOW oral bioavailability
- LARGE fraction of absorbed dose is extracted by the liver
- Distribution is primarily to the LIVER, but also to the SPLEEN, ADRENAL GLANDS and SKELETAL MUSCLE
- Metabolized by CYP 3A4
- Predominantly eliminated in the FECES, with minimal RENAL excretion
Rosuvastatin (Crestor)
- ___ oral bioavailability
- _____ fraction of absorbed dose extracted by the liver
- Distribution is primarily to the _____, but also to _______ ______
- Describe metabolism of Crestor
- Predominantly eliminated in the _____, minimal ______ excretion
- LOW oral bioavailability
- LARGE fraction of absorbed dose extracted by the liver
- Distribution is primarily to the LIVER but also to SKELETAL MUSCLE
- Not extensively metabolized
- Predominantly eliminated in the FECES, minimal RENAL excretion
What is an important consideration when administering Rosuvastatin?
Plasma rosuvastatin concentrations are approximately 2x higher in Asian patients when compared to Caucasian patients - the initial dose in Asian patients should be 5mg (lowest dose we can give)
In general, statins are well tolerated, however there are some adverse effects. What are they?
Myopathy
Rhabdomyolysis
hepatotoxicity
Muscle lysis with severe muscle pain. Diagnosed by measuring blood levels of this enzyme.
Rhabdomyolysis
Creatine kinase - released during muscle injury
Rhabdomyolysis is accompanied by large increases in blood _______ (called __________) and may cause acute ______ failure.
potassium (hyperkalemia)
acute kidney failure
Describe treatment of rhabdomyolysis.
Treatment is targeted at preserving kidney function by IV administration of fluids
Although there is a low incidence of __________ associated with statin use, _____ function tests should be performed ________ initiating therapy and periodically ________.
hepatotoxicity
liver
before
thereafter
In what types of patients should statins not be used?
Pregnant women, or women trying to become pregnant
What is the mechanism of action of nicotinic acid (Niacin)?
Inhibits the hepatic secretion of VLDL
How does nicotinic acid decrease LDL?
Since LDL is a by-product of VLDL degradation, nicotinic acid effectively reduces both VLDL and LDL
What is another beneficial effect of nicotinic acid use?
Raises blood HDL levels
Side effects limit the use of nicotinic acid in many patients, what are the side effects?
Facial flushing, hepatotoxicity, hyperglycemia, skin rash and increased uric acid levels
Negatively charged molecules produced by the liver from CYP7A1 mediated cholesterol metabolism.
Bile acids
Bile acids are secreted into the intestine and function to aid in the absorption of dietary ____ and ____ _______ vitamins.
fats
fat soluble vitamins
Bile acids are ______-charged.
negatively
Bile acids undergo ________ ________ and are therefore reabsorbed from the intestine.
enterohepatic recycling
Describe the mechanism of action of Bile acid sequestrants.
Bile acid sequestrants are largely positively charged molecules, which attract and bind bile acids in the intestine and prevent their reabsorption
This causes an increased demand for bile acid synthesis in the liver
This causes an increase in LDL receptors, uptake of LDL from the blood and a subsequent decrease in plasma LDL cholesterol levels
Why do bile acid sequestrants not have systemic side effects?
They are not absorbed at all, and therefore do not have systemic side effects
What are adverse effects of bile acid sequestrants?
GI sides - constipation and bloating
also may decreased absorption of certain drugs
Bile acid sequestrants decreases the absorption of these drugs.
Thiazide diuretics, warfarin, digoxin and certain antibiotics
A specific transport protein called _______ is responsible for the intestinal uptake of the majority of dietary cholesterol.
NPC1L1
The only cholesterol absorption inhibitor on the market is ________ (_____).
Ezetimibe (Zetia)
Decreased intestinal absorption of cholesterol by ezetimibe can produce a compensatory increase in this.
Hepatic cholesterol synthesis
Ezetimibe is often prescribed how?
As an adjunct therapy along with a statin
A recently approved combination pill called ______ contains a statin (______) with ezetimibe.
vytorin
simvastatin
Most effective class of drugs for lowing plasma triglyceride levels.
Fibric acid derivatives/Fibrates
Other than affecting plasma triglyceride levels, how do fibric acid derivatives affect cholesterol levels?
raise HDL cholesterol, but have no effect on LDL cholesterol levels
What is the mechanism of action of Fibrates?
Bind to and activate the PPAR-alpha receptor (peroxisome activated receptor alpha).
Activation of PPAR-alpha leads to these effects.
1 - Increased synthesis of lipoprotein lipase
2 - Decreased apolipoprotein C-III production
3 - Increased apolipoprotein A-1 and apolipoprotein A-II levels
Enzyme that enhances the clearance of triglyceride rich lipoproteins.
lipoprotein lipase
Inhibitor of lipoprotein lipase.
Apolipoprotein C-III
Responsible for increased HDL levels associated with fibrates.
Increased apolipoprotein A-I and A-II levels
What are the adverse effects of fibrates?
Increased risk of gallstones
Myopathy
Hepatotoxicity
If patients are taking statins with fibrates, what should they be monitored for?
Myopathy, and to a lesser degree, hepatotoxicity
