Hyperlipidemia Flashcards
What is the function of LDL?
Carries cholesterol from liver to peripheral tissues (breakdown produce of VLDL, very low TG content and high cholesterol content).
Leftover LDL is uptaken by liver LDL-R.
What is the major apoprotein expressed on LDL, and what is its function?
Apo B-100, organizes the particle and acts as the ligand for LDL removal by binding LDL-R in liver
What does HDL do?
Mediates reverse cholesterol transport by uptaking excess cholesterol from the periphery, including macrophages / foam cells, transfers it to VLDL or back to liver (B1 scavenger receptor)
What is the primary mechanism by which LDL induces thrombo-embolism?
Oxidized-LDL accumlates in arterial wall, monocytes are recruited and become macrophages -> foam cells. Foam cells are lodged in arterial wall and cause stenosis, may burst and recruit more macrophages for oxidized-LDL uptake.
If the plaque ruptures, a clot may be formed on it, which can lodge in a coronary artery (MI) or brain (stroke)
What drug inhibits the dietary intake of cholesterol and how does it do this? Is it used alone?
Ezetimibe - inhibits intestinal cholesterol transporter (NPC1L1) - typically used in combination with statins (monotherapy shows minimal cholesterol reduction)
What other pathways will be affected via statin use?
- Protein lipidation
- Coenzyme-Q formation -> underlies myopathy of statins
- Steroid hormones, vitamin D, bile acids
How does LDL-R endocytosis work and when is it upregulated?
Clathrin-mediated endocytosis once the ligand binds
Low cholesterol levels in the liver needed for bile acid synthesis and membrane maintenance signals upregulation of LDL-R and a further reduction in circulating LDL (key mechanism of cholesterol meds).
What are the two most common forms of familial hypercholesterolemia?
- Mutated LDL-R (endocytosis does not work properly)
- Mutated and upregulated PCSK9 - protease which binds LDL-R and induces its endocytosis and lysosomal degradation independent of LDL binding. -> lack of LDL-R will increase LDL and heart attack risk
What are the two PCSK9 inhibitors and who uses them? How do they work?
- Alirocumab
- Evolucumab
Used as a second line to statins when LDL remains high or statin side effects are high, but very expensive.
Increases the expression of LDL-R on liver by monoclonally binding PCSK9
How do statins work? Where do they act?
Competitive inhibition of HMG-CoA reductase, which converts HMG-CoA into mevalonate.
Act primarily in the liver, which is the major site of cholesterol storage and synthesis
What is the primary way in which statins reduce LDL-C? What does this have to do with effectiveness in familial hypercholesterolemia?
Lowered intracellular cholesterol levels lead to upregulation of LDL-R transcription, increasing LDL endocytosis
-> familial hypercholesterolemia -> LDL-R gene is mutated so there is only a minor LDL-reduction
Which two statins have the longest half-life?
Atorvastatin and rosuvastatin -> 20 hours, only need to be taking once daily. (Lipitor and crestor)
What effect do statins have on triglycerides and why?
Large reduction, often 30-50%, due to decreased VLDL production from lack of cholesterol, and scavenging of VLDL from LDL-receptor (since it also expresses Apo-B100)
What is the most common statin side effect and sub-side effect?
Myopathy - potentially due to inhibition of Co-Q10 synthesis.
Rhabdomyolysis may occur - fatal statin toxicity leading to induced muscle breakdown (Autoimmune) -> may lead to kidney failure
What metabolic syndrome do statins put you at risk for?
Type 2 diabetes, although CV risk reduction outweighs this
Why do people think statins cause memory loss?
Cholesterol is an important part of neuronal membranes
What are the statins metabolized via CYP3A4 and what drugs can make this a problem?
Simvastatin, lovastatin, and atorvastatin
Macrolides, azole antifungals, and HIV protease inhibitors may decrease their metabolize and increase risk of myopathy / rhabdomyolysis
What drug commonly increases plasma levels of statins and what can be taken instead?
Gemfibrizol, a fibrate to lower triglycerides
Can take fenofibrate instead
When are statin combination therapies used?
Patients seeing insufficient LDL-C lowering with statins alone, or who are unable to take high doses of statins due to side effects (myopathy)
When are statins + niacin given?
High LDL-C and low HDL-C levels
When are statins + fenofibrate given?
High triglycerides + high LDL-C
What are the risk factors for coronary heart disease?
- Diabetes
- Age (males over 45 or females over 55)
- Gender - males at higher risk
- Dyslipidemia
- Family history of CHD
- Hypertension
- Current smoker
- Obesity
- Sedentary lifestyle
What is primary vs secondary prevention of CHD?
Primary prevention = prevention before any cardiac event (i.e. MI or stroke)
Secondary prevention = prevention (i.e. statin use) following a cardiac event
What is the high vs low total cholesterol range?
Low / desirable: <200 mg/dL
High: >240 mg/dL
What is the low vs high HDL cholesterol range?
Low: <40 mg/dL
High (goal): >60 mg/dL
What is low vs high LDL?
Low (good): <100 mg/dL
High: >160, >190 is very high
What are normal vs high TG levels?
Normal: <150 mg/dL
High: >200, can be in the thousands
How well does a reduction in LDL-C correlate with cardiac risk?
A 40 mg/dL drop translates to a 20% reduction in 10 year MI / stroke risk
How do bile acid sequestrants work?
50% of daily cholesterol synthesis is used for bile acid synthesis.
These are insoluble, gel-like substances which reside in intestine and bind to bile acids, are eventually eliminated in feces -> more cholesterol diverted to bile acid synthesis, more LDL-R scavenging of LDL is needed
What are the bile acid sequestrants and are they used as a monotherapy?
Cholestyramine and colestipol
Not given as monotherapy -> biosynthesis would be unrepgulated. Work well in combination with statins
What are the effects of major niacin supplementation?
Reduced LDL, increased HDL, reduced triglyerides
What is the mechanism of action of niacin?
Binds to and activates GPCR in adipose tissue, decreasing release of free fatty acids from stored triglycerides, reducing need for VLDL packaging by liver, and reduction in LDL.
HDL is increased by improved stability of Apoprotein A1
Is niacin used as a monotherapy, and what are its adverse effects?
Typically used with statins, especially when HDL levels are low
Main side effect: Extreme flushing and itching (turn bright red), and you have to eat a lot of it. Must take NSAIDs to reduce flushing.
What are the two fibrates typically used?
gemfibrozil (may have interaction with statins)
fenofibrate
What is the mechanism of action of fibrates?
Activates PPARalpha -> ligand activated steroid receptor, lowers release of VLDL in liver and upregulates lipoprotein lipase to decrease tags
Reduces triglyceride levels, minimal effects of HDL/LDl
Why do we care about lowering triglyceride levels?
High TGs (>500 mg/dL) are associated with increased risk of pancreatitis, part of metabolic syndrome
What is metabolic syndrome?
Central obesity, insulin resistance, high blood pressure, and fatty liver (presence of multiple risk factors together)
