Module 2: Drugs that Normalize Lipids

Question 1

Classes of Lipoproteins

Answer 1

Classes of lipoproteins
 Six major classes of plasma lipoproteins
 Three relevant to coronary atherosclerosis
* Very-low-density lipoproteins (VLDLs)
 Triglycerides
* Low-density lipoproteins (LDLs)
 Cholesterol primary core lipid
 Greatest contributor to coronary heart disease (CHD)
* High-density lipoproteins (HDLs)
 Cholesterol

Question 2

Role of LDL Cholesterol
in Atherosclerosis

Answer 2

LDLs initiate and fuel development of
atherosclerosis

 Process begins with transport of LDLs from the
arterial lumen into endothelial cells, then into the
space underlying the arterial epithelium

Question 3

Atherogenesis

Answer 3

-process of leading to atherosclerosis in arteries

More than just deposit of lipids
 Now considered primarily a chronic inflammatory
process
Atherosclerosis is now recognized as an inflammatory condition, not just a simple buildup of cholesterol. It involves the interplay between lipids, endothelial cells (cells lining the blood vessels), immune cells, and inflammatory mediators.

 Infiltration of macrophages, T lymphocytes, and
other inflammatory mediators
-Macrophages: These are a type of white blood cell that play a significant role in atherogenesis. They consume and digest lipids, becoming foam cells, which are a hallmark of atherosclerotic plaque.
-T Lymphocytes: Another type of immune cell involved in the process. They contribute to the inflammatory response within the arterial wall.

Stages of Atherogenesis:
-The process begins with damage to the endothelium, the inner lining of the artery. This damage can be caused by factors like high blood pressure, smoking, diabetes, or high cholesterol.
Once the endothelium is damaged, lipids, particularly low-density lipoprotein (LDL) cholesterol, begin to accumulate in the arterial wall.
This accumulation of lipids triggers an inflammatory response, attracting immune cells like macrophages and T lymphocytes.

These immune cells attempt to digest the lipids but become engorged, turning into foam cells and contributing to the formation of a plaque.

Over time, the plaque grows and can become unstable, potentially leading to a heart attack or stroke if it ruptures and forms a clot.

Other Inflammatory Mediators:
The process also involves various cytokines and chemokines, which are signaling proteins that attract and activate more immune cells, perpetuating the inflammatory response.

Question 4

Detecting High Cholesterol

Answer 4

Cholesterol screening
 Every 5 years for adults older than 20 years
 Total cholesterol
* HDL cholesterol
 Less than 40 mg/dL: Low to undesirable
* LDL cholesterol
 Less than 100 mg/dL: Desirable
 Triglycerides (TGs)

Question 5

Identifying Risk

Answer 5

Identifying CHD Risk Factors:
Key risk factors include high blood pressure, high cholesterol, smoking, obesity, physical inactivity, unhealthy diet, age, family history of heart disease, and certain genetic factors.

Lifestyle factors and medical history play a significant role in determining overall risk.

Calculating 10-Year CHD Risk:
Tools like the Framingham Risk Score or the American College of Cardiology/American Heart Association (ACC/AHA) risk calculator are used.
These tools consider factors like age, gender, cholesterol levels, blood pressure, diabetes status, and smoking history to estimate the risk of developing CHD within the next 10 years.

Identifying CHD Risk Equivalents:
Conditions that confer a similar risk to CHD are considered “risk equivalents.” These include:
Diabetes: Increases the risk of CHD significantly.
Atherosclerotic Disease Other Than CHD: Peripheral arterial disease, abdominal aortic aneurysm, and carotid artery disease are examples.

Framingham Risk Score Greater Than 20%: Indicates a high risk of developing CHD.

Identifying an Individual’s CHD Risk Category:
The risk category is determined based on the presence and severity of risk factors and risk equivalents.

Types of dyslipidemia (abnormal levels of lipids in the blood) each contribute independently to CHD risk. For instance, high levels of low-density lipoprotein (LDL) cholesterol, low levels of high-density lipoprotein (HDL) cholesterol, and high levels of triglycerides each increase CHD risk.

Question 6

Treatment of High LDL

Answer 6

Smoking Cessation:
Smoking is a major risk factor for heart disease. Quitting smoking can improve heart health significantly, as it reduces the damage to the walls of arteries, lowers the risk of blood clots, and enhances overall cardiovascular function.
Smoking cessation also helps to increase the levels of HDL (good) cholesterol.

The TLC Diet:
The Therapeutic Lifestyle Changes diet is specifically designed to help lower LDL cholesterol through dietary choices.

Key Components:
Low in Saturated Fat and Cholesterol: Limiting foods high in saturated fats (like red meat, dairy products made with whole milk) and cholesterol (like egg yolks).

High in Fiber: Incorporating more soluble fiber, which can reduce the absorption of cholesterol in the bloodstream. Good sources include oats, fruits, vegetables, and legumes.

Adding Plant Sterols and Stanols: These substances are found in plants and can help block the absorption of cholesterol. They are added to certain foods like margarines, orange juice, and yogurts.

Heart-Healthy Fats: Including more monounsaturated and polyunsaturated fats in the diet, such as those found in olive oil, nuts, and fish.

Exercise:
Regular physical activity is crucial in managing high LDL cholesterol.

Exercise helps boost HDL cholesterol, improves overall heart health, and can aid in weight loss or maintenance.

The American Heart Association recommends at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous aerobic activity per week, or a combination of both, for adults.

Question 7

Drug Therapy for High LDLs

Answer 7

Drugs to be used only if other methods fail

HMG-CoA Reductase Inhibitors (Statins):
Mechanism: These drugs work by inhibiting the enzyme HMG-CoA reductase, which plays a key role in cholesterol synthesis in the liver. By blocking this enzyme, statins effectively reduce the production of cholesterol.

Effect: They primarily lower LDL cholesterol but can also modestly reduce triglycerides (TGs) and slightly increase high-density lipoprotein (HDL) cholesterol.
Examples: Atorvastatin, simvastatin, rosuvastatin.
Benefits: Statins are not only effective in lowering LDL cholesterol but also reduce the risk of heart attacks and strokes.

Bile-Acid Sequestrants:
Mechanism: These drugs work in the intestines by binding to bile acids (which contain cholesterol) and preventing them from being reabsorbed into the bloodstream. This forces the liver to use more cholesterol to make bile acids, thereby lowering blood cholesterol levels.

Effect: Primarily lower LDL cholesterol.
Examples: Cholestyramine, colestipol.
Considerations: They can interfere with the absorption of other medications and may cause gastrointestinal side effects.

Nicotinic Acid (Niacin):
Mechanism: Niacin works by reducing the liver’s production of VLDL (very low-density lipoprotein), which is converted to LDL in the blood.
Effect: It can lower LDL cholesterol and triglycerides and significantly raise HDL cholesterol.

Considerations: Side effects can include flushing, itching, increased blood sugar, and liver damage, especially at higher doses.

Fibrates:
Mechanism: Fibrates primarily lower triglycerides by reducing the production of VLDL and speeding up the removal of triglycerides from the blood.
Effect: While they are effective in lowering triglyceride levels, their effect on LDL cholesterol is less pronounced and can sometimes even increase LDL levels.

Examples: Fenofibrate, gemfibrozil.
Considerations: They are particularly useful in patients with high triglycerides and are often used in combination with statins for comprehensive lipid management.

Question 8

Metabolic Syndrome

Answer 8

Metabolic syndrome
 High blood glucose
 High triglycerides
 High apolipoprotein B
 Low HDL cholesterol
 Small LDL particles
 Prothrombotic state
 Proinflammatory state
 Hypertension
 High triglycerides
 Levels above 150 mg/dL

Question 9

HMG-CoA Reductase
Inhibitors (Statins)

Answer 9

Most effective drugs for lowering LDL
 Reduction of LDL cholesterol
 Elevation of HDL cholesterol
 Reduction of triglyceride levels
 Nonlipid beneficial cardiovascular actions
-Promote plaque stability
-Reduce the risk for cardiovascular (CV) events
-Increased bone formation

Mechanism of cholesterol reduction
 Administer at night
 Clinical trials
**Therapeutic uses
 Hypercholesterolemia
 Primary and secondary prevention of CV events
 Post-MI therapy
 Diabetes
 Potential uses

Beneficial actions
 Reduction of LDL cholesterol
 Elevation of HDL cholesterol
 Reduction of triglyceride levels
 Nonlipid beneficial cardiovascular actions
 Increased bone formation

Adverse effects
 Common
* Headache
* Rash
* GI disturbances
 Rare
* Myopathy/rhabdomyolysis
* Hepatotoxicity
* New-onset diabetes
* Cataracts

Drug interactions
 Most other lipid-lowering drugs (except bile-acid
sequestrants)
 Drugs that inhibit CYP3A4
 Use in pregnancy
**Dosing: Once daily in the evening
 Endogenous cholesterol synthesis increases
during the night
 Statins have greatest impact when given in the
evening

Question 10

Nicotinic Acid (Niacin)

Answer 10

Reduces LDL and TG levels
 Increases HDL levels more effectively than any
other drug
 Effect on plasma lipoproteins
 Lowers TG levels
 Raises HDL cholesterol

Adverse effects
 Skin (flushing, itching)
* Intense flushing initially; can pretreat with aspirin
* Decreased with sustained-release (SR) version of niacin
 Gastrointestinal
 Hepatotoxicity
 Hyperglycemia
 Gouty arthritis
 Can raise blood levels of uric acid

Question 11

Bile-Acid Sequestrants

Answer 11

Previously were first-line drugs
 Now primarily used as adjuncts to statins
 Cholestyramine
 Colestipol
 Colesevelam
 Newest and better-tolerated drug
 Does not decrease uptake of fat-soluble vitamins (as other bile sequestrants do)
 Does not significantly reduce the absorption of statins, warfarin, digoxin, and most other drugs studied

Reduces LDL cholesterol
 Increases VLDL levels in some patients
 Mechanism of action
* Increases LDL receptors on hepatocytes
* Prevents reabsorption of bile acids
 Therapeutic use
* Reduces LDL cholesterol (in conjunction with modified diet
and exercise)
 Adverse effects
* Constipation

Question 12

Ezetimibe

Answer 12

Mechanism of action and impact on plasma
lipids
 Inhibits cholesterol absorption
 Therapeutic use
 Reduces total cholesterol, LDL cholesterol, and
apolipoprotein B
 Approved for monotherapy and combined use with statins

Adverse effects
 Myopathy
 Rhabdomyolysis
 Hepatitis
 Pancreatitis
 Thrombocytopenia
 Drug interactions
 Statins
 Fibrates
 Bile-acid sequestrants
 Cyclosporine

Question 13

Fibric Acid Derivatives (Fibrates)

Answer 13

Most effective drugs available for lowering TG levels
 Can raise HDL cholesterol
 Little or no effect on LDL cholesterol
 Can increase the risk for bleeding in patients taking warfarin
 Can increase the risk for rhabdomyolysis in patients taking statins
***Three drugs in the United States
 Gemfibrozil [Lopid]
 Fenofibrate [Tricor, others]
 Fenofibric acid [TriLipix]

Question 14

Gemfibrozil

Answer 14

Effects on plasma lipoproteins
 Decreases plasma TG content
 Lowers VLDL levels
 Can raise HDL cholesterol
 Mechanism
 Appears to interact with a specific receptor subtype (PPAR alpha)
 Drug interactions
 Displace warfarin from plasma albumin
 Measure international normalized ratio (INR) frequently

Therapeutic uses
 Reduces high levels of plasma triglycerides (VLDLs)
 Treatment reserved for patients who have not responded to diet
modification
 Less effective than statins in reducing LDL
 Can raise HDL (not approved for this use)
 Adverse effects
 Rashes
 Gastrointestinal disturbances
 Gallstones
 Myopathy
 Liver injury (hepatotoxic)