Module 12 - Drugs to Lower Blood Cholesterol and Triglycerides

Question 1

Coronary Heart disease

Answer 1

• Coronary heart disease occurs when coronary blood circulation fails to adequately supply the heart with blood.
• Coronary heart disease is primarily caused by atherosclerosis.
• The risk of developing coronary heart disease is directly related to the levels of cholesterol in the blood. Therefore people with high blood cholesterol are at risk of developing coronary heart disease.

Question 2

What is Atherosclerosis

Answer 2

Atherosclerosis occurs when plaque builds up on the walls of the arteries. This causes the artery to narrow and results in decreased blood flow to the heart.

Question 3

Cholesterol

Answer 3

It is an essential component of cell membranes, a precursor of steroid hormones and a precursor of bile salts.
- We obtain cholesterol through dietary sources (exogenous cholesterol) or through synthesis (endogenous cholesterol) which occurs primarily in the liver.
- Approximately 80% of the cholesterol in the body is synthesized by the liver, whereas 20% is obtained from dietary sources. Although cholesterol is an essential molecule for the reasons described above, high blood levels are linked to atherosclerosis and heart disease.

Question 4

Structure and Function of Plasma Lipoproteins

Answer 4

The outer hydrophilic shell is made up of phospholipids. This allows lipoproteins to be soluble in plasma. In contrast, the core is composed of lipophilic cholesterol and triglycerides.

the primary function of lipoproteins is to transport cholesterol and triglycerides in the blood. Since cholesterol and triglycerides are lipophilic, they require lipoproteins in order to be soluble in the blood.

All lipoproteins also have apolipoproteins embedded in the phospholipid shell. Apolipoproteins have three functions:
1. Allow recognition by cells which may bind and ingest lipoproteins.
2. Activate enzymes that metabolize lipoproteins.
3. Increase the structural stability of lipoproteins.

Lipoproteins that contain apolipoprotein A-I transport cholesterol from non-hepatic tissue back to the liver whereas lipoproteins that contain apolipoprotein B-100 transport cholesterol to non-hepatic tissue.

Question 5

Classes of Lipoproteins

Answer 5

Lipoproteins are named based on their density. Protein has a higher density than lipid so lipoproteins with a high percentage of protein will have a high density. Conversely, lipoproteins with a low percentage of protein will have a relatively low density.

In terms of coronary heart disease and atherosclerosis, three classes of lipoproteins are particularly important. They are Very-Low Density Lipoproteins (VLDL), Low Density Lipoproteins (LDL) and High Density Lipoproteins (HDL).

Question 6

Very Low Density Lipoproteins (VLDL)

Answer 6

VLDL’s deliver triglycerides from the liver to adipose tissue and muscle.

They have a triglyceride rich core and account for almost all of the triglyceride content in blood.

The link between VLDL and atherosclerosis is controversial with some, but not all studies, suggesting that high VLDL contribute to atherosclerosis.

VLDL particles contain one apolipoprotein B-100 molecule, which allows them to bind to cells and transfer their lipid (mostly triglyceride) to cells.

Question 7

Low Density Lipoproteins (LDL)

Answer 7

LDL’s deliver cholesterol to non-hepatic tissue.

Have a cholesterol rich core and account for 60 – 70% of the cholesterol in blood.

LDL particles contain one apolipoprotein B-100 molecule, which allows them to bind to cells and transfer their lipid (mostly cholesterol) to cells.

There is a clear link between LDL cholesterol and development of atherosclerosis. The higher the blood LDL level, the greater the risk of developing coronary heart disease.

Reducing blood LDL levels halts or even reverses atherosclerosis and has been proven to decrease death from coronary heart disease.

Because of the role it plays in coronary heart disease, LDL cholesterol is often referred to as “bad cholesterol”

Question 8

High Density Lipoproteins (HDL)

Answer 8

HDL’s deliver cholesterol from non-hepatic tissue back to the liver. Therefore, HDL’s promote cholesterol removal from the blood.

Similar to LDL, HDL’s have cholesterol as their main core lipid and account for 20 – 30% of total blood cholesterol.

The effect of HDL on coronary heart disease is opposite to that of LDL. Therefore, elevated HDL decreases the risk of coronary heart disease.

HDL particles may contain multiple apolipoproteins including A-I, A-II and A-IV. The A-I apolipoprotein is believed to mediate the beneficial effects of HDL cholesterol.

Since HDL cholesterol protects against atherosclerosis, it is often referred to as “good cholesterol”.

Question 9

Role of LDL cholesterol in Atherosclerosis

Answer 9

• LDL’s promote the initiation of atherosclerosis.
• Atherosclerosis is initiated when LDL’s move from the blood into the sub-endothelial space of the arterial epithelium. In the sub-endothelial space LDL’s may become oxidized, a crucial step in the initiation of atherosclerosis.
• Oxidation of LDL cholesterol causes recruitment of monocytes (a type of immune cell) to the sub-endothelial space.
• Monocytes are then converted to macrophages. Macrophages are another type of immune cell that are capable of “ingesting” foreign material.
• Macrophages then take up oxidized LDL. During this process they become larger and vacuolated. In this form they are referred to as foam cells.
• As more foam cells accumulate beneath the epithelium, a fatty streak appears. This is followed by platelet adhesion, smooth muscle migration and collagen synthesis.
• The end result is an atherosclerotic lesion characterized by a lipid core and a tough fibrous plaque.

Question 10

What process is atherosclerosis primarily

Answer 10

Although LDL cholesterol plays a critical role in the development of atherosclerosis, it is important to note that atherosclerosis is PRIMARILY an inflammatory process.

LDL penetration of the arterial wall can be thought of as causing a mild injury to the arterial endothelium. It is the subsequent inflammatory response (i.e. monocyte/macrophage infiltration) that mediates the development of atherosclerosis.

Question 11

Cholesterol Screening

Answer 11

In Canada cholesterol screening is recommended for all males over the age 40 and all females over the age of 50 or females that are post-menopausal.

Testing is also recommended in all patients, regardless of age, who:
- have diabetes
- have heart disease or a family history of heart disease
- have hypertension
- have central obesity: a waist circumference greater than 102 cm (40 inches) for men and 88 cm (35 inches) for women
- Smoke or have recently stopped smoking
- have inflammatory (i.e. arthritis, lupus) or renal disease

Question 12

Cardiovascular Risk Assessment

Answer 12

The most commonly used form of cardiovascular risk assessment is called the Framingham Risk Score (abbreviated FRS). - uses gender, age, total blood cholesterol, smoking status, HDL cholesterol and systolic blood pressure in a formula to calculate a risk score.

The risk score represents the patient’s 10 year risk of developing coronary heart disease.

Patients with a Framingham 10 year risk score greater than 20% are considered high risk, between 10-19% are considered moderate risk and a score below 10% is considered low risk.

It is important to note the Framingham score has been shown to underestimate risk in youth, women and patients with metabolic syndrome.

Question 13

Metabolic Syndrome

Answer 13

Is a combination of medical disorders that cause increased risk of coronary heart disease and type II diabetes.

Metabolic syndrome is diagnosed when patients have three or more of:
1. Central obesity – Waist circumference > 102 cm (40 inches) for men or 88 cm (35 inches) for women
2. Elevated triglycerides – Blood triglycerides > 1.7 mmol/L
3. Low HDL cholesterol - HDL cholesterol < 1.03 mmol/L in men or 1.29 mmol/L in women.
4. Hyperglycemia – Fasting blood glucose > 5.6 mmol/L.
5. Hypertension – Blood pressure > 135/85 mmHg

Treatment of metabolic syndrome is targeted at decreasing the risk for coronary heart disease and type II diabetes.
- one in four Canadians have metabolic syndrome.

Question 14

Diet

Answer 14

Modification of diet is targeted towards decreasing LDL cholesterol and establishing a healthy body weight. Dietary recommendations suggest intake of less than 200 mg/day of total cholesterol and intake of saturated fats of 7% or less of total calories. Further recommendations suggest the intake of soluble fiber of 10 – 25 grams/day and plant stanols and sterols of 2 grams/day.

Question 15

Weight Control

Answer 15

Obesity is one of the leading causes of heart disease in Canada and the USA. In most people this is a modifiable risk factor. Weight loss by dietary modification and exercise lowers LDL cholesterol and decreases the risk of coronary heart disease.

Question 16

Exercise

Answer 16

More and more Canadians are living sedentary lifestyles making the need for regular exercise greater than ever. Cardiovascular exercise has many benefits which include decreasing LDL cholesterol, elevating HDL cholesterol along with decreasing insulin resistance and blood pressure. Recommendations suggest that all people should exercise for between 30-60 minutes per day.

Question 17

Cigarette Smoking

Answer 17

Smoking cigarettes decreases HDL cholesterol and increases LDL cholesterol therefore increasing risk of coronary heart disease. Smoking has been called the “leading preventable cause of death and disease” and is an especially important risk factor in younger (under 50) men and women.

Question 18

Classes of Drugs used to treat elevated blood lipids include:

Answer 18

1. Statins
2. Bile Acid Sequestrants
3. Nicotinic Acid
4. Cholesterol Absorption Inhibitors
5. Fibric Acid Derivatives

Question 19

Site of action for Statin drugs

Answer 19

The mevalonic acid pathway. The enzyme that converts HMG CoA to mevalonic acid is called HMG CoA Reductase

Question 20

Mevalonic acid pathway (cholesterol synthesis)

Answer 20

acetyl CoA —-> HMG CoA —-> Mevalonic Acid —-> Multiple other products —-> Cholesterol

Question 21

Statins mechanism of action

Answer 21

Statins decrease the hepatic synthesis of cholesterol by inhibiting the enzyme HMG CoA reductase, the rate-limiting step of cholesterol synthesis.

inhibition of HMG CoA reductase causes an upregulation of hepatic LDL receptors. This allows the liver to remove more cholesterol from blood. The net effect is a decrease in LDL cholesterol blood levels.

acetyl CoA —-> HMG CoA X (blocked) Mevalonic Acid —-> Multiple other products —-> Cholesterol

Statins inhibit the enzyme HMG CoA Reductase therefore blocking the conversion of HMG CoA to Mevalonic Acid.

Question 22

Benefits of Statins

Answer 22

decrease LDL
increase HDL
decrease triglycerides

Question 23

Primary prevention studies (Statin)

Answer 23

Primary prevention is targeted at preventing the development of cardiovascular disease. Statins are effective in the primary prevention of coronary heart disease. Multiple recent studies have shown that statins decrease the incidence of coronary events (i.e. heart attack and stroke) even in low risk patients with no history of coronary heart disease.

Question 24

Secondary prevention studies (statins)

Answer 24

Secondary prevention aims to prevent the recurrence of cardiovascular events. For example, preventing a patient who has had a heart attack from having another heart attack. Statins are effective drugs for preventing recurrent cardiovascular events in higher risk patients.

Question 25

Pharmacokinetics of Statins (Atorvastatin)

Answer 25

• Low oral bioavailability (~14%)
• Large fraction of absorbed dose is extracted by the liver (the site of drug action).
• Distribution is primarily to the liver but also to the spleen, adrenal glands and skeletal muscle.

Metabolized by CYP3A4
- Predominantly eliminated in the feces, minimal renal excretion.

Question 26

Pharmacokinetics of Statins (rosuvastatin)

Answer 26

• Low oral bioavailability (~20%)
• Large fraction of absorbed dose is extracted by the liver (the site of drug action).
• Distribution is primarily to the liver but also to skeletal muscle.
• Not extensively metabolized.
• Predominantly eliminated in the feces, minimal renal excretion.
• Plasma rosuvastatin concentrations are approximately two times higher in Asian patients when compared to Caucasian patients. The initial dose in Asian patients should be 5 mg

Question 27

Adverse effects of statins

Answer 27

• mild myopathy
• Rhabdomyolysis (rare) Rhabdo occurs when damaged muscle tissue releases its proteins and electrolytes into the blood
• not used in pregnant women

Question 28

Nicotinic Acid (Niacin)

Answer 28

• Inhibits the hepatic secretion of VLDL. Since LDL is a by-product of VLDL degradation, nicotinic acid effectively reduces both VLDL and LDL.
• Also increases blood levels of HDL cholesterol.

Side effects include intense facial flushing, hepatotoxicity, hyperglycemia, skin rash and increase uric acid levels.

Question 29

What are bile-acids

Answer 29

• Bile acids are negatively charged molecules produced in the liver from CYP7A1 mediated cholesterol metabolism.
• Bile acids are secreted into the intestine and function to aid in the absorption of dietary fats and fat soluble vitamins.

Bile acids undergo enterohepatic recycling and are therefore reabsorbed from the intestine. Over 95% of bile acids are normally reabsorbed from the intestine.

Question 30

Mechanism of Action – Bile Acid Sequestrants

Answer 30

• Bile acid sequestrants are large positively charged molecules.

They function by attracting and binding bile acids (negatively charged) in the intestine and prevent their absorption.

Since over 95% of bile acids are normally reabsorbed, this causes an increased demand for bile acid synthesis in the liver.

In order to synthesize more bile acids in the liver, LDL cholesterol is required. Therefore liver cells increase the number of LDL receptors. This results in increased uptake of cholesterol from the blood to the liver, causing a decrease in plasma LDL cholesterol levels.

Question 31

Adverse effects of bile acid sequestrants

Answer 31

Bile-acid sequestrants are not absorbed at all and therefore do not have any systemic side effects.

Predominant side effects are limited to the GI tract and include constipation and bloating.

As bile acid sequestrants are designed to bind to negatively charged molecules, they may decrease the absorption of some drugs such as thiazide diuretics, digoxin, warfarin and certain antibiotics.

Question 32

Cholesterol Absorption Inhibitors

Answer 32

transport protein called NPC1L1 is responsible for the intestinal uptake of the majority of dietary cholesterol. A recent strategy to lower blood cholesterol is to inhibit this transporter

The only cholesterol inhibitor on the market is ezetimibe (Zetia) which has been shown to decrease intestinal cholesterol absorption by 54% and lower blood LDL cholesterol by 15 - 20%.

Decreased intestinal absorption of cholesterol by ezetimibe can produce a compensatory increase in hepatic cholesterol synthesis. Therefore ezetimibe is often prescribed as an adjunct therapy along with a statin.

A recently approved combination pill called vytorin contains a statin (simvastatin) with ezetimibe. This can reduce LDL cholesterol by up to 60%.

Question 33

Fibric acid derivatives (fibrates)

Answer 33

Are the most effective class of drugs for lowering plasma triglyceride levels.

They also increase HDL cholesterol but have almost no effect on LDL cholesterol levels.

Fibrates act by binding to and activating a receptor in the liver called PPARα (peroxisome-proliferator activated receptor-alpha).

Question 34

Activation of PPARα has what effects (fibrates)

Answer 34

1. Increased synthesis of the enzyme lipoprotein lipase. Lipoprotein lipase is an enzyme that enhances the clearance of triglyceride rich lipoproteins.
2. Decreased apolipoprotein C-III production. Apolipoprotein C-III is an inhibitor of lipoprotein lipase. Decreased apolipoprotein C-III allows for increased lipoprotein lipase activity.
3. Increased apolipoprotein A-I and apolipoprotein A-II levels. This is responsible for the increased HDL levels associated with fibrates.

Question 35

Adverse effects of fibrates

Answer 35

Increased risk of gallstones

Myopathy – Fibrates alone may cause myopathy in a small fraction of patients. If fibrates are combined with a statin, a low dose of statin should be used and the patient should be carefully monitored for signs of myopathy.

Hepatotoxicity