6 - Drugs to Lower Blood Cholesterol and Triglycerides Flashcards
(28 cards)
Coronary Heart Disease
Coronary heart disease
- occurs when coronary blood circulation fails to adequately supply the heart with blood.
- is primarily caused by atherosclerosis
→Atherosclerosis occurs when plaque builds up on the walls of the arteries.
→ causes the artery to narrow and results in decreased blood flow to the heart - The risk of developing coronary heart disease is directly related to levels of blood cholesterol
→ high blood cholesterol = at risk of developing CHD.
→ this is why drugs are designed to lower blood levels of cholesterol. - In Canada, CV disease causes 1/3 of all deaths (more than any other illness)
Cholesterol
- Cholesterol is an essential component of cell membranes, a precursor of steroid hormones (i.e. testosterone and estrogen) 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.
- Approx 80% of the cholesterol in the body is synthesized by the liver, whereas 20% is obtained from dietary sources.
- high blood levels are linked to atherosclerosis and heart disease.
→ this is why, most drugs used to target decreasing cholesterol target the liver to decrease synthesis rather than targeting dietary absorption
Plasma Lipoproteins
- The structure of lipoproteins
→ the outer hydrophilic shell is made up of phospholipids - allows lipoproteins to be soluble in plasma
→ The core is composed of lipophilic (free) cholesterol and triglycerides
→ lipophilic - not soluble in blood if not surrounded by phospholipids - The primary function of lipoproteins is to transport cholesterol and triglycerides in the blood.
→ Since cholesterol and triglycerides are lipophilic, they require lipoproteins to be soluble in the blood. - All lipoproteins have apolipoproteins embedded in the phospholipid shell.
- Apolipoproteins have 3 functions:
- Allow recognition by cells which bind and ingest lipoproteins.
- Activate enzymes that metabolize lipoproteins.
- Increase the structural stability of lipoproteins.
- Lipoproteins can contain variety of apolipoproteins which differentiates the function they have
○ Ex. Lipoprotein that contains apolipoprotein A1 transports cholesterol from non-hepatic tissue back to the liver
○ Ex. lipoproteins that contain apolipoprotein B-100 transport cholesterol to non-hepatic tissue
Classes of Lipoproteins
- Lipoproteins are named based on density.
- Protein has a higher density than lipid so lipoproteins with a high % of protein will have a high density. (HDLP)
- Lipoproteins with a low % of protein will have a relatively low density (LDLP)
- 3 classes of lipoproteins are important for coronary heart disease and atherosclerosis
1. Very-Low Density Lipoproteins (VLDL)
2. Low Density Lipoproteins (LDL)
3. High Density Lipoproteins (HDL).
- 3 classes of lipoproteins are important for coronary heart disease and atherosclerosis
Very Low Density Lipoprotein
- VLDL’s deliver triglycerides from the liver to adipose tissue and muscle.
- They have a triglyceride core and account for almost all of the triglyceride content in blood.
- high VLDL (is suggested to) contribute to atherosclerosis and CV disease
- VLDL particles contain 1 apolipoprotein B-100 molecule
→ allows them to bind to cells (muscle and adipose) and transfer their lipid (mostly triglyceride) to cells.
Low Density Lipoprotein (LDL)
- 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 1 apolipoprotein B-100 molecule, which allows them to bind to cells and transfer their lipid (mostly cholesterol) to cells.
- There is a 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 reverses atherosclerosis and decreases death from coronary heart disease.
- LDL is known as “bad cholesterol” (bc of role in CHD)
High Density Lipoprotein (HDL)
- HDL’s deliver cholesterol from non-hepatic tissue back to the liver
→ 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.
- Effect of HDL on coronary heart disease is opposite to that of LDL
→ elevated HDL decreases the risk of coronary heart disease.
→ HDL cholesterol; brings lipids and cholesterol back to liver (site of metabolism) so it lowers blood levels of cholesterol - HDL particles may contain multiple apolipoproteins including A-I, A-II and A-IV.
→ The A-I apolipoprotein mediates the beneficial effects of HDL cholesterol and allows binding of HDL particles back to liver to allow liver to take up cholesterol from blood - HDL is known as “good cholesterol” (it protects against atherosclerosis)
The Role of LDL Cholesterol in Atherosclerosis
- LDL’s promote the initiation of atherosclerosis.
1) Atherosclerosis is initiated when LDL’s move from the blood into the sub-endothelial
space of the arterial epithelium
2) In the sub-endothelial space LDL’s may become
oxidized, a crucial step in the initiation of atherosclerosis.
3) Oxidation of LDL cholesterol causes recruitment of monocytes (type of immune cell) to the sub-endothelial space.
4) Monocytes are then converted to macrophages. →Macrophages are a type of
immune cell that “ingests” foreign material.
5) Macrophages then take up oxidized LDL.
→During this process they become larger and
vacuolated. In this form they are referred to as foam cells.
6) As more foam cells accumulate beneath the epithelium, a fatty streak appears.
7) This is followed by platelet adhesion, smooth muscle migration and collagen synthesis.
8) The end result is an atherosclerotic lesion characterized by a lipid core and a tough fibrous plaque.
- 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 that mediates the development of atherosclerosis.
Cholesterol Screening
- Cholesterol values are presented in mg/dL (American) whereas in Canada we report cholesterol in mmol/L.
- 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 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: waist circumference > 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 - Testing is recommended for these patients bc they have other confounding factors that increase the risk of developing coronary heart disease
Cardiovascular Risk Assessment
- Cardiovascular risk assessment is used by health care practitioners to estimate the risk a patient has of developing cardiovascular disease.
- It provides health care professionals with guidelines and treatment targets.
- The most commonly used form of cardiovascular risk assessment is called the Framingham Risk Score (abbreviated FRS).
- The Framingham Risk Score uses:
1. Gender
2. Age
3. Total blood cholesterol
4. Smoking status
5. HDL cholesterol
6. systolic blood pressure - uses 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
→ > 20%: high risk
→ between 10-19%: moderate risk
→ < 10%: low risk. - the Framingham score underestimates risk in youth, women and patients with metabolic syndrome.
- Physicians use the Framingham risk score to guide treatment of cholesterol using the following table.
- LDL cholesterol is NOT on the list
- Look through each categories to find where you match add up total # of points and compare to final table
- there are 2 different tables, for men and women,that take into account same factors but scale values are different (with different values)
Framingham Risk Assessment
HIGH Risk
- FRS > 20%
- Patients with Diabetes
- Patients with Heart Disease
Treatment: All patients should be treated
LDL Target
- < 2mmol
- 50% decrease in LDLcholesterol
MODERATE Risk
- FRS: 10%-19%
Treatment when :
→ LDL-cholesterol > 3.5 mmol/L
→Ratio of triglycerides/ HDLcholesterol is > 5.0
→ Significant inflammation present
LDL Target
- < 2mmol
- 50% decrease in LDL cholesterol
LOW Risk
- FRS < 10%
Treatment when:
→ LDL-cholesterol is > 5.0 mmol/L
LDL Target
→ 50% decrease in LDL cholesterol
*FRS does not take into account LDL cholesterol levels
→ So if LDL cholesterol levels are >5mol (this is really high); cholesterol lowering treatment should be administered even if the patient is considered low risk according to the framingham score
Metabolic Syndrome
- 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 3 or more of:
- Central obesity – Waist circumference > 102 cm (40 inches) for men or 88 cm (35 inches) for women
- Elevated triglycerides – Blood triglycerides > 1.7 mmol/L
- Low HDL cholesterol - HDL cholesterol < 1.03 mmol/L in men or 1.29 mmol/L in women.
- Hyperglycemia – Fasting blood glucose > 5.6 mmol/L.
- Hypertension – Blood pressure > 135/85 mmHg
- Treatment of metabolic syndrome is targeted at decreasing the risk for coronary heart disease and type II diabetes.
Non-Drug Treatment of LDL Cholesterol
- Drug therapy is NOT the first line treatment for elevated LDL cholesterol.
- The primary treatment for high LDL cholesterol is lifestyle changes including modification to diet, weight, exercise plan and smoking status.
1) Diet
→ Modification of diet is targeted towards decreasing LDL cholesterol and establishing a healthy body weight.
→ Dietary recommendations suggest intake of < 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.
→ Should include: more fiber (beans, nuts, fruits)
2) Weight Control
→ 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.
3) Exercise
→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.
4) Cigarette Smoking
→ 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.
→ All patients should be counselled to quit smoking
Drug Treatment of Blood Lipids
- When target cholesterols levels are not achieved by lifestyle alone, we initiate drug treatment
- When target cholesterol levels are not achieved by lifestyle changes, drug treatment is initiated. T
- Classes of drugs used to treat elevated LDL cholesterol/blood lipids include:
- Statins
- Bile Acid Sequestrants
- Nicotinic Acid
- Cholesterol Absorption Inhibitors
- Fibric Acid Derivatives
Cholesterol Synthesis
- Approximately 80% of total body cholesterol is synthesized in the liver.
- Hepatic cholesterol synthesis occurs in the mevalonic acid pathway.
- In this pathway, acetyl CoA (from the citric acid cycle) is converted to 3- hydroxy-3-methylglutaryl CoA (HMG CoA).
- HMG CoA is then enzymatically converted to mevalonic acid by the enzyme HMG CoA Reductase.
→ Most important step - After other enzymatic steps, cholesterol is formed.
- Conversion of HMG CoA into mevalonic acid is the rate-limiting step in cholesterol synthesis.
→ Rate limiting step in cholesterol synthesis = One of the best targets for blocking cholesterol synthesis - Cholesterol synthesis is greatest during the night.
→Treating a patient with high cholesterol would be best in the evening when its highest
The Mevalonic acid pathway
- Acetyl CoA
- HMG CoA
- Mevalonic ACid
- Many other products
- Cholesterol
- The enzyme that converts HMG CoA to mevalonic acid is called HMG CoA Reductase; which is the site of action for statin drug
Statins
- 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.
→ allows the liver to remove more cholesterol from blood.
→ The net effect is a decrease in LDL cholesterol blood levels. - Statin’s block HMG CoA reductase - blocks the conversion from HMG CoA to mevalonic acid
- If you add statins, they decrease hepatic cholesterol syntheses
→ Hepatocytes need to get cholesterol form somewhere else
→So they try and take it form the blood
→ The cell will upregulate the # of LDL receptors found on surface of hepatocytes - The LDL receptors bring cholesterol from blood to inside the liver where they can be used to be metabolized into other things such as bile acids
- The cholesterol has left the blood due to statin, go into liver
Benefits of Statins
↓LDL cholesterol
↑HDL cholesterol
↓ Triglycerides
- Statins are imp in primary and secondary prevention of CV disease
- Primary Prevention Studies
→ Primary prevention is targeted at preventing the development of cardiovascular disease.
→ Statins are effective in the primary prevention of coronary heart disease.
→ 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 - Secondary Prevention Studies → Secondary prevention aims to prevent the recurrence of cardiovascular events.
→ Ex. 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. - Due to their ability to prevent the onset and progression of cardiovascular disease, statins are among the highest prescribed drugs in the world.
- Atorvastatin (Lipitor) is the highest prescribed drug in Canada and the USA, while rosuvastatin (Crestor) is the 4th highest prescribed drug in Canada.
Statin Pharmacokinetics
Atorvastatin
- 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 (metabolizes most drugs)
- Predominantly eliminated in the feces, minimal renal excretion
Rosuvastatin
- 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. (only a small fraction gets metabolized)
- Predominantly eliminated in the feces, minimal renal excretion.
- Plasma rosuvastatin concentrations are approximately 2x higher in Asian patients when compared to Caucasian patients.
→The initial dose in Asian patients should be 5 mg and caution should be used before deciding to increase the dose.
→ We don’t know the reason
Statins - Adverse Effects
- In general statins are well tolerated.
- The most common adverse event is myopathy (muscle injury).
→ Mild myopathy characterized by muscle aches and weakness occurs in 1-5% of patients. - Rhabodomyolysis: rare but serious adverse effect associated with statin use.
→ defined as muscle lysis with severe muscle pain.
→ diagnosed by measuring blood levels of the muscle enzyme creatine kinase (blood creatine kinase is 10x higher than normal)
→ During significant muscle injury as in rhabdomyolysis, the muscle cell releases large amounts of creatine kinase into the bloodstream.
→ accompanied by large increases in blood potassium (hyperkalemia) and may cause acute kidney failure. - Treatment is targeted at preserving kidney function by IV administration of fluids.
- There is a low incidence of hepatotoxicity associated with statin use.
- Liver function tests should be performed before initiating therapy and periodically thereafter.
- Cholesterol is required for the synthesis of cell membranes and many hormones.
- Statins should not be used in females who are pregnant or trying to become pregnant.
→ It is potentially teratogenic
Nicotinic Acid
- Inhibits the hepatic secretion of VLDL.
→ Since LDL is a by-product of VLDL degradation, nicotinic acid effectively reduces both VLDL and LDL. (reduced triglycerides and LDL cholesterol in the blood) - Also increases blood levels of HDL cholesterol.
- Side effects limit its use in many patients.
→ SE: intense facial flushing, hepatotoxicity, hyperglycemia, skin rash, increase uric acid levels.
Bile Acid Sequesterants
- Bile acids are negatively charged molecules produced in the liver
- The enzymes CYP7A1 forms bile acids by metabolizing cholesterol .
- 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
→ > 95% of bile acids are normally reabsorbed from the intestine.
→ Although they are secreted into bile, majority of bile acids are taken back up into the liver
Bile Acid Sequesterants - Mechanism of Action
- They function by attracting and binding bile acids (negatively charged) in the intestine and prevent their absorption back into the body
- 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.
→liver cells increase the number of LDL receptors.
→ results in increased uptake of cholesterol from the blood to the liver causing a decrease in plasma LDL cholesterol levels.
