Pharmacology 2060A/B Lecture 12: Module 12
15 May 2018
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Module 12 – Drugs to Lower Blood Cholesterol and Triglycerides
12.1 – Introduction
Coronary heart disease
- Coronary heart disease occurs when coronary blood circulation fails to adequately supply the
heart with blood
- Coronary heart disease is primarily caused by atherosclerosis
o Atherosclerosis occurs when plaque builds up on the walls of the arteries
o This causes the artery to narrow and results in decreased blood flow to the heart
- Blood cholesterol levels are directly proportional to risk of developing coronary heart disease
- 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. For this reason, large efforts have gone into designing drugs to lower blood levels of
cholesterol to prevent disease
- In Canada, cardiovascular disease causes one third of all deaths. This is more than any other
illness
12.2 – Cholesterol
- Cholesterol is an important molecule that supports many physiological roles
- It is an essential component of cell membranes, a precursor of steroid hormones (i.e.
testosterone and estrogen) and a precursor of bile salts (absorption of dietary fats)
- We obtain cholesterol through:
o Dietary sources (exogenous cholesterol) OR
o Through synthesis (endogenous cholesterol) which occurs primarily in the liver → body
synthesizes cholesterol
- Approximately 80% of the cholesterol in the body is synthesized by the liver, whereas 20% is
obtained from dietary sources
- Most drugs used to target decreasing cholesterol target the liver to decrease the synthesis of
cholesterol rather than targeting dietary absorption
- Although cholesterol is an essential molecule for the reasons described above, high blood levels
are linked to atherosclerosis and heart disease
Plasma lipoproteins – structure and function
- The basic structure of lipoproteins is shown in the figure.
o Notice the outer hydrophilic shell is made up of phospholipids
o This allows lipoproteins to be soluble in plasma
o In contrast, the core is composed of lipophilic cholesterol and triglycerides (lipophilic –
not soluble in blood unless 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 in order to be soluble
in the blood
- All lipoproteins also have apolipoproteins embedded in the phospholipid shell
- Apolipoproteins have three functions:
o 1. Allow recognition by cells which may bind and ingest lipoproteins
o 2. Activate enzymes that metabolize or degrade lipoproteins
o 3. Increase the structural stability of lipoproteins
- Lipoproteins contain a variety of apoliporpteins and this will differentiate the function they have
- Lipoproteins that contains apolipoprotein A-I transports cholesterol from non-hepatic tissue
back to the liver whereas lipoproteins that contain apolipoprotein B-100 transport cholesterol to
nonhepatic tissue
Class of lipoproteins
- 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 (HDLs)
- 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
o They are Very-Low Density Lipoproteins (VLDL), Low Density Lipoproteins (LDL) and High
Density Lipoproteins (HDL)
1. Very low density lipoproteins (VLDLs)
- 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 (cardiovascular disease) 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
(muscle and adipose cells) and transfer their lipid (mostly triglyceride) to cells
- PURPOSE OF VLDLS: transfer triglycerides from the liber to adipose + muscle → they can do this
because of apolipoprotein B-100 that allows them to attach to cells
2. Low density lipoproteins (LDLs)
- LDL’s deliver cholesterol to non-hepatic tissue (e.g. muscle)
- 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
o 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”
3. High density lipoproteins (HDL)
- HDL’s deliver cholesterol from non-hepatic tissue back to the liver (site of metabolism)
- 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
o Therefore, elevated HDL decreases the risk of coronary heart disease
o It does this by lowering blood levels of cholesterol
- HDL particles may contain multiple apolipoproteins including A-I, A-II and A-IV
o The A-I apolipoprotein is believed to mediate the beneficial effects of HDL cholesterol
and allows the binding to HDL particles back to the liver to allow it to take up cholesterol
from our blood
Document Summary
Module 12 drugs to lower blood cholesterol and triglycerides. Coronary heart disease occurs when coronary blood circulation fails to adequately supply the heart with blood. Coronary heart disease is primarily caused by atherosclerosis: 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. Blood cholesterol levels are directly proportional to risk of developing coronary heart disease. 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. For this reason, large efforts have gone into designing drugs to lower blood levels of cholesterol to prevent disease. In canada, cardiovascular disease causes one third of all deaths. Cholesterol is an important molecule that supports many physiological roles.
