Lecture 12 Flashcards
Drugs to lower blood cholesterol and triglyceride levels (76 cards)
1
Q
when does coronary heart disease occur?
A
- when coronary blood corculation fails to adequately supply the heart with blood
2
Q
What us CHD primarily caused by?
A
atherosclerosis
3
Q
What is atherosclerosis?
A
plaque builds up on the walls of the arteries causing them to narrow resulting in decreased blood flow to the heart
4
Q
relationship between CHD and cholesterol levels?
A
- direct relationship: high blood cholesterol = high risk of developing CHD
5
Q
Where is cholesterol found?
A
- component of cell membranes
- precursor of steroid hormones (testosterone, estrogen)
- precursor of bile salts (which help us digest fats)
6
Q
Where do we get cholesterol from?
A
- mostly endogenous sources( i.e synthesized in the liver)
- rest from exogenous sources (i.e dietary sources)
7
Q
What is the basic structure of a lipoprotein?
A
- outer hydrophilic shell made up of phospholipids (allows them to be soluble in plasma)
- lipophilic core composed of cholesterol and triglycerides
- have apolipoproteins embedded in outer shell
8
Q
What is the primary function of lipo-proteins?
A
- transport cholesterol and triglycerides in the blood (since they are lipophilic they need a transporter to be soluble in blood)
9
Q
What are the 3 main functions of apolipoproteins?
A
- allow recognition by cells which may bind and ingest lipoproteins
- activate enzymes that metabolize lipoproteins
- increase the structural stability of lipoproteins
10
Q
What is the difference between lipoproteins with apolipoprotein A-I and lipoproteins with apolipoprotein B-100?
A
A-I: transport cholesterol from non-hepatic tissue back to the liver
B-100: transport cholesterol to non-hepatic tissue
11
Q
How are lipoproteins named?
A
- named based on their density (protein density > lipid density)
- high % protein = high density
- low % protein = low density
12
Q
What 3 classes of lipoproteins are important with coronary heart disease and atherosclerosis
A
- Very-Low Density lipoproteins (VLDL)
- Low density LP (LDL)
- High density LP (HDL)
13
Q
What are VLDL’s made of and found the most?
A
- have triglyceride rich core
- contain 1 ALP B-100 molecule = they can bind to cells and transfer their lipid (mostly triglycerides) to cells
- make up almost all of the triglyceride content in blood
14
Q
What do VLDL’s do?
A
- deliver triglycerides from the liver to adipose tissue and muscle
15
Q
What is the link between VLDLs and atherosclerosis?
A
- controversial relationship
- some studies suggest high VLDL contribute to atherosclerosis
16
Q
What are LDLs made of and found the most?
A
- cholesterol rich core
- contain 1 ALP B-100 molecule = allows them to bind to cells to transfer their lipid (mostly cholesterol) to cells
- account for a lot of the cholesterol in the blood
17
Q
What do LDLs do?
A
- deliver cholesterol to non-hepatic tissue (ex. muscle)
18
Q
What is the link between LDLs and atherosclerosis?
A
- clear link
- promote the initiation of atherosclerosis
- higher the blood LDL level, the greater the risk of developing coronary heart disease (reducing LDL blood levels halts/reverses atherosclerosis)
- often referred to as “bad cholesterol”
19
Q
What are HDLs made of and found the most?
A
- cholesterol core, account for the rest of the blood cholesterol levels
- contain multiple APL including A-I, A-II, and A-IV (A-I may mediate the beneficial effects of HDL)
20
Q
What do HDLs do?
A
- deliver cholesterol from non-hepatic tissue back to the liver
- promote cholesterol removal from the blood
21
Q
What is the link between HDLs and atherosclerosis?
A
- effect on coronary heart disease is the opposite of that of LDL
- high HDL lvls = decreased risk of CHD
- known as the “good cholesterol” since it protects against atherosclerosis
22
Q
What is the first step in the process by which atherosclerosis develops?
A
- initiated when LDL’s move from the blood into the sub-endothelial space of the arterial epithelium where it becomes oxidized (crucial step)
23
Q
What is the second step in the process by which atherosclerosis develops?
A
- Oxidation of LDL causes recruitment of monocytes (a type of immune cell) to the sub-endothelial space
24
Q
What is the third step in the process by which atherosclerosis develops?
A
- monocytes are converted to macrophages (type of immune cell) that are capable of ‘ingesting’ foreign material
25
What is the fourth step in the process by which atherosclerosis develops?
-macrophages take up oxidized LDL, become larger and vacuolated = foam cells
26
What is the fifth step in the process by which atherosclerosis develops?
-foam cells accumulate beneath the epithelium creating a fatty streak, followed by platelet adhesion, smooth muscular migration, and collagen synthesis forming a fibrous cap
27
What is the sixth step in the process by which atherosclerosis develops?
- atherosclerotic lesion characterized by a lipid core and a tough fibrous plaque
- cap can rupture from moving blood = an aggregation of platelets (thrombus) = blockage
28
Atherosclerosis and inflammation
- atherosclerosis is primarily an inflammatory process
- LDL penetration of arterial wall = mild injury
- monocyte/macrophage infiltration is the inflammatory response that mediates the development of atherosclerosis
29
How can damage to endothelium be mediated?
- hypertension
- smoking
- elevated blood lipids
- hemodynamic factors
- immune rxns
30
What unit of measurement does Canada use for reporting cholesterol?
mmol/L (milimole per litre)
31
Who (in canada) is Cholesterol screening recommended for?
- males over 40
- females over 50
- post-menopausal females
- patients with diabetes
- heart disease
- hypertension
- central obesity
- smoke (or recently stopped)
- have inflammatory or renal disease
32
What is cardiovascular risk assessment used for?
- to estimate the risk a patient has of developing cardiovascular disease
- provides health care professionals with guidelines and treatment targets
33
What is the most commonly used form of cardiovascular risk assessment?
- Framingham Risk Score (FRS)
34
What is used to determine Framingham Risk Score?
- gender
- age
- total blood cholesterol
- smoking status
- HDL cholesterol
- systolic blood pressure
35
What does the FRS represent?
- 10 year risk of developing coronary heart disease
36
Who does the FRS underestimate risk in?
- youth
- women
- those with metabolic syndrome
37
What is metabolic syndrome?
- combination of medical disorders that cause increased risk of coronary disease and type II diabetes
38
When is metabolic syndrome diagnosed?
- in patients that have 3 or more of:
- central obesity
- elevated triglycerides
- low HDL cholesterol
- hyperglycemia
- hypertension
39
What does treatment of metabolic syndrome target?
-targeted at decrease the risk of coronary heart disease and type II diabetes
40
Non-drug treatment of LDL cholesterol
- diet
- weight control
- exercise
- cigarette smoking
41
What does weight control?
- lowers LDL cholesterol
| - decreases risk of coronary heart disease
42
What does exercise control?
- decreases LDL cholesterol
- elevating HDL cholesterol
- decreasing insulin resistance and blood pressure
43
What does smoking do?
- increases LDL cholesterol
| - decreases HDL cholesterol
44
What are the classes of drugs to treat elevated blood lipids?
- statins (HMG-CoA Reductase inhibitors)
- bile acid sequestrants
- nicotinic acid
- cholesterol absorption inhibitors
- fibric acid derivatives
45
Where is most of total body cholesterol synthesized?
- in the liver
46
Where does hepatic cholesterol synthesis occur?
- in the mevalonic acid pathway
47
Explain what happens in the mevalonic acid pathway?
- acetly CoA (from citric acid cycle) converted to 3-hydroxyl-3-methylglutaryl CoA (HMG CoA)
- HMG CoA then enzymatically converted to melavonic acid by HMG CoA reductase (rate-limiting step)
- after several enzymatic steps cholesterol is formed
48
When is cholesterol synthesis greatest?
-at night
49
What is the site of action for statin drugs?
- HMG CoA Reductase
50
What is the mechanism of Action for Statins?
- decrease hepatic synthesis of cholesterol by inhibiting the enzyme HMG CoA reductase (rate limiting step)
- this causes upregulation of hepatic LDL receptors
- allows liver to remove more cholesterol from blood = decrease in LDL cholesterol blood lvls
51
Benefits of Statins
- decreased LDL cholesterol
- increased HDL cholesterol
- decreased triglycerides
52
Primary Prevention Studies and Statins
- primary prevention targets preventing heart disease
| - statins are effective is prevention of coronary heart disease
53
Secondary prevention studies and Statins
- aims to prevent reoccurrence of cardiovascular friends
| - statins effective in these
54
What are the highest prescribed Statins in the world
- atorvastatin (Lipitor)
| - rosuvastatin (Crestor)
55
Oral bioavailability of Atorvastatin?
low
56
Pharmacokinetics of atorvastatin?
- large fraction of absorbed dose extracted by liver (site of action)
- distribution primarily to the liver but also to spleen, adrenal glands, and skeletal muscle
57
What is atorvastatin metabolized by?
-CYP3A4
58
How are atorvastatin eliminated?
- in feces
| - minimal renal excretion
59
oral bioavailability of rosuvastatin?
- low
60
Pharmacokinetics of Rosuvastatin?
- large fraction absorbed by liver (site of action)
- distribution primarily to liver but also to skeletal muscle
- not extensively metabolized
61
How is rosuvastatin eliminated?
- in feces
| minmal renal excretion
62
Plasma rosuvastatin concentrations and race?
- lvls 2x higher in Asian patients (vs caucasians)
| - initial dose should be 5 mg
63
What are the adverse side effects of statins?
- generally well tolerated
- myopathy most common (muscle injury)
- Rhadbodomyolysis (rare but serious): muscle lysis with severe muscle pain
- low incidence of hepatotoxicity
- should not be used in pregnant females
64
How is Rhadbodomyolysis diagnosed?
- measuring blood levels of the muscle enzyme creatine kinase (10x higher than normal)
- accompanied by increased blood potassium (hyperkalemia)
- may cause acute kidney failure
65
How does Nicotinic Acid (niacin) work?
- inhibits hepatic secretion of VLDL (which degrades into LDL) so reduces VLDL and LDL
- increased HDL lvls
66
What are the side effects of Nicotinic Acid?
- intense facial flushing
- hepatotoxicity
- hyperglycaemia
- skin rash
- increase uric acid lvls
67
Are bile acids charged and where are they produced?
- negatively charged
| - produced in liver from CYP7A1 mediated cholesterol metabolism
68
pharmacokinetics of bile acids?
- secreted into intestine and aid int he absorption of dietary fats and fat soluble vitamins
- undergo enterohepatic recycling and are reabsorbed into the intestine (most are)
69
Mechanism of action of bile acid Sequestrants
- largely positive molecules
- attract and bind bile acids in the intestine & prevent absorption
- results in increased demand for bile acid synthesis in the liver
-LDL cholesterol required to synthesize more bile acids so liver increases LDL receptor #
= increased uptake of cholesterol from the blood to the liver causing a decrease in plasma LDL cholesterol lvls
70
Adverse effects of bile acid sequestrants
- do not have systemic side effects bc not absorbed all the way
- constipation and bloating
- decrease the absorption of some drugs such as thiazide diuretics, digoxin, warfarin, and some antibiotics
71
How do cholesterol absorption inhibitors like ezetimibe (Zetia) work?
- inhibit NPC1L1 transporter (responsible for intestinal uptake of dietary cholesterol)
- increases hepatic cholesterol synthesis
72
What is ezetimibe (Zetia) usually prescribed with?
- statins
example:
vytorin + ezetimibe reduces LDL cholesterol
73
What are Fibric acid derivatives (fibrates)?
- most effective class of drugs for lowering plasma triglyceride lvls
- they increase HDL cholesterol but have no effect on LDL cholesterol lvls
74
How do fibrates work?
- bind to and activate a receptor in the liver called PPAR- alpha (Peroxisome-proliferator activated receptor-alpha)
75
What effects does the activation of PPARalpha have?
- increased synthesis of lipoprotein lipase (which enhances the clearance of triglyceride rich lipoproteins
- decreased apolipoprotein C-III production (an inhibitor of lipoprotein lipase) which allows for increased lipoprotein lipase activity
- increased apolipoprotein A-I and A-II levels (= increased HDL levels)
76
What are the adverse effects of fibrates?
- increased risk of gallstones
- myopathy (especially with statins)
- hepatotoxicity
