complete the following attached questions.The next day lovastatin and ezetimibe were added to the therapeutic regimen. Which of the drugs received by this patient acts primarily in the cytoplasmic
Understanding Terminology
1. ____ A dietary lipid normally synthesized in the body
a. myalgia
2. ____ A protein in the plasma that transports triglycerides and
Cholesterol.
b. hyperlipidemia
3. ____ Abnormally high levels of lipids on the plasma
c. foam cells
4. ____ A dietary lipid normally used in the body
d. lipoprotein
5. ____ A drug used to lower plasma lipid levels
e. Rhabdomyolysis
6. ____ A type of cell formed after macrophages in the artery wall
Digest LDL-cholesterol.
f. hypolipidemic
7. ____ The rapid breakdown of skeletal muscle
g. cholesterol
8. ____ Pain in a muscle or group of muscles
h. triglycerides
9. Explain how plaques are formed and the role in atherosclerosis and arterial heart disease.
10. Discuss the importance of lipids, lipoproteins and cholesterol and triglycerides.
11. Identify five classes of drugs used to treat hyperlipidemia and explain the mechanism of action.
12. Explain why HMG-CoA inhibitors are more effective than other hypolipidemic drugs.
13. Describe the mechanism of action of the cholesterol absorption inhibitors.
14. Identify the bile acid sequestrants.
15. Describe the action of the other anti-hyperlipidemic drugs, niacin, and fibrates.
16. Explain the absolute contraindications and drug interactions with drugs used for
antihyperlipidemia.
17. What diseases are associated with hyperlipidemia
18. List the adverse effects of niacin.
19. Some patients may experience persistent flushing when taking which one of the
hypolipidemics? What advice might be helpful for the patient to avoid this side effect?
20. Identify the main lipids that each drug class reduces
21. A 49-year old man was brought to the ER with the admitting diagnosis of myocardial infarction.
Emergency therapy was stared, which included alteplase, aspirin, heparin and metoprolol. The
next day lovastatin and ezetimibe were added to the therapeutic regimen. Which of the drugs
received by this patient acts primarily in the cytoplasmic compartment of the liver cells? Identify
each drug and its mechanism of action and therapeutic use.
22. A 52-year old obese man suffering from gout and hypertension was found to have the following:
LDL (360 mg/dl), serum uric acid (15.5 mg/dl) other lab values were within normal limits. A lipidlowering therapy was prescribed. Which of the following antihyperlipidemic drugs would be
contraindicated in this patient? If so, why?
a.
b.
c.
d.
e.
Choletryramine
Niacin
Ezetimibe
Lovastatin
Gemfibrozil
Understanding Terminology
1. ____ A dietary lipid normally synthesized in the body
a. myalgia
2. ____ A protein in the plasma that transports triglycerides and
Cholesterol.
b. hyperlipidemia
3. ____ Abnormally high levels of lipids on the plasma
c. foam cells
4. ____ A dietary lipid normally used in the body
d. lipoprotein
5. ____ A drug used to lower plasma lipid levels
e. Rhabdomyolysis
6. ____ A type of cell formed after macrophages in the artery wall
Digest LDL-cholesterol.
f. hypolipidemic
7. ____ The rapid breakdown of skeletal muscle
g. cholesterol
8. ____ Pain in a muscle or group of muscles
h. triglycerides
9. Explain how plaques are formed and the role in atherosclerosis and arterial heart disease.
10. Discuss the importance of lipids, lipoproteins and cholesterol and triglycerides.
11. Identify five classes of drugs used to treat hyperlipidemia and explain the mechanism of action.
12. Explain why HMG-CoA inhibitors are more effective than other hypolipidemic drugs.
13. Describe the mechanism of action of the cholesterol absorption inhibitors.
14. Identify the bile acid sequestrants.
15. Describe the action of the other anti-hyperlipidemic drugs, niacin, and fibrates.
16. Explain the absolute contraindications and drug interactions with drugs used for
antihyperlipidemia.
17. What diseases are associated with hyperlipidemia
18. List the adverse effects of niacin.
19. Some patients may experience persistent flushing when taking which one of the
hypolipidemics? What advice might be helpful for the patient to avoid this side effect?
20. Identify the main lipids that each drug class reduces
21. A 49-year old man was brought to the ER with the admitting diagnosis of myocardial infarction.
Emergency therapy was stared, which included alteplase, aspirin, heparin and metoprolol. The
next day lovastatin and ezetimibe were added to the therapeutic regimen. Which of the drugs
received by this patient acts primarily in the cytoplasmic compartment of the liver cells? Identify
each drug and its mechanism of action and therapeutic use.
22. A 52-year old obese man suffering from gout and hypertension was found to have the following:
LDL (360 mg/dl), serum uric acid (15.5 mg/dl) other lab values were within normal limits. A lipidlowering therapy was prescribed. Which of the following antihyperlipidemic drugs would be
contraindicated in this patient? If so, why?
a.
b.
c.
d.
e.
Choletryramine
Niacin
Ezetimibe
Lovastatin
Gemfibrozil
Lipids
Lipids are necessary molecules for life
Cholesterol and phospholipids are essential for cell membranes, steroid hormones
and nerve tissue
Triglycerides, composed of three fatty acids and glycerol are oxidized to generate
energy for muscle contraction and metabolic rxns
Elevated blood levels of cholesterol and triglycerides lead to CAD and other
disorders
Hyperlipidemia – elevated lipids
Hyperlipoproteinemia – elevated lipoproteins
Hypercholesterolemia – elevated concentrations of cholesterol
Hypertrigleridemia – elevated levels of triglerides more than 12% of adults age
20 and older had total cholesterol higher than 240 mg/dL, and more than 18% had
high-density lipoprotein (HDL, or “good”) cholesterol levels less than 40 mg/dL.
95 million U.S. adults age 20 or older have total cholesterol levels higher than 200
mg/dL. Nearly 29 million adult Americans have total cholesterol levels higher than
240 mg/dL.
7% of U.S. children and adolescents ages 6 to 19 have high total cholesterol.
High cholesterol has no symptoms, so many people don’t know that their
cholesterol is too high. A simple blood test can check cholesterol levels.
High blood cholesterol raises the risk for heart disease, the leading cause of death,
and for stroke, the fifth leading cause of death.
Introduction to Hyperlipidemia
Coronary Artery Disease (CAD) is the leading cause of death in both genders in
the U.S.
Hyperlipidemia is correlated with elevated levels of low-density lipoprotein
cholesterol (LDL-C; ‘bad” cholesterol) and triglycerides and low levels of highdensity lipoprotein cholesterol (HDL-C; “good cholesterol”)
Elevated levels are extremely common in general population
risk factor for cardio vascular diseases, due to influence of cholesterol.
Risk factors for atherosclerosis (deposition of fats at walls of arteries, forming
plaque)
cigarette smoking, diabetes, obesity and, hypertension
Plasma lipids are transported in lipoproteins
Abnormally elevated plasma lipoproteins
Hyperlipidemia or Hyperlipoproteinemia
Acute pancreatitis and atherosclerosis
Hyperlipemia denotes increased levels of triglycerides.
Atherosclerosis resulting from Hyperlipidemia
Introduction to Hyperlipidemia
Plasma lipids include: cholesterols, triglycerides and phospholipids.
Lipids are insoluble in plasma and are transported in a capsule known as an
apoprotein
When an apoprotein joins cholesterol it is referred to as a lipoprotein
5 different densities, but only 3 mentioned
LDL, VLDL and HDL
Types of Lipoproteins
Low Density Lipoprotein (LDL) – “Low Down Lipoprotein” Bad cholesterol,
transports cholesterol to damaged areas in arteries and forms plaque. Increased
levels lead to increased risk of CAD
Very Low Density Lipoprotein (VLDL) – (TGs and cholesterol) endogenously
synthesized in liver. Degraded into free fatty acids (FFA) for storage in adipose
tissue and for oxidation in tissues such as cardiac and skeletal muscle. Moderate
elevation contribute to increased risk of CAD
High Density Lipoprotein (HDL) – “healthy, protective” remove cholesterol
from the artery walls, inhibits the oxidation of LDL and inhibits platelet
aggregation at plaque sites. cigarette smoke decreases HDL and reverses effects.
Increased levels decrease risk of CAD
Liver is site of lipoprotein processing
Chylomicrons formed in intestine and transport dietary triglycerides from diet into
blood, liver disposes of chylomicrons
VLDL made in liver carry lipids to adipose tissue for storage or become LDL
containing cholesterol
cells obtain cholesterol from LDL for membrane synthesis
HDL produced in liver pick up cholesterol from other organs
HDL retrieves cholesterol and phospholipids to the liver where it is sent to the bile
as bile acids and removed
Etiology of hyperlipidemias
Primary hyperlipidemia – (genetic origin) hereditary.
Secondary hyperlipidemia – caused by other outside factors
diseases e.g. hypothyroidism, diabetes, Drugs (β blockers, alcohol, thiazides,
antidepressants)
over weight
lack of exercise and inactive life style
higher levels of female hormones
increases or changes in cholesterol levels eg: women on birth control pills.
Smoking does not cause higher cholesterol levels, but it can reduce the HDL,
which is good cholesterol.
Management of Hyperlipidemias
Diet
Avoid saturated fatty acids (animal fats) and give unsaturated fatty acids (plant
fats).
Regular consumption of fish oil which contain omega 3 fatty acids and vitamins E
and C (antioxidants).
Exercise
↑ HDL and insulin sensitivity
Drug therapy – each class works at a specific location within the liver or intestine
with a different MOA to affect cholesterol, triglycerides and lipoproteins
decrease levels of LDL
increase levels of HDL
Lipid Profile
Measures total cholesterol (TC), HDL-cholesterol (HDL), and triglycerides (TG)
LDL-cholesterol is calculated from the values for TC, HDL and TG
LDL = TC – HDL – TG/5
The recommended serum values to prevent heart disease for these lipoproteins
LDL < 100 mg/dl
HDL > 40 mg/dl
TC < 200 mg/dl
TG/5 < 150
Drugs used in Hyperlipidemia
Diet necessary to achieve full potential of drug therapy
Avoided in pregnant, lactating and women likely to become pregnant
Use requires adjustment of dose of anticoagulants
Not usually indicated in children before age 16
In absence of multiple risk factors or genetic dyslipidemia
Each drug class can lower cholesterol levels
differ how much can reduce total cholesterol, LDL and triglyceride levels
Anti-hyperlipidemics
HMG CoA Reductase Inhibitors (Statins)
Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, Simvastatin
Fibrates
Fenofibrate, Gemfibrozil, Clofibrate.
Nicotinic acid
Niacin
Bile Acid Sequestrants
Colesevelam, Colestipol, Cholestyramine
Cholesterol Absorption Inhibitors
Ezetimibe.
Omega-3 Fatty Acids
Docosahexaenoic and Eicosapentaenoic acids
HMG-CoA Reductase Inhibitors (Statins)
Used for tx of primary hyperlipidemia and to slow progression of atherosclerosis to
reduce the risk of acute coronary episodes and sudden death
lovastatin (Mevacor) was the prototype to alter cholesterol synthesis by inhibiting
HMG-CoA reductase
Naturally occurring found in red yeast rice
Four of widely used statins are derived from a variety of fungi and synthetically
made
Structural analogs of HMG-CoA (3-hydroxy-3methyhlglutaryl-coenzyme A)
Standard practice to initiate reductase inhibitor therapy immediately following
ACS
Lovastatin and simvastatin are inactive prodrugs
All have high first pass extraction by liver, mostly excreted via bile
Most t1/2 of 1-3 hours, except atorvastatin (14 hours)
reduce LDL up to 30%, if greater reduction required
Simvastatin (Zocor), atorvastatin (Lipitor) and rosuvastatin (Crestor) which
reduces LDL by more than 45% are used (Lipitor and Crestor up to 60%)
Reductions are patient and dose dependent
Most would not req. dec. > 40%
increase HDL up to 20%
lovastatin (Mevacor)
rosuvastatin (Crestor)
atorvastatin (Lipitor)
fluvastatin (Lescol)
pravastatin (Pracachol)
pitavastatin (Livalo)
simvastatin (Zocor)
Combination statin and lipid lowering drug
advicor (niacin + lovastatin)
vytorin (simvastatin + ezetimibe)
Significantly decrease LDL cholesterol, also decrease triglycerides and increase
HDL cholesterol
Mechanism of action – a competitive inhibitor of HMG-CoA reductase which
mediates the first step and rate limiting step in cholesterol biosynthesis in the liver
Structural analog of HMG-CoA reductase to inhibit the conversion of HMG-CoA
to Mevalonate
Causes a decrease in LDL
Therapeutic use – used alone or with resins, niacin or ezetimibe in reducing levels
of LDL
Contraindicated in pregnancy, lactating or women who may become pregnant
Pharmacokinetics – all well abs p.o., lovastatin (Mevacor) better abs w/meals, all
highly protein bound (95 – 98%), recommended to take in evening, most
cholesterol produced at night
most potent (rosuvastatin) least potent (lovastatin)
atorvastatin (Lipitor) taken anytime
Side effects – myopathy, h/a, dizziness, alteration of taste, diarrhea, flatulence,
abdominal cramping, hepatotoxicity, photosensitivity, myalgias, leg ache and
muscle weakness
Toxicity – increases serum aminotransferase activity (3x normal) caution in
underlying liver disease and chronic alcohol abuse
Contraindications – liver disease and pregnancy, P450 inhibitors
Serum aminotransferase [such as aspartate aminotransferase (AST) and alanine
aminotransferase (ALT)] is commonly used as an indicator of liver disease. The
aim of the study was to determine the degree to which aminotransferase results are
associated with increased mortality at the population level
Fibrates
gemfibrozil (Lopid) and fenofibrate (Tricor)
Mechanism of Action –the peroxisome proliferator-activated receptors (PPAR-α)
causing increased expression of lipoprotein lipase leading to increased lipolysis of
lipoprotein triglyceride
Therapeutic use – decreases triglyceride, used to treat hypertriglyceridemia, only
modest effect on LDL cholesterol . (May increase LDL in genetic condition
(familial combined hyperlipoproteinemia (FCH) which is a combined increase in
VLDL and LDL) often used in combination with other cholesterol-lowering drugs
in tx of pts. with elevated concentration of both LDL and VLDL. Improved
absorption when taken with food.
Side effects – nausea, skin rash, decrease in WBC and hematocrit, may potentiate
anticoagulants, increased risk of cholesterol gallstones, used with caution in
women, obese and Native Americans (increased cholesterol content in bile)
Niacin (Nicotinic Acid)
Niacin, Niacor, Niaspan, B3, Nicotinic Acid
Mechanism of Action – decrease lipolysin in adipose tissue
Therapeutic use – increases HDL, decreases LDL, decreases TG
Pharmacokinetics – Niacin (Vit. B3)
Adverse effects – niacin decreases circulating fibrinogen and increases tissue
plasminogen activator
Toxicity – monitor liver enzymes
Contraindications – gout and liver disease
binds the niacin receptor to reduce the outflow of free fatty acids from our fat cells.
deprives the liver of an essential substrate for triglyceride synthesis and secretion
as VLDL, which is a precursor for LDL.
increases HDL by inhibiting HDL uptake in the liver
Bile Acid Sequestrants (binding resins)
Decrease LDL, increase HDL, no effect on TG
Cholestyramine (Questran), Colestipol (Colestid), Colesevelam ( Welchol)
Mechanism of Action – act as ion-exchange resins that exchange anions for bile
acids. Bind bile acids and sequester them from enterohepatic circulation, excreted
in feces.
Bile acids are made from cholesterol and secreted from GI tract. 99% is reabsorbed
into body, loss of 1% of bile acid is typical means of removing cholesterol from
body
Therapeutic use – used tx of patients with primary hypercholestrolemia
Pharmacokinetics – impaired absorption of certain drugs;
Digitalis glycosides, thiazides, warfarin, tetracycline, thyroxine, pravastatin,
Fluvastatin, ezetimibe, folic acid, aspirin and ascorbic acid
Side effects – bad taste, constipation, diarrhea, bloating, flatulence, malabsorption
of other drug, fat soluble vitamins (DEAK)
Toxicity –
Cholesterol Absorption Inhibitors
Ezetimibe (Zetia)
Decreases LDL levels and atherosclerotic plaques
Mechanism of Action – decrease absorption of cholesterol from small intestine,
which decreases the available cholesterol to liver, which decreases the circulating
cholesterol
Therapeutic use – synergistic with statins
Pharmacokinetics – average reduction ~ 18%,
Side effects – myalgia, h/a, transaminitis