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Questions and Answers
What is the effect of decreased intracellular cholesterol concentrations on hepatic uptake of cholesterol-containing LDL-C particles?
What is a common side effect of cholestyramine?
What is the mechanism of action of ezetimibe?
What is the indication for using colesevelam in addition to its use in hyperlipidemias?
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What is the effect of PCSK9 enzyme on LDL receptors?
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What is the indication for using proprotein convertase subtilisin kexin type 9 inhibitors?
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What is the advantage of colesevelam over other bile acid sequestrants?
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What is the effect of ezetimibe on LDL-C when used as monotherapy?
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What is the indication for using cholestyramine?
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What is the percentage of LDL-C lowering when PCSK9 inhibitors are combined with statin therapy?
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What is the primary site of PCSK9 enzyme production?
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What is a common adverse drug reaction associated with PCSK9 inhibitors?
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In which patients may PCSK9 inhibitors be considered as an additional therapy?
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What is the name of the target enzyme inhibited by PCSK9 inhibitors?
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What is the class of antihyperlipidemic drugs that PCSK9 inhibitors belong to?
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What is the primary mechanism by which fibrates increase HDL levels?
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Which of the following side effects of fibrates can be increased when used in combination with statins?
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What is the effect of fibrates on LDL levels?
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What is the effect of fibrates on triglyceride levels?
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Which of the following is a common adverse effect of fibrates?
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What is the effect of fibrates on warfarin?
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Which of the following antihyperlipidemic drugs works by inhibiting the absorption of dietary cholesterol?
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Which of the following antihyperlipidemic drugs is most likely to increase high-density lipoprotein (HDL) cholesterol levels?
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Which of the following antihyperlipidemic drugs can cause skin rash as a side effect?
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Which of the following antihyperlipidemic drugs works by inhibiting the production of very-low-density lipoprotein (VLDL) in the liver?
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Which of the following antihyperlipidemic drugs can cause muscle pain as a side effect?
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Which of the following antihyperlipidemic drugs is most likely to reduce triglyceride levels?
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Which of the following antihyperlipidemic drugs can cause gastrointestinal side effects such as diarrhea?
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Which of the following antihyperlipidemic drugs is most likely to increase the risk of liver damage?
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Which of the following statements about the mechanism of action of bile acid sequestrants is TRUE?
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Which of the following side effects is LESS likely to occur with colesevelam compared to other bile acid sequestrants?
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What is the effect of ezetimibe on the absorption of fat-soluble vitamins?
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Which of the following statements about PCSK9 inhibitors is FALSE?
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What is the effect of PCSK9 inhibitors on LDL receptors?
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Which of the following statements about the effect of ezetimibe on LDL-C is TRUE?
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Which of the following medications is indicated for the treatment of familial hyperlipidemia?
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What is the primary mechanism of action of fibrates?
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Which of the following side effects is associated with niacin treatment?
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What is the effect of fibrates on HDL levels?
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Which of the following medications is contraindicated with statin therapy?
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What is the effect of fibrates on LDL levels?
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What is the primary mechanism by which bile acid sequestrants decrease plasma LDL-C?
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Which of the following antihyperlipidemic drugs is NOT indicated for type 2 diabetes?
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What is a common side effect of bile acid sequestrants that is minimized with colesevelam?
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What is the effect of proprotein convertase subtilisin kexin type 9 inhibitors on LDL receptors?
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Which of the following antihyperlipidemic drugs is used in addition to maximally tolerated statin therapy in patients with heterozygous or homozygous familial hypercholesterolemia?
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What is the mechanism by which ezetimibe reduces LDL-C?
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What is a potential interaction between bile acid sequestrants and other medications?
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What is the approximate percentage reduction in LDL-C when ezetimibe is used as monotherapy?
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Study Notes
Hyperlipidemia
- Elevated levels of circulating lipids, specifically cholesterol and triglycerides (TG)
- Correlated with an increased incidence of atherosclerosis and coronary artery disease (CAD)
Factors Influencing Hyperlipidemia
- Age
- Sex
- Family history
- Smoking
- Alcoholic
- Hypertension
- Diabetes
- Obesity
- Low HDL levels
Treatment of Hyperlipidemia
-
Non-Pharmacological Therapy (First Line)
- Diet modification:
- Decrease intake of total fat and especially saturated fat
- Increase fiber intake
- Increase Omega-3-fatty acids (found in fish)
- Increase fruits and vegetables (antioxidants)
- Decrease simple sugars (sucrose)
- Exercise (↑ HDL levels)
- Diet modification:
Antihyperlipidemic Drugs
- Statins
- Niacin
- Fibrates
- Bile acid sequestrants
- Cholesterol absorption inhibitors
- Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors
Statins
- Competitive inhibitor of HMG CoA reductase, the rate-limiting step in cholesterol synthesis
- Reduce hepatic cholesterol, resulting in:
- Increased LDL receptor expression
- Increased removal of LDL-C from the blood
- Decreased cholesterol synthesis
- Decreased VLDL synthesis and secretion
- Side effects:
- Elevated liver enzymes
- Myopathy and rhabdomyolysis
- Enzyme CYP-3A4 interaction
- GIT disturbance
- Contra-indicated in pregnancy
- Indications:
- Used in hypercholesterolemia
- Used in Coronary Artery Disease (CAD)
- Used in patients with triglycerides levels higher than 250 mg/dL and with reduced HDL-C levels
Niacin (Nicotinic acid)
- Inhibits lipolysis in adipose tissue, resulting in:
- Decreased hepatic VLDL synthesis
- Decreased production of LDL in the plasma
- Decreased LDL and TG levels by 25 and 50%, respectively
- Increased HDL by 35%
- Side effects:
- Prostaglandin-mediated flushing and pruritus
- Nausea and abdominal discomfort
- Hyperuricemia and hepatotoxicity
- Indications:
- Familial hyperlipidemia
- Mixed elevation of LDL-C and TG (in combination with statins)
- Elevation of TG (VLDL) and low levels of HDL
Fibrates (gemfibrozil and fenofibrate)
- Primarily used for reducing TG and increasing HDL serum levels
- Mechanism of action:
- Activators of the nuclear transcription factor peroxisome proliferator-activated receptor α (PPARα)
- Increased LPL expression
- Increased TG clearance from circulating VLDL
- Increased expression of HDL levels
- Side effects:
- Mild GI disturbances
- Gallstones (increased biliary cholesterol excretion)
- Myalgia and rhabdomyolysis have been reported in patients taking gemfibrozil and statins together
- Both fibrates may increase the effects of warfarin
Bile Acid Sequestrants (Cholestyramine, colestipol, and colesevelam)
- LDL-C lowering effects
- Mechanism of action:
- Bind negatively charged bile acids and bile salts in the small intestine
- Resin/bile acid complex is excreted in the feces
- Lowering bile acid concentration leads to:
- Increased conversion of cholesterol to bile acids
- Increased hepatic uptake of cholesterol-containing LDL-C particles
- Decrease in plasma LDL-C
- Indications:
- Type IIA and type IIB hyperlipidemias
- Cholestyramine can also relieve pruritus caused by biliary stasis
- Colesevelam is also indicated for type 2 diabetes due to its glucose-lowering effects
- Side effects:
- GI disturbances (constipation, nausea, and flatulence)
- Impairment of absorption of fat-soluble vitamins (A, D, E, and K)
- Interference with the absorption of many drugs (digoxin, warfarin, and thyroid hormone)
Inhibitors of Cholesterol Absorption (Ezetimibe)
- Mechanism of action:
- Prevention of absorption of dietary cholesterol and cholesterol that is excreted in bile
- Increased LDL receptors in liver and increased removal of LDL-C from the blood
- Indications:
- Used in hypercholesterolemia
- As monotherapy, ezetimibe reduces LDL-C by about 18%
- When combined with a statin, it is even more effective
- Side effects:
- Well tolerated
Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors (Alirocumab and Evolocumab)
- Mechanism of action:
- Inhibit the PCSK9 enzyme, leading to:
- Increased LDL receptors on the surface of hepatocytes
- Increased clearance of LDL-C from the serum
- Inhibit the PCSK9 enzyme, leading to:
- Indications:
- Used in addition to maximally tolerated statin therapy in patients with heterozygous or homozygous familial hypercholesterolemia
- Clinical ASCVD who require additional LDL-C lowering
Fibrates
- Increase HDL by 35%
- Indications: Familial hyperlipidemia, Mixed elevation of LDL-C and TG, Elevation of TG and low levels of HDL
- Side effects: Prostaglandin-mediated flushing and pruritus, Nausea and abdominal discomfort, Hyperuricemia and hepatotoxicity
- Mechanism of action: Activators of PPARα, increase LPL expression, increase TG clearance from circulating VLDL, increase expression of HDL levels
- Adverse effects: Mild GI disturbances, Gallstones, Myalgia and rhabdomyolysis (with statins), Increased effects of warfarin
Bile Acid Sequestrants
- Mechanism of action: Bind negatively charged bile acids and bile salts in the small intestine, reduce bile acid concentration, increase conversion of cholesterol to bile acids
- Indications: High LDL-C, Statin intolerance
- Side effects: GI disturbances, Impaired absorption of fat-soluble vitamins (A, D, E, K), Interference with absorption of certain drugs
PCSK9 Inhibitors
- Mechanism of action: Inhibit PCSK9 enzyme, increase LDL receptors, increase clearance of LDL-C from serum
- Indications: Familial hypercholesterolemia, Clinical ASCVD, High ASCVD risk and statin intolerance
- Side effects: Injection site reactions, Immunologic or allergic reactions, Nasopharyngitis, Upper respiratory tract infections
Inhibitors of Cholesterol Absorption
- Mechanism of action: Prevent absorption of dietary cholesterol and cholesterol in bile, increase LDL receptors in liver, increase removal of LDL-C from blood
- Indications: Hypercholesterolemia
- Side effects: Well tolerated
Hyperlipidemia
- Hyperlipidemia is a condition characterized by elevated levels of circulating lipids, specifically cholesterol and triglycerides (TG).
- It is correlated with an increased incidence of atherosclerosis and coronary artery disease (CAD).
Risk Factors
- Age
- Sex
- Family history
- Smoking
- Alcoholic
- Hypertension
- Diabetes
- Obesity
- Low HDL levels
Treatment of Hyperlipidemia
Non-Pharmacological Therapy
- Diet modification:
- Decrease intake of total fat and especially saturated fat
- Increase fiber intake
- Increase Omega-3-fatty acids (found in fish)
- Increase fruits and vegetables (antioxidants)
- Decrease simple sugars (sucrose)
- Exercise (increases HDL levels)
Pharmacological Therapy
Antihyperlipidemic Drugs
-
- Statins
-
- Niacin:
- Increases HDL by 35%
- Indications:
- Familial hyperlipidemia
- Mixed elevation of LDL-C and TG (in combination with statins)
- Elevation of TG (VLDL) and low levels of HDL
- Side effects:
- Prostaglandin-mediated flushing and pruritus
- Nausea and abdominal discomfort
- Hyperuricemia and hepatotoxicity
-
- Fibrates (gemfibrozil and fenofibrate):
- Primarily used for reducing TG and increasing HDL serum levels
- Mechanism of action: Activators of the nuclear transcription factor peroxisome proliferator-activated receptor α (PPARα)
- Adverse Effects:
- Mild GI disturbances
- Gallstones (increase biliary cholesterol excretion)
- Myalgia and rhabdomyolysis have been reported in patients taking gemfibrozil and statins together
-
- Bile acid sequestrants (Cholestyramine, colestipol, and colesevelam):
- Mechanism of action: Bind negatively charged bile acids and bile salts in the small intestine
- Indications:
- Type IIA and type IIB hyperlipidemias
- Cholestyramine can also relieve pruritus caused by biliary stasis
- Colesevelam is also indicated for type 2 diabetes due to its glucose-lowering effects
- Side effects:
- GI disturbances, such as constipation, nausea, and flatulence
- Impair the absorption of the fat-soluble vitamins (A, D, E, and K)
-
- Inhibitors of cholesterol absorption (Ezetimibe):
- Mechanism of action: Prevention of absorption of dietary cholesterol and cholesterol that is excreted in bile
- Indications:
- Hypercholesterolemia
- As monotherapy, ezetimibe reduces LDL-C by about 18%
- When combined with a statin, it is even more effective
- Side effects: Generally well-tolerated
-
- Proprotein convertase subtilisin kexin type 9 inhibitors (Alirocumab and evolocumab):
- Mechanism of action: Inhibit the PCSK9 enzyme, leading to an increase in LDL receptors on hepatocytes
- Indications:
- Used in addition to maximally tolerated statin therapy in patients with heterozygous or homozygous familial hypercholesterolemia
- Clinical ASCVD who require additional LDL-C lowering
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