(4.7) HLD DRUGS (HARD QUIZ)

Lecture #30: Hyperlipidemia Pharmacology

• Julia Hum, PhD, is the Primary Course Instructor
• Course meets Monday/Wednesday/Friday, 2:00-2:50pm
• Office hours are Monday/Wednesday/Friday, 11:00am-12:00pm (317B or WebEx)
• Marian University, College of Osteopathic Medicine

L30: Learning Objectives

• Describe treatment goals for hyperlipidemia
• Recognize main treatment options and mechanisms of action
• Compare and contrast statin therapy regimens
• Differentiate between hyperlipidemia and heterozygous familial hypercholesterolemia
• Predict relevant drugs given a lipid panel and medical history
• Explain how combination therapy treats hyperlipidemia

ASCVD: Coronary Heart Disease

• Hyperlipidemia is an abnormally high concentration of fats or lipids (cholesterol and triglycerides) in the blood
• It results from a combination of genetic and lifestyle factors
• Appropriate lifestyle changes and drug therapy can reduce mortality by 30% to 40%
• Antihyperlipidemic drugs are often taken indefinitely to control plasma lipid levels

Treatment Goals of Hypercholesterolemia

• Clinically important lipoproteins (decreasing order of atherogenicity): LDL, VLDL/chylomicrons, HDL
• High total cholesterol and elevated LDL are positively associated with coronary heart disease (CHD) risk
• High levels of HDL correlate with a decreased risk of CHD
• Reducing LDL is the primary goal of cholesterol-lowering therapy

MPP in the News

• A study found that low HDL cholesterol increased heart disease risk in white adults but not black adults
• Current high-density lipoprotein cholesterol-based risk calculations may be inaccurate for black adults

Treatment Goals of Hypercholesterolemia: Effect of circulating LDL and HDL on risk of CHD

• Past guidelines recommended treating to specific LDL targets
• Recent guidelines emphasize high-intensity or moderate-intensity statin therapy

Treatment options for Hypercholesterolemia

• HMG CoA reductase inhibitors (statins) are the primary treatment option
• Statin therapy is recommended for four major groups

Drugs for Hyperlipidemia

• Antihyperlipidemic drugs include HMG-CoA reductase inhibitors (statins), niacin, fibrates, bile acid-binding resins, cholesterol absorption inhibitors, and omega-3 fatty acids
• These drugs may be used alone or in combination
• Drug therapy should always be accompanied by lifestyle modifications (exercise and a diet low in saturated fats)

Drugs for Hyperlipidemia: HMG CoA reductase inhibitors

• 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) lower elevated LDL
• Resulting in a substantial reduction in coronary events and death from CHD
• Statins are first-line treatment for patients with elevated risk of atherosclerotic cardiovascular disease (ASCVD)

Drugs for Hyperlipidemia: HMG CoA reductase inhibitors (cont.)

• Therapeutic benefits include plaque stabilization, improved coronary endothelial function, inhibition of platelet thrombus formation, and anti-inflammatory activity
• The value of lowering LDL with statins has been demonstrated in patients with and without established CHD
• Mechanism of action: competitive inhibitors of HMG CoA reductase, the rate-limiting step in cholesterol synthesis
• Inhibits de novo cholesterol synthesis, depleting intracellular cholesterol supply
• Causes the cell to increase the number of surface LDL receptors, leading to decreased cholesterol synthesis and increased LDL catabolism
• Pharmacokinetics: variable absorption (30% to 85%) following oral administration; metabolized in the liver.

Drugs for Hyperlipidemia: HMG CoA reductase inhibitors (cont.)

• Adverse effects: elevated liver enzymes and myopathy may occur
• Liver function should be evaluated prior to starting therapy
• Hepatic insufficiency can cause drug accumulation

Inhibitors of Cholesterol Absorption

• Reduce cholesterol absorption in the small intestine
• Reduce reabsorption of biliary cholesterol
• Inhibitors of cholesterol absorption decrease LDL cholesterol by inhibiting hepatic production of VLDL (very-low-density lipoprotein)

Inhibitors of Cholesterol Absorption - Niacin

• MOA: strongly inhibits lipolysis in adipose tissue, reducing FFA production
• Reduced liver triglyceride levels decrease hepatic VLDL production, thus reducing LDL plasma concentrations
• Niacin reduces LDL by 10% to 20% and increases HDL
• It also lowers triglycerides by 20% to 35% at typical doses

Inhibitors of Cholesterol Absorption - Fibrates

• Fenofibrate and gemfibrozil are derivatives of fibric acid; lower triglycerides and increase HDL levels
• MOA: PPARs (peroxisome proliferator-activated receptors) are members of the nuclear receptor family regulating lipid metabolism; increased expression of lipoprotein lipase causes decreased triglyceride concentrations
• PPAR activation increases expression of apoAI (apolipoprotein AI) and apoAII
• Fibrates increase HDL cholesterol levels by increasing expression of apoAI and apoAII

Inhibitors of Bile Acid Absorption: Resins

• Bile acid sequestrants (resins) lower LDL cholesterol
• MOA: bind negatively charged bile acids and salts in the small intestine; this resin/bile acid complex is excreted in the feces, thus lowering bile acid concentration
• This causes hepatocytes to increase conversion of cholesterol to bile acids, which lowers intracellular cholesterol concentrations
• This activates increased hepatic uptake of cholesterol-containing LDL particles, leading to lowered plasma LDL concentration
• Mediated by up-regulation of cell surface LDL receptors
• Clinical uses: hyperlipidemia, often in combination with diet or niacin

Cholesterol absorption inhibitor: Ezetimibe

• Selectively inhibits absorption of dietary and biliary cholesterol in the small intestine by blocking Niemann-Pick C1-like 1 (NPC1L1)
• Leads to a decrease in the delivery of intestinal cholesterol to the liver
• Causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood
• Ezetimibe lowers LDL cholesterol by approximately 17%

Combination Therapy

• Often necessary to use two antihyperlipidemic drugs to achieve treatment goals in plasma lipid levels
• Combining an HMG CoA reductase inhibitor with a bile acid-binding agent has been shown to be very useful in lowering LDL levels
• Simvastatin and niacin are currently available as a combined medication.