Lipid-Lowering Drugs

Kirk Mykytyn, Ph.D.

Department of Pharmacology

mykytyn.1@osu.edu

Learning Objectives

At the end of the module

you will know the mechanisms of action, indications, and major side effects of drugs used in the treatment of disorders of lipid metabolism

Learning Resources

1. Lilly’s Pathophysiology of Heart Disease, 5th ed. Chapter 5 p. 127-130 and Chapter 17 p. 431-435

2. Dr. Mehta’s lecture on Lipid Metabolism

Introduction: Hyperlipidemia Definition:

Elevated levels of circulating lipids, specifically cholesterol and triglycerides (TG)

Hyperlipidemia and disease: Hyperlipidemia (and especially high levels of low-density lipoprotein (LDL))

is correlated with an increased incidence of atherosclerosis and coronary artery disease (CAD) Total serum cholesterol level of 240 mg/dl = 2X ↑risk of CAD vs. 200

mg/dl Combination with other risk factors

Age/Sex/Family history Smoking Hypertension Diabetes Obesity Low HDL levels

Introduction: Hyperlipidemia

Hyperlipidemia and disease:• Pancreatitis (if

extremely elevated TG)• Xanthomas (cholesterol

deposits) especially around the eyes or along the Achilles tendon

Treatment of Hyperlipidemia

Non-Pharmacologic: Diet Exercise

Pharmacologic:Decrease the production of lipoproteins

Increase breakdown or removal

Decrease absorption of

lipids

Overview of Lipoprotein Metabolism

HMG-CoA Reductase Inhibitors (Statins) Most effective and best-tolerated agents for reducing LDL

fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, and pitavastatin

LDL 20-55%, TG 7-30%, HDL 5-15% Other cardioprotective effects

Improve endothelial function, promote plaque stability, inhibit platelet aggregation, and suppress inflammation

HMG CoA Reductase Inhibitors (statins)

Harvey RA. Lippincott’s Illustrated Reviews: Pharmacology. 5th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2012.

HMG-CoA Reductase Inhibitors (Statins)

Mechanism of action Analog of HMG CoA Competitive inhibitor of HMG CoA reductase, the rate limiting step in

cholesterol synthesis Reduced hepatic cholesterol results in LDL receptor expression, which

the removal of LDL from the blood Reduced hepatic cholesterol results in VLDL synthesis and secretion

Adverse Effects Hepatotoxicity (less than 1% of patients) Myopathy (2 to 10% of patients) – rarely leads to rhabdomyolysis Contraindicated in pregnancy

Niacin

Niacin (nicotinic acid, vitamin B3) is one of the oldest lipid-regulating drugs and favorably affects virtually all lipid parameters

Most effective agent for raising HDL cholesterol LDL 5-25%, TG 20-50%, HDL 15-35%

Overview of Lipoprotein Metabolism

Niacinǁ

Niacin

Niacin

Mechanism of action Decreases hormone-sensitive lipase (HSL) activity in adipose tissue

flux of free fatty acid to the liver, hepatic TG production, VLDL secretion

Enhances lipoprotein lipase (LPL) in adipose and muscle cells TG clearance from circulating VLDL

Increases the half-life of apoAI, the major apolipoprotein in HDL HDL levels, without disturbing hepatic retrieval of cholesterol

Adverse Effects Transient cutaneous flushing and itching

Prevented by aspirin, regular use, or timed-release formulations Hyperuricemia, impaired insulin sensitivity, hepatotoxicity, and myopathy

Fibrates

Fibric acid derivatives (gemfibrozil and fenofibrate) Primarily used for reducing TG and increasing HDL serum levels

LDL 0-20%, TG 20-50%, HDL 10-20%

Overview of Lipoprotein Metabolism

Fibrates

Fibrates

Mechanism of action Activators of the nuclear transcription factor peroxisome proliferator-

activated receptor α (PPARα) LPL expression, TG clearance from circulating VLDL expression apoAI, HDL levels

Adverse Effects Mild GI disturbances Gallstones ( biliary cholesterol excretion) Myalgia

Bile Acid-Binding Resins Large, highly positively charged molecules that

bind negatively charged bile acids and bile salts in the small intestines LDL 15-30%, TG, HDL 3-5%

Mechanism of action Bile acids are prevented from returning to the

liver and are excreted in feces hepatic cholesterol conversion to bile acids,

hepatic cholesterol concentrations, LDL receptor expression

Hepatic cholesterol synthesis also stimulated VLDL production, serum TG levels

Adverse Effects Interference with absorption of fat-soluble

vitamins and certain drugs GI effects: constipation, nausea, and bloating

Cholesterol Absorption Inhibitors

Ezetimibe

• Selective inhibitor of cholesterol uptake at the brush border of epithelial cells in the small intestine

• Acts by competitively inhibiting the Niemann-Pick C1-like 1 transporter protein

• absorption of dietary and biliary cholesterol

• LDL 15-20%, TG 0-5%, HDL 1-2%

Plant Sterols/Stanols

• Similar in molecular structure to cholesterol, naturally present in fruits and vegetables, block absorption of cholesterol

• Some foods come fortified with plant sterols (ex. Benecol)

Treatment Guidelines for Hyperlipidemia

Harvey RA. Lippincott’s Illustrated Reviews: Pharmacology. 5th ed. Baltimore, MD: Lippincott, Williams & Wilkins; 2012.

Emerging Therapeutics

Proprotein convertase subtilisin/kexin type 9 (PCSK9) routes LDL and LDL receptor complexes for degradation in lysosomes

Monoclonal antibodies against PCSK9 block the interaction of PCSK9 with the LDL receptor, allowing LDL receptor recycling to the cell surface, which leads to a decrease in circulating LDL

Lipid Lowering Drugs Quiz

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