Drugs Used in Hyperlipidemia By Dr. Sasan Zaeri PharmD, PhD

Introduction Cholesterol Serves as a component of cell membranes and intracellular organelle membranes Is involved in the synthesis of certain hormones including estrogen, progesterone, testosterone, adrenal corticosteroids Needed for the synthesis of bile salts which are needed for digestion and absorption of fats

Origin of cholesterol Liver Acetyl CoA is converted to mevalonic acid and ultimately to cholesterol by HydroxyMethyl Glutaryl Coenzyme A (HMG-CoA) reductase Endogenous synthesis of cholesterol increases at night

Lipoproteins Serve as carriers for transporting lipids (cholesterol and triglycerides) in the blood

Lipoproteins

Embedded in the lipoprotein shell Three functions Apolipoproteins Embedded in the lipoprotein shell Three functions Serve as recognition sites for cell-surface receptors; allowing cells to bind and ingest the lipoprotein Activate enzymes that will metabolize the lipoprotein ↑ structural stability of the lipoprotein

Types of lipoproteins

Types of lipoproteins

VLDL (very low density lipoprotein) Contain triglycerides (TGs) and some cholesterol Account for nearly all TGs in the blood Contain Apo B-100 Deliver triglycerides from the liver to adipose tissues and muscles

LDL (low density lipoprotein) “Bad cholesterol” Contains cholesterol Accounts for 60-70% of cholesterol in the blood Contains Apo B-100 Delivers cholesterol to peripheral tissues Makes the greatest contribution to coronary atherosclerosis Oxidized LDL contributes to atherosclerotic plaque

HDL (high-density lipoprotein) “Good cholesterol” Contain cholesterol Account for 20-30% of cholesterol in the blood Some contain Apo A-I and Apo A-II Apo A-I is cardioprotective Transports cholesterol from the peripheral tissues back to the liver – promotes cholesterol removal Antiatherogenic

Metabolism of Lipoproteins of Hepatic Origin

Classification of Plasma Lipid Levels Total cholesterol   <200 mg/dl Desirable HDL-C <40 mg/dl Low (consider <50 mg/dl as low for women) LDL-C <70 mg/dl Optimal for very high risk (minimal goal for CHD equivalent patients) <100 mg/dl Optimal Triglycerides <150 mg/dl Normal

Why to Treat Hyperlipidemia To prevent or slow progression of atherosclerosis To reduce the risk of coronary artery disease To prolong life

Treatment of hyperlipidemia Non-Pharmacological Therapy – first line treatment Diet modification Decrease intake of total fat and especially saturated fat Increase fiber intake Increase Omega-3-fatty acids (found in fish) ↑ fruits and vegetables (antioxidants) ↓ simple sugars (sucrose) Exercise (↑ HDL levels) Pharmacological Therapy

Sites of Drugs Action

Treatment of hyperlipidemia Drug therapy HMG-CoA Reductase Inhibitors (Statins) Bile Acid-binding Resins (e.g. Cholestyramine, Cholestipol) Inhibitors of cholesterol absorption (Ezetimibe) Niacin (Nicotinic Acid) Fibric Acid Derivatives (e.g. Gemfibrozil)

Statins (Atorvastatin, Lovastatin, Fluvastatin, Simvastatin etc.) MOA Inhibits hepatic HMG CoA reductase >>> Inhibition of cholesterol synthesis causes hepatocytes to synthesize more LDL receptors >>> Hepatocytes will remove more LDLs from the blood Most Effective for ↓ LDL-C Decrease production of apolipoprotein B-100, thereby ↓ production of VLDL ↓ Plaque cholesterol content and ↓ inflammation at the plaque site (Ani-atherosclorotic properties)

STATINS: effects on lipoproteins LDL-C: 20-55% TG: 7-45% (for TG>250 mg/dL, the percent is same as that of LDL; for TG<250 mg/dL maximum 25% reduction) HDL-C: 5-15%

Statins-Indication: Used in hypercholesterolemia Atorvastatin is most efficacious agent for use in severe hypercholesterolemia (>40-50% LDL-C lowering) ↓ LDL within 2 weeks; max reduction in 4-6 weeks Used in Coronary Artery Disease (CAD) Clinical trials have shown that they reduce mortality in patients with ischemic heart disease Used in patients with triglycerides levels higher than 250 mg/dL and with reduced HDL-C levels

Some Points about Statins Statins have high first pass extraction by liver Prodrugs – lovastatin and simvastatin Statins have greatest efficacy when taken at night Atorvastatin has the longest half-life Tolerated best among other hypolipemic drugs

Statins – Adverse Effects Rash GI disturbances (dyspepsia, cramps, flatulence, constipation, abdominal pain) Hepatotoxicity Myopathy (myositis and rhabdomyolysis) Risk highest especially in combination with fibrates Cyp450 3A4 drug interactions Statins are pregnancy category X

Bile Acid-Binding Resins (Cholestyramine and Colestipol) MOA Binding to bile acids (the metabolites of cholesterol) in the intestinal lumen and inhibition from their reabsorption >>> ↑ LDL receptors by liver cells to capture more cholesterol and synthesize bile acids

Bile-acid binding resins- Indications Used in hypercholesterolemia (↓ LDL-C 15-20%) Normally used as adjuncts to the statins to ↓ LDL-C (by 50%) Can be used to relieve pruritis in patients with cholestasis Can be used for severe digitalis toxicity Available in powder form (must be mixed with fluid) Must be taken with meals

Bile Acid-Binding Resins- Adverse Effects and Drug Interactions GI discomfort: (bloating, dyspepsia, nausea, constipation) Large doses may impair absorption of fats or fat soluble vitamins (A, D, E, and K) Resins bind many drugs e.g. digoxin, warfarin, tetracycline, thyroxine etc. These agents should be given either 1 hour before or 4 hours after the resins

Inhibitors of cholesterol absorption (Ezetimibe) MOA: Prevention of absorption of dietary cholesterol and cholesterol that is excreted in bile >>> ↑ LDL receptors in liver and ↑removal of LDL-C from the blood

Ezetimibe- Indication Used in hypercholesterolemia As monotherapy, ezetimibe reduces LDL-C by about 18% When combined with a statin, it is even more effective Ezetimibe is well tolerated

Niacin (Nicotinic acid)

Decreases HDL catabolic rate MOA of Niacin (Nicotinic acid) Inhibits VLDL secretion into the blood thereby preventing production of LDL Increases clearance of VLDL via lipoprotein lipase pathway Inhibits FFA release from adipose tissues by inhibiting the intracellular lipase system Decreases HDL catabolic rate

NICOTINIC ACID: effects on lipoproteins LDL-C: 5-25 %; TG: 20-50 % HDL-C: 15-35 %

Niacin- Indications Hypertriglyceridemia Mixed elevation of LDL-C and TG (in combination with statins) Elevation of TG (VLDL) and low levels of HDL Start with low dose and gradually increase

Niacin - Adverse effects Flushing Prostaglandin-mediated Occurs after drug is started or ↑ dose Lasts for the first several weeks Can give 325mg aspirin 30 minutes before morning dose (prevents prostaglandin synthesis) Nausea and abdominal discomfort Hyperuricemia, hepatotoxicity Niacin is NOT well-tolerate

Fibrates (Gemfibrozil, Fenofibrate, Clofibrate) Little or no effect on LDL, ↓VLDL (TG), moderate ↑ of HDL MOA: Activation of Peroxisome Proliferator-Activated Receptor-α (PPAR- α) ↑ Activity of endothelial lipoprotein lipase ↑ FFA oxidation in hepatocytes ↓ Secretion of VLDL by liver ↑ HDL levels moderately by ↑ Apo AI and Apo AII

Hepatic & Peripheral Effects of Fibrates Hepatic and peripheral effects of fibrates. These effects are mediated by activation of peroxisome proliferator-activated receptor-, which modulates the expression of several proteins. LPL, lipoprotein lipase; VLDL, very-low-density lipoproteins

Fibrates - Indications Hypertriglyceridemia Mixed elevation of LDL-C and TG (in combination with statins)

Fibrates - Adverse Effects Nausea (most prevalent) Rashes (prevalent) Cholesterol gallstones (Gemfibrozil) Use with caution in patients with biliary tract dx, women, obese people Myopathy (muscle injury) Will increase risk of statin-induced myopathy when used together