Med Phys Pharm 551 L30 Hyperlipidemia Pharm PDF

Lecture #30: Hyperlipidemia Pharmacology Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L30: Learnin...

Lecture #30: Hyperlipidemia Pharmacology Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L30: Learning Objectives 1. Describe the treatment goal(s) of hyperlipidemia 2. Recognize the main treatment options for hyperlipidemia and identify their respective mechanism(s) of action 3. Compare and contrast different types of statin therapy regimes 4. Identify the difference between hyperlipidemia and heterozygous familial hypercholesterolemia 5. Predict the most clinically relevant drug(s) for hyperlipidemia given a lipid panel and relevant medical history 6. How does combination therapy help treat hyperlipidemia? Unless otherwise noted, figures in today’s lecture are from: Principles of Pharmacology 3e Baca, Golan (Ch. 19), Lippincott Illustrated Reviews: Pharmacology 6e Yellepeddi (Ch. 23) ASCVD: Coronary Heart Disease Hyperlipidemias - an abnormally high concentration of fats or lipids in the blood (cholesterol and triglycerides) Combination of genetic and lifestyle factors Appropriate lifestyle changes and drug therapy can lead to a 30% to 40% reduction in mortality Antihyperlipidemic drugs are often taken indefinitely to control plasma lipid levels  Treatment Goals of Hypercholesterolemia: Effect of circulating LDL and HDL on risk of CHD The clinically important lipoproteins in decreasing order of atherogenicity: LDL VLDL and chylomicrons HDL The occurrence of CHD is positively associated with high total cholesterol and more strongly with elevated LDL High levels of HDL have been associated with a decreased risk for heart disease Total cholesterol = LDL + VLDL+ HDL Reduction of LDL is the primary goal of LO1 cholesterol-lowering therapy MPP in the News!  MPP in the News! Race-Dependent Association of High-Density Lipoprotein Cholesterol Levels With Incident Coronary Artery Disease Low HDL-C was associated with increased CHD risk in White but not Black adults, and high HDL-C was not protective in either group. Current high-density lipoprotein cholesterol–based risk calculations could lead to inaccurate risk assessment in Black adults.  Treatment Goals of Hypercholesterolemia: Effect of circulating LDL and HDL on risk of CHD Past cholesterol guidelines recommended treating to specific targets for LDL Recent cholesterol guidelines do not recommend targets but instead emphasize high-intensity or moderate-intensity statin therapy LO1  Treatment options for Hypercholesterolemia Treatment with HMG CoA reductase inhibitors (statins) is the primary treatment option for hypercholesterolemia Statin therapy is recommended for four major groups LO1,3 LO1,3  Drugs for Hyperlipidemia Antihyperlipidemic drugs include the HMG CoA reductase inhibitors, niacin, fibrates, bile acid– binding resins, a cholesterol absorption inhibitor, and omega-3 fatty acids May be used alone or in combination Drug therapy should always be accompanied by lifestyle modifications Exercise and a diet low in saturated fats LO2  Drugs for Hyperlipidemia: HMG CoA reductase inhibitors #8 Atorvastatin (Lipitor) 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (“statins”) Lower elevated LDL Resulting in a substantial reduction in coronary https ://sta ti c01. ny t.com/i mag e s/2013/07/12/sc ienc e/12ask well drug s/12a skwe lldrugs -tma gArtic le. jpg events and death from CHD LO2,3  Drugs for Hyperlipidemia: HMG CoA reductase inhibitors First-line treatment for patients with elevated risk of ASCVD Therapeutic benefits: 1. plaque stabilization 2. improvement of coronary endothelial function 3. inhibition of platelet thrombus formation https ://sta ti c01. ny t.com/i mag e s/2013/07/12/sc ienc e/12ask well drug s/12a skwe lldrugs -tma gArtic le. jpg 4. anti-inflammatory activity The value of lowering LDL with statins has been demonstrated in patients with and without LO2,5 established CHD  Drugs for Hyperlipidemia: HMG CoA reductase inhibitors Mechanism of action: Lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, pitavastatin, and rosuvastatin are competitive inhibitors of HMG CoA reductase the rate-limiting step in cholesterol synthesis LO2,5  Drugs for Hyperlipidemia: HMG CoA reductase inhibitors By inhibiting de novo cholesterol synthesis they deplete the intracellular supply of cholesterol Causes the cell to increase the number of cell surface LDL receptors that can bind and internalize circulating LDLs Plasma cholesterol is reduced by both decreased cholesterol synthesis and increased LDL catabolism LO2,5  Drugs for Hyperlipidemia: HMG CoA reductase inhibitors Pharmacokinetics: Absorption of the statins is variable (30% to 85%) following oral administration All statins are metabolized in the liver LO2,5  Drugs for Hyperlipidemia: HMG CoA reductase inhibitors Adverse effects: Elevated liver enzymes may occur with statin therapy Liver function should be evaluated prior to starting therapy Hepatic insufficiency can cause drug accumulation LO2,5  Drugs for the treatment of Hypercholesterolemia: Inhibitors of Cholesterol Absorption Reduce cholesterol absorption by the small intestine This includes reduced absorption of dietary cholesterol The more important effect is reduced reabsorption of biliary cholesterol comprises the majority of intestinal cholesterol Inhibitors of cholesterol absorption reduce LDL cholesterol by inhibiting hepatic production of VLDL Statins and bile acid sequestrants reduce LDL cholesterol LO2,5 principally by increasing LDL clearance via the LDL receptor  Drugs for the treatment of Hypercholesterolemia: Inhibitors of Cholesterol Absorption - Niacin MOA: strongly inhibits lipolysis in adipose tissue, reducing production of FFA The liver normally uses circulating FFA as a major precursor for triglyceride synthesis Reduced liver triglyceride levels decrease hepatic VLDL production, which in turn reduces LDL plasma concentrations Niacin can reduce LDL by 10% to 20% and is the most effective agent for increasing HDL It also lowers triglycerides by 20% to 35% at typical doses Niacin can be used in combination with statins LO2,5  Drugs for the treatment of Hypercholesterolemia: Inhibitors of Cholesterol Absorption - Fibrates Fenofibrate and gemfibrozil are derivatives of fibric acid that lower serum triglycerides and increase HDL levels MOA: The peroxisome proliferator–activated receptors (PPARs) are members of the nuclear receptor family that regulates lipid metabolism PPARs function as ligand-activated TFs Upon binding to their natural ligands (fatty acids) or fibrates, PPARs are activated LO2,5  Drugs for the treatment of Hypercholesterolemia: Inhibitors of Cholesterol Absorption - Fibrates Lower serum triglycerides and increase HDL levels MOA (continued): Leads to decreased triglyceride concentrations through increased expression of lipoprotein lipase and decreasing apoC-III concentration Fibrates also increase the level of HDL cholesterol by increasing the expression of apo AI and apo AII LO2,5  Drugs for treatment of Hyperlipidemia: Inhibitors of Bile Acid Absorption: Resins Bile acid sequestrants (resins) have significant LDL cholesterol–lowering effects Benefits are less than those observed with statins MOA: bind negatively charged bile acids and bile salts in the small intestine The resin/bile acid complex is excreted in the feces lowering the bile acid concentration LO2,5  Drugs for treatment of Hyperlipidemia: Inhibitors of Bile Acid Absorption: Resins This causes hepatocytes to increase conversion of cholesterol to bile acids Consequently intracellular cholesterol concentrations decrease Activates an increased hepatic uptake of cholesterol-containing LDL particles leading to a fall in plasma LDL Mediated by an up-regulation of cell surface LDL receptors Clinical uses: Hyperlipidemia - The bile acid–binding resins are useful, often in combination with diet or niacin LO2,5  Drugs for treatment of Hyperlipidemia: Cholesterol absorption inhibitor: Ezetimibe MOA: 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% Due its modest LDL-lowering effects, ezetimibe is often used as an adjunct to statin therapy LO2,5 LO1,3  Combination Therapy It is often necessary to use two antihyperlipidemic drugs to achieve treatment goals in plasma lipid levels The combination of an HMG CoA reductase inhibitor with a bile acid–binding agent has been shown to be very useful in lowering LDL levels LO6  Combination Therapy Simvastatin and niacin are currently available combined in one pill to treat elevated LDL cholesterol More clinical information is needed to determine whether combination therapy produces better long-term benefits than the use of a high-dose statin Until this uncertainty is resolved experts recommend maximizing statin dosages and adding niacin or fibrates only in those with persistently elevated triglycerides (greater than 500 mg/dL) LO6  Newer Combination Therapy FDA Approves Althera’s Roszet (rosuvastatin and ezetimibe) Tablets, a New Oral Therapy for Powerful Cholesterol Reduction  Study Aid Table Class of Drug Effect on LDL Effect on HDL Statins Fibrates Niacin Bile Acid Sequestrants Cholesterol Absorption Inhibitor