Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 35. Drugs Used in the Treatment of Hyperlipidemias

Drugs Used in the Treatment of Hyperlipidemias: Introduction

Atherosclerosis is the leading cause of death in the Western world. Drugs discussed in this chapter prevent the sequelae of atherosclerosis (heart attacks, angina, peripheral arterial disease, ischemic stroke) and decrease mortality in patients with a history of cardiovascular disease and hyperlipidemia. Although the drugs are generally safe and effective, they can cause problems, including drug-drug interactions and toxic reactions in skeletal muscle and the liver.

High-Yield Terms to Learn

Lipoproteins Macromolecular complexes in the blood that transport lipids Apolipoproteins Proteins on the surface of lipoproteins; they play critical roles in the regulation of lipoprotein metabolism and uptake into cells Low-density lipoprotein (LDL) Cholesterol-rich lipoprotein whose regulated uptake by hepatocytes and other cells requires functional LDL receptors; an elevated LDL concentration is associated with atherosclerosis High-density lipoprotein (HDL) Cholesterol-rich lipoprotein that transports cholesterol from the tissues to the liver; a low concentration is associated with atherosclerosis Very-low-density lipoprotein (VLDL) Triglyceride- and cholesterol-rich lipoprotein secreted by the liver that transports triglycerides to the periphery; precursor of LDL HMG-CoA reductase 3-Hydroxy-3-methylglutaryl-coenzyme A reductase; the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis Lipoprotein lipase (LPL) An enzyme found primarily on the surface of endothelial cells that releases free fatty acids from triglycerides in lipoproteins; the free fatty acids are taken up into cells Proliferator-activated receptor-alpha (PPAR-) Member of a family of nuclear transcription regulators that participate in the regulation of metabolic processes; target of the fibrate drugs

Hyperlipoproteinemia

Pathogenesis

Premature or accelerated development of atherosclerosis is strongly associated with elevated concentrations of certain plasma lipoproteins, especially the low-density lipoproteins (LDL) that participate in cholesterol transport. A depressed level of high-density lipoproteins (HDL) is also associated with increased risk of atherosclerosis. In some families, hypertriglyceridemia is similarly correlated with atherosclerosis. Chylomicronemia, the occurrence of chylomicrons in the serum while fasting, is a recessive trait that is correlated with a high incidence of acute pancreatitis and managed by restriction of total fat intake (Table 35-1).

TABLE 35-1 Primary hyperlipoproteinemias and their drug treatment.

Condition/Cause Manifestations, Cause Single Drug Drug Combination Primary chylomicronemia Chylomicrons, VLDL increased; deficiency in LPL or apoC-II Niacin, fibrate Niacin plus fibrate Familial hypertriglyceridemia Severe VLDL, chylomicrons increased; decreased clearance of VLDL Niacin, fibrate Niacin plus fibrate Moderate VLDL increased, chylomicrons may be increased; increased production of VLDL Niacin, fibrate Familial combined hyperlipoproteinemia Increased hepatic apoB and VLDL production VLDL increased Niacin, fibrate, statin Two or 3 of the individual drugs LDL increased Niacin, statin, ezetimibe Two or 3 of the individual drugs VLDL, LDL increased Niacin, statin Niacin or fibrate plus statin Familial dysbetalipoproteinemia VLDL remnants, chylomicron remnants increased; deficiency in apoE Fibrate, niacin Fibrate plus niacin, or either plus statin Familial hypercholesterolemia LDL increased; defect in LDL receptors Heterozygous Statin, resin, niacin, ezetimibe Two or 3 of the individual drugs Homozygous Niacin, atorvastatin, rosuvastatin, ezetimibe Niacin plus statin plus ezetimibe

Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009.

Regulation of plasma lipoprotein levels involves a complex interplay of dietary fat intake, hepatic processing, and utilization in peripheral tissues (Figure 35-1). Primary disturbances in regulation occur in a number of genetic conditions involving mutations in apolipoproteins, their receptors, transport mechanisms, and lipid-metabolizing enzymes. Secondary disturbances are associated with a Western diet, many endocrine conditions, and diseases of the liver or kidneys.

FIGURE 35-1

Metabolism of lipoproteins of hepatic origin. The heavy arrows show the primary pathways. Nascent VLDL are secreted via the Golgi apparatus. They acquire additional apoC lipoproteins and apoE from HDL. VLDL is converted to VLDL remnants by lipolysis via lipoprotein lipase associated with capillaries in peripheral tissue supplies. In the process, C apolipoproteins and a portion of apoE are given back to HDL. Some of the VLDL remnants are converted to LDL by further loss of triglycerides and loss of apoE. A major pathway for LDL degradation involves the endocytosis of LDL by LDL receptors in the liver and the peripheral tissues, for which apoB-100 is the ligand. Dark color denotes cholesteryl esters; light color, triglycerides; the asterisk denotes a functional ligand for LDL receptors; triangles indicate apoE; circles and squares represent C apolipoproteins. FFA, free fatty acid; RER, rough endoplasmic reticulum.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 35-1.)

Treatment Strategies

Diet

Cholesterol and saturated fats are the primary dietary factors that contribute to elevated levels of plasma lipoproteins. Dietary measures designed to reduce the total intake of these substances constitute the first method of management and may be sufficient to reduce lipoprotein levels to a safe range. Because alcohol raises triglyceride and very-low-density lipoprotein (VLDL) levels, it should be avoided by patients with hypertriglyceridemia.

Drugs

For an individual patient, the choice of drug treatment is based on the lipid abnormality. The drugs that are most effective at lowering LDL cholesterol include the HMG-CoA reductase inhibitors, resins, ezetimibe, and niacin. The fibric acid derivatives (eg, gemfibrozil) and niacin are most effective at lowering triglyceride and VLDL concentrations and raising HDL cholesterol concentrations (Table 35-2).

TABLE 35-2 Lipid-modifying effects of antihyperlipidemic drugs.

Drug or Drug Group LDL Cholesterol HDL Cholesterol Triglycerides Statins Atorvastatin, rosuvastatin, simvastatin -25 to -50% +5 to +15%  Lovastatin, pravastatin -25 to -40% +5 to +10%  Fluvastatin -20 to -30% +5 to +10%  Resins -15 to -25% +5 to +10% ±a

Ezetimibe -20% +5% ± Niacin -15 to -25% +25 to +35%  Gemfibrozil -10 to -15%b

+15 to + 20% 

LDL, low-density lipoprotein; HDL, high-density lipoprotein; ±, variable, if any.

aResins can increase triglycerides in some patients with combined hyperlipidemia.

bGemfibrozil and other fibrates can increase LDL cholesterol in patients with combined hyperlipidemia.

Modified and reproduced, with permission, from McPhee SJ, Papadakis MA, Tierney LM, editors: Current Medical Diagnosis & Treatment, 46th ed. McGraw-Hill, 2006.

HMG-CoA Reductase Inhibitors

Mechanism and Effects

The rate-limiting step in hepatic cholesterol synthesis is conversion of hydroxymethylglutaryl coenzyme A ( HMG-CoA) to mevalonate by HMG-CoA reductase. The statins are structural analogs of HMG-CoA that competitively inhibit the enzyme (Figure 35-2). Lovastatin and simvastatin are prodrugs, whereas the other HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, pravastatin, and rosuvastatin) are active as given.

FIGURE 35-2

Sites of action of HMG-coA reductase inhibitors, niacin, ezetimibe, and bile acid-binding resins. Low-density lipoprotein (LDL) receptor synthesis is increased by treatment with drugs that reduce the hepatocyte reserve of cholesterol.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 35-2)

Although the inhibition of hepatic cholesterol synthesis contributes a small amount to the total serum cholesterol-lowering effect of these drugs, a much greater effect derives from the response to a reduction in a tightly regulated hepatic pool of cholesterol. The liver compensates by increasing the number of high-affinity LDL receptors, which clear LDL and VLDL remnants from the blood (Figure 35-1). HMG-CoA reductase inhibitors also have direct anti-atherosclerotic effects, and have been shown to prevent bone loss.

Clinical Use

Statins can reduce LDL cholesterol levels dramatically (Table 35-2), especially when used in combination with other cholesterol-lowering drugs (Table 35-1). These drugs are used commonly because they are effective and well tolerated. Large clinical trials have shown that they reduce the risk of coronary events and mortality in patients with ischemic heart disease, and they also reduce the risk of ischemic stroke.

Rosuvastatin, atorvastatin, and simvastatin have greater maximal efficacy than the other HMG-CoA reductase inhibitors. These drugs also reduce triglycerides and increase HDL cholesterol in patients with triglycerides levels that are higher than 250 mg/dL and with reduced HDL cholesterol levels. Fluvastatin has less maximal efficacy than the other drugs in this group.

Toxicity

Mild elevations of serum aminotransferases are common but are not often associated with hepatic damage. Patients with preexisting liver disease may have more severe reactions. An increase in creatine kinase (released from skeletal muscle) is noted in about 10% of patients; in a few, severe muscle pain and even rhabdomyolysis may occur. HGM-CoA reductase inhibitors are metabolized by the cytochrome P450 system; drugs or foods (eg, grapefruit juice) that inhibit cytochrome P450 activity increase the risk of hepatotoxicity and myopathy. Because of evidence that the HMG-CoA reductase inhibitors are teratogenic, these drugs should be avoided in pregnancy.

Skill Keeper: Angina

(See Chapter 12)

The antihyperlipidemic drugs, especially the HMG-CoA reductase inhibitors, are commonly used to treat patients with ischemic heart disease. One of the most common manifestations of ischemic heart disease and coronary atherosclerosis is angina.

1. What are the 3 major forms of angina?

2. Name the 3 major drug groups used to treat angina and specify which form of angina each is useful for.

The Skill Keeper Answers appear at the end of the chapter.

Resins

Mechanism and Effects

Normally, over 90% of bile acids, metabolites of cholesterol, are reabsorbed in the gastrointestinal tract and returned to the liver for reuse. Bile acid-binding resins (cholestyramine, colestipol, and colesevelam ) are large nonabsorbable polymers that bind bile acids and similar steroids in the intestine and prevent their absorption (Figure 35-2).

By preventing the recycling of bile acids, bile acid-binding resins divert hepatic cholesterol to synthesis of new bile acids, thereby reducing the amount of cholesterol in a tightly regulated pool. A compensatory increase in the synthesis of high-affinity LDL receptors increases the removal of LDL lipoproteins from the blood.

The resins cause a modest reduction in LDL cholesterol (Table 35-2) but have little effect on HDL cholesterol or triglycerides. In some patients with a genetic condition that predisposes them to hypertriglyceridemia and hypercholesterolemia (familial combined hyperlipidemia), resins increase triglycerides and VLDL.

Clinical Use

The resins are used in patients with hypercholesterolemia (Table 35-1). They have also been used to reduce pruritus in patients with cholestasis and bile salt accumulation.

Toxicity

Adverse effects from resins include bloating, constipation, and an unpleasant gritty taste. Absorption of vitamins (eg, vitamin K, dietary folates) and drugs (eg, thiazide diuretics, warfarin, pravastatin, fluvastatin) is impaired by the resins.

Ezetimibe

Mechanism and Effects

Ezetimibe is a prodrug that is converted in the liver to the active glucuronide form. This active metabolite inhibits a transporter that mediates gastrointestinal uptake of cholesterol and phytosterols (plant sterols that normally enter gastrointestinal epithelial cell but then are immediately transported back into the intestinal lumen.)

By preventing absorption of dietary cholesterol and cholesterol that is excreted in bile, ezetimibe reduces the cholesterol in the tightly regulated hepatic pool. A compensatory increase in the synthesis of high-affinity LDL receptors increases the removal of LDL lipoproteins from the blood.

As monotherapy, ezetimibe reduces LDL cholesterol by about 18% (Table 35-2). When combined with an HMG-CoA reductase inhibitor, it is even more effective.

Clinical Use

Ezetimibe is used for treatment of hypercholesterolemia and phytosterolemia, a rare genetic disorder that results from impaired export of phytosterols.

Toxicity

Ezetimibe is well tolerated. When combined with HMG-CoA reductase inhibitors, it may increase the risk of hepatic toxicity. Serum concentrations of the glucuronide form are increased by fibrates and reduced by cholestyramine.

Niacin (Nicotinic Acid)

Mechanism and Effects

Through multiple actions, niacin (but not nicotinamide) reduces LDL cholesterol, triglycerides, and VLDL and also often increases HDL cholesterol. In the liver, niacin reduces VLDL synthesis, which in turn reduces LDL levels (Figures 35-1 and 35-2). In adipose tissue, niacin appears to activate a signaling pathway that reduces hormone-sensitive lipase activity and thus decreases plasma fatty acid and triglyceride levels. Consequently, LDL formation is reduced, and there is a decrease in LDL cholesterol. Increased clearance of VLDL by the lipoprotein lipase associated with capillary endothelial cells has also been demonstrated and probably accounts for the reduction in plasma triglyceride concentrations. Niacin reduces the catabolic rate for HDL. Finally, niacin decreases circulating fibrinogen and increases tissue plasminogen activator.

Clinical Use

Because it lowers serum LDL cholesterol and triglyceride concentrations and increases HDL cholesterol concentrations, niacin has wide clinical usefulness in the treatment of hypercholesterolemia, hypertriglyceridemia, and low levels of HDL cholesterol.

Toxicity

Cutaneous flushing is a common adverse effect of niacin. Pretreatment with aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the intensity of this flushing, suggesting that it is mediated by prostaglandin release. Tolerance to the flushing reaction usually develops within a few days. Dose-dependent nausea and abdominal discomfort often occur. Pruritus and other skin conditions are reported. Moderate elevations of liver enzymes and even severe hepatotoxicity may occur. Severe liver dysfunction has been associated with an extended-release preparation, which is not the same as the sustained-release formulation. Hyperuricemia occurs in about 20% of patients, and carbohydrate tolerance may be moderately impaired.

Fibric Acid Derivatives

Mechanism and Effects

Fibric acid derivatives (eg, gemfibrozil, fenofibrate) are ligands for the peroxisome proliferator-activated receptor-alpha (PPAR-a) protein, a receptor that regulates transcription of genes involved in lipid metabolism. This interaction with PPAR- results in increased synthesis by adipose tissue of lipoprotein lipase, which associates with capillary endothelial cells and enhances clearance of triglyceride-rich lipoproteins (Figure 35-1). In the liver, fibrates stimulate fatty acid oxidation, which limits the supply of triglycerides and decreases VLDL synthesis. They also decrease expression of apoC-III, which impedes the clearance of VLDL, and increase the expression of apoA-I and apoA-II, which in turn increases HDL levels. In most patients, fibrates have little or no effect on LDL concentrations. However, fibrates can increase LDL cholesterol in patients with a genetic condition called familial combined hyperlipoproteinemia, which is associated with a combined increase in VLDL and LDL.

Clinical Use

Gemfibrozil and other fibrates are used to treat hypertriglyceridemia. Because these drugs have only a modest ability to reduce LDL cholesterol and can increase LDL cholesterol in some patients, they often are combined with other cholesterol-lowering drugs for treatment of patients with elevated concentrations of both LDL and VLDL.

Toxicity

Nausea is the most common adverse effect with all members of the fibric acid derivatives subgroup. Skin rashes are common with gemfibrozil. A few patients show decreases in white blood count or hematocrit, and these drugs can potentiate the action of anticoagulants. There is an increased risk of cholesterol gallstones; these drugs should be used with caution in patients with a history of cholelithiasis. When used in combination with reductase inhibitors, the fibrates significantly increase the risk of myopathy.

Combination Therapy

All patients with hyperlipidemia are treated first with dietary modification, but this is often insufficient and drugs must be added. Drug combinations are often required to achieve the maximum lowering possible with minimum toxicity and to achieve the desired effect on the various lipoproteins (LDL, VLDL, and HDL).

Certain drug combinations provide advantages (Table 35-1), whereas others present specific challenges. Because resins interfere with the absorption of certain HMG-CoA reductase inhibitors (pravastatin, cerivastatin, atorvastatin, and fluvastatin), these must be given at least 1 h before or 4 h after the resins. The combination of reductase inhibitors with either fibrates or niacin increases the risk of myopathy.

Skill Keeper Answers: Angina

(See Chapter 12)

1. The 3 major forms of angina are (1) angina of effort, which is associated with a fixed plaque that partially occludes 1 or more coronary arteries; (2) vasospastic angina, which involves unpredictably timed, reversible coronary spasm; and (3) unstable angina, which often immediately precedes a myocardial infarction and requires emergency treatment.

2. The 3 major drug groups used in angina are nitrates, calcium channel blockers, and  blockers. Nitrates are used in all 3 types of angina. Calcium channel blockers are useful for treatment of angina of effort and vasospastic angina. They can be added to  blockers and nitroglycerin in patients with refractory unstable angina.  blockers are not useful in vasospastic angina or for an acute attack of angina of effort. They are primarily used for prophylaxis of angina of effort and also in emergency treatment of acute coronary syndromes.

Checklist

When you complete this chapter, you should be able to:

 Describe the proposed role of lipoproteins in the formation of atherosclerotic plaques.

 Describe the dietary management of hyperlipidemia.

List the 5 main classes of drugs used to treat hyperlipidemia. For each, describe the mechanism of action, effects on serum lipid concentrations, and adverse effects.

 On the basis of a set of baseline serum lipid values, propose a rational drug treatment regimen.

 Argue the merits of combined drug therapy for some diseases, and list 3 rational drug combinations.

Drug Summary Table: Drugs for the Treatment of Hyperlipidemias

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Drug Interactions Statins Atorvastatin, simvastatin, rosuvastatin Inhibit HMG-CoA reductase Atherosclerotic vascular disease (primary and secondary prevention); acute coronary syndromes Oral administration; CYP450-dependent metabolism (3A4, 2C9) interacts with CYP inhibitors Myopathy, hepatic dysfunction, teratogen Fluvastatin, pravastatin, lovastatin: Similar but somewhat less efficacious Fibrates Gemfibrozil, fenofibrate PPAR- agonists Hypertriglyceridemia, low HDL cholesterol Oral administration Myopathy, hepatic dysfunction, cholestasis Bile acid-binding resins Colestipol Prevents reabsorption of bile acids from the gastrointestinal tract Elevated LDL cholesterol, pruritus Oral administration; interferes with absorption of some drugs and vitamins Constipation, bloating Cholestyramine, colesevalam: Similar to colestipol Sterol absorption inhibitor Ezetimibe Reduces intestinal uptake of cholesterol by inhibiting sterol transporter Elevated LDL cholesterol, phytosterolemia Oral administration Rarely, hepatic dysfunction, myositis Niacin Decreases VLDL synthesis and LDL cholesterol concentrations; increases HDL cholesterol Low HDL cholesterol, elevated VLDL and LDL Oral administration Gastrointestinal irritation, flushing, hepatic toxicity, hyperuricemia, may reduce glucose tolerance

PPAR-, proliferator-activated receptor-alpha.



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