Antihyperlipidemic Drugs Flashcards
Primary and Secondary Hyperlipidemia
Primary disorders, the most common cause of dyslipidemia in children, do not cause a large percentage of cases in adults. Secondary causes contribute to most cases of dyslipidemia in adults. The most important secondary cause in developed countries is a sedentary lifestyle with excessive dietary intake of saturated fat, cholesterol, and trans fatty acids.
Other secondary factors can lead to hyperlipidemia:
Alcohol intake increases synthesis of fatty acids, which are then esterified to form triglycerides. Therefore, excess alcohol consumption can result in increased VLDL production.
Hypertriglyceridemia in type 2 diabetes mellitus results from increased VLDL synthesis and reduced chylomicron and VLDL catabolism by LPL. Insulin normally suppresses VLDL production by the liver, and insulin resistance in the liver causes increased VLDL production. Furthermore, apoCIII levels are increased in association with insulin resistance, and this reduces the catabolism of chylomicrons and VLDL particles.
Hypothyroidism is an important and common cause of secondary hyperlipidemia.
Statins
HMG-CoA REDUCTASE INHIBITORS (Statins)
Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, and Simvastatin
Statins are analogs of 3-OH-3-methylglutarate (HMG). They are competitive inhibitors of HMG-CoA reductase, the enzyme that catalyzes the first committed step of cholesterol biosynthesis. By inhibiting the de novo cholesterol synthesis they deplete the intracellular supply of cholesterol. Depletion of intracellular cholesterol causes the cell to up-regulate LDL receptors; this results in increased clearance of LDL from the blood.
Statins are more effective than other drugs in lowering LDL. They also cause a decrease of plasma TG and a small increase in HDL.
Rosuvastatin is the most potent statin in lowering LDL. Atorvastatin is the next most potent, followed by simvastatin. Lovastatin and pravastatin are similar in potency. Fluvastatin is the least potent.
The potency of statins at lowering TG is similar to their potency at lowering LDL. The most significant TG reductions are seen with rosuvastatin and atorvastatin.
Lovastatin and simvastatin are prodrugs. They are inactive lactones that are hydrolyzed in the gastrointestinal tract to yield the active β-hydroxyl derivatives.
Statin Uses
Statins are the drug class of choice for LDL reduction and are by far the most widely used class of lipid-lowering drugs.
Statins reduce cardiovascular mortality. They are effective in lowering LDL levels in all types of hyperlipidemias.
Patients who are homozygous for familial hypercholesterolemia lack functional LDL receptors and thus benefit much less from treatment with statins.
Statins are useful alone or in combination with bile acid-binding resins, niacin or ezetimibe.
Women who are pregnant, lactating or likely to become pregnant should not receive statins.
Who should be treated with a statin according to the new ACC/AHA guidelines?
There are four major statin benefit groups:
Patients with clinical atherosclerotic cardiovascular disease (ASCVD).
Patients with LDL 190 mg/dL or higher.
Patients age 40-75 years of age with diabetes and LDL 70-189 mg/dL.
Patients without ASCVD or diabetes with LDL 70-189 mg/dL with an estimated 10-year risk of ASCVD of 7.5% or higher.
Adverse Effects of Statins
OTHER EFFECTS OF STATINS
Improve endothelial function.
Decrease platelet aggregation.
Stabilize atherosclerotic plaque.
Reduce inflammation.
ADVERSE EFFECTS
Elevation of aminotransferases. Usually not associated with other evidence of liver toxicity. Aminotransferase activity should be measured at baseline, at 1–2 months, and then every 6–12 months.
Myopathy and rhabdomyolysis have rarely been reported. Rhabdomyolysis may cause myoglobinuria, leading to renal injury. CK should be measured at baseline. If muscle pain, or weakness appears, CK should be measured immediately and the drug discontinued if activity is significantly elevated.
Niacin
Mechanism of Action
NIACIN (NICOTINIC ACID)
Niacin favorably affects virtually all lipid parameters. Niacin decreases VLDL, LDL and Lp(a) levels in most patients. It often increases HDL levels significantly. Niacin is the most effective agent for increasing HDL and the only agent that may reduce Lp(a). Despite its favorable effects on lipids, niacin has adverse effects which limit its use.
MECHANISM OF ACTION
Niacin inhibits adenylyl cyclase in adipocytes through activation of a Gi-protein- coupled receptor. This leads to inhibition of adipocyte hormone-sensitive lipase, which reduces transport of fatty acids to the liver and decreases hepatic TG synthesis.
In the liver niacin reduces TG synthesis by inhibiting both the synthesis and esterification of fatty acids. As a consequence, there is a decrease in hepatic VLDL production and release, leading to a reduction of LDL levels.
Niacin also increases LPL activity, which promotes clearance of chylomicrons and VLDL TGs.
The catabolic rate for HDL is decreased, therefore HDL increases.
Fibrinogen levels decrease and levels of tissue plasminogen activator increase. Therefore, niacin can reverse some of the endothelial cell dysfunction contributing to thrombosis associated with hypercholesterolemia and atherosclerosis.
Uses and Adverse Effects of Niacin
USES
Niacin is the most effective drug for raising HDL levels.
Useful in patients with combined hyperlipidemia and low HDL levels.
Effective in combination with statins.
ADVERSE EFFECTS
Most persons experience an intense cutaneous flush after each dose of niacin when the drug is started or the dose increased. Administration of aspirin 30 minutes prior to taking niacin decreases the flush, which is prostaglandin-mediated.
Pruritus, rashes, dry skin and acanthosis nigricans have been reported.
Nausea and abdominal discomfort.
The most serious side effects are hepatotoxicity and hyperglycemia. Hepatotoxicity is manifested as elevated serum transaminases.
Niacin should be used cautiously in patients with diabetes mellitus, since niacin- induced insulin resistance can cause severe hyperglycemia.
Niacin elevates uric acid levels and may precipitate gout.
Rarely, niacin may cause atrial arrhythmias.
Rarer adverse effects include toxic amblyopia and toxic maculopathy.
Fibrates
Name the two drugs in this class and their Mechanism of Action
THE FIBRATES
Gemfibrozil, Fenofibrate
Fibrates lower serum TG and increase HDL levels.
MECHANISM OF ACTION
Fibrates activate the nuclear receptor, peroxisome proliferator-activated receptor- α (PPAR-α). PPAR-α receptors are expressed primarily in liver and brown adipose tissue and to a lesser extent in kidney, heart and skeletal muscle.
The decrease in plasma TG levels is caused by increased expression of lipoprotein lipase, decreased hepatic expression of apoC-III, and increased hepatic oxidation of fatty acids.
Only modest reductions of LDL occur in most patients. In others, especially those with combined hyperlipidemia (hypercholesterolemia plus hypertryglyceridemia), LDL often increases as TG are reduced.
HDL increases moderately.
Fibrates Uses, Adverse Effects, and Drug Interactions
USES
Fibrates are the drugs of choice in severe hypertriglyceridemia, and are a reasonable consideration in moderate hypertriglyceridemia.
ADVERSE EFFECTS
Mild GI disturbances.
Myositis can occur. Patients with renal insufficiency may be at risk. Rhabdomyolysis has occurred rarely.
Fibrates should be avoided in patients with hepatic or renal dysfunction.
Lithiasis. Fibrates increase biliary cholesterol excretion, therefore there is a predisposition to formation of gallstones.
DRUG INTERACTIONS
Gemfibrozil inhibits hepatic uptake of statins by OATP1B1, thus increasing plasma concentration of statins. Additionally, gemfibrozil competes for the same glucuronosyl transferases that metabolize most statins. As a consequence, levels of both drugs may be increased when they are co-administered. This increases the risk of rhabdomyolysis.
Fenofibrate does not inhibit statin metabolism, and is much less likely to increase the risk of rhabdomyolysis.
Bile Acid-Binding Resins
Name the three drugs under this group and their Mechanism of Action
BILE ACID-BINDING RESINS
Cholestyramine, Colestipol, Colesevelam
Useful only in hyperlipoproteinemias involving isolated increases in LDL. In patients who have hypertriglyceridemia as well as elevated LDL levels, VLDL levels may be further increased during treatment with the resins.
These agents are insoluble in water and have very large molecular weights (> 10^6), therefore they are neither absorbed nor metabolically altered by the intestine. They are totally excreted in the feces.
MECHANISM OF ACTION
These agents are polymeric anion exchange resins that are insoluble in water. They bind to anionic bile acids in the intestinal lumen and prevent their reabsorption. The resin-bile acid complex is excreted in the feces, thus preventing bile acids from returning to the liver by the enterohepatic circulation.
The reduction in bile acid concentration causes hepatocytes to increase conversion of cholesterol to bile acids. As a result, intracellular cholesterol decreases, which leads to up-regulation of LDL receptors in the liver. The increase of hepatic LDL receptors increases liver uptake of LDL, leading to a decrease in plasma LDL levels.
This effect is partially offset by the increased cholesterol synthesis, caused by upregulation of HMG-CoA reductase.
HDL rises modestly.
Adverse Effects, Drug Interactions and Uses of Bile Acid-Binding Resins
USES
Bile acid sequestrants are usually used with statins or niacin to increase LDL reduction.
They are drugs of choice for children and women who are or are planning to become pregnant.
In individuals who completely lack functional LDL receptors these drugs have little effect on plasma LDL levels.
ADVERSE EFFECTS
Bile acid sequestrants are safe, but their use is limited by adverse effects of bloating, nausea, cramping and constipation.
Colesevelam is better tolerated than cholestyramine or colestipol, with fewer GI adverse effects.
They may increase TG, so they are contraindicated in hypertryglyceridemia.
DRUG INTERACTIONS
Cholestyramine and colestipol, but not colesevelam, interfere with absorption of other drugs. They also impair the absorption of liposoluble vitamins (A, D, E & K).
Ezetimibe
Mechanism of Action
CHOLESTEROL ABSORPTION INHIBITORS
Ezetimibe
Ezetimibe inhibits intestinal absorption of cholesterol and phytosterols. Its primary clinical effect is to lower LDL. .
MECHANISM OF ACTION
Ezetimibe is a selective inhibitor of a transport protein (NPC1L1) in jejunal enterocytes, which takes up cholesterol from the lumen.
Ezetimibe reduces cholesterol absorption by 54%, precipitating a compensatory increase in cholesterol synthesis (which can be inhibited with a statin).
Reduced delivery of intestinal cholesterol to the liver leads to upregulation of LDL receptors, which enhances LDL clearance from plasma.
The maximal efficacy of ezetimibe for lowering LDL is only about 15-20% when used as monotherapy.
The actions of ezetimibe are complementary to those of statins. Statins inhibit cholesterol synthesis and increase cholesterol absorption. Ezetimibe inhibits cholesterol absorption and increases cholesterol synthesis. Combined therapy with ezetimibe and a statin prevents enhanced cholesterol synthesis and the increase in cholesterol absorption. This combination provides additive reductions in LDL levels.
Ezetimibe is effective even in the absence of dietary cholesterol because it inhibits reabsorption of cholesterol excreted in bile.
No convincing data are available showing that ezetimibe improves cardiovascular outcomes.
Uses, Adverse Effects and Drug Interactions of Ezetimibe
USES
Ezetimibe is particularly useful in combination with a statin in patients unable to reach their LDL goal on statin monotherapy.
Ezetimibe is only used as monotherapy in patients who do not tolerate statins.
ADVERSE EFFECTS
Low incidence of reversible impaired hepatic function. Small increase in incidence when ezetimibe is given with a statin.
Myositis has been reported rarely.
DRUG INTERACTIONS
Bile-acid sequestrants inhibit absorption of ezetimibe. Therefore the two agents should not be administered together.
ω-3 FATTY ACIDS
Name the one FDA drug approved in this class
The ω-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), also referred to as fish oils, reduce plasma TG in a dose-dependent way (25 - 40% with EPA/DHA 4 g/day). By incompletely understood molecular mechanisms, fish oils reduce TG biosynthesis and increase fatty acid oxidation in the liver. With long-term intake, they may increase HDL. ω-3 fatty acids may increase total LDL as they lower TG levels.
ω-3 fatty acids are available over the counter as nutritional supplements in the form of fatty acid ethyl esters. Supplied in capsules.
There is no evidence that fish oil supplements prevent cardiovascular disease or improve outcomes in patients who have it.
LOVAZA
FDA-approved ω-3-product. Ethyl esters of ω-3 fatty acids. Indicated as an adjunct to diet to reduce triglyceride levels in adult patients with very high (> 500 mg/dL) TG levels. Supplied as a liquid-filled gel capsule for oral administration.
ANTIHYPERLIPIDEMIC DRUGS IN PREGNANCY
Statins are absolutely contraindicated in pregnancy. Category X.
Gemfibrozil and fenofibrate are teratogenic in animals. Category C. Should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The safety of niacin in lipid-lowering doses is unknown. Category C.
Cholestyramine and colestipol might interfere with absorption of important nutrients. Category C.
Colesevelam appears to be safe in animal reproductive studies. Category B. Should be used during pregnancy only if clearly needed.
Ezetimibe has caused skeletal defects in some animal studies. Category C.
