Pharmacology - Antihyperlipidemic Drugs

Front 1

Define Hyperlipidemia

Back 1

- elevation of plasma cholesterol and/or TAG's or a low HDL level

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Hyperlipidemia and Cardiovascular disease

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- elevated levels of LDL or decreased HDL levels --> inc risk of cardiovascular mortality
- hypertriglyceridemia = another risk factor

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Type I - Familial Hyperchylomicronemia

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- increased chylomicrons
- etiology = deficiency in LPL or apoCII
- rare

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Type IIA - Familial hypercholesterolemia

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- increased LDL
- etiology = decreased or no functional LDL receptor expression

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Type IIB - Familial combined hyperlipidemia

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- increased LDL and VLDL
- etiology = overproduction of VLDL by the liver
- relatively common

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Type III - Familial dysbetalipoproteinemia

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- increased IDL
- etiology = abnormal apoE

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Type IV - Familial hypertriglyceridemia

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- increased VLDL
- etiology = overproduction and/or impaired catabolism of VLDL
- relatively common

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Type V = Familial mixed hypertriglyceridemia

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- increased chylomicrons and VLDL
- etiology = increased prod or decreased clearance of VLDL and chylomicrons

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Secondary Hyperlipidemia

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- most common in adults
- due to a sedentary lifestly w/ excessive dietary intake of saturated fat, cholesterol, and trans fatty acids

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Antihyperlipidemic Drugs

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- HMG-CoA reductase inhibitors
- Niacin
- Bile acid-binding resins
- Fibrates
- Cholesterol absorption inhibitors

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HMG-CoA Reductase Inhibitors (Statins)

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- Atorvastatin - potent
- Fluvastatin
- Lovastatin
- Pravastatin
- Rosuvastatin - potent
- Simvastatin

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HMG-CoA Reductase Inhibitors (Statins) - MOA

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- Statins are competitive inhibitors of HMG-CoA reductase, the enzyme that catalyzes the first committed step of cholesterol biosynthesis
- Statins deplete intracellular supply of cholesterol --> up-regulation of LDL receptors --> increased clearance of LDL from blood

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HMG-CoA Reductase Inhibitors (Statins) - Uses

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- DOC for LDL reduction in all types of hyperlipidemias (reduce CV mortality)

- other: improve endothelial fxn, decrease platelet agg, reduce inflammation, dec plasma levels of CRP

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HMG-CoA Reductase Inhibitors (Statins) - Contraindications

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- Homozygotes for familial hypercholesterolemia lack functional LDL receptors and so benefit less from tx w/ statins
- Contraindicated in pregnancy

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HMG-CoA Reductase Inhibitors (Statins) - AE

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- Elevation of aminotransferases
- Myopathy and rhabdomyolysis (rare)
- Creatine kinase levels should be determined regularly
- Rhabdomyolysis may cause myoglobinuria --> renal injury

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Niacin (Nicotinic acid)

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Most effective agent for increasing HDL and only agent that may reduce Lipoprotein A

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Niacin - MOA

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- inhibits adenylyl cyclase in adipocytes --> inhibition of adipocyte hormone-sensitive lipase --> decreased plasma free fatty acid transport to the liver --> decreased hepatic TAG synthesis

- decreases hepatic VLDL production and release (b/c of dec hepatic TAG synthesis)

- increases LPL activity (promotes clearance of chylomicrons, VLDL, and TAG)

- decreases catabolic rate of HDL (so increases HDL)

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Niacin - AE

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- intense cutaneous flush
- admin of aspirin prior to niacin decreases the flush (which is PG mediated)
- acanthosis nigricans**, pruritis, rashes, and dry skin
- most serious = hepatotoxicity (elevated serum transaminases) and hyperglycemia
- niacin-induced insulin resistance can cause severe hyperglycemia in pts w/ diabetes mellitus
- niacin elevates uric acid levels and can precipitate gout

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Fibrates

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- Gemfibrozil
- Fenofibrate

- Fibrates lower VLDL levels and increase HDL levels

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Fibrates - MOA

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- activate peroxisome proliferator-activated receptor-alpha (PPAR-alpha)

- PPAR-alpha receptors are expressed primarily in liver and brown adipose tissue and activation of these receptors --> decrease in plasma TAG levels and increase in plasma HDL

- decrease in plasma TAG is caused by inc muscle expression of LPL, decreased hepatic expression of apoCIII, and inc hepatic oxidation of fatty acids

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Fibrates - Uses

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- hypertryglyceridemiaa in which VLDL predominate

- dybetalipoproteinemia

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Fibrates - AE

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- mild GI disturbances
- myositis; pts w/ renal insufficiency may be at risk; rhabdomyolysis rarely occurs
- lithiasis; fibrates increase biliary cholesterol excretion, so may cause gallstones

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Bile acid-binding resins

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- Cholestyramine
- Colestipol
- Colesevelam

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Bile acid-binding resins - Uses

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- hyperlipidemias involving isolated increases in LDL
- DOC for pregnant women and children
- neither absorbed nor metabolized; totally excreted in the feces

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Bile acid-binding resins - MOA

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- bind to anionic bile acids in the intestinal lumen and prevent their reabsorption
- resin-bile acid complex is excreted in the feces, thus preventing bile acids from returning to the liver by the enterohepatic circulation
- reduction in bile acid conc --> hepatocytes to increase conversion of cholesterol to bile acids --> intracellular cholesterol decreases --> up-regulation of LDL receptors in the liver --> decreased plasma LDL

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Bile acid-binding resins - AE

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- Colesevelam produces fewer GI adverse effects than cholestyramine or colestipol
- They may increase TAG: contraindicated in hypertriglyceridemia

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Cholesterol Absorption Inhibitors

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Ezetimibe

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Ezetimibe

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- inhibits intestinal absorption of cholesterol and phytosterols
- primary clinical effect = lower LDL
- small increase in HDL and mild decrease in TAG

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Cholesterol Absorption Inhibitors - MOA

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- Ezetimibe inhibits an intestinal transport protein, which takes up cholesterol from the lumen --> 3 things
(i) - cholesterol syn increases
(ii) - decrease in incorporation of cholesterol into chylomicrons
(iii) - upregulation of LDL receptors, enhancing LDL clearance from plasma

Front 30

Cholesterol Absorption Inhibitors and Statins

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Ezetimibe = complementary to statins:

Statins inhibit chol syn and inc chol absorption

Ezetimibe inhibits chol absorption and increases cholesterol synthesis

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Cholesterol Absorption Inhibitors - AE

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- low incidence of reversible impaired hepatic function
- small increase in incidence when ezetimibe given w/ a statin
- myositis has been reported rarely

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Omega-3 Fatty Acids

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- Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce TAG biosynthesis and increase fatty acid oxidation in the liver
- long-term = increased HDL
- omega-3 fatty acids may increase total LDL as they lower TAG levels

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Omega-3 Fatty Acids - Drugs

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Lovaza
- given as an adjunt to pts with very high TAG levels

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Antihyperlipidemic Drug Combinations - Uses

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used when:
- pts unable to reach their LDL goal on a single drug
- pts w/ combined hypertriglyceridemia and hypercholesterolemia that cant be controlled w/ a single drug
- pts w/ high LDL and low HDL

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Antihyperlipidemic Drug Combinations

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- statins + resin/ezetimibe
- vytorin = simvastatin + ezetimibe
- advicor = combination of extended-release niacin + lovastatin
- statin-fibrate combinations are associated with an increased incidence of severe myopathy and rhabdomyolysis

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Antihyperlipidemic Drugs in Pregnancy

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Statins - ABSOLUTELY CONTRAINDICATED (Category X)

Fibrates, Niacin, Ezetimibe - Category C

Cholestyramine and colestipol - might interfere w/ absorption of nutrients - Category C

Colesevelam - Category B (used during preg only if clearly needed)