Drugs for Hyperlipidemias Dr.A.Shyam Sundar. M.Pharm.,Ph.D, Assistant Professor in Pharmacology And Toxicology University Of Nizwa Sultanate of Oman Source: Henry Hitner and Barbara Nagle

Atherosclerosis Atherosclerosis is a progressive condition that leads to CAD and PAD. Fat buildup inside the arteries—plaque CAD—coronary artery disease PAD—peripheral artery disease Learning Outcomes 29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis. Atherosclerosis is a progressive condition that leads to coronary artery disease (CAD) and peripheral artery disease (PAD). It is the leading cause of illness and death in the United States. Atherosclerosis is a disease that begins in early adulthood, even childhood, in which fat builds up inside the smooth lining of the arteries. This accumulated fat, called plaque, is mostly cholesterol with calcium, cell debris, and other substances found in the blood.

Hepatic Cholesterol Synthesis Only pathway for cholesterol degradation Rate Limiting Energetically expensive; prefer to conserve what is already made/acquired – LDL receptor pathway Cholesterol and Atherosaclerosis, Grundy)

Dyslipidemia Dyslipidemia can be primary or secondary. The normal range of plasma total CHO concentration < 6.5 mmol/L. There are smooth gradations of increased risk with elevated LDL CHO conc, and with reduced HDL CHO conc. Dyslipidemia can be primary or secondary. The primary forms are genetically determined Secondary forms are a consequence of other conditions such as diabetes mellitus, alcoholism, nephrotic sy, chronic renal failure, administration of drug…

Lipoproteins There are several different lipoproteins: Low-density lipoprotein (LDL) Very-low-density lipoprotein (VLDL) High-density lipoprotein (HDL) Learning Outcomes 29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis.

Triglycerides Main form of fat from diet Provide body with energy Chylomicrons: Very large lipoproteins that deliver triglycerides to muscle and fat tissue Learning Outcomes 29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis.

Monitoring the Disease Risk factors for atherosclerosis Age History of smoking Hypertension Premature menopause Obesity Diabetes mellitus Hyperthyroidism Learning Outcomes 29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis.

Monitoring the Disease The goals of treatment are: Lowering LDL cholesterol Reducing total serum cholesterol and triglycerides Increasing HDL cholesterol Learning Outcomes 29.1 Explain the importance of triglycerides and cholesterol and their role in atherosclerosis.

Lipid-lowering drugs Several drugs are used to decrease plasma LDL-CHO Drug therapy to lower plasma lipids is only one approach to treatment and is used in addition to dietary management and correction of other modifiable cardiovascular risk factors

Hypolipidemic Drugs There are five groups of drugs used in the management of hyperlipidemia: HMG-CoA reductase inhibitors Cholesterol absorption inhibitors Bile acid sequestrants Fibric acid derivatives Nicotinic acid Learning Outcomes 29.2 Discuss the treatment of hyperlipidemia. 29.3 Explain the mechanism of action of five different hypolipidemic drugs. There are five groups of drugs that are used alone or as adjunctive treatment to diet: in the management of hyperlipidemias, for the prevention of coronary events in patients at risk, for the treatment of clinically evident coronary heart disease, to slow the progression of atherosclerosis. The groups are the HMG-CoA reductase inhibitors (known as the statins), cholesterol absorption inhibitors, bile acid sequestrants, fibric acid derivatives, and nicotinic acid.

Hypolipidemic Drugs

HMG-CoA Reductase Inhibitors Also referred to as statins MOA—inhibit enzyme that causes cholesterol synthesis IND—adjunct to dietary treatment to decrease total serum and LDL cholesterol: Reduce LDL level up to 30% Raise HDL level up to 20% Learning Outcomes 29.3 Explain the mechanism of action of five different hypolipidemic drugs. 29.4 Explain why the HMG-CoA inhibitors are more effective than other hypolipidemic drugs.

HMG-CoA Reductase Inhibitors Adverse effects: Headache, dizziness, alteration of taste, insomnia, abdominal cramping and photosensitivity May cause myalgias, leg ache, and muscle weakness Contraindicated during pregancy Learning Outcomes 29.3 Explain the mechanism of action of five different hypolipidemic drugs. 29.4 Explain why the HMG-CoA inhibitors are more effective than other hypolipidemic drugs.

Cholesterol Absorption Inhibitors Ezetimibe: MOA—blocks absorption of cholesterol in the intestines Decreases VLDL Decreases circulating LDL cholesterol IND—treatment of hyperlipidemia in conjunction with diet alteration Learning Outcomes 29.2 Discuss the treatment of hyperlipidemia. 29.3 Explain the mechanism of action of five different hypolipidemic drugs. 29.6 Explain the essential terminology associated with atherosclerosis and hypolipidemic drugs.

Cholesterol Absorption Inhibitors Ezetimibe: Modestly reduces total cholesterol, LDL, and triglyceride blood levels Ideal to combine with other hypolipidemic drugs Adverse effects—abdominal pain, fatigue, coughing, diarrhea, back pain, and arthralgia Learning Outcomes 29.2 Discuss the treatment of hyperlipidemia. 29.3 Explain the mechanism of action of five different hypolipidemic drugs. 29.6 Explain the essential terminology associated with atherosclerosis and hypolipidemic drugs.

Bile Acid Sequestrants MOA—bind bile salts and cholesterol in the GI tract, preventing absorption of both IND—hyperlipidemia: Increased elimination of bile salts, cholesterol, and other fats in the feces. Adverse effects include GI disturbances, severe constipation, and fecal impaction. Most serious adverse effect is intestinal obstruction. Learning Outcomes 29.2 Discuss the treatment of hyperlipidemia. 29.3 Explain the mechanism of action of five different hypolipidemic drugs.

Nicotinic Acid MOA—affects cholesterol synthesis through a G proteinScoupled receptor: Inhibits triglyceride lipase Stimulates lipoprotein lipase Decreases free fatty acid release and removes triglycerides IND—hyperlipidemia Adverse effects—flushing, nausea, vomiting, and diarrhea Learning Outcomes 29.2 Discuss the treatment of hyperlipidemia. 29.3 Explain the mechanism of action of five different hypolipidemic drugs.

Fibric Acid Derivatives Gemfibrozil: MOA—inhibits breakdown of fat into triglycerides, and limits liver production of triglycerides IND—to decrease triglycerides Adverse effects—nausea, vomiting, diarrhea, and flatulence Learning Outcomes 29.2 Discuss the treatment of hyperlipidemia. 29.3 Explain the mechanism of action of five different hypolipidemic drugs.

Preferred Therapy All hypolipidemic drugs are indicated as adjunctive therapy to reduce elevated cholesterol levels. HMG-CoA reductase inhibitors are the most prescribed. Cholestyramine can also be used in the treatment of partial biliary obstruction. Learning Outcomes 29.2 Discuss the treatment of hyperlipidemia. 29.3 Explain the mechanism of action of five different hypolipidemic drugs.

Contraindications Systemic hypolipidemic drugs should not be used in patients with liver dysfunction. Bile acid sequestrants should not be used in patients with biliary obstruction. Statins should not be used in pregnant women. Learning Outcomes 29.2 Discuss the treatment of hyperlipidemia. 29.3 Explain the mechanism of action of five different hypolipidemic drugs.

Drug Interactions Learning Outcomes 29.6 Explain the essential terminology associated with atherosclerosis and hypolipidemic drugs. The bile acid sequestrants stay in the lumen of the intestine and trap other subtances during transit through the intestine. Cholestyramine binds with fat-soluble vitamins (A, D, and K), folic acid, and many drugs, thus reducing their GI absorption. Supplementation at time intervals when the bile acids are no longer in the absorption area may be necessary to avoid vitamin deficiencies. Taking some medication in the presence of grapefruit juice can significantly decrease drug metabolism at the intestinal wall and increase its bioavailability. Increasing a drug’s bioavailability will increase risk of developing adverse effects. Grapefruit juice interacts only with drugs that are administered orally. Atorvastatin, lovastatin, and simvastatin are definitely affected by grapefruit. Although the studies concerning grapefruit interactions with pravastatin, fluvastatin, or rosuvastatin were not as significant, it probably would be prudent not to consume grapefruit a few hours before or after taking these medications. Orange juice does not have any effect on absorption of these drugs. Drugs that are potent inhibitors of CYP3A4 and also cause an increase in statin blood levels include cyclosporine, itraconazole, ketoconazole, erythromycin, clarithromycin, and HIV protease inhibitors. For patients who require antifungal therapy, the statins should be stopped until the fungal treatment is discontinued.

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