Antihyperlipidemic Drugs Overview

Antihyperlipidemic Drugs

• Used to lower abnormally increased blood levels of lipids such as cholesterol, triglycerides and phospholipids.
• Elevated lipid levels increase risk for coronary artery disease (CAD).
• Medications in this class decrease low-density lipoprotein (LDL) levels, but generally have no significant impact on High-density lipoprotein (HDL).
• Useful for treating pruritus associated with liver failure and diarrhea after gallbladder removal.
• May bind with acidic drugs in the gastrointestinal tract decreasing absorption and effectiveness.
• Reduces absorption of lipid-soluble vitamins, such as vitamins A, D, E and K.
• Use of fibric acid derivatives and HMG-CoA reductase inhibitors increase the risk of rhabdomyolysis.

HMG-CoA Reductase Inhibitors (Statins)

• Statins lower lipid levels by interfering with cholesterol synthesis.
• These drugs include: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin.
• Inhibit HMG-CoA reductase, the enzyme that catalyzes the first step in cholesterol biosynthesis in the liver.
• Increase the concentration of LDL receptors on hepatocytes resulting in increased uptake of LDL and very-low-density lipoprotein (VLDL) from the serum.
• Taking statin drugs with other medications (amiodarone, clarithromycin, cyclosporine, erythromycin, fluconazole, gemfibrozil, itraconazole, ketoconazole, or niacin) increases the risk of myopathy or rhabdomyolysis.

Adverse Reactions

• GI upset
• Gallstone formation
• Myalgias

Nicotinic Acid (Niacin/Vit B3)

• A water-soluble vitamin that decreases cholesterol, triglyceride, and apolipoprotein B levels and increases HDL level.
• Available in immediate-release and extended-release tablets.
• Decreases lipolysis in adipose tissue decreasing the concentration of precursors for VLDL and LDL production.
• Inhibits triglyceride synthesis in the hepatocyte.
• May inhibit lipase breakdown increasing HDL levels.
• Nicotinic acid is rapidly and extensively absorbed following oral administration.
• Moderately bound to plasma proteins (60-70%)

Adverse Reactions

• High doses of nicotinic acid may produce vasodilation and cause flushing.
• Extended release forms tend to produce less severe vasodilation than immediate-release forms.
• Can cause hepatotoxicity.
• Hepatotoxicity risk is greater with extended-release forms.
• Eczema or acanthosis nigricans may develop.
• Hyperuricemia may occur
• Other adverse reactions include: nausea, vomiting, diarrhea, and epigastric or substernal pain.

Drug Interactions

• Nicotinic acid and HMG-CoA reductase inhibitors may increase the risk of myopathy or rhabdomyolysis.
• Bile acid sequestrants bind with nicotinic acid and decrease its effectiveness.
• Nicotinic acid may increase the risk of hepatotoxicity when taken with other medications.

Cholesterol Absorption Inhibitors

• Inhibit the absorption of cholesterol and related phytosterols from the intestine.
• Ezetimibe is the main drug in this class.

Mechanism of Action

• Decreases the absorption of cholesterol in the intestine.
• Decreased intestinal cholesterol absorption leads to a decrease in hepatic cholesterol stores.
• Hepatocytes respond to lower levels of intracellular cholesterol by increasing the concentration of LDL receptors on the cellular surface, which results in increased uptake of serum LDL into the cell with a resulting decrease in serum LDL.

Pharmacokinetcis

• Ezetimibe is rapidly and extensively absorbed following oral administration.
• Readily absorbed and is highly bound to plasma proteins.
• Primarily metabolized in the small intestine and excreted by the liver and kidneys.

Pharmacodynamics

• Ezetimibe reduces blood cholesterol levels by inhibiting the absorption of cholesterol by the small intestine.
• Binds to NPC1L1 and inhibits its ability to interact with the clathrin AP2 complex that is necessary for endocytosis.
• Leads to decreases in delivery of intestinal cholesterol to the liver.
• Causes a decrease in hepatic cholesterol.
• Ultimately increases clearance of LDL cholesterol from the circulation.

Side Effects

• Diarrhea
• Fatigue
• Back pain (associated with lower stored ATP in skeletal muscles)

Omega-3 Fatty Acids (Miscellaneous)

• Docosahexanoic Acid (DHA), Eicosapentaenoic Acid (EPA) & Omega-3 Derivative Icosapent Ethyl.
• Used primarily for their triglyceride lowering effects which are thought to be caused by inhibition of VLDL and triglyceride synthesis in the liver.

Side Effects

• GI disturbances, diarrhea, and fishy aftertaste with fish-derived omega-3s.

Drugs Restricted to Patients with Homozygous Familial Hypercholesterolemia

• Familial hypercholesterolemia is a genetic condition where high levels of cholesterol, particularly low-density lipoprotein (LDL) cholesterol, is inherited.

PCSK9 Inhibitors

• Evolocumab and Alirocumab are humanized antibodies to the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9).
• PCSK9's function is to transport the LDL receptor to the lysosome for degradation.
• Can reduce LDL by up to 70%.

Adverse Effects

• Local reactions at the injection site, upper respiratory issues and flu-like symptoms.

Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9)

• Responsible for transporting LDL receptors to the lysosome for degradation.
• Target of Evolocumab and Alirocumab (antibodies used in Familial Hypercholesterolemia/HF)

Monoclonal Antibodies (MABs)

• Bind to NPC1L1 and inhibit its ability to interact with the clathrin AP2 complex that is necessary for endocytosis, this leads to decreases in delivery of intestinal cholesterol to the liver.
• Causes a decrease in hepatic cholesterol.
• Ultimately increases clearance of LDL cholesterol from the circulation.

Side Effects

• Flu-like symptoms
• Neurocognitive problems

This quiz reviews antihyperlipidemic drugs, emphasizing their role in lowering lipid levels and preventing coronary artery disease. It specifically covers HMG-CoA reductase inhibitors, commonly known as statins, and their mechanisms of action, side effects, and drug interactions.