Pharmacology I: Hyperlipidemia Drugs

Background of Hyperlipidemia

• Cholesterol and triglycerides are essential substrates for cell membrane formation and hormone synthesis, and provide a source of free fatty acids.
• Cholesterol plays a central role in the pathogenesis of atherosclerosis.
• Hyperlipidemia leads to acute pancreatitis and atherosclerosis, which can cause clinical outcomes such as angina, myocardial infarction (MI), arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death.

Atherosclerosis

• Atherosclerosis lesions arise from the transport and retention of plasma LDL through the endothelial cell layer into the extracellular matrix of the subendothelial space.
• Oxidized LDL recruits monocytes into the artery wall, which transform into macrophages that accelerate LDL oxidation.
• Oxidized LDL provokes an inflammatory response mediated by chemoattractants and cytokines.

Lipoproteins

• Lipoproteins are spherical particles with surfaces consisting largely of phospholipid, free cholesterol, and protein, and cores composed mostly of triglyceride and cholesterol ester.
• Apolipoproteins (Apos) serve four main purposes: required for assembly and secretion of lipoproteins, serve as major structural components of lipoproteins, act as ligands for binding to receptors on cell surfaces, and can be cofactors for inhibition of enzymes involved in the breakdown of triglycerides from chylomicrons and VLDL.

Cholesterol Synthesis

• Increased intracellular cholesterol inhibits the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme for intracellular cholesterol biosynthesis.
• Increased intracellular cholesterol also reduces synthesis of LDL receptors and accelerates activity of acyl coenzyme-A: cholesterol acyltransferase to facilitate cholesterol storage within cells.

HDL

• HDL transfers cholesterol to either VLDL and LDL or to the liver for secretion into bile or conversion into bile acids.
• Apolipoprotein A-I production is increased by estrogens, leading to higher HDL levels in women and individuals receiving estrogen.

Dyslipidemia

• Dyslipidemia is characterized by elevated blood levels of lipoproteins (cholesterol, triglycerides, phospholipids) and lipoprotein abnormalities.
• Dyslipidemia can be primary (familial) or secondary, such as in diabetes mellitus.
• Dyslipidemia is diagnosed when total cholesterol is ≥ 240 mg/dl, LDL cholesterol is > 160 mg/dl, triglyceride levels are > 200 mg/dl, and HDL cholesterol levels are < 40 mg/dl.

Pharmacology of Drugs Used in Hyperlipidemia

• HMG-CoA reductase inhibitors are the recommended drug of choice for hyperlipidemia and can reduce LDL-cholesterol by ≥ 50%.
• These drugs work by reducing the production of cholesterol in the liver, leading to a decrease in LDL levels.
• They also decrease triglycerides and increase HDL-C, and have been shown to prevent bone loss.

Mechanism of Action of HMG-CoA Reductase Inhibitors

• These drugs work mainly on the liver, where they inhibit HMG-CoA reductase, the rate-limiting enzyme for cholesterol biosynthesis.

Pharmacokinetics of HMG-CoA Reductase Inhibitors

• Lovastatin and simvastatin are inactive lactone prodrugs that are hydrolyzed in the gastrointestinal tract to the active β-hydroxyl derivatives.
• Pravastatin, atorvastatin, fluvastatin, and rosuvastatin are active as given.
• Absorption of the ingested doses varies from 40% to 75%, with the exception of fluvastatin, which is almost completely absorbed.
• Most of the absorbed dose is excreted in the bile, with 5–20% excreted in the urine.
• Plasma half-lives of these drugs range from 1 to 3 hours, except for atorvastatin (14 hours), pitavastatin (12 hours), and rosuvastatin (19 hours).

Clinical Use of HMG-CoA Reductase Inhibitors

• These drugs are effective in lowering plasma cholesterol levels in all types of hyperlipidemias.
• However, patients who are homozygous for familial hypercholesterolemia lack LDL receptors and, therefore, benefit much less from treatment with these drugs.

Adverse Effects of HMG-CoA Reductase Inhibitors

• Mild elevations of serum aminotransferases are common but are not often associated with hepatic damage.
• Patients with preexisting liver diseases may suffer more.
• 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.
• Mild transient gastrointestinal symptoms, headache, sleep disturbances, and fatigue are also common.