Understanding Hyperlipidemia and Treatment

• Antihyperlipidemic drugs treat hyperlipidemia, addressing the dangers of excess fat intake.

What is Hyperlipidemia?

• Hyperlipidemia, a common disorder in developed countries and a major contributor to coronary heart disease, stems from abnormalities in lipid metabolism or plasma lipid transport.
• Synthesis and degradation issues of lipoproteins can also cause it.

Causes of Hyperlipidemia

• Hyperlipidemia often results from lifestyle habits or treatable medical conditions, and can be inherited.
• Risk factors include obesity, inactivity, smoking, diabetes, obstructive jaundice, and an underactive thyroid.

Biochemistry of Plasma Lipids

• Lipids, mixtures of fatty acids and alcohol, include cholesterol and its esters, triglycerides, and phospholipids.

Cholesterol

• Cholesterol, a C27 steroid, is a key component of cell membranes and a precursor for bile acids, steroid hormones, and fat-soluble vitamins.
• It supports new cell formation and repair.
• Adrenal glands use it to form hormones like cortisol, testicles for testosterone, and ovaries for estrogen and progesterone.
• Cholesterol comes from liver production and meat/dairy consumption.

Triglycerides and Phospholipids

• Triglycerides provide immediate energy to muscles or store fat for later use.
• Phospholipids form cell membranes, create second messengers, and store fatty acids for prostaglandin generation.

Lipoproteins

• Lipoproteins contain proteins and lipids bound to apolipoproteins, which enable fat movement in and out of cells and provide structural support.
• They also bind to receptors.

Classification of Lipoproteins

• Chylomicrons transport dietary triglycerides (99%) to adipose tissue and muscle (1% protein).
• VLDL transports endogenous triglycerides (90% lipids, 10% protein) to adipose tissue and muscle.
• IDL is intermediate between VLDL and LDL, usually undetectable in blood.
• LDL transports endogenous cholesterol from the liver to tissues (80% lipids, 20% protein).
• HDL collects cholesterol from tissues (60% lipids, 40% protein) and returns it to the liver.

Classification of Hyperlipidemia

• Hyperlipidemias are classified by the Fredrickson classification, based on lipoprotein patterns via electrophoresis or ultracentrifugation, later adopted by the World Health Organization (WHO).
• The Fredrickson classification does not account for HDL or distinguish among the different genes that may be partially responsible for some of these conditions.
• Hyperlipidemia can be primary/familial or secondary.
• Current classifications depend on blood lipid abnormality patterns.

Primary Familial Hyperlipoproteinaemia

• Primary familial hyperlipoproteinemia is divided into six phenotypes (I, IIa, IIb, III, IV, V), based on elevated lipoproteins and lipids.
• Type I hyperlipoproteinemia (Buerger-Gruetz syndrome) features increased chylomicrons due to reduced LPL; treatment involves diet control.
• Type IIa ("Polygenic hypercholesterolaemia") features increased LDL+TG with treatment of bile acid sequestrants, statins and niacin.
• Type IIb hyperlipoproteinemia ("Combined hyperlipidemia") includes LDL and VLDL, treated with statins, niacin, or fibrates.
• Type III (Familial dysbetalipoproteinemia) has increased IDL; treatment includes fibrates and statins.
• Type IV is Familial hyperlipidemia with increased VLDL, treated with fibrates, niacin, or statins.
• Type V ("Endogenous hypertriglyceridemia") has increased VLDL and chylomicrons. Treatment includes niacin and fibrates.

Secondary Hyperlipidemias

• Secondary hyperlipidemias can result from hypothyroidism, nephrotic syndrome, diabetes mellitus (NIDDM), or chronic renal failure.

Classification of Antihyperlipidemic Drugs

• Drug classes vary in mechanism of action, type of lipid reduction, and reduction magnitude.
• Classes include: HMG CoA reductase inhibitors, fibric acid derivatives, bile acid sequestrants, LDL oxidation inhibitors, pyridine derivatives, cholesterol absorption inhibitors, and miscellaneous agents.

HMG-CoA Reductase Inhibitors (Statins)

• HMG-CoA Reductase Inhibitors (statins) are the most effective and best-tolerated drugs.
• Examples include Lovastatin, Pravastatin, Simvastatin, Atorvastatin, Fluvastatin, and Rosuvastatin.

Mechanism of Action

• Statins inhibit HMG-CoA reductase, inhibiting cholesterol biosynthesis and depleting cholesterol in hepatocytes.
• This activates Scap (SREBP cleavage activating protein), stimulating proteolytic cleavage of SREBP and translocation to the nucleus.
• Ultimately, LDL-R expression on hepatocytes increases which decreases hepatic uptake of LDL, reducing plasma LDL by 20-55%.
• Major effect is dose and agent dependent, with a 6% reduction with doubling of dose.

HMG-CoA Reductase

• HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate to start the synthetic pathway of cholesterol.
• Lovastatin was isolated from Aspergillus terreus and Natural statins include Lovastatin (mevacor), Pravastatin (pravachol), and Simvastatin (Zocor).
• Synthetic Statins include Atorvastatin (Lipitor) and Fluvastatin (Lescol).
• Statins competitively inhibit HMG-CoA reductase. Because statins are bulky, they get stuck in the active site preventing the enzyme from binding with its substrate, HMG-CoA.
• Statins decrease VLDL by decreasing hepatic VLDL synthesis, reducing cholesterol, and reducing LDL-C by ~25%.
• In homozygous familial hypercholesterolemia, LDLR is absent.
• If TGs are >250 mg/dL, the % decrease ~ % decrease in LDL-C.
• If TGs are <250 mg/dL, the % decrease in LDL-C generally > with statin use.

Explore hyperlipidemia, its causes, and the role of antihyperlipidemic drugs. Learn about the biochemistry of plasma lipids, including cholesterol, and the impact of lifestyle habits on lipid metabolism. Hyperlipidemia is a disorder in developed countries and a major contributor to coronary heart disease.