Anti-hyperlipidemic Agents

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Topics of Special Interest
Lecture Slides
Handout
Hyperlipidemia
Types of hyperlipidemia
Structure of LDL particles
Mechanism of Lipid Transport
Strategies for treating Hyperlipidemias
Statins
Fibrates
Bile Acid Sequestering Agents
Hyperlipidemia
More than 650,000 people die every year of coronary heart disease (CHD) in the US alone. In 1984 it was demonstrated for the first time that there exists a link between serum cholesterol levels and risk to CHD. A 1% drop in serum cholesterol reduces the risk for CHD by 2%. Positive risk factors for CHD include Age (men>45 yrs, women>55 yrs); family history of premature CHD; smoking; hypertension (>140/90 mm Hg); low HDL cholesterol (<35>30% overweight); diabetes; and high LDL (>160 mg/dl). Negative risk factors include high HDL levels (>60 mg/dl). What is cholesterol? Its structure is The structure suggests a highly non-polar nature indicating that it should be reasonably insoluble in aqueous solution. Thus we expect it to be not soluble in plasma. Yet we see values as high as 250 mg per deciliter which gives an amount of 2.5 g / L in plasma. How does this occur?
This comes about because cholesterol does not occur alone in plasma. It is always associated with lipoproteins. Lipoproteins are proteins carrying lipids. Cholesterol is one of the lipids. Long chain fatty acids are also carried by these lipoproteins in the form of triglycerides (TG). Lipoproteins are actually aggregrates. There are several forms of lipoproteins, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL), and high density lipoproteins (HDL), depending on the density of their packing or alternatively their size. The term hyperlipidemia refers to the excessive lipid content in the blood plasma. A lipid profile of patient's blood plasma is the distribution in concentration of various forms lipoproteins.
The major lipid components of a lipoprotein are :
triglycerides
phospholipids
cholesterol
cholesterol esters
Classification of Lipoproteins
Composition
Density
Size
Chylomicrons
TG >> C, CE
low
large
VLDL
TG > CE
higher than chylomicrons
smaller than chylomicrons
ILDL
CE > TG
higher than VLDL
smaller than VLDL
LDL
CE >> TG
higher than ILDL
smaller than ILDL
HDL
CE > TG
highest
smallest
Mechanism of Lipid Transport
Dietary fat including cholesterol and triglycerides are absorbed in the intestine and released in the blood stream as chylomicrons. These are least dense particles having very high proportion of triacylglycerides. Lipoprotein lipase acts on these particles to release some free fatty acids that deposit in adipose tissues. The remnants of chylomicrons are picked up by the liver which has a receptor specific to chylomicron remnants. After further clean up liver releases particles called the very low density lipoproteins in the blood. These have lower triacyl glycerides than chylomicrons. Once again LPL works on these VLDL particles releasing more free fatty acids and changing the content of the particles to IDL and LDL. There are LDL receptors on the cell membranes of the extrahepatic cells which can pick up the LDL particles. This is how cholesterol reaches the interior of normal cells. Within cells, LDL particles are repackaged. Excess cholesterol is esterified and stored. Excess cholesterol suppresses the biosynthesis of LDL-receptors so that intake of cholesterol decreases. It also suppresses cholesterol biosynthesis. Repackaged LDL particles called HDL particles are then released into the blood stream. These particles are sensed by the liver through the HDL-receptors. Thus the liver gets constant information as to how much LDL and HDL are present in the blood.

Strategies for treating Hyperlipidemias

Statins
Statins inhibit the rate-limiting step in the biosynthesis of cholesterol - HMG -CoA reductase. Decreased cholesterol biosynthesis steps up the levels of the LDL-receptor resulting in the positive cycle for lowered cholesterol levels in serum. For patients who have familial hypercholesterolemia due to defective LDL-receptor genes these drugs are not effective.
Statins are most effective cholesterol lowering drugs. Statins lower total cholesterol and LDL particles. These are competitive inhibitors. The HMG-CoA has a conformation similar to the lactone moiety of statins resulting in binding at the same site without any productive effect.
Similarity in conformation of the active moiety
All statins are highly protein bound (95-98%) except for pravastatin (50%, due to carboxylate moiety). Most statins have a short half-life of about 1-3 hr except for atorvastatin which has a t1/2 of about 14 h. A 15-30 point drop in LDL could be reasonably expected with most statins after a therapy of about 1 month. A combination therapy (with bile acid sequestering agents) is helpful for particularly difficult cases. Although possible, statins typically do not affect the concentrations of steroid hormones in circulation.
Fibrates

Gemfibrozil was introduced in 1981 and remains the second most useful antilipidemic agent. It primarily decreases serum triglycerides. Newer drugs including beclofibrates, ciprofibrates, fenofibrates, are more effective in lowering serum LDL cholesterol. However, the fibrates are almost never used alone. They are mostly used in combination with bile acid sequestering agents.

The antitriglycedemic effect of clofibrate in human is related to the increased catabolism of serum TG-rich proteins (VLDL and VLDL remnants), but not to any effect on hepatic TG or VLDL synthesis and release from liver. The action of clofibrate is related to an increase in adipose tissue or muscle LPL activity which accelerates the rate of intravascular catabolism of VLDL to IDL and LDL.
Clofibrate is metabolized to chlorophenoxyisobutyric acid (CPIB) which is the active form of the drug. The drug is high protein bound with a half-life of around 15 hrs.
Bile Acid Sequestering (BAS) Agents
Colestipol and cholestyramine are anion exchange resins that are approved in 1970s for the reduction of elevated serum cholesterol in patients with hypercholesterolemia. These resins are water insoluble, inert to digestive enzymes in the intestinal tract and are not absorbed. Both resins are quaternized at stomach pH and exchange anions for bile acids dramatically reducing the reabsorption of bile acids. The liver senses that bile acid concentrations have gone down and hence turns on cholesterol metabolism. Serum HDL and TG levels remain unchanged. LDL levels are found to decrease.

The fall in LDL concentration is apparent in 4 to 7 days. The decline in serum cholesterol is usually evident by 1 month. When the resins are discontinued, the serum cholesterol usually returns to baseline within a month. When bile acid secretion is partially blocked, serum bile acid concentration rises. For these patients, cholestyramine reduces bile acid deposits in the dermal tissues. One of greatest advantage of these polymeric agents is that they can be safely used for pregnant women. However, exercise caution for nursing women because presence of these cationic polymeric agents in the GI tract might lower the absorption of vitamin D. BAS agents may also lower the amount of anticoagulants (warfarin, coumadin) absorbed due to sequestration.
Nicotinic Acid
Pharmacologic doses of nicotinic acid reduce serum cholesterol and TG levels in types II, III, IV, and V hyperlipoproteinemias. TG and VLDL are reduced by 20 to 40% in 1 to 4 days, LDL reduction may be seen in 5-7 days. The decrease in LDL is usually greater if niacin is used with a BAS resin. HDL is increased by 20%. The exact mechanism is unknown. It is known that niacin decreases lipolysis in adipose tissue, decreases TG esterification in the liver and increase LPL activity. Niacin is rapidly absorbed.
Nicotinic Acid (Niacin)