The Antihyperlipidemic Medications l Classifications of Lipoproteins – Chylomicrons l Formed in the mucosal cells of the gut l Protein coated dietary lipids

l Carried in the blood to fat depots and transported across the vasculature with the help of Capillary-Bound LPL l Chylomicron remnants goes back to the liver to be used to synthesize TGs

l Very Low Density Lipoproteins (VLDL) – Triglyceride rich particle – Made in the liver – VLDL is the transport form for TGs made in the liver going to the periphery

l Cholesterol containing particle l LPL transports TGs into fat depots l Remainder is a cholesterol rich particle now called LDL

l Low Density Lipoprotein (LDL) l Contains the major portion of the plasma cholesterol l Associated with a higher risk for CAD

l In the liver LDL is recycled for its cholesterol content l LDL in the liver acts to regulate liver uptake of additional LDL

l High Density Lipoprotein (HDL) l These particles scavenge cholesterol from the peripheral vessels l Carries cholesterol back to the liver to be used for steroid synthesis, hormone synthesis or the making of bile salts

l Types of hyperlipoproteinemias l Type I - Idiopathic Familial Variety – Decreased VLDL, LDL, & HDL – Elevated TGs, Chylomicrons & cholesterol

l Type IIa - Essential Familial Variety l Elevated LDL, TGs & Cholesterol

l Type IIb - Familial Combined Variety l Elevated LDL & VLDL

l Type IV - Endogenous Hypertriglyceridemia l Elevated VLDL, TGs, & Cholesterol l Early CAD l Positive family history for an MI

The Antihyperlipidemic Drugs l HMG-CoA Reductase Inhibitors l The Fibric Acids l Bile Acid Binding Resins l Nicotinic Acid

HMG-CoA Reductase Inhibitors l Lovastatin (Mevacor) l Simvastatin (Zocor) l Mevastatin (Compactin) l Pravastatin

Mechanism Of Action l HMG-CoA Reductase Inhibitors l Blocks the synthesis of cholesterol in the liver by inhibiting the rate limiting enzyme called HMG-CoA Reductase

l There is a compensatory drop in plasma LDL due to the up- regulation of the LDL receptor and enhanced clearance of LDL from the plasma

l These medications may lower the cholesterol content of the VLDL particle such that when VLDL disposes of its TGs becoming LDL, there is an enhanced attraction for the cholesterol poor LDL particle and its receptor - greater LDL clearance

Adverse Side Effects l Flatulence & Diarrhea l Dyspepsia (Indigestion) l Headaches l Elevations of the liver enzymes - CPK, LDH, and AST - due to hepatotoxicity

Medical Uses l To treat hypercholesterolemia (>250 mg/dl) l Patients with elevated LDL, VLDL & TGs

The Fibric Acids l Gemfibrozil (Lopid) l Clofibrate (Atromide-S)

Mechanisms of Action l Decrease TG synthesis l Decrease liver lipoprotein synthesis l Decrease the excretion of lipoproteins from the liver, especially VLDL

l Decrease the synthesis of cholesterol l Increase the production of sterols l Increases the blood levels of HDL

Medical Uses l Lower cholesterol l Lower serum triglycerides l Lower VLDL levels l Lower LDL levels l These drugs are cardioprotective

Adverse Side Effects l GI distress - diarrhea, nausea, vomiting l Alopecia - loss of hair l lower testosterone levels and impotence

l Gall stone formation l Hepatotoxic - liver enzymes - LDH, CPK, & AST

Bile Acid Binding Resins l Cholestyramine (Questran) l Colestipol (Colestid)

Mechanism of Action l Bind bile salts in the gut l Bile Acid Binding Resins are not absorbed across the gut into the blood - bile and cholesterol are irreversibly bound in the gut and disposed of in the feces

l The net effect - causes the liver to scavenge more cholesterol from the body to make additional bile salts l Liver up-regulates the LDL receptors clearing more LDL from the blood

Adverse Side Effects l Nausea, Vomiting l Indigestion l Flatulence l Constipation l Binds to other medications

Nicotinic Acid l Mechanism of Action l Inhibits the liver from secreting VLDL l Reduces the blood levels of LDL

l Inhibits the destruction of HDL thus allowing a permissive rise in HDL l Niacin increases the excretion of sterols in the feces thus using up more cholesterol

Adverse Side Effects l Flushing l Vomiting l Nausea l Dyspepsia l Flatulence

Medical Uses l To reduce VLDL l To reduce LDL l To increase HDL l Given to most hyperlipidemics