Medical Pharmacology Topics   

GI Pharmacology: Lipid Lowering Drugs

Lipids absorbed in the intestine are packaged into lipoprotein particles called chylomicrons for delivery to tissue. The remanants of chylomicrons are taken up by the liver, which then repackage lipids into very low density lipoporoteins (VLDL) for delivery to tissues. The particles comig from tisue are intermediate density lipoproteins (IDL) and may become low density lipoporoteins (LDL). IDLs anmd LDLs are taken up by the liver. LDLs are also taken up by extrahepatic tisues, where they are conbverted into high density lipoproteins (HDL). HDL particles are made up mostly of cholesterol. In plasma, HDL particles are converted to IDL.

Lipid lowering drugs may be bile acid-binding resins, inhibitors of HMG-CoA reductase, nicotinic acid, fibric acids, probucol and the herbal remedies. Lipid-lowering drugs increase long-term survival for atients with inherited syndromes involving extreme elevation of plasma lipids and the generalpopulation with mildly elevated lipids.

HMG-CoA Reductase Inhibitors

HMG-CoA Reductase catalyzes the rate-limiting step in cholesterol synthesis. Drugs like lovastatin, simvasatin and other "statins" are competitive inhibitors of HMG-CoA reductase, leading to reduced production of mevalonic acid and ultimately cholesterol. They are the first choice for most patients.

Lovastatin and simvastatin are prodrugs hydrolized in the GI tract to active metabolites. Atorvastatin, prevastatin and fluvastatin are administered as the active drugs. All the statins have a high first-pass extraction, which accouts for their high efficacy in liver. They reduce LDL levels by increasing hepatic uptake of LDL and LDL precursors (VLDL remanants), induce modest increases in triacyglycerides and decrease HDL. Statins have been shown to reduce the incidence of recurrent MI and total mortality.

Some major side effects caused by the statins are myopathy, a lupus-like syndrome, neuropathy and hepatic dysfunction (up to 3-fold elevation of transaminase).The myopathy is reversible but if severe poses a risk of rhabdomyolysis and renal failure. Minor side effects include headache, GI disturbances, rash, muscle cramps and insominia.

Nicotinic Acid

Until statins were available, nicotinic acid (niacin) was the only lipid-lowering drug to reduce the incidence of recurrent MI and total mortality. It probably inhibits hepatic secretion of VLDL, thus decreasing production of LDL, and increasing the clerarance of VLDL in adipose tissue by enhancing the activity of lipoprotein lipase. Overall, nicotinic acid reduces VLDL and LDL, and increases HDL, more than any other drug. It has no effect on net synthesis of cholesterol or excretion of bile acids.

As a vitamin, niacin is needed at about 20 mg/day, while the lipid-lowering dose is between 1,5-6.0 g/day. It has a short half-life, thus requent dosing is needed. Advrese effects may cause up to 40% of patients to discontinue the drug, and include facial flushing, nausea, vomiting, diarrhea, peptic ulcer, hepatic toxicity and orthostatic hypotension.

Bile Acid-Binding Resins

Cholestyramine and colestipol bind anionic bile acids in the intestinal lumen, preventing their reabsorption up to 95%. Since bile acids are synthesized from cholesterol, these agents will decrease circulaiting HDL levels by increasing cholesterol demand for bile synthesis. Bile acid-binding resins cause a 10-fold increase in the synthesis of bile acids from cholesterol. They also increase the amount of LDL receptors in the liver, thus increasing uptake of LDL and IDL from plasma.

Bile acid-binding resins are useful only when LDL is elevated and are contraindicated in 1st degree hypertriglycemias without elevated LDL. Adverse side effects include constipation, bloating, diarrhea and impaired absorption of other drugs (digitalis, warfarin, thyroxine, others). Other medications can be taken 1 our before or 3 hours after the resin to prevent malabsorption.

Other Agents

Fibric acid derivatives like clofibrate, gemfibrozil and bezafibrate increase the activity of lipoprotein lipase, especially in skeletal muscle, and decrease the synthesis of VLDL. Overall, they decrease VLDL, increase HDL, decrease triacylglycerides, and may increase or decrease LDL. They are eliminated as glucuronides by the liver. The incidence of side effects is high but not severe enough to affect compliance: GI disturbances, hair loss, impotense and headache. Myopathy may occur especially when combined with a statin. Fibric acid derivatives are contraindicated in hepatic and renal failure.

Probucol is not a first-line lipid-lowering agent because of its erratic absorption and performance. It is used primarily in patients with homozygous familial hypercholesterolemia. In such patients, probucol is the only rug that lowers cholesterol and causes regression of xanthomas. It reduces LDL cholesterol by 15-20%. It also reduces HDL and cholesterol synthesis. It is generally well tolerated but may cause GI disturbances and ventricular dysrrhythmias.

Garlic and psyllum are herbal remedies effective in the treatment of high cholesterol. Psyllum (plantago) seed is a bulk-forming laxative that causes modest decreases in serum cholesterol and triacylglycerols, probably by binding bile acids.

Garlic may reduce LDL as much as dietary modification, and although not suitable for conventional medication may be beneficial in combination with other medications. The active ingredient in garlic is allicin, an odiferous chemical biosynthesized from alliin by allinase. The usual dosage is 0.5-1 clove of garlic twice or three times per day, or 600-900 mg powdered garlic (enteric coated) standarized to 1.3% alliin or 0.6 allicin. Garlic may interact with anticouagulant and antiplatelet drugs by augmenting their effect.

Combination therapy can be used when bile acid-binding resins fail to normalize LDL, when both VLDL and LDL are elevated, or when VLDL increases during resin therapy. Effective combinations are niacin plus resin, niacin plus statin, resin plus statin, niacin plus resin and statin, or niacin plus gemfibrozil. The combination of niacin plus resin is the first chopice against heterozygous familial hypercholesterolemia, whith the advantage that the acid-neutralizing properties of the resin oposes the GI disturbances due to niacin. A maximum effectiveness is obtained by combining niacin plus resin and statin. Although the combination of niacin plus genfibrozil is effective, iy may increase the incidence of gall stones.

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