Medical Pharmacology Topics   

Preliminary Outline

Lipid-Lowering Drugs   Bile-Binding Resins          Cholestyramine          Cholestipol   HMG-CoA Reductase      Inhibitors (Statins)          Lovastatin          Simvistatin          Pravastatin          Atorvastatin          Fluvastatin   Fibric Acids          Clofibrate          Gemfibrozil          Bezafibrate    Herbal Remedies          Psyllium          Garlic   Other          Nicotinic Acid          Probucol

Lipid-Lowering Drugs

Lipid-lowering drugs may be classified as bile-binding, HMG-CoA reductase inhibitors, fibric acids and herbal remedies. In addition, nicotinic acid and probucol are lipid-lowering drugs. HMG-CoA reductase inhibitors are the usually the first choice for most patients.

Resins like cholestyramine and cholestipol bind anionic bile acids in the intestinal lumen. They block 95% of bile reabsorption and cause a ten-fold increase in the bile synthesis rate. The increased cholesterol demand promotes an increase in hepatic LDL receptors.

Resins are useful only when LDL is elevated and are contraindicated in first-degree hypertriglycerimias without elevated LDL. Adverse effects may include constipation and bloating or diarrhea, and impaired absorption of other drugs (digitalis, warfarin, thyroxin, etc., may be taken 1-3 hrs before resin).

Competitive inhibitors of HMG-CoA reductase, like lovastatin, simvistatin, pravastatin, atorvastatin and fluvastatin, reduce the biosynthesis of cholesterol. They reduce LDL levels by increasing hepatic uptake of LDL and its precursors (VLDL and remnants). These lead to a modest increase in triglycerides and decreased HDL. Statins have been shown to reduce the incidence of recurrent myocardial infraction and total mortality. They have a treatment failure of only 15% (compared to 35% for resins).

Lovastatin and simvistatin are prodrugs hydrolyzed in the GI. All "statins" have a high first-pass extraction rate, which accounts for their high efficacy in the liver. Minor side effects include headache, GI disturbances, rash, muscle cramps and insomnia. Major side effects include  reversible myopathy (muscle pain/weakness, 1%), lupus-like syndrome, neuropathy and hepatic dysfunction.  If severe, statin-induced myopathy may lead to rhabdomyolysis (muscle breakdown) and renal failure. Statin-induced hepatic dysfunction manifests as up to three-fold elevation of transaminase levels. Long-term effects of statins are unknown.

The nicotinic acid component of niacin (but not nicotinamine) was the only cholesterol lowering drug shown to reduce the incidence of recurrent myocardial infraction and total mortality before statins were introduced. Nicotinic acid probably inhibits hepatic secretion of VLDL, which in turn decreases the production of LDL. It also increases the clearance of VLDL in adipose tissue by enhancing lipoprotein lipase activity. 

Overall, nicotinic acid reduces VLDL and LDL, and increases HDL, more than any other drug. Dosage is about 20 mg/day when taken as a vitamin, vs. 1.5-6 g/day when taken as a drug. Adverse effects include facial flushing, nausea, vomiting, diarrhea, peptic ulcer, hepatotoxicity, headache and orthostatic hypotension.

Fibric acid derivatives like clofibrate, gemfibrozil and bezafibrate increase lipoprotein lipase activity, especially in skeletal muscle. They decrease VLDLsynthesis, increase HDL levels, decrease triglyceride levels, and may increase or decrease LDL.

Fibric acids are eliminated by glucuronide conjugation in the liver. Adverse effects are not as severe as for statins or nicotinic acid and include upset GI, urticaria, hair loss, impotence and headache. The incidence of myopathy increases to 5% when combined with a statin. Fibric acids interact with anticoagulants and are contraindicated in hepatic and renal failure.

The use of probucol to lower cholesterol almost obsolete. It is not a first line agent because of erratic absorption and performance. Its use is primarily limited to patients with homozygous familial hypercholesterolemia. This is the only drug that lowers cholesterol and causes regression of xanthomas in these patients. Probucol reduces LDL by 15-20%. It also reduces HDL and cholesterol synthesis. It is generally well tolerated but may cause GI disturbances and ventricular dysrhythmias.

Garlic and psyllium are herbal remedies that lower cholesterol. Psyllium (or plantago) seed has bulk-forming properties (laxative) and causes a modest fall in serum cholesterol and triglycerides probably by binding bile acids.

Garlic may reduce LDL cholesterol as much as dietary modification. The active agent in garlic responsible for lowering cholesterol is alliin, which also gives its characteristic odor. Alliin is a prodrug and must be converted by allinase to the active allicin in the intestine <need to verify this>. The recommended dose  is 0.5 -1 clove two or three times a day. Powdered garlic in enteric-coated capsules are recommended (600-900 mg standardized to 0.6-1.3% allicin) so they will dissolve in the intestine. Garlic may interact with anticoagulant and antiplatelet drugs. Overall, garlic is mildly effective, not a suitable substitute for conventional medications but possibly in combination with them.

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