Drugs used for the treatment of Hyperlipidemia are called Antihyperlipidemic. The aim of the treatment is to lower the concentration of VLDL and LDL and raise HDL.
1. Antihyperlipidemic Drugs which Primarily Reduce Plasma Triglycerides
i. Nicotinic acid (niacin, B3): It is a water soluble vitamin. It lowers plasma triglyceride levels. Vitamin B3 reduces the levels of circulating FFAs by strongly inhibiting lipolysis in adipose tissue. It acts by inhibiting the hepatic triglyceride production and VLDL secretion due to decreased supply of FFAs which act as a major precursor for triglyceride.
So this antihyperlipidemic reduces LDL levels indirectly because it is derived from VLDL in plasma. HDL is increased modestly. It stimulates secretion of tissue plasminogen activator and lowers plasma fibrinogen. Due to this, it reverses some of the hypercholesterolaemic associated endothelial cell dysfunction contributing to thrombosis.
It is contra- indicated in pregnancy. Important side effects of this antihyperlipidemic agent are flushing, dizziness and palpitation. It is used to treat several types of hyperlipidaemias in combination with a bile acid-binding resin (colestipol or chloestyramine).
In hypercholesterolaemia, it has been given in combination with lovastatin or neomycin. The usual dosage of nicotinic acid is 2—8 g daily.
ii. Fibric acid derivatives (fibrates): Fibrates include clofibrate, gemfibrozil, benzafibrate and fenofibrate.
These antihyperlipidemic lower the plasma concentrations of cholesterol and triglyceride. These drugs have marked effect in lowering the VLDL, and hence triglycerides, with a modest (approximately 10%) reduction in LDL and an approximately 10% increase in HDL These drugs act:
• By stimulating lipase (LPA) activity due to activation of a nuclear receptor (transcription factor) termed peroxisomal proliferation activated receptor factor (PPAR-u).
• By stimulating hydrolysis of triglycerides in the plasma.
• By reducing the incorporation of fatty acids into VLDL in the liver. So they inhibit the synthesis and secretion of VLDL.
The fibrates are Antihyperlipidemic drugs that are absorbed orally, partly metabolized in the liver and excreted in urine. They are contraindicated in the presence of severe hepatic or renal dysfunctions, and in pregnant woman. Side effects are relatively low and mild. Nausea, diarrhoea, abdominal discomfort, skin rash and impotence are reported.
They are used in hyperlipidaemias. Fenofibrate also has uricosuric effect. So it is used where hyperuricaemia coexists with hyperlipidaemia.
iii. Guggulipid: It is a mixture of sterones. It is obtained from an ayurvedic herb Coinmiphora mukul. It is a useful drug for the treatment of mild hyperlipidaemia, atherosclerosis, and obesity. It decreases cholesterol biosynthesis and also increases excretion of it through the gut.
This antihyperlipidemic agent also stimulates thyroid activity and reduces platelet aggregation. Although it is claimed to be free from toxicity, special precaution, however, is needed while using in patients with hepatic disease, dysentery or diarrhoea.
iv. Omega-3 marine triglycerides: These are derived from some marine fish oils. They may induce profound lowering of plasma triglycerides, but increase plasma cholesterol.
2. Antihyperlipidemic Drugs which Primarily Reduce Plasma Cholesterol
i. Anion-exchange resins (colestipol, and cholestyramine): These are quarternary ammonium ion-exchange resins. They are insoluble in water and have a very high molecular weight. One gram of this antihyperlipidemic drug can bind about 100 mg of bile salts. They enhance the excretion of bile salts in the faeces by sequestering bile acids in the intestine and preventing their reabsorption and entrohepatic circulation.
So there occurs decreased absorption of exogenous cholesterol and increased metabolism of endogenous into bile acids in the liver. This leads to increased expression of LDL receptors on the liver cells and increased removal of LDL from blood to liver. They are, therefore, mainly useful when high blood cholesterol is due to raised LDL concentration.
They are neither absorbed nor metabolized in liver. Important side effects of these antihyperlipidemic agents are nausea, abdominal discomfort, indigestion and constipation. They may interfere with the absorption of fat soluble vitamins A, D, E, and K from the intestine.
These antihyperlipidemic may also interfere with the absorption of several drugs. So other drugs may be taken 1 hour before or 4 hours after the administration of these drugs. These drugs are used for treating hypercholesterolaemia.
ii. Neomycin: It is an aminoglycoside antibiotic which is poorly absorbed from gut. It inhibits re-absorption of cholesterol and bile acids. It is not a safe antihyperlipidemic drug because intestinal sterilization may give rise to super-infection and gastrointestinal symptomê.
iii. Plant sterols: Betasitosterol and a new synthetic drug ezetimibe block uptake of cholesterol in the intestine by competition for its absorption sites, without themselves getting absorbed. Due to this, they reduce total cholesterol, LDL, triglycerides and APO-B while increase HDL. They are used to treat familial hypercholesterolaemia, familial combined hyperlipidaemia and hyperlipoproteinaemias.
iv. Cholesterol synthesis inhibitors (statins):
The important members of this group of antihyperlipidemic are atorvastatin, lovastatin, mevastatin, simvastatin, pravastatin, fluvastatin and rosuvastatin.
Cholesterol is synthesized in liver from mevalonic acid. Statins act by competitively inhibiting the conversion of acetyl coenzyme-A to mevalonic acid by HMGCoA reductase enzyme. So there occurs depletion of hepatic intracellular supply of cholesterol which is compensated by liver by increasing the uptake of plasma LDL by increasing number of LDL receptors.
Due to this, plasma LDL level is decreased. Statins also produce a moderate lowering of triglycerides level due to reduction of VIDL secretion by the liver and increased uptake of IDL and VLDL remnants by LDL receptors. However, there occurs slight increase in HDL.
One of the limiting factors in the use of Statins is diminished effect after prolonged use even with increased dosages. This ceiling-dose effect is due to “feedback compensatory induction” of HMG-CoA reductase enzyme which tends to increase cholesterol biosynthesis.
Different statins differ in their potency. Plasma half-lives of these drugs range from 1—3 hours, except for atorvastatin (14 hrs.) and rosuvastatin (19 hrs.). So with the exception of these two antihyperlipidemic drugs, other HMGCoA reductase inhibitors are administered at night because cholesterol biosynthesis takes place predominantly at night.
They are used to treat elevated plasma low density lipoproteins and cholesterol in familial or multi-factorial hypercholesterolaemia or combined familial hyperlipidaemia either alone or in combination with niacin or bile-acid-binding resins.
Recently, it has been suggested that statins may lower the risk of stroke, dementia, Alzheimer’s disease and may improve bone density in postmenopausal women.
These antihyperlipidemic drugs may cause hepatotoxicity, myositis and lenticular opacity. They are contraindicated in pregnancy, lactation, children and liver diseases.
v. Probucol: It causes a moderate fall in plasma cholesterol levels. It probably acts by inhibiting sterol synthesis and improves transport of it from the periphery to liver. At present, it is no more used as an antihyperlipidemic drug because it reduces HDL levels and LDL levels only marginally.
It also has antioxidant action and has been shown to inhibit atherogenesis because it directly prevents the oxidation of LDL. It, thus, exerts an antiatherogenic effect because macrophages consume LDL in oxidized form.
Important side effects are nausea, vomiting, flatulence, diarrhoea, abdominal pain. Rarely angioneurotic oedema and hypersensitivity reactions are reported. This antihyperlipidemic agent is given in a dose of 500 mg twice daily with food.
Combination Antihyperlipidemic Drug Therapy
It is very useful in the treatment of severe hyperlipoproteinemia (HLP) and familial hypercholesterolaemia (F-HC) in whom satisfactory plasma levels of LDL-C are not achieved with single drug.