Antihyperlipidemic agents

Hyperlipidemia is the most prevalent indicator for.suscep-nbility to atherosclerotic heart disease it is a term u.sed to ilrvribc elevated plasma levels of lipids that are usually in liefonn of lipoproteins. Hyperlipidemia may be caused by 

The various lipoproteins found in plasma can be separated by ultraccntrifugal techniques into chylomicrons, vcry-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). These correlate with the electrophoretic separations of the lipoproteins as follows chylomicrons, pre-/3-lipoprotcin (VLDL). broad )3-lipoprotein (IDL). /3-lipoprotein (LDL). and ar-lipoprotcin (HDL). 

Chylomicrons contain 90% triglycerides by weight and originate from exogenous fat from the diet. They are the least dense of the lipoproteins and migrate the least under the 

The rate at which cholesterol and triglycerides enter the circulation from the liver and small intestine depends on the supply of the lipid and proteins necessary to form the lipoprotein complexes. Although the protein component must he synthesized, the lipids can be obtained either from de novo biosynthesis in the ti.ssucs or from the diet. Reduction of plasma lipids by diet can delay the development of atherosclerosis. Furthermore, the u.sc of drugs that decrease assimilation of lipids into the body plus diet decreases mortality from cardiovascular disca.se.  

Lipid transport mechanisms exist that shuttle cholesterol and triglycerides among the liver, intestine, and other tissues. Normally, plasma lipids, including lipoprotein cholesterol, are cycled into and out of plasma and do not cause extensive accumulation of dcpo.sits in the walls of arteries. Genetic factors and changes in hormone levels affect lipid transport by altering enzyme concentrations and apoprotein content, as well us the number and activity of lipoprotein receptors. This complex relationship makes the treatment of all hyperlipoproteinemias by a singular approach difficult, if not impractical. 

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Nicotinyl alcohol (3-pyridinylcarbinol, 3-pyridinemethanol) (27) has use as an antilipemic and peripheral vasodilator. It is available from either the reductions of nicotinic acid esters or preferably, the reduction of the nitrile to the amine followed by dia2otation and nucleophilic displacement. It is frequently adininistered in the form of the tartrate (Eig. 7). Nicotinic acid is frequently used as a salt in conjunction with basic dmgs such as the peripheral vasodilator xanthinol niacinate (28). Nicotinic acid and its derivatives have widespread use as antihyperlipidemic agents and peripheral vasodilators (1). 

Clastogenic. Giving rise to or inducing disruption or breakages, as of chromosomes. Clofibrate. An antihyperlipidemic agent used to reduce elevated serum lipids when administered orally. 

Some plant-derived drugs come from lower organisms, such as fungi (e.g., the antihyperlipidemic agent lovastatin from Aspergillus terreus and the immunosuppressant cyclosporin from Beauveria nivea) whereas others are obtained from higher plants (see Table 5.3 and Table 5.4). 

Therapeutic uses Niacin lowers plasma levels of both cholesterol and triacylglycerol. Therefore, it is particularly useful in the treatment of Type lib and IV hyperlipoproteinemia, in which both VLDL and LDL are elevated. Niacin is also used to treat other severe hypercholesterolemias, often in combination with other antihyperlipidemic agents (see p. 215). In addition, it is the most potent antihyperlipidemic agent for raising plasma HDL levels. 

These antihyperlipidemic agents inhibit de novo cholesterol synthesis, and deplete the intracellular supply of cholesterol. This prompts the cell to increase the number of specific cell-surface LDL receptors that can bind and internalize circulating LDLs. Thus the end result is a reduction in plasma cholesterol, both by lowered cholesterol synthesis and by increased catabolism of LDL. 

Moss JN, Dajani EZ (1971) Antihyperlipidemic agents. In Turner RA, Hebborn P (eds) Screening Methods in Pharmacology. Vol. II. Academic Press, New York, London, pp 121-143... 

Ezetimibe is an antihyperlipidemic agent that inhibits absorption of cholesterol by the small intestine. It is indicated to be administered alone or with HMG-CoA reductase inhibitors as adjnnctive therapy to diet for reduction of elevated total cholesterol, LDL, and apolipoprotein (Apo) in patients with primary hypercholesterolemia with atorv-astatin or simvastatin for the reduction of elevated total cholesterol and LDL levels in patients with homozygous familial hypercholesterolemia as an adjunct to other lipidlowering treatments or if such treatments are unavailable and as adjnnctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygons familial sitosterolemia. 

Probucol, an antihyperlipidemic agent (500 mg twice daily with meals), is indicated in the reduction of elevated serum... 

Nicotinic acid exerts a variety of effects on lipoprotein metabolism (7,16,49). One of its most important actions is the inhibition of lipolysis in adipose tissue. This initial inhibition, like those of previously discussed antihyperlipidemic agents, produces a sequence of events that ultimately result in the lowering of plasma triglycerides and cholesterol. Impaired lipolysis decreases the mobilization of free fatty acids, thus reducing their plasma levels and their delivery to the liver. In turn, this decreases hepatic triglyceride synthesis and results in a decreased production of VLDL. Enhanced clearance of VLDL through stimulation of lipoprotein lipase also has been proposed to contribute to the reduction of plasma VLDL levels. Because LDL is derived from VLDL (Fig. 30.5), the decreased production of VLDL ultimately leads to a decrease in LDL levels. The sequential nature of this process has been clinically demonstrated. The reduction in triglyceride levels occurs within several hours after ... 

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