Dyslipidaemia and lipid-lowering drugs

15 Dyslipidaemia and lipid-lowering drugs





Questions



image Why are dyslipidaemias a health risk?

image What drugs are used in the treatment of dyslipidaemia?


Physiology of lipoproteins


The metabolism of lipoproteins is complex (Fig. 3.15.1) and alterations in lipid metabolism can result in dyslipidaemias characterized by elevated levels of low density lipoprotein (LDL) and reduced levels of high density lipoprotein (HDL). Physiologically, HDL plays a ‘protective’ role against atherosclerotic disease in the sense that it lacks class B and E lipoproteins needed for LDL particle uptake by extrahepatic tissue and it has a role in ‘reverse cholesterol transport’ from extrahepatic tissue to the liver. Alterations in the levels of lipoproteins predispose individuals to the formation of atherosclerotic plaques, resulting in coronary artery disease. A variety of factors including a poor diet, lack of exercise and genetic predisposition (e.g. type IIa dyslipidaemia or familial hypercholesterolaemia caused by a defect in the LDL receptor) result in high plasma cholesterol levels and cardiovascular disease.


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Fig. 3.15.1 Metabolism of lipoproteins. 1. Cholesterol and free fatty acids (FFA) are absorbed from the small intestine with the aid of bile acids and form chylomicrons. 2. Lipoprotein lipase on the capillary epithelium of skeletal muscle and adipocytes removes FFAs. 3. The chylomicron remnant is absorbed by the liver via the low density lipoprotein (LDL) receptor and cholesterol is utilized in the formation of bile acids and steroid precursors. 4. Surplus cholesterol is transported to peripheral cells as very low density lipoproteins (VLDL). 5. Cholesterol is carried away from the tissues to the liver as high density lipoproteins (HDL).



Treatment of high cholesterol and triacylglycerols


There are three major drug classes used to reduce circulating cholesterol and triacylglycerols (triglycerides): those that inhibit cholesterol absorption (bile acid-binding resins), those reducing its synthesis (statins) and those promoting its metabolism (fibrates) (Fig. 3.15.2).


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Fig. 3.15.2 Treatment of hypercholesterolaemia. 1. Bile acid-binding resins reduce enterohepatic recycling of bile acids, leading to a compensatory increase in bile acid synthesis from cholesterol. The negative feedback effect of cholesterol on HMG-CoA reductase and on expression of LDL receptor is reduced and leads to increased uptake of LDL from plasma. 2. Statins are competitive reversible inhibitors of HMG-CoA reductase and so reduce cholesterol synthesis in the liver. This again reduces plasma LDL. They also have other useful non-lipid roles (see text). 3. Fibrates modify the transcription of genes involved in lipid metabolism, increasing the activity of lipoprotein lipase in extrahepatic tissue, promoting uptake of triacylglycerol-rich VLDL and chylomicrons into target tissues, thereby reducing plasma triacylglycerols, and reducing VLDL synthesis in the liver. 4. Nicotinic acid inhibits hormone-sensitive lipase in adipose tissue, reduces triacylglycerol synthesis in the liver and formation of VLDL. CEPT, cholesteryl ester transfer protein.

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Jul 18, 2016 | Posted by in PHARMACY | Comments Off on Dyslipidaemia and lipid-lowering drugs

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