Antihyperlipidemics Tomáš Goněc 5.11.2012 Major lipids in blood stream  Cholesterol and its esters  Triglycerides  Phospholipids  Excess of one or more of these fractions = hyperlipidaemia Cholesterol Cholesterol biosynthesis Cholesterol – hepatobiliar circulation Lipoproteins and lipid circulation Hyperlipoproteinaemias  primary – result of genetic mutations / insufficiencies of APO-lipoproteins and their tissue receptors  secondary – result of isufficient biosynthesis of APO-lipoproteins and their tissue receptors Associated with diabetes II, hypothyroidism, renal and liver diseases Diseases and disorders caused by hyperlipoproteinaemias  Coronary heart disease (myocardial infarction, ischemic heart disease, angina pectoris) Role of LDL cholesterol in atherosclerosis Drugs affecting lipoprotein metabolism  bile acid sequestrants  HMGCoA reductase inhibitors  fibrates  niacin and its derivatives  probucol  often used in combination Bile acid sequestrants Bile acid sequestrants – mechanism of action  basic nitrogens binds bile acids and together are excreted in the feces  lower uptake of bile acids leads to increased LDL receptor expression and increased liver uptake of LDL fraction  contraindicated in patients with cholelithiasis or biliary obstruction  minimal side effects – decrease oral absorption of some drugs and lipid soluble vitamins HMGCoA reductase inhibitors HMGCoA reductase inhibitors HMGCoA reductase inhibitors: Structure-activity relationships  Two main structural types A ring: OH in R1 improves specifity methyl in R2 improves activity B ring: 5 or 6 membered heterocycle with nitrogen in W or X orY additional substitution with second phenyl improves activity HMGCoA reductase inhibitors  Lower plasma cholesterol levels  Increase LDL uptake  Reduces VLDL precursors HMGCoA reductase inhibitors  rare but serious adverse effect: rhabdomyolysis (massive muscle necrosis) – life threatening state  clinical monitoring necessary  2001Cerivastatin withdrawn from the market Fibrates Fibrates – structure-activity relationship  essential isobutyric acid group  p-chloro substituted aromatic cycle prolongs biological half-time Fibrates – mechanism of action  not fully elucidated yet  PPARs (peroxyzome proliferator activated receptors) activators  decreases VLDL (significantly)  increases HDL (moderate)  variable effect on LDL Fibrates  serious adverse effects  long-term administration of clofibrate increases morbidity and mortality  all fibrates may cause myopathy and rhabdomyolysis Clofibrate synthesis  Gemfibrozil synthesis Fenofibrate synthesis Nicotinic acid (niacin)  niacin is a nicotinic acid metabolite Nicotinic acid – mechanism of action  NA acts via its specific tissue receptor (NA receptor)  inhibits lipolysis in adipose tissue  decrease all lipid fractions (VLDL, triglycerides and LDL) Nicotinic acid – side effects  often side effects (20 – 50% patients)  flushing and pruritus  gastrointestinal intolerance Nicotinic acid synthesis  Probucol  Unknown mechanism of action  Decrease overall plasma level of cholesterol, primary LDL