Antihyperlipidemic+Agents



=**Overview**= =Antilipemics=


 * History:** The first lipid-lowering agent, cholestyramine, was approved in 1964. Clofibrate and dextrothyroxine were released in 1967, followed by colestipol and probucol in 1977. Lovastatin, the first HMG-CoA reductase inhibitor, was approved in 1987. Since then, several other HMG-CoA reductase inhibitors have been made available. This class of antilipemic drugs has proved to be the most effective therapy for primary hypercholesterolemia, although these drugs are less effective for hypertriglyceridemia. In July, 1995, the FDA acknowledged that simvastatin, a HMG-CoA-reductase inhibitor, was effective to reduce the risk of sustaining a myocardial infarction in selected patients. The first combination antilipemic agent, niacin; lovastatin (Advicor™), was approved by the FDA in December 2001. In addition, the first generic HMG-CoA-reductase inhibitor (lovastatin) received final approved in December 2001.


 * Antilipemic agents can be subdivided** into **bile acid sequesterants** (cholestyramine, colestipol); **HMG-CoA reductase inhibitors** (fluvastatin, lovastatin, pravastatin, simvastatin); **fibric acid derivatives** (clofibrate, gemfibrozil); and **miscellaneous agents** (dextrothyroxine, nicotinic acid, probucol).

The National Cholesterol Education Program (NCEP) issues guidelines periodically which details the current goals in practice for cholesterol-lowering strategies.


 * Mechanism of Action:** Vascular endothelium plays an active role in determining vascular function. Vascular endothelium is known to release paracrine factors such as nitric oxide, that can affect vascular tone, and thromboxane, a prostaglandin that can stimulate platelet aggregation. LDL cholesterol, and, particularly, oxidized modification of LDL cholesterol by endothelial tissue, is thought to be an important step in the atherosclerosis process. A relationship between elevated plasma lipids and coronary artery dysfunction has been noted. Oxidized LDL cholesterol can impair endothelium-mediated arterial relaxation. Loss of endothelium-mediated vasodilation is thought to be involved in the pathogenesis of coronary ischemia. Several studies have demonstrated a relationship between elevated plasma lipids and reactivity of coronary arteries to acetylcholine-induced vasoconstriction.

**Hyperlipidemia** (or more appropriately hyperlipoproteinemia) is defined as an increase in plasma lipoproteins which lead to elevations in cholesterol and/or triglycerides. Increases in plasma lipid levels are associated with increased risk of atherosclerosis and heart attack and can be caused by genetic factors (e.g. genetic reduction in LDL receptors), disease (hypothyroidism), and certain types of drugs (e.g. diluting segment and loop diuretics). [|**Learn more about hyperlipidemias**]**.** **LIPOPROTEIN** none intense cutaneous flushing, GI distress, hyperuricemia GI distress, myositis, cholelithiasis and cholecystitis "bad" **cholesterol** - transports chole- sterol out to cells where it's used to make membranes, hormones, etc... GI distress, headache, myositis. Consequences of inhibiting synthesis? constipation, decreased absorption of some vitamins and drugs intense cutaneous flushing, GI distress, hyperuricemia "good" **cholesterol** - (transports chole- sterol back to the liver) none - but increased levels (which reduce the risk of heart attack) are associated with the use of statins, niacin)
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 * Treatment is directed towards reducing plasma lipids by:**
 * 1) decreasing production (e.g. the "statins" which inhibit cholesterol synthesis)
 * 2) //increasing degradation// (e.g. fibric acid derivatives which increase the activity of lipoprotein lipase
 * 3) //increasing removal// (e.g. bile sequestering agents which prevent the recycling of bile (bile is composed of cholesterol breakdown products) |||| ||
 * Requirements for therapeutic intervention**
 * 1) identification of the lipoprotein(s) causing the hyperlipidemias - this determines which (if any) drug can be used for treatment.
 * 2) //some hyperlipidemias can only be treated by altering dietary intake of fat// (e.g. hypertriglyceridemias associated with elevated chylomicrons)
 * 3) //most hyperlipidemias can be reduced by a strict diet// (this should be tried before adding drugs to a therapeutic regimen)
 * 4) //diet should always be combined with drug therapy//
 * 5) be certain that the hyperlipidemia is a direct result of altered lipid metabolism some hyperlipidemias are secondary to diseases and the use of certain drugs. || ||
 * 1) identification of the lipoprotein(s) causing the hyperlipidemias - this determines which (if any) drug can be used for treatment.
 * 2) //some hyperlipidemias can only be treated by altering dietary intake of fat// (e.g. hypertriglyceridemias associated with elevated chylomicrons)
 * 3) //most hyperlipidemias can be reduced by a strict diet// (this should be tried before adding drugs to a therapeutic regimen)
 * 4) //diet should always be combined with drug therapy//
 * 5) be certain that the hyperlipidemia is a direct result of altered lipid metabolism some hyperlipidemias are secondary to diseases and the use of certain drugs. || ||
 * LIPID CARRIED**
 * DRUG TREATMENT**
 * SIDE EFFECTS**
 * chylomicrons**
 * triglycerides** of dietary origin
 * SIDE EFFECTS**
 * chylomicrons**
 * triglycerides** of dietary origin
 * triglycerides** of dietary origin
 * triglycerides** of dietary origin
 * very low density lipo- proteins (VLDLs)**
 * triglycerides** syn- thesized in the liver
 * niacin** - reduces lipolysis in adipose tissue, reduces VLDL-TG synthesis in liver (hours), and LDL-cholesterol (days)
 * fibric acid derivatives** [e.g. gemfibrozil (LOPID)] inceases activity of lipo- protein lipase
 * niacin** - reduces lipolysis in adipose tissue, reduces VLDL-TG synthesis in liver (hours), and LDL-cholesterol (days)
 * fibric acid derivatives** [e.g. gemfibrozil (LOPID)] inceases activity of lipo- protein lipase
 * fibric acid derivatives** [e.g. gemfibrozil (LOPID)] inceases activity of lipo- protein lipase
 * low density lipoproteins (LDLs)**
 * low density lipoproteins (LDLs)**
 * the "statins"** (e.g. levostatin -MEVACOR) - inhibit the synthesis of cholesterol
 * bile sequestering agents** (e.g. cholestyramine -QUESTRAN) which prevent bile recycling
 * niacin** - reduces lipolysis in adipose tissue, reduces VLDL-TG synthesis in liver (hours), and LDL-cholesterol (days)
 * niacin** - reduces lipolysis in adipose tissue, reduces VLDL-TG synthesis in liver (hours), and LDL-cholesterol (days)
 * high density lipoproteins (HDLs)**
 * high density lipoproteins (HDLs)**


 * HMG-CoA reductase inhibitors** compete with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme. Interference with this enzyme's activity reduces the quantity of mevalonic acid, a precursor of cholesterol. This process occurs within the hepatocyte and is one of two mechanisms that generate cholesterol. Cholesterol also can be taken up from LDL by endocytosis. Because //de novo// synthesis of cholesterol is impaired by HMG-CoA reductase inhibitors, cholesterol uptake from LDL is augmented.

Lovastatin has been shown to attenuate acetylcholine-induced coronary artery vasoconstriction[622] and this action appeared to be potentiated by probucol, an antilipemic with proposed antioxidant properties.[623] Since it is possible that coronary arteries containing atherosclerotic plaques impair vasodilatory responses, it is thought that lowering LDL cholesterol with HMG-CoA reductase inhibitors could stabilize the atherosclerotic plaque, thereby preventing ischemia due to vasoconstriction. Pravastatin has been shown to reduce the incidence of coronary vasculopathy and reduce the incidence of rejection causing hemodynamic compromise in cardiac transplantation, entertaining the possibility that HMG-CoA reductase inhibitors possess an immunologic action


 * Bile acid sequesterants**, such as cholestyramine and colestipol, form chemical complexes with bile acids as they undergo enterohepatic recirculation, thereby removing them. Thus, these agents act mainly within the lumen of the GI tract.

The mechanism of action of the **fibric acid derivatives** is unclear. The primary action appears to be related to an increase in the activity of lipoprotein lipase, but these drugs also might decrease the hepatic synthesis and secretion of VLDL.

The exact mechanism of dextrothyroxine's action is unknown, but catabolism and biliary excretion of cholesterol is accelerated. The predominant effect is exerted on LDL. Although a compensatory increase in LDL synthesis occurs, the breakdown of LDL is increased more than synthesis is stimulated.

The mechanism of **niacin's antilipemic effect is also unknown** but is unrelated to its biochemical role as a vitamin. Several mechanisms have been proposed including decreased hepatic synthesis of LDL and VLDL, inhibition of free fatty acid release from adipose tissue, and inhibition of lipolysis. This last mechanism could be due to niacin's inhibitory action on lipolytic hormones.


 * Probucol** may inhibit the transport of cholesterol from the intestine and may interfere with the conversion of acetate to mevalonic acid, an early stage in cholesterol synthesis. It is known not to affect the later stages of cholesterol synthesis. Probucol also might increase the fecal excretion of cholesterol and bile acids via the bile. High serum cholesterol concentrations are reduced by the drug, but its effects on high serum triglyceride concentrations are variable. It decreases both low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol concentrations but has little effect on very low-density lipoprotein (VLDL) cholesterol. //In vitro// and animal studies suggest that probucol may also possess antioxidant properties.


 * Distinguishing Features:** Because bile acid sequesterants, such as cholestyramine and colestipol, act within the lumen of the GI tract, these agents are preferred for use during pregnancy.

Lovastatin and simvastatin are inactive prodrugs, while pravastatin is administered as an active product. Peripheral distribution of lovastatin and simvastatin is limited, leading some researchers to propose that these two HMG-CoA reductase inhibitors are more hepatoselective, although this point is controversial. For the same reason, it is proposed that lovastatin and simvastatin should produce fewer or less severe adverse reactions.


 * Dextrothyroxine** sodium is the sodium salt of thyroxine, the principal secretion of the thyroid gland. Unlike levothyroxine, however, dextrothyroxine possesses minimal thyroid hormone effects. Any thyroid hormone effects from dextrothyroxine are likely attributable to contamination from levothyroxine. Nevertheless, to minimize the risk of cardiac stimulation, some clinicians reserve dextrothyroxine for use only in younger patients.


 * Adverse Reactions:** For drugs that must be consumed chronically, adverse reactions become a major cause of non-compliance. Niacin is known to cause hepatotoxicity when administered in sustained-release forms and, in doses used for the treatment of hyperlipidemia, also causes cutaneous vasodilation, which many patients find uncomfortable. Although bile acid sequesterants are not absorbed and adverse reactions to these agents are limited mainly to the GI tract, unpleasant adverse clinical events still readily. Niacin, followed by bile acid sequestrants, were the types of antilipemics most often discontinued by patients; the rate of discontinuation was much lower for either gemfibrozil or Myositis and rhabdomyolysis are serious potential adverse reactions to HMG-CoA reductase inhibitors, although the incidence appears to be low. Clofibrate has been associated with hepatic tumors and cholelithiasis. Probucol has been associated with prolonged QT syndrome.