Statins pravastatin

Statins Pravastatin Atrovastatin Cervistatin Pitavastatin Rosuvastatin... 

HMG-CoA reductase inhibitors [statins] -statin Pravastatin, simvastatin Hyperlipidemia (25)... 

The hydrophilic statins (pravastatin, rosuvastatin) are only partly metabolised by the liver [1, 17, 19]. Pravastatin is also metabolised in the stomach [26]. The pharmacokinetics of pravastatin have been shown to change in liver disease, despite its dual route (renal and hepatic) of elimination [27]. Nonetheless, it has been used in liver disease and has been suggested as the statin of choice [26]. Liver metabolism is of minor importance in the clearance of rosuvastatin and its pharmacokinetics are not altered by mild to moderate liver impairment. However, the area under the curve (AUC) is increased in severe liver impairment [1]. Clinical experience with rosuvastatin in liver disease is lacking, and it therefore cannot be recommended. 

Ann Jeina was treated with a statin (pravastatin) and cholestyramine, a bile acid sequestrant. With the introduction of the cholesterol absorption blocker ezetimibe, the use of cholestyramine with its high level of gastrointestinal side effects may decline. Ezetimibe reduces the percentage of absorption of free cholesterol present in the lumen of the gut and hence the amount of cholesterol available to the enteroc5de to package into chylomicrons. This, in turn, reduces the amount of cholesterol returning to the liver in chylomicron remnants. The net result is a reduction in the cholesterol pool in hepatocytes. The latter induces the synthesis of an increased number of LDL receptors by the hver cells. As a consequence, the capacity of the liver to increase hepatic uptake of LDL from the circulation leads to a decrease in serum LDL levels. 

The cholesterol-lowering agents called statins, such as simvastatin (Zocor) and pravastatin (Pravachol), are among the most widely prescribed drugs in the world. Identify the functional groups in both, and tell how the two substances differ. 

There are currently marketed four naturally derived statins (lovastatin, pravastatin, simvastatin, and rosuvas-tatin) and two synthetic statins (atorvastatin and fluvas-tatin). The structure of these statins is shown in Fig. 2. 

Over the last decade, several studies in tens of thousands of patients have revealed that lowering cholesterol, specifically lowering LDL cholesterol with statins, is effective for both primary and secondary prevention of IHD-related events. Statins shown to decrease morbidity and mortality associated with IHD include lovastatin, simvastatin, pravastatin, and atorvas-tatin.22,23 A recent meta-analysis showed that the risk of major adverse cardiac events is reduced by 21% with the use of statins in patients at high risk for IHD-related events.23... 

With the exception of pravastatin which is mainly metabolized by isomerization in the gut to a relatively inactive metabolite, the other statins undergo biotransformation by the cytochrome P-450 system. Therefore, drugs known to inhibit statin metabolism should be used cautiously. The time until maximum effect on lipids for statins is generally 4 to 6 weeks. 

Lipoprotein (a) is an independent risk factor for coronary artery disease [68]. It consists of two components an LDL particle and apolipoprotein (a) which are linked by a disulfide bridge. Apo(a) reveals a genetically determined size polymorphism, resulting from a variable number of plasminogen kringle IV-type repeats [69]. Statins either do not affect Lp(a) or may even increase Lp(a) [70, 71]. In a study of 51 FH patients, treated with 40 mgd 1 pravastatin, it has been shown that the increase in Lp(a) was greatest in patients with the low molecular-weight apo(a) phenotypes [70]. 

It has been found that the 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) inhibitors statins (atorvastatin, pravastatin, and cerivastatin), widely prescribed cholesterol-lowering agents, are able to inhibit phorbol ester-stimulated superoxide formation in endothelial-intact segments of the rat aorta [64] and suppress angiotensin II-mediated free radical production [65]. Delbose et al. [66] found that statins inhibited NADPH oxidase-catalyzed PMA-induced superoxide production by monocytes. It was suggested that statins can prevent or limit the involvement of superoxide in the development of atherosclerosis. It is important that statin... 

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

Baycol (cerivastatin, sold as Lipobay in Europe, Bayer) is a statin, a class of cholesterol-lower drugs. Statins are the most prescribed drugs in the United States, with more than 12 million people taking them, and more than 700,000 people in the United States taking cerivastatin. It received marketing approval on June 26, 1997 and was voluntarily removed from the market on August 8, 2001 because of its link to 100 deaths and several injuries from potentially the muscle disease rhabdomyolysis. The other statins — lovas-tatin (Mevacor Merck) pravastatin (Pravachol Bristol-Myers Squibb) simvastatin (Zocor Merck) fluvastatin (Lescol Novartis) atorvastatin (Lipitor Parke-Davis) rosuvastatin... 

The most important class of cholesterol-lowering agents is the statins. These include lovastatin (Mevacor), simvastatin (Zocor), pravastatin (Pravachol), and atorvastatin (Lipitor), among others. These molecules work, in modest part, by inhibiting biosynthesis of cholesterol and, in larger part, by increasing the rate at which cholesterol is eliminated by the body. Let s have a look at this in more detail. 

The statins, e.g. pravastatin, are a group of HMGR inhibitors that possess functionalities that mimic the half-reduced substrate mevaldate hemithioacetal. The affinity of these agents towards HMG-CoA reductase is some 10" -fold more than the natural substrate, making them extremely effective inhibitors of the enzyme, and powerful drugs in coronary care. 

The statins, lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), cerivastatin, and atorvastatin, inhibit HMG CoA reductase. The active group of L, S, P, and F (or their metabolites) resembles that of the physiological substrate of the enzyme (A). L and S are lactones that are rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed into active metabolites. P and F represent the active form and, as acids, are actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the selective hepatic uptake of the mycotoxin, amanitin (A), Atorvastatin has the longest duration of action. 

Endocrine effects Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Small declines in total testosterone with no commensurate elevation in LH have been noted with the use of fluvastatin. Pravastatin showed inconsistent results with regard to possible effects on basal steroid hormone levels atorvastatin, lovastatin, rosuvastatin, and simvastatin did not reduce basal plasma cortisol concentration or basal plasma testosterone concentration or impair adrenal reserve. Appropriately evaluate patients who display clinical evidence of endocrine dysfunction. Exercise caution when administering HMG-CoA reductase inhibitors with drugs that affect steroid levels or activity, such as ketoconazole, spironolactone, and cimetidine. 

The first generation of statins to be approved for the treatment of hypercholesterolemia was based upon the natural product compactin, an HMG-CoA reductase inhibitor originally isolated from cultures of Penicillium. The most widely prescribed of these first-generation statins are simvastatin (4, Fig. 12.2), marketed as Zocor , and pravastatin (5), marketed as Pravacol . Based in large part on the clinical effectiveness of these early... 

Rosuvastatin (Crestor ) is the most recent HMG-CoA reductase inhibitor to be widely approved for the treatment of hypercholesterolemic patients. It has established an impressive record of clinical efficacy and is often prescribed to patients that do not respond well to earlier HMG-CoA reductase inhibitors (Schuster, 2003). This fully synthetic statin, developed by Astra-Zeneca and Shionogi Research Laboratories, has been shown to potently inhibit cholesterol biosynthesis in rat hepatocytyes (IC50 =1.12 nM). By comparison, pravastatin (5) was > 100-fold less active in the same assay (IC50 =198 nM) (Hirai et al., 1993 Watanabe et al., 1997). 

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