Cholesterol simvastatin

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. 

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... 

LC is a 51 -year-old female with a history of CHD (stent placement in the left anterior descending coronary artery 3 years prior) and type 2 diabetes who is referred to you for follow-up of her cholesterol. She is taking simvastatin 20 mg once daily in the evening for her cholesterol, and metformin 2000 mg once daily in the evening and piogliti-zone 15 mg once daily for diabetes. Her diabetes is well controlled. Her laboratory test results are within normal limits, except for her fasting lipid profile total cholesterol 215 mg/dL (5.57 mmol/L), triglycerides 135 mg/dL (1.53 mmol/L), HDL cholesterol 51 mg/dL (1.32 mmol/L), and LDL cholesterol 137 mg/dL (3.55 mmol/L). 

Simvastatin is an important cholesterol-lowering drug and is currently synthesized from the natural product lovastatin via a tedious multistep chemical synthesis. A one-step, whole-cell... 

E4 carriers and patients with other genotypes were equally responsive to simvastatin treatment in terms of LDL cholesterol lowering [59]. 

Heath KE, Gudnason V, Humphries SE, Seed M. The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia. Atherosclerosis 1999 143 41-54. 

This potent inhibitor of cholesterol biosynthesis has been synthesized178 by one-pot esterification of the alcohol 210 with the acid chloride of 2,2-dimethylbutanoic[l-14C] acid, obtained by carbonation of the Grignard reagent prepared from 2-chloro-2-methylbutane (equation 74). Desilylation of 211 afforded [14C]simvastatin 209 in 29% radiochemical yield from 14C-labelled C02. This 14C-labelled drug was needed for elucidation of its metabolic fate in experimental animals. 

A 45-year-old male takes simvastatin for hypercholesterolemia however, his cholesterol level remains above target at maximal doses. Cholestyramine is added to the therapeutic regimen. What drug-drug interaction can occur ... 

Lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin T LDL catabolism i LDL synthesis i Cholesterol Tldl... 

Ezetimibe interferes with the absorption of cholesterol from the brush border of the intestine, a novel mechanism that makes it a good choice for adjunctive therapy. It is approved as both monotherapy and for use with a statin. The dose is 10 mg once daily, given with or without food. When used alone, it results in an approximate 18% reduction in LDL cholesterol. When added to a statin, ezetimibe lowers LDL by about an additional 12% to 20%. A combination product (Vytorin) containing ezetimibe 10 mg and simvastatin 10, 20, 40, or 80 mg is available. Ezetimibe is well tolerated approximately 4% of patients experience GI upset. Because cardiovascular outcomes with ezetimibe have not been evaluated, it should be reserved for patients unable to tolerate statin therapy or those who do not achieve satisfactory lipid lowering with a statin alone. 

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... 

An enzyme (see Section 2.6) called HMG-CoA reductase is involved in the biosynthesis of cholesterol. Drugs such as atorvastatin (Lipitor) and simvastatin (Zocor) are competitive inhibitors of HMG-CoA reductase. They inhibit cholesterol synthesis by increasing the number of LDL receptors to take up the LDL. 

Atorvastatin (Lipitor, Pfizer) and simvastatin (Zocor, Merck) HMG-coenzyme A inhibitors for the reduction of cholesterol level in blood (refer to Exhibit 1.3). 

Inhibit Enzymes Many drugs are competitive inhibitors of key enzymes in pathways. The statin drugs (lovastatin, simvastatin), used to control blood cholesterol levels, competitively inhibit 3-hvdroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. 

Treatment of Hypercholesterolemia Cholestyramine and other drugs that increase elimination of bile salts force the liver to increase their synthesis from cholesterol, thus lowering the internal level of cholesterol in the hepatocytes. Decreased cholesterol within the cell increases LDL receptor expression, allowing the hepatocyte to remove more LDL cholesterol from the blood. HMG-CoA reductase inhibitors such as lovastatin and simvastatin inhibit de novo cholesterol synthesis in the hepatocyte, which subsequently increases LDL receptor expression. 

A 42-year-old man presents with a chief complaint of intermittent claudication during exercise. His fomHy history is significant for the presence of cardiovascular disease on his fether s side, but not on his mother s side. Physical exam reveals xanthelasmas and bilateral tendon xanthomas. A plasma lipid profile reveals a cholesterol level of 340 mg/dL, with a high LDL/HDL ratio. He is given instructions for dietary modifications and a prescription for Zocor (simvastatin). 

The anticholesterolemic action of simvastatin is based on its effectiveness as a competitive inhibitor of the rate-limiting enzyme in cholesterol biosynthesis. The reaction product normally produced by this enzyme is... 

Eleart Protection Study Collaborative Group. (2002) MRC/BHF Heart Protection study of cholesterol lowering with simvastatin in 20,506 high-risk individuals a randomized placebo-controlled trial. Lancet, 360, 7-22. 

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. 

Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004 363 757-67. 

Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease ... 

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. 

Ezetimibe/Simvastatin (Vytorin) [Antilipemic/HMG CoA Reductose Inhibitor] Uses H rp cholest olemia Action X Absorption of cholesterol phytost ol w/ HMG-CoA reductase inhibitor Dose 10/10-10/80 mg/d PO w/ cyclosporine or danazol 10/10 mg/d max w/ amio-darone or verapamil 10/20 mg/d max -1- w/ sev e renal insuff Caution [X, -] w/ CYP3A4 inhibitors (Table VI-8), gemfibrozil, niacin >lg/d, danazol, amiodarone, verapamil Contra PRG/lactation livCT Dz, t LFTs Disp Tabs SE HA, GI upset, myalgia, myopathy (muscle pain, weakness, or tendOTiess w/ CK 10 x ULN, rhab-domyolysis), Hep, Infxn Interactions t Risk of myopathy W7 clarithromycin, erythromycin, itraconazole, ketoconazole EMS None OD Sxs unknown symptomatic and supportive... 

Fluvastatin, launched in 1994, was the first S5mthetic HMG-CoA reductase inhibitor to be approved for the treatment of hypercholesterolemia. This statin was developed by Novartis (Sandoz), and it is marketed as a racemate under the trade name Lescol (Asberg and Holdaas, 2004). In laboratory studies, fluvastatin was shown to potently inhibit HMG-CoA reductase (IC50 = 8 nM) and effectively block cholesterol biosynthesis in hepatoc5de cells (IC50 = 52 nM) (Parker et al., 1990). Clinically, fluvastatin is prescribed less frequently than simvastatin, atorvastatin, or rosuvastatin, but it nevertheless remains an important medication for the treatment of hypercholesterolemia moreover, as the first completely S5mthetic statin to be approved, it offers a compelling synthetic story (Repic et al., 2001). 

A reduced response to simvastatin was noted after phenytoin was added for epilepsy the cholesterol level increased from 9.4 mmol/1 to 15.99 mmol/1. The level decreased again when phenytoin was discontinued. Phenytoin induces the CYP3A4 isoform which is involved in simvastatin metabolism. Some other examples of this type of interaction are shown in Table 5. 

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