HMG-CoA reductase inhibitors simvastatin

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. 

Kureishi Y Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 2000 6 1004-1010. 

The high-value HMG-CoA reductase inhibitor Simvastatin (8) is marketed by Merck under the name Zocor. The active ingredient is obtained from a fermentation approach. It is very similar in structure to lovastatin, which has fallen from the top-sellers list. Lovastatin (9) is also a cholesterol-reducing drug that is isolated from Aspergillus terreus.51-60 It is still obtained by fermentation,61 and with the current advances in molecular biology,62 64 chemical approaches are not able to compete in a cost-effective manner.65-67 The usage of lipases allows for the manipulation of the butyric acid sidechain to access other HMG-CoA reductase inhibitors such as simvastatin.68 A number of routes to various portions of lovastatin have been reported.69... 

Lovastati n 1 0, 20, 40 mg tablets 1 0 to 80 mg/day as a single dose (with evening meal) or divided twice daily with food Approximate equivalent doses of HMG-CoA reductase inhibitors are atorvastatin 10 mg, fluvastatin 80 mg, lovastatin 40 mg, pravastatin 40 mg, simvastatin 20 mg, and rosuvastatin 5 mg. 

Lilja, J. L., Kivisto, K. L., Neuvonen, P. J., Grapefruit juice-simvastatin interaction effect on serum concentrations of simvastatin and HMG-CoA reductase inhibitors, Clin. Pharmacol. Ther. 1998, 64, 477-483. 

Reports about the influence of HMG-CoA-reductase inhibitors are conflicting (F7, H42, J8, K22, K29, L15, M3, S33, T5). In general, the effect is minimal or nonexistent some statins, such as simvastatin and lovastatin, are even reported to have an increasing influence (H42, J8, S33, Ul). Fibrates and derivatives are reported to exert a lowering effect (B13, F4, M3). 

As a result of these and other factors, some HMG-CoA reductase inhibitors are administered as the lactone prodrug form (e.g., lovastatin, simvastatin, and dalvastatin), while others are used as the active hydroxy acids (e.g., pravastatin and fluvastatine) [185][187]. 

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. 

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. 

Drugs that may be affected by HMG-CoA reductase inhibitors include oral contraceptives, diclofenac, digoxin, glyburide, phenytoin, and warfarin. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3A4 they may interact with CYP3A4 inhibitors. 

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... 

Chemotherapy Cyclophosphamide, erlotlnlb, ifos-famide, paclitaxel, tamoxifen, vinblastine, vincristine HIV protease inhibitors Amprenavir, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir HMG-CoA reductase inhibitors Atorvastatin, lovastatin, simvastatin... 

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... 

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). 

Contraindications Concurrent use of a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin) in patients with active hepatic disease or unexplained persistent elevations in serum transaminase levels, moderate or severe hepatic insufficiency... 

Hydroxy-3-Methylgluteryl (HMG)-CoA reductase inhibitors atorvastatin calcium fluvastatin sodium lovastatin pravastatin sodium simvastatin... 

HDL level and it is administered with HMG CoA reductase inhibitors e.g. simvastatin. 

Le Goff-Klein N, Koffel JC, Jung L, Ubeaud G. In vitro inhibition of simvastatin metabolism, a HMG-CoA reductase inhibitor in human and rat liver by bergamottin, a component of grapefruit juice. Eur J Pharm Sci 2003 18(l) 31-35. 

Simvastatin (Zocor) [Anrilipemic/HMG-CoA Reductase Inhibitor] Uses X Cholesterol Action HMG-CoA reductase inhibitor Dose Adults. 5-80 mg PO w/ meals X in renal insuff Peds. 10-17 y 10 mg, 40 mg/daily max Caution [X, —] Avoid concurrent use of gemfibrozil Contra PRG, liver Dz Disp Tabs 5,10, 20, 40, 80 mg SE HA, GI upset, myalgia, myopathy (muscle pain, tenderness or weakness w/ creatine kinase 10 x ULN), Hep Interactions T Effects OF digoxin, warfarin T risk of myopathy/iiiabdomyolysis W/ amiodarone, cyclosporine, CYP3A4 inhibitors, fibrates, HIV protease inhibitors, macrolides, niacin, verapamil, grapefruit juice X effects W/ cholestyramine, colestipol, fluvas-tatin, isradipine, propranolol EMS T Effects of warfarin use amiodarone and... 

HMG CoA reductase inhibitors can be associated with small rises in alanine transaminase activity, but have not been definitely associated with severe morbidity involving altered hepatic function. The results of randomized trials do not suggest that statins in standard doses are hepato-toxic. In none of the large randomized studies in which standard doses were assessed (atorvastatin 10 mg/day, fluvastatin 40-80 mg/day, pravastatin 40 mg/day, simvastatin 20-40 mg/day) was there any clear excess risk of hepatitis or any other serious liver-related adverse events. Long-term large randomized trials have confirmed an excess of persistent rises in transaminases with atorvastatin 80 mg/day compared with lower doses or placebo, and similarly some excess with simvastatin 80 mg/day, but hepatitis and liver failure were not reported (4). 

Eckernas SA, Roos BE, Kvidal P, Eriksson LO, Block GA, Neafus RP, Haigh JR. The effects of simvastatin and pravastatin on objective and subjective measures of nocturnal sleep a comparison of two structurally different HMG CoA reductase inhibitors in patients with primary moderate hypercholesterolaemia. Br J Clin Pharmacol 1993 35(3) 284-9. 

Lilja, J.J., K.T. Kivisto, and P.J. Neuvonen. 1998. Grapefruit juice-simvastatin interaction Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 64 477. 

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

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