他汀作用副作用和治疗.docx

1、他汀作用副作用和治疗5 他汀：作用，副作用和治疗Statins: Actions, side effects, and administrationAuthorRobert S Rosenson, MDSection EditorMason W Freeman, MDDeputy EditorDavid M Rind, MDDisclosuresAll topics are updated as new evidence becomes available and ourpeer review processis complete.Literature review current throu

2、gh:Apr 2013.|This topic last updated:四月 11, 2013.INTRODUCTIONLipid altering agents encompass several classes of drugs that include HMG CoA reductase (hydroxymethylglutaryl CoA reductase) inhibitors or statins, fibric acid derivatives, bile acid sequestrants, cholesterol absorption inhibitors, and ni

3、cotinic acid. These drugs differ with respect to mechanism of action and to the degree and type of lipid lowering. Thus, the indications for a particular drug are influenced by the underlying lipid abnormality. Conventional dosing regimens and common adverse reactions are described in a table (table

4、 1) and the range of expected changes in the lipid profile are listed in a separate table (table 2).Lipid lowering, at least with statins, is beneficial in patients with dyslipidemias for both primary and secondary prevention of coronary heart disease. (SeeClinical trials of cholesterol lowering for

5、 primary prevention of coronary heart diseaseandClinical trials of cholesterol lowering in patients with coronary heart disease or coronary risk equivalents.)The mechanisms of benefit seen with lipid lowering are incompletely understood. Regression of atherosclerosis occurs in only a minority of pat

6、ients; furthermore, clinical benefits of lipid lowering are seen in as little as six months, before significant regression could occur. Thus, other factors must contribute; these include plaque stabilization, reversal of endothelial dysfunction, and decreased thrombogenicity. (SeeMechanisms of benef

7、it of lipid-lowering drugs in patients with coronary heart disease.)The characteristics and efficacy of the statins will be reviewed here (table 3). Possible noncardiovascular benefits of statins are discussed separately. (SeeStatins: Possible noncardiovascular benefits.) The efficacy of fibrates, l

8、ipid lowering drugs other than statins and fibrates, and diet and dietary supplements are also discussed separately. (SeeLipid lowering with fibric acid derivativesandLipid lowering with drugs other than statins and fibratesandLipid lowering with diet or dietary supplements.)Therapeutic decision mak

9、ing in patients with elevated lipid levels, including indications for and dosing of statins, is discussed in detail separately: (SeeTreatment of lipids (including hypercholesterolemia) in primary prevention.) (SeeTreatment of lipids (including hypercholesterolemia) in secondary prevention.) (SeeInte

10、nsity of lipid lowering therapy in secondary prevention of coronary heart disease.)MECHANISM OF ACTIONCurrently available statins includelovastatin,pravastatin,simvastatin,fluvastatin,atorvastatin,rosuvastatin, and, in some countries,pitavastatin(table 3). These agents are competitive inhibitors of

11、HMG CoA reductase, the rate-limiting step in cholesterol biosynthesis (figure 1). They occupy a portion of the binding site of HMG CoA, blocking access of this substrate to the active site on the enzyme 1.A reduction in intrahepatic cholesterol leads to an increase in LDL receptor turnover that resu

12、lts from an enhanced rate of hepatic LDL receptor cycling 2. Statins also reduce VLDL production, via an effect mediated by hepatic apo B secretion 3,4, and it is associated with a diminished rate of recovery of HMG CoA reductase activity after drug treatment 5.Most of the statins have modest HDL-ch

13、olesterol (HDL-C) raising properties (about 5 percent), althoughrosuvastatinhas a larger effect (seeEffect on HDLbelow). Triglyceride concentrations fall by an average of 20 to 40 percent depending upon the statin and dose used (seeEffect on triglyceridesbelow). The reduction in plasma triglycerides

14、 is due to a decrease in VLDL synthesis and to clearance of VLDL remnant particles by apoB/E(LDL) receptors.The mechanisms by which statins may affect cardiovascular disease are discussed separately. (SeeMechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease.)EFFICACYT

15、he statins are commonly used in the treatment of hypercholesterolemia and mixed hyperlipidemia.Effect on LDL cholesterolPotencyThe statins are the most powerful drugs for lowering LDL-cholesterol (LDL-C), with reductions in the range of 30 to 63 percent (table 3)6-10. When switching between statin d

16、rugs, equipotent doses with regard to LDL-C reduction can be found in the figure (figure 2).Rosuvastatinis somewhat more potent thanatorvastatin10,11, and both these agents are significantly more potent thansimvastatin,lovastatin,pravastatin, andfluvastatin11,12. At maximal prescribed doses, LDL-C r

17、eduction is greater with rosuvastatin and atorvastatin than with the other available statins (figure 2).At doses of up to 40mg/day,fluvastatinis the least potent statin (figure 2). However, at doses of 80mg/day,fluvastatin is as effective on lowering LDL-C as most statins other thanrosuvastatinandat

18、orvastatin13. Fluvastatin is less likely to have drug interactions or produce muscle toxicity than some other statins. (SeeSide effectsbelow.)Althoughsimvastatin80mg/dayis a moderately-potent dose of statin, given high rates of myopathy 14 and the availability ofrosuvastatinand genericatorvastatin,

19、we suggest not treating patients with doses of simvastatin above 40mg/day.Additionally, clinicians should strongly consider switching even patients who are currently tolerating simvastatin 80mg/dayto one of these other statin options, since future medication therapy or illness could increase the ris

20、k for development of myopathy on high-dose simvastatin. High-dose simvastatin may be appropriate for a small number of patients who have tolerated it well for many years or who are intolerant of other high-potency statin options.There is an additive hypolipidemic effect when any of the statins is us

21、ed in combination with a bile acid sequestrant (figure 3) 15-17, or the cholesterol absorption inhibitorezetimibe. (SeeLipid lowering with drugs other than statins and fibrates, section on Ezetimibe.)LDL subfractionsStatins are the most effective agents for lowering total LDL particle concentration,

22、 however they are nonselective for reducing LDL subclasses; they reduce the predominant subclass 18. Among patients with the atherogenic dyslipidemia profile, the reduction in the predominant subclass of small, dense LDL particles results in a shift of the LDL subfractions to more buoyant, and poten

23、tially less atherogenic, LDL 19-21. (SeeInherited disorders of LDL-cholesterol metabolism, section on Small dense LDL (LDL phenotype B)andLipoprotein classification; metabolism; and role in atherosclerosis, section on Intermediate density lipoprotein (remnant lipoproteins)andLipoprotein classificati

24、on; metabolism; and role in atherosclerosis, section on Low density lipoprotein.)Effect on HDLSimvastatin(40 to 80mg/day)appears to be more effective thanatorvastatin(20 to 40mg/day)for increasing serum HDL-C and apolipoprotein A-I concentrations 22. However,rosuvastatinmay be even more effective, r

25、aising HDL-C by up to 10 percent 11. In metabolic syndrome patients, rosuvastatin (10 to 20mg/day)was more effective than atorvastatin (10 to 20mg/day)in increasing large HDL particles 18. Whether this is clinically important is uncertain. (SeeHDL metabolism and approach to the patient with abnormal

26、 HDL-cholesterol levels.)Effect on triglyceridesAtorvastatinandrosuvastatinare more effective at lowering triglycerides (14 to 33 percent) than other statins in patients with hypercholesterolemia 11,23-25. The magnitude of triglyceride lowering with statins may be larger in patients with hypertrigly

27、ceridemia.The effects ofatorvastatinandrosuvastatinon serum triglycerides are dose-dependent 11,23. As an example, in a series of 56 patients with primary hypertriglyceridemia in whom the average triglyceride concentration was 600mg/dLand LDL-C concentration was 120mg/dL(3.1mmol/L),the administratio

28、n of atorvastatin at doses of 5, 20, or 80mg/dayproduced reductions in triglycerides of 27, 32, and 46 percent, respectively, and in LDL-C of 17, 33, and 41 percent, respectively 23.Genetic/ethnic effectsPart of the variability in the response to and side effects with statins may be related to genet

29、ic differences in the rate of drug metabolism. As an example, CYP2D6 is a member of the cytochrome P450 superfamily of drug oxidizing enzymes. CYP2D6 is functionally absent in 7 percent of Caucasians and African-Americans, while deficiency is rare among Asians.The CYP2D6 phenotype appears to be impo

30、rtant in patients treated withsimvastatin, as it can affect both the degree of lipid lowering and tolerability 26. Polymorphisms in the gene coding for HMG CoA reductase also appear to affect the LDL-C response to statins, but not the HDL-C response 27.Concerns have been raised that Asians may have

31、greater responses to low doses of statins than Caucasians 28. Prescribing information forrosuvastatinrecommends starting therapy at a lower initial dose in Asians than in other groups, given observed differences in pharmacokinetics 29. There is no strong evidence supporting such an approach with oth

32、er statins.Prevention of cardiovascular diseaseThe major use of statins is in the primary and secondary prevention of cardiovascular disease. This use is discussed extensively elsewhere: (SeeTreatment of lipids (including hypercholesterolemia) in primary prevention.) (SeeTreatment of lipids (including hypercholesterolemia) in secondary prevention.) (SeeIntensity of lipid lowering therapy