他汀作用副作用和治疗Word文档格式.docx
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他汀作用副作用和治疗Word文档格式.docx
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iscomplete.
Literaturereviewcurrentthrough:
Apr2013.
|
Thistopiclastupdated:
四月11,2013.
INTRODUCTION
—
LipidalteringagentsencompassseveralclassesofdrugsthatincludeHMGCoAreductase(hydroxymethylglutarylCoAreductase)inhibitorsorstatins,fibricacidderivatives,bileacidsequestrants,cholesterolabsorptioninhibitors,andnicotinicacid.Thesedrugsdifferwithrespecttomechanismofactionandtothedegreeandtypeoflipidlowering.Thus,theindicationsforaparticulardrugareinfluencedbytheunderlyinglipidabnormality.Conventionaldosingregimensandcommonadversereactionsaredescribedinatable(table1)andtherangeofexpectedchangesinthelipidprofilearelistedinaseparatetable(table2).
Lipidlowering,atleastwithstatins,isbeneficialinpatientswithdyslipidemiasforbothprimaryandsecondarypreventionofcoronaryheartdisease.(See
"
Clinicaltrialsofcholesterolloweringforprimarypreventionofcoronaryheartdisease"
and
Clinicaltrialsofcholesterolloweringinpatientswithcoronaryheartdiseaseorcoronaryriskequivalents"
.)
Themechanismsofbenefitseenwithlipidloweringareincompletelyunderstood.Regressionofatherosclerosisoccursinonlyaminorityofpatients;
furthermore,clinicalbenefitsoflipidloweringareseeninaslittleassixmonths,beforesignificantregressioncouldoccur.Thus,otherfactorsmustcontribute;
theseincludeplaquestabilization,reversalofendothelialdysfunction,anddecreasedthrombogenicity.(See
Mechanismsofbenefitoflipid-loweringdrugsinpatientswithcoronaryheartdisease"
Thecharacteristicsandefficacyofthestatinswillbereviewedhere(table3).Possiblenoncardiovascularbenefitsofstatinsarediscussedseparately.(See
Possiblenoncardiovascularbenefits"
.)Theefficacyoffibrates,lipidloweringdrugsotherthanstatinsandfibrates,anddietanddietarysupplementsarealsodiscussedseparately.(See
Lipidloweringwithfibricacidderivatives"
Lipidloweringwithdrugsotherthanstatinsandfibrates"
Lipidloweringwithdietordietarysupplements"
Therapeuticdecisionmakinginpatientswithelevatedlipidlevels,includingindicationsforanddosingofstatins,isdiscussedindetailseparately:
▪(See
Treatmentoflipids(includinghypercholesterolemia)inprimaryprevention"
Treatmentoflipids(includinghypercholesterolemia)insecondaryprevention"
Intensityoflipidloweringtherapyinsecondarypreventionofcoronaryheartdisease"
MECHANISMOFACTION
Currentlyavailablestatinsinclude
lovastatin,
pravastatin,
simvastatin,
fluvastatin,atorvastatin,
rosuvastatin,and,insomecountries,
pitavastatin
(table3).TheseagentsarecompetitiveinhibitorsofHMGCoAreductase,therate-limitingstepincholesterolbiosynthesis(figure1).TheyoccupyaportionofthebindingsiteofHMGCoA,blockingaccessofthissubstratetotheactivesiteontheenzyme[1].
AreductioninintrahepaticcholesterolleadstoanincreaseinLDLreceptorturnoverthatresultsfromanenhancedrateofhepaticLDLreceptorcycling[2].StatinsalsoreduceVLDLproduction,viaaneffectmediatedbyhepaticapoBsecretion[3,4],anditisassociatedwithadiminishedrateofrecoveryofHMGCoAreductaseactivityafterdrugtreatment[5].
MostofthestatinshavemodestHDL-cholesterol(HDL-C)raisingproperties(about5percent),althoughrosuvastatin
hasalargereffect(see
'
EffectonHDL'
below).Triglycerideconcentrationsfallbyanaverageof20to40percentdependinguponthestatinanddoseused(see
Effectontriglycerides'
below).ThereductioninplasmatriglyceridesisduetoadecreaseinVLDLsynthesisandtoclearanceofVLDLremnantparticlesbyapo
B/E(LDL)receptors.
Themechanismsbywhichstatinsmayaffectcardiovasculardiseasearediscussedseparately.(See"
EFFICACY
Thestatinsarecommonlyusedinthetreatmentofhypercholesterolemiaandmixedhyperlipidemia.
EffectonLDLcholesterol
Potency
ThestatinsarethemostpowerfuldrugsforloweringLDL-cholesterol(LDL-C),withreductionsintherangeof30to63percent(table3)
[6-10].Whenswitchingbetweenstatindrugs,equipotentdoseswithregardtoLDL-Creductioncanbefoundinthefigure(figure2).
Rosuvastatin
issomewhatmorepotentthan
atorvastatin
[10,11],andboththeseagentsaresignificantlymorepotentthan
pravastatin,and
fluvastatin
[11,12].Atmaximalprescribeddoses,LDL-Creductionisgreaterwithrosuvastatinandatorvastatinthanwiththeotheravailablestatins(figure2).
Atdosesofupto40
mg/day,
istheleastpotentstatin(figure2).However,atdosesof80
mg/day,fluvastatinisaseffectiveonloweringLDL-Casmoststatinsotherthan
rosuvastatin
[13].Fluvastatinislesslikelytohavedruginteractionsorproducemuscletoxicitythansomeotherstatins.(See
Sideeffects'
below.)
Although
simvastatin
80
mg/day
isamoderately-potentdoseofstatin,givenhighratesofmyopathy[14]andtheavailabilityof
andgeneric
atorvastatin,wesuggestnottreatingpatientswithdosesofsimvastatinabove40
mg/day.
Additionally,cliniciansshouldstronglyconsiderswitchingevenpatientswhoarecurrentlytoleratingsimvastatin80
tooneoftheseotherstatinoptions,sincefuturemedicationtherapyorillnesscouldincreasetheriskfordevelopmentofmyopathyonhigh-dosesimvastatin.High-dosesimvastatinmaybeappropriateforasmallnumberofpatientswhohavetolerateditwellformanyyearsorwhoareintolerantofotherhigh-potencystatinoptions.
Thereisanadditivehypolipidemiceffectwhenanyofthestatinsisusedincombinationwithabileacidsequestrant(figure3)[15-17],orthecholesterolabsorptioninhibitor
ezetimibe.(See
sectionon'
Ezetimibe'
LDLsubfractions
StatinsarethemosteffectiveagentsforloweringtotalLDLparticleconcentration,howevertheyarenonselectiveforreducingLDLsubclasses;
theyreducethepredominantsubclass[18].Amongpatientswiththeatherogenicdyslipidemiaprofile,thereductioninthepredominantsubclassofsmall,denseLDLparticlesresultsinashiftoftheLDLsubfractionstomorebuoyant,andpotentiallylessatherogenic,LDL[19-21].(See
InheriteddisordersofLDL-cholesterolmetabolism"
SmalldenseLDL(LDLphenotypeB)'
and"
Lipoproteinclassification;
metabolism;
androleinatherosclerosis"
Intermediatedensitylipoprotein(remnantlipoproteins)'
Lowdensitylipoprotein'
EffectonHDL
Simvastatin
(40to80
mg/day)
appearstobemoreeffectivethan
(20to40
mg/day)forincreasingserumHDL-CandapolipoproteinA-Iconcentrations[22].However,
maybeevenmoreeffective,raisingHDL-Cbyupto10percent[11].Inmetabolicsyndromepatients,rosuvastatin(10to20
mg/day)wasmoreeffectivethanatorvastatin(10to20
inincreasinglargeHDLparticles[18].Whetherthisisclinicallyimportantisuncertain.(See
HDLmetabolismandapproachtothepatientwithabnormalHDL-cholesterollevels"
Effectontriglycerides
Atorvastatin
aremoreeffectiveatloweringtriglycerides(14to33percent)thanotherstatinsinpatientswithhypercholesterolemia[11,23-25].Themagnitudeoftriglycerideloweringwithstatinsmaybelargerinpatientswithhypertriglyceridemia.
Theeffectsof
onserumtriglyceridesaredose-dependent[11,23].Asanexample,inaseriesof56patientswithprimaryhypertriglyceridemiainwhomtheaveragetriglycerideconcentrationwas600mg/dL
andLDL-Cconcentrationwas120
mg/dL
(3.1
mmol/L),
theadministrationofatorvastatinatdosesof5,20,or80
producedreductionsintriglyceridesof27,32,and46percent,respectively,andinLDL-Cof17,33,and41percent,respectively[23].
Genetic/ethniceffects
Partofthevariabilityintheresponsetoandsideeffectswithstatinsmayberelatedtogeneticdifferencesintherateofdrugmetabolism.Asanexample,CYP2D6isamemberofthecytochromeP450superfamilyofdrugoxidizingenzymes.CYP2D6isfunctionallyabsentin7percentofCaucasiansandAfrican-Americans,whiledeficiencyisrareamongAsians.
TheCYP2D6phenotypeappearstobeimportantinpatientstreatedwith
simvastatin,asitcanaffectboththedegreeoflipidloweringandtolerability[26].PolymorphismsinthegenecodingforHMGCoAreductasealsoappeartoaffecttheLDL-Cresponsetostatins,butnottheHDL-Cresponse[27].
ConcernshavebeenraisedthatAsiansmayhavegreaterresponsestolowdosesofstatinsthanCaucasians[28].Prescribinginformationfor
recommendsstartingtherapyatalowerinitialdoseinAsiansthaninothergroups,givenobserveddifferencesinpharmacokinetics[29].Thereisnostrongevidencesupportingsuchanapproachwithotherstatins.
Preventionofcardiovasculardisease
Themajoruseofstatinsisintheprimaryandsecondarypreventionofcardiovasculardisease.Thisuseisdiscussedextensivelyelsewhere:
Intensityoflipidloweringtherapy
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