8

Alia Abbadi

Enter

Enter

Enter

AliaAbbadi

ZaidKhaleel

MunirGharaibeh

8

OmarIsmail

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Inthislecture,we’lltalkaboutsomeanti-hyperlipidemicdrugs.Enjoy.

Abnormallevelsoflipidsinthebloodhavemanynegativeeffectsonthebody.Noticehowinthefollowingtable,veryhighlevelsofLDLcholesterol(LDL-C)“badcholesterol”andlowlevelsofHDLcholesterol(HDL-C)“goodcholesterol”highlyincreasethechanceofdevelopingcoronaryheartdisease.TheymayevenbestrongerriskfactorsforCHDthansmoking,hyperglycemiaandahistoryofMI.So,controllinglipidbloodlevelsisimportantforthepreventionandtreatmentofCHD.

Thisfigureshowsonetypeoflipoproteins(theirmainfunctionistotransporthydrophobiclipidsinwater).Lipoproteinshavehydrophobiccoreregionscontainingcholesterylestersandtriglyceridessurroundedbycholesterol,phospholipids,andapoproteins.Hyperlipoproteinemiasareagroupofdiseaseswithdistinctnomenclature,causes,manifestationsandtreatment.Youcanrefertoslide6ifyouwanttoknowmoreaboutthedifferenttypes.

Rememberthatcholesteroliscarriedbydifferenttypesoflipoproteins(LDL,HDL,VLDL…).Takeaquicklookatthedesirable&highvaluesofdifferentcholesteroltypes&triglycerideswhicharealsolipids.

• AlsonotethatHDLlevelsdifferbetweenmenandwomen.

Hyperlipidemiareferstothepresenceofhighlevelsoflipidsintheblood.Generally,it’salsocalledhyperlipoproteinemia,hyperlipemia,dyslipidemia,hypercholesterolemia.

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Cholesterolisoneofseveraltypesoflipids.It’seithersuppliedfromthedietorsynthesizeddenovointhebody(especiallyintheliver).Cholesterolmetabolismisacomplexprocess,butrememberthatitinvolvestheformationofbileacidswhicharepartiallyexcretedinfecesbutmostlyreabsorbedfromtheintestinebackintothebody.

Differentdrugsaffectdifferentstepsinthemetabolismofcholesterol.Forexample,fibratesaffectcholesterolcatabolismwhilebileacidsequestersaffectthereaborptionofbileacids.Statinsaffectthedenovosynthesisofcholesterol(byinhibitingHMGCoAreductase).Now,We’lltalkmoreaboutallofthesedrugsplussomemore.Havefun.

§ NicotinicAcidorVitaminB3,isoneoftheoldestdrugsusedinthetreatmentofhyperlipidemia.

§ Water-solubleB-complexvitamin,functionsonlyafterconversiontoNAD+orNADP+nicotinamide.

§ Niacinhashypolipidemiceffectsonlyinlargedoses;i.e.ithaslowpotency.§ Affectsalllipidparameters:

ü BestagenttoincreaseHDL-C(35-40%).ü Lowerstriglycerides(35-45%).ü DecreasesLDL-Cproduction(20-30%),butotherdrugsarepreferredforthis

function.ü Reducesfibrinogenlevels,rememberthatfibrinogenhasanimportantinthe

formationofthrombi.ü Increasesplasminogenactivator,whichisathrombolyticagent.

§ MECHANISMOFACTION:I. Inadiposetissue,itcausesinhibitionoflipolysisoftriglyceridesbyinhibiting

adipocyteadenylylcyclaseandintracellularlipaseàreductionintransportoffreefattyacids(FFA)totheliveranddecreaseinhepatictriglyceridesynthesis.

II. Mayalsoinhibitdiacylglycerolacetyltransferase2whichisarate–limitingenzymeoftriglyceridesynthesis.

ð Theresult:ReductionoftriglyceridesynthesiswhichreduceshepaticVLDLandLDL.

6:43 NIACIN

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§ PHARMACOKINETICS:Completelyabsorbed,peakswithin1hr,half-lifeisabout1hr,soitneedstobegiventwiceorthricedaily.(inconvenient)

N TOXICITY(manytroublesomesideeffectsbuttheyarenotsevere)ü Harmlesscutaneousvasodilationandsensationofwarmthwhichcanbe

preventedbyNSAIDS.(thefirstsideeffectthat’sexperiencedafteradministrationandthepatienthastoexperienceitevery-timethedrugisadministeredL2-3timesdaily).

ü Pruritus,rashes,dryskinandmucusmembranes.Alsocausesacanthosisnigricanswhichisablackdiscolorationoftheskininsomeareasinthebody,checkthepictures.

ü Nausea,vomiting,abdominaldiscomfort,diarrhea.

ü Elevationsintransaminasesandpossiblehepatotoxicity.

ü Insulinresistance&hyperglycemia.ü Hyperuricemia&gout.ü Cardiacarrhythmias.ü Blurringofvision,amblyopia(extra:itisa

disorderofsightinwhichthebrainfailstoprocessinputsfromoneeyeandovertimefavorstheothereye)

§ ThefirstdrugwasClofibratein1962butitwasdiscontinuedin1987.§ Others:Fenofibrate,Bezafibrate,Gemfibrozel.

§ MECHANISMOFACTION:

ItactivatesPPAR-α(PeroxisomeProliferatorActivatedReceptor-α)whichstimulatesfattyacidoxidation1,increaseslipoproteinlipase(LPL)synthesis2,reducesexpressionofapoC-III3,andincreasesapoA-IandapoA-IIexpression4whicharethemajorapolipoproteinsinHDL.

§ LIPIDPARAMETERSAFFECTED:ü Increaselipolysisoflipoprotein

triglycerideviaLPL.ü DecreaselevelsofVLDLandLDL.ü ModeratelyincreaseHDL.(REMEMBER:niacinisbetteratincreasingHDL)ü Alsohaveanticoagulantandfibrinolyticactivities.ü Drugsofchoiceinseverehypertriglyceridemia.(TAGlevelscanreach1000

mg/dLofblood)

Fibrates; Fibric Acid Derivatives; PPARs 11:56 Activators

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N TOXICITY:ü Myalgia rhabdomyolysisandmyopathyfatigue,, )�� ةلتق لكام ھلاح سحب ضیرملا(

whichisbreakdownofmusclefibersresultinginthereleaseofmusclefibercontents(myoglobin)intothebloodstream.Increasedmyoglobinlevelsmayaffectthekidneys.

ü Usedwithcautioninrenalfailure.ü Rashes,urticaria,hairloss,headache,GITsymptoms,impotence,andanemia.ü Riskofcholesterolgallstones.ü Interactwithstatins(willbediscussedsoon),levelsofbothdrugswillincrease

àtoxicityofbothdrugsincreased.ü Elevatedtransaminasesoralkalinephosphatasewhichareindicatorsofhepatic

injury.

§ Bileacidbindingresins.§ Theyarelargepolymericanionic-exchangeresins,insolubleinwater.§ Examples:Colestipol,Cholestyramine,Colesevelam.

§ MECHANISMOFACTION:

Theybindthenegativelychargedbileacidsintheintestinallumenandpreventtheirreabsorptionàleadingtodepletionofbileacidpoolàincreasedhepaticsynthesisofbileacids(increaseduseofcholesterol)àHepaticcholesterolcontentisdecreasedàstimulationofLDLreceptorsproductionwhichleadstoincreasedLDLclearancefrombloodandloweredLDL-Cholesterollevels.

§ However,thiseffectispartiallyoffsetbytheenhancedcholesterolsynthesiscausedbyup-regulationofHMG-CoAreductase(animportantenzymeindenovocholesterolsynthesis)àcausessometypeoftolerancetothedrugsàincreasedcholesterollevelsmayreachpretreatmentlevelsL

§ Mayincreasetriglyceridelevelstoo.

§ INDICATIONS:highdosesrequiredü LowerLDLbyasmuchas25%,butwillcauseGIsideeffects.ü Relievepruritusincholestasis(abnormalbileflow)ü Digitalistoxicity,canbinddigitoxinandenhanceitsexcretion,becauseit’s

metabolizedintheliver.

Bile acid sequestrants 17:37

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N TOXICITY:Probablythesafestdrugs,sincetheyarenotabsorbedfromtheintestinebecauseoftheirlargesize.Maximaldosesareeffectivebutcausesideeffects(mainlyGITsideeffects)

ü Grittysensationisunpleasantbutcanbetolerated.ü Constipationandbloating.ü Heartburn.ü MalabsorptionofVitaminK.ü Gallstones.ü Impairedabsorptionofmanydrugs(digitalis,propranolol,thiazides,warfarin,

folicacid,statins,aspirin…etc.)

§ CompetitiveInhibitorsofHMG-CoAReductase§ Mostcommonlyprescribeddrugsworldwide.§ IsolatedfromamoldcalledPenicilliumCitrinum,in1976. § MosteffectivedrugsinloweringLDL.

§ MECHANISMOFACTION:

I. Majoreffect:Competitivelyinhibittheearlyrate-limitingenzymeindenovosynthesisofcholesterol(3-hydroxy-3-methylglutarylcoenzymeAreductaseakaHMG-CoAreductase)àReducedfreecholesterolinhepatocytesactivatesaproteasewhichwillcleavemembrane-boundSREBP{Sterol regulatory element-binding protein}whichwillbetranslocatedtothenucleustostimulatetranscriptionofLDLreceptorsàIncreasednumberofLDLreceptorswillincreaseremovalofLDL-CfromthebloodthusloweringbloodLDL-ClevelsandpreventingCHD.

II. Minoreffect:canreduceLDLlevelsbyenhancingtheremovalofLDLprecursors(VLDLandIDL)andbydecreasinghepaticVLDLproduction.

§ HigherdosescanreducetriglyceridelevelscausedbyelevatedVLDLlevels.§ Some(simvastatinandrosuvastatin)canraiseHDL-Clevels.§ DecreaseoxidativestressandvascularinflammationbyenhancingNOproduction.§ Reduceplateletaggregation.

Thelast2pointsareconsideredadditionaladvantagesthatenhancethetreatmentandpreventionofCHD.

Statins 23:49

Statinsinclude:MevastatinSimvastatinLovastatinPravastatinFluvastatinAtorvastatinRosuvastatin

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N TOXICITYsafedrugs;saferthanfibratesbutnotniacinü Itisdose-related,associatedwithadvancedage,hepaticorrenaldysfunction,

smallbodysize,associateddiseases,hypothyroidismandconcomitantdrugs.ü átransaminases(whichareusuallyindicatorsofliverdiseaseorinjury)butin

thiscasetheincreasedlevelsareactuallyintermittentandnotassociatedwithstrongevidenceofliverfailure.

ü Rhabdomyolysis,causingmyoglobinuriaandrenalinjury,failureorevendeath.Itisextremelyrare(lessthanonein10,000people),lessthanfibrates.

ü áincreatinekinase(CK)activity:indicationofmuscledestruction.ü Lupus-likedisorderandperipheralneuropathy.

§ Statinsaregoodexampleontheprincipleofpharmacogenetics.Thisisbecausethey

aremetabolizedbytheCYP450enzymesystem,whichissubjecttoindividualgeneticdifferences.Geneticvariationsresultindifferencesin:

A. Therapeuticresponsetothesedrugs.B. SideEffects;somepeoplemaydevelopmildsideeffects,othersmay

developmoreserioussideeffects.

Ø Example;Ezetimibe:§ InhibitorofNPC1L1,aproteininjejunalbrushborder,essentialforcholesterol

absorption.§ Reducescholesterolabsorptionandreabsorptionby54%àReducestransportof

dietarycholesteroltoliverviachylomicronsàThiswillstimulatetheexpressionofthehepaticLDLreceptorleadingtoenhancedLDL-Cclearancefromtheplasma(15-20%reduction).{duetodecreaseinabsorptionofcholesterol,compensatoryincreaseincholesterolsynthesisprecipitates}

§ Actioniscomplementarytostatins(togethertheycause60%reductioninLDL-C).§ Cancauseallergicreactions,reversibleimpairmentofliverfunctiontestsand

myopathy.

ð Generally:allanti-hyperlipidemicdrugscausemyopathyexceptforNiacin.

Inhibitors of Sterol Absorption 35:22

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§ Includethefollowingdrugs:Torcetrapibwhichwaswithdrawn.AnacetrapibDalcetrapib.

§ MECHANISMOFACTION:Asthenameindicates,they’reinhibitorsofcholesterylestertransferprotein(CETP).

• CETPisaplasmaglycoproteinsynthesizedbytheliverthatmediatesthetransferofcholesterylestersfromHDLtotriglyceride-richlipoproteinsandLDLinexchangeforamoleculeoftriglyceride.

ðso,theyinhibitthistransferprocess,resultinginincreasedlevelsofHDL.

§ CanincreaseHDLlevelsby45-106%inhumans;soit’seffectiveinpatientswhosemainproblemislowlevelsofHDL.

¯GOOD LUCK¯

Inhibitors of Cholesteryl Ester Transfer Protein