PharmacologyPharmacologyPharmacology

DrugsDrugs thatthat AffectAffect thethe CardiovascularCardiovascular SystemSystem TopicsTopicsTopics

•• Electrophysiology Electrophysiology •• Vaughn-Williams Vaughn-Williams classificationclassification •• Antihypertensives Antihypertensives •• Hemostatic Hemostatic agentsagents CardiacCardiacCardiac FunctionFunctionFunction

•• Dependent Dependent uponupon –– Adequate Adequate amountsamounts ofof ATPATP –– Adequate Adequate amountsamounts ofof CaCa++++ –– Coordinated Coordinated electricalelectrical stimulusstimulus AdequateAdequateAdequate AmountsAmountsAmounts ofofof ATPATPATP

•• Needed Needed to:to: –– Maintain Maintain electrochemicalelectrochemical gradientsgradients –– Propagate Propagate actionaction potentialspotentials –– Power Power musclemuscle contractioncontraction AdequateAdequateAdequate AmountsAmountsAmounts ofofof CalciumCalciumCalcium

•• Calcium Calcium isis ‘glue’‘glue’ that that linkslinks electricalelectrical andand mechanicalmechanical events.events. CoordinatedCoordinatedCoordinated ElectricalElectricalElectrical StimulationStimulationStimulation •• Heart Heart capablecapable ofof automaticityautomaticity •• Two Two typestypes ofof myocardialmyocardial tissuetissue –– Contractile Contractile –– Conductive Conductive •• Impulses Impulses traveltravel throughthrough ‘action‘action potentialpotential superhighway’.superhighway’. A.P.A.P.A.P. SuperHighwaySuperHighwaySuperHighway

•• Sinoatrial Sinoatrial node node •• Atrioventricular Atrioventricular nodenode •• Bundle Bundle ofof HisHis •• Bundle Bundle BranchesBranches –– Fascicles Fascicles •• Purkinje Purkinje NetworkNetwork ElectrophysiologyElectrophysiologyElectrophysiology

•• Two Two typestypes ofof actionaction potentialspotentials –– Fast Fast potentialspotentials •• Found Found in in contractile contractile tissue tissue –– Slow Slow potentialspotentials •• Found Found inin SA,SA, AVAV nodenode tissuestissues FastFastFast PotentialPotentialPotential Phase 1 +20 Phase 2 0

-20 Phase 3 -40

-60 Phase 4 -80 controlled by Na+ RMP channels = “fast channels” -80 to 90 mV FastFastFast PotentialPotentialPotential

•• Phase Phase 0:0: NaNa++influxinflux “fast“fast sodiumsodium channels”channels” •• Phase Phase 1:1: KK ++effluxefflux •• Phase Phase 2:2: (Plateau)(Plateau) KK ++effluxefflux –– AND AND CaCa ++ + +influxinflux •• Phase Phase 3:3: KK++effluxefflux •• Phase Phase 4:4: RestingResting MembraneMembrane PotentialPotential CardiacCardiacCardiac ConductionConductionConduction CycleCycleCycle SlowSlowSlow PotentialPotentialPotential dependent upon Ca++ channels = “slow channels”

0

-20 Phase 4 Phase 3 -40

-60

-80 SlowSlowSlow PotentialPotentialPotential •• Self-depolarizing Self-depolarizing –– Responsible Responsible forfor automaticityautomaticity •• Phase Phase 44 depolarizationdepolarization –– ‘slow ‘slow sodium-calciumsodium-calcium channels’channels’ –– ‘leaky’ ‘leaky’ to to sodiumsodium •• Phase Phase 33 repolarizationrepolarization –K–K++effluxefflux CardiacCardiacCardiac PacemakerPacemakerPacemaker DominanceDominanceDominance •• Intrinsic Intrinsic firingfiring rates:rates: –SA–SA == 6060 –100–100 –– AV AV == 4545 –– 60 60 –– Purkinje Purkinje == 1515 -- 45 45 CardiacCardiacCardiac PacemakersPacemakersPacemakers

•• SA SA isis primaryprimary –– Faster Faster depolarizationdepolarization raterate •Faster•Faster CaCa++++‘leak’‘leak’ •• Others Others areare ‘backups’‘backups’ –– Graduated Graduated depolarizationdepolarization raterate •• Graduated Graduated Ca Ca++++leakleak raterate PotentialPotentialPotential TermsTermsTerms RRP relative refractory period

ERP effective refractory period

APD action potential duration DysrhythmiaDysrhythmiaDysrhythmia GenerationGenerationGeneration

•• Abnormal Abnormal genesisgenesis –– Imbalance Imbalance ofof ANSANS stimulistimuli –– Pathologic Pathologic phasephase 44 depolarizationdepolarization •• Ectopic Ectopic focifoci DysrhythmiaDysrhythmiaDysrhythmia GenerationGenerationGeneration

•• Abnormal Abnormal conductionconduction •Analogies:•Analogies: –– One One wayway valvevalve –– Buggies Buggies stuckstuck inin muddymuddy roadsroads ReentrantReentrantReentrant CircuitsCircuitsCircuits Warning!Warning!Warning! •• All All antidysrhythmicsantidysrhythmics havehave arrythmogenicarrythmogenic propertiesproperties •• In In otherother words,words, theythey allall cancan CAUSECAUSE dysrhythmiasdysrhythmias too!too! AHAAHAAHA RecommendationRecommendationRecommendation ClassificationsClassificationsClassifications •• Describes Describes weightweight ofof •• ViewView AHAAHA definitionsdefinitions supportingsupporting evidenceevidence NOTNOT mechanismmechanism •• Class Class II •• Class Class IIaIIa •• Class Class IIbIIb •• Indeterminant Indeterminant •• Class Class IIIIII VaughnVaughnVaughn-Williams--WilliamsWilliams ClassificationClassificationClassification •• Class Class 11 •• Description Description ofof –Ia–Ia mechanismmechanism NOTNOT –Ib–Ib evidenceevidence –Ic–Ic •• Class Class IIII •• Class Class IIIIII •• Class Class IVIV •• Misc Misc ClassClassClass I:I:I: SodiumSodiumSodium ChannelChannelChannel BlockersBlockersBlockers •• Decrease Decrease NaNa++movementmovement inin phasesphases 00 andand 44 •• Decreases Decreases raterate ofof propagationpropagation (conduction)(conduction) viavia tissuetissue withwith fastfast potentialpotential (Purkinje)(Purkinje) –– Ignores Ignores thosethose withwith slowslow potentialpotential (SA/AV)(SA/AV) •• Indications: Indications: ventricularventricular dysrhythmiasdysrhythmias ClassClassClass IaIaIaAgentsAgents Agents

•• Slow Slow conductionconduction •PDQ•PDQ:: throughthrough ventriclesventricles –– procainamide procainamide (Pronestyl®®) •• Decrease Decrease (Pronestyl ) repolarizationrepolarization raterate –– disopyramide disopyramide (Norpace(Norpace®®)) –– Widen Widen QRSQRS andand QTQT – qunidine intervalsintervals – qunidine – (Quinidex®®) •• MayMay promote promote Torsades Torsades – (Quinidex ) desdes Pointes! Pointes! ClassClassClass IbIbIbAgentsAgents Agents

•• Slow Slow conductionconduction •• LTMD LTMD:: throughthrough ventriclesventricles –l–lidocaineidocaine (Xylocaine(Xylocaine®®)) •• Increase Increase raterate ofof –t–tocainideocainide (Tonocard (Tonocard®®)) repolarizationrepolarization –m–mexiletineexiletine (Mexitil (Mexitil®®)) – phenytoin (Dilantin®®) •• Reduce Reduce automaticityautomaticity – phenytoin (Dilantin ) –– Effective Effective forfor ectopicectopic focifoci •• May May havehave otherother usesuses ClassClassClass IcIcIcAgentsAgents Agents

•• Slow Slow conductionconduction •• flecainide flecainide throughthrough ventricles,ventricles, (Tambocor(Tambocor®®)) atriaatria && conductionconduction •• propafenone propafenone systemsystem (Rythmol(Rythmol®®)) •• Decrease Decrease repolarizationrepolarization raterate •• Decrease Decrease contractilitycontractility •• Rare Rare lastlast chancechance drugdrug ClassClassClass II:II:II: BetaBetaBeta BlockersBlockersBlockers

•Betareceptors in heart attached to Ca++++ •Beta11 receptors in heart attached to Ca channelschannels –Gradual–Gradual CaCa++++influxinflux responsibleresponsible forfor automaticityautomaticity •Betablockade decreases Ca++++influx •Beta11 blockade decreases Ca influx –– Effects Effects similarsimilar toto ClassClass IVIV (Ca(Ca++++channelchannel blockers)blockers) •• Limited Limited ## approvedapproved forfor tachycardiastachycardias ClassClassClass II:II:II: BetaBetaBeta BlockersBlockersBlockers

•• propranolol propranolol (Inderal (Inderal®®)) •• acebutolol acebutolol (Sectral (Sectral®®)) •• esmolol esmolol (Brevibloc (Brevibloc®®)) ClassClassClass III:III:III: PotassiumPotassiumPotassium ChannelChannelChannel BlockersBlockersBlockers •• Decreases Decreases KK++effluxefflux duringduring repolarizationrepolarization •• Prolongs Prolongs repolarizationrepolarization •• Extends Extends effectiveeffective refractoryrefractory periodperiod •• Prototype: Prototype: bretylliumbretyllium tosylatetosylate (Bretylol(Bretylol®®)) –– Initial Initial norepinorepi dischargedischarge maymay causecause temporarytemporary hypertension/tachycardiahypertension/tachycardia –– Subsequent Subsequent norepinorepi depletiondepletion maymay causecause hypotensionhypotension ClassClassClass IV:IV:IV: CalciumCalciumCalcium ChannelChannelChannel BlockersBlockersBlockers •• Similar Similar effect effect as as ß ß •• verapamil verapamil (Calan (Calan®®)) blockersblockers •• diltiazem diltiazem (Cardizem (Cardizem®®)) •• Decrease Decrease SA/AVSA/AV automaticityautomaticity •• Decrease Decrease AVAV conductivityconductivity •• Note: Note: nifedipinenifedipine •• Useful Useful inin breakingbreaking doesn’tdoesn’t workwork onon heartheart reentrantreentrant circuit circuit •• Prime Prime side side effect: effect: hypotensionhypotension & & bradycardiabradycardia Misc.Misc.Misc. AgentsAgentsAgents

•• adenosine adenosine (Adenocard(Adenocard®®)) –– Decreases Decreases CaCa++++influxinflux && increasesincreases KK++effluxefflux viavia 22ndndmessengermessenger pathwaypathway •• Hyperpolarization Hyperpolarization of of membranemembrane •• Decreased Decreased conduction conduction velocity velocity via via slow slow potentials potentials •• No No effect effect on on fast fast potentials potentials •• Profound Profound sideside effectseffects possiblepossible (but(but short-short- lived)lived) Misc.Misc.Misc. AgentsAgentsAgents

•• Cardiac Cardiac GlycocidesGlycocides •• digoxin digoxin (Lanoxin(Lanoxin®®)) –– Inhibits Inhibits NaKATPNaKATP pump pump –– Increases Increases intracellularintracellular CaCa++++ •via•via NaNa++-Ca-Ca++++exchangeexchange pumppump –– Increases Increases contractilitycontractility –– Decreases Decreases AVAV conductionconduction velocityvelocity PharmacologyPharmacologyPharmacology

AntihypertensivesAntihypertensives AntihypertensiveAntihypertensiveAntihypertensive ClassesClassesClasses

•• diuretics diuretics •• beta beta blockersblockers •• angiotensin-converting angiotensin-converting enzymeenzyme (ACE)(ACE) inhibitorsinhibitors •• calcium calcium channelchannel blockersblockers •• vasodilators vasodilators BloodBloodBlood PressurePressurePressure === COCOCO XXX PVRPVRPVR

•• Cardiac Cardiac OutputOutput == SVSV xx HRHR •• PVR PVR == AfterloadAfterload BPBP == COCO xx PVRPVR

cardiac factors circulating volume heart rate 1. Beta Blockers salt ACEi’s 2. CCB’s contractility 3. C.A. Adrenergics aldosterone Diuretics

Key:

CCB = calcium channel blockers CA Adrenergics = central-acting adrenergics ACEi’s = angiotensin-converting enzyme inhibitors BP = CO x PVR

Hormones Peripheral Sympathetic 1. vasodilators Receptors 2. ACEI’s alpha beta 3. CCB’s 1. alpha blockers 2. beta blockers

Central Nervous System Local Acting 1. CA Adrenergics 1. Peripheral-Acting Adrenergics AlphaAlphaAlpha111 BlockersBlockersBlockers

Stimulate alpha receptors -> hypertension Stimulate alpha11 receptors -> hypertension Block alpha receptors -> hypotension Block alpha11 receptors -> hypotension

•• doxazosin doxazosin (Cardura (Cardura®®)) •• prazosin prazosin (Minipress (Minipress®®)) •• terazosin terazosin (Hytrin (Hytrin®®)) CentralCentralCentral ActingActingActing AdrenergicsAdrenergicsAdrenergics

• Stimulate alpha receptors • Stimulate alpha22 receptors – inhibit alpha stimulation – inhibit alpha11 stimulation •• hypotension hypotension

•• clonidine clonidine (Catapress(Catapress®®)) •• methyldopa methyldopa (Aldomet(Aldomet®®)) PeripheralPeripheralPeripheral ActingActingActing AdrenergicsAdrenergicsAdrenergics

•• reserpine reserpine (Serpalan (Serpalan®®)) •• inhibits inhibits thethe releaserelease ofof NENE •• diminishes diminishes NENE storesstores •• leads leads toto hypotensionhypotension •• Prominent Prominent sideside effecteffect ofof depressiondepression –– also also diminishesdiminishes seratoninseratonin AdrenergicAdrenergicAdrenergic SideSideSide EffectsEffectsEffects

•• Common Common –– dry dry mouth,mouth, drowsiness,drowsiness, sedationsedation && constipationconstipation –– orthostatic orthostatic hypotensionhypotension •• Less Less commoncommon –– headache, headache, sleepsleep disturbances,disturbances, nausea,nausea, rashrash && palpitationspalpitations RAAS ACEACEACE InhibitorsInhibitorsInhibitors Angiotensin I .

ACE

Angiotensin II

1. potent vasoconstrictor - increases BP 2. stimulates Aldosterone + -Na & H2O reabsorbtion ReninReninRenin-Angiotensin--AngiotensinAngiotensin AldosteroneAldosteroneAldosterone SystemSystemSystem •• Angiotensin Angiotensin IIII == vasoconstrictorvasoconstrictor •• Constricts Constricts bloodblood vesselsvessels && increasesincreases BPBP •• Increases Increases SVRSVR oror afterloadafterload •• ACE-I ACE-I blocksblocks thesethese effectseffects decreasingdecreasing SVRSVR && afterloadafterload ACEACEACE InhibitorsInhibitorsInhibitors

•• Aldosterone Aldosterone secretedsecreted fromfrom adrenaladrenal glandsglands causecause sodiumsodium && waterwater reabsorptionreabsorption •• Increase Increase bloodblood volumevolume •• Increase Increase preloadpreload •• ACE-I ACE-I blocksblocks thisthis andand decreasesdecreases preloadpreload AngiotensinAngiotensinAngiotensin ConvertingConvertingConverting EnzymeEnzymeEnzyme InhibitorsInhibitorsInhibitors •• captopril captopril (Capoten(Capoten®®)) •• enalapril enalapril (Vasotec (Vasotec®®)) •• lisinopril lisinopril (Prinivil (Prinivil®®&& ZestrilZestril®®)) •• quinapril quinapril (Accupril (Accupril®®)) •• ramipril ramipril (Altace (Altace®®)) •• benazepril benazepril (Lotensin (Lotensin®®)) •• fosinopril fosinopril (Monopril (Monopril®®)) CalciumCalciumCalcium ChannelChannelChannel BlockersBlockersBlockers

•• Used Used for:for: •Angina•Angina •• Tachycardias Tachycardias •• Hypertension Hypertension CCBCCBCCB SiteSiteSite ofofof ActionActionAction

diltiazem & verapamil

nifedipine (and other dihydropyridines) CCBCCBCCB ActionActionAction

•• diltiazem diltiazem & & verapamilverapamil •• decrease decrease automaticity automaticity & & conduction conduction in in SA SA & & AV AV nodes nodes •• decrease decrease myocardial myocardial contractility contractility •• decreased decreased smooth smooth muscle muscle tone tone •• decreased decreased PVR PVR •• nifedipine nifedipine •• decreased decreased smooth smooth muscle muscle tone tone •• decreased decreased PVR PVR SideSideSide EffectsEffectsEffects ofofof CCBsCCBsCCBs

•• Cardiovascular Cardiovascular •• hypotension, hypotension, palpitationspalpitations && tachycardiatachycardia •• Gastrointestinal Gastrointestinal •• constipation constipation && nauseanausea •Other•Other •• rash, rash, flushingflushing && peripheralperipheral edemaedema CalciumCalciumCalcium ChannelChannelChannel BlockersBlockersBlockers

•• diltiazem diltiazem (Cardizem (Cardizem®®)) •• verapamil verapamil (Calan(Calan®®,, IsoptinIsoptin®®)) •• nifedipine nifedipine (Procardia (Procardia®®,, AdalatAdalat®®)) DiureticDiureticDiuretic SiteSiteSite ofofof ActionActionAction

. Distal tubule proximal tubule Collecting duct

loop of Henle MechanismMechanismMechanism

•• Water Water followsfollows NaNa++ + •• 20-25% 20-25% ofof allall NaNa+isis reabsorbedreabsorbed intointo thethe bloodblood streamstream inin thethe looploop ofof HenleHenle •• 5-10% 5-10% inin distaldistal tubuletubule && 3%3% inin collectingcollecting ductsducts •• If If itit cancan notnot bebe absorbedabsorbed itit isis excretedexcreted withwith thethe urineurine •• ⇓⇓BloodBlood volumevolume == ⇓⇓preloadpreload !! SideSideSide EffectsEffectsEffects ofofof DiureticsDiureticsDiuretics

•• electrolyte electrolyte losseslosses [[NaNa++&& KK++]] •• fluid fluid losseslosses [dehydration][dehydration] •• myalgia myalgia •• N/V/D N/V/D •dizziness•dizziness •• hyperglycemia hyperglycemia DiureticsDiureticsDiuretics

•• Thiazides: Thiazides: •• chlorothiazide chlorothiazide (Diuril (Diuril®®)) && hydrochlorothiazidehydrochlorothiazide (HCTZ(HCTZ®®,, HydroDIURILHydroDIURIL®®)) •• Loop Loop DiureticsDiuretics •• furosemide furosemide (Lasix (Lasix®®),), bumetanidebumetanide (Bumex (Bumex®®)) •• Potassium Potassium SparingSparing DiureticsDiuretics •• spironolactone spironolactone (Aldactone (Aldactone®®)) MechanismMechanismMechanism ofofof VasodilatorsVasodilatorsVasodilators

•• Directly Directly relaxesrelaxes arteriolearteriole smoothsmooth musclemuscle •• Decrease Decrease SVRSVR == decreasedecrease afterloadafterload SideSideSide EffectsEffectsEffects ofofof VasodilatorsVasodilatorsVasodilators

•• hydralazine hydralazine (Apresoline (Apresoline®®)) –– Reflex Reflex tachycardiatachycardia •• sodium sodium nitroprussidenitroprusside (Nipride (Nipride®®)) –– Cyanide Cyanide toxicitytoxicity inin renalrenal failurefailure –– CNS CNS toxicitytoxicity == agitation,agitation, hallucinations,hallucinations, etc.etc. VasodilatorsVasodilatorsVasodilators

•• diazoxide diazoxide [Hyperstat [Hyperstat®®]] •• hydralazine hydralazine [Apresoline [Apresoline®®]] •• minoxidil minoxidil [Loniten [Loniten®®]] •• sodium sodium NitroprussideNitroprusside [Nipride[Nipride®®]] PharmacologyPharmacologyPharmacology

DrugsDrugs AffectingAffecting HemostasisHemostasis HemostasisHemostasisHemostasis

•• Reproduce Reproduce figurefigure 11-9,11-9, pagepage 359359 SherwoodSherwood PlateletPlateletPlatelet AdhesionAdhesionAdhesion CoagulationCoagulationCoagulation CascadeCascadeCascade

•• Reproduce Reproduce followingfollowing componentscomponents ofof cascade:cascade: –– Prothrombin Prothrombin -> -> thrombinthrombin •• Fibrinogen Fibrinogen ->-> fibrinfibrin –– Plasminogen Plasminogen -> -> plasminplasmin PlateletPlateletPlatelet InhibitorsInhibitorsInhibitors

•• Inhibit Inhibit thethe aggregationaggregation ofof plateletsplatelets •• Indicated Indicated inin progressingprogressing MI,MI, TIA/CVATIA/CVA •• Side Side Effects:Effects: uncontrolleduncontrolled bleedingbleeding •• No No effecteffect onon existingexisting thrombithrombi AspirinAspirinAspirin

–– Inhibits Inhibits COXCOX •• Arachidonic Arachidonic acid acid (COX)(COX) ->-> TXA2TXA2 ((⇓⇓aggregation)aggregation) GPGPGP IIB/IIIAIIB/IIIAIIB/IIIA InhibitorsInhibitorsInhibitors

GP IIb/IIIa Receptor

Fibrinogen

GP IIb/IIIa Inhibitors GPGPGP IIB/IIIAIIB/IIIAIIB/IIIA InhibitorsInhibitorsInhibitors

•• abciximab abciximab (ReoPro (ReoPro®®)) •• eptifibitide eptifibitide (Integrilin (Integrilin®®)) •• tirofiban tirofiban (Aggrastat (Aggrastat®®)) AnticoagulantsAnticoagulantsAnticoagulants

•• Interrupt Interrupt clottingclotting cascadecascade atat variousvarious pointspoints –– No No effecteffect onon plateletsplatelets •• Heparin Heparin && LMWLMW HeparinHeparin (Lovenox(Lovenox®®)) •• warfarin warfarin (Coumadin (Coumadin®®)) HeparinHeparinHeparin

•• Endogenous Endogenous –– Released Released from from mast mast cells/basophils cells/basophils •• Binds Binds withwith antithrombinantithrombin IIIIII •• Antithrombin Antithrombin IIIIII bindsbinds withwith andand inactivatesinactivates excessexcess thrombinthrombin toto regionalizeregionalize clottingclotting activity.activity. –– Most Most thrombinthrombin (80-95%)(80-95%) capturedcaptured inin fibrinfibrin mesh.mesh. •• Antithrombin-heparin Antithrombin-heparin complexcomplex 1000X1000X asas effectiveeffective asas antithrombinantithrombin IIIIII alonealone HeparinHeparinHeparin

•• Measured Measured inin Units,Units, notnot milligramsmilligrams •• Indications: Indications: –– MI, MI, PE,PE, DVT,DVT, ischemicischemic CVACVA •• Antidote Antidote forfor heparinheparin OD:OD: protamine.protamine. –– MOA: MOA: heparinheparin isis stronglystrongly negativelynegatively charged.charged. ProtamineProtamine is is stronglystrongly positivelypositively charged.charged. warfarinwarfarinwarfarin(( (CoumadinCoumadinCoumadin®®®)))

•• Factors Factors II,II, VII,VII, IXIX andand XX allall vitaminvitamin KK dependentdependent enzymesenzymes •• Warfarin Warfarin competes competes withwith vitaminvitamin KK inin thethe synthesissynthesis ofof thesethese enzymes.enzymes. •• Depletes Depletes thethe reservesreserves ofof clottingclotting factors.factors. •• Delayed Delayed onsetonset (~12(~12 hours)hours) duedue toto existingexisting factorsfactors ThrombolyticsThrombolyticsThrombolytics

•• Directly Directly breakbreak upup •• streptokinase streptokinase clotsclots (Streptase(Streptase®®)) –– Promote Promote naturalnatural •• alteplase alteplase (tPA (tPA®®,, thrombolysis thrombolysis ActivaseActivase®®)) • Enhance activation • Enhance activation •• anistreplase anistreplase (Eminase (Eminase®®)) ofof plasminogenplasminogen •• reteplase reteplase (Retevase (Retevase®®)) •• ‘Time ‘Time isis Muscle’Muscle’ •• tenecteplase tenecteplase (TNKase (TNKase®®)) OcclusionOcclusionOcclusion MechanismMechanismMechanism tPAtPAtPAMechanismMechanism Mechanism CholesterolCholesterolCholesterol MetabolismMetabolismMetabolism

•• Cholesterol Cholesterol importantimportant componentcomponent inin membranesmembranes andand asas hormonehormone precursorprecursor •• Synthesized Synthesized inin liverliver –– Hydroxymethylglutaryl Hydroxymethylglutaryl coenzyme coenzyme AA reductasereductase –(–(HMGHMG CoACoA reductase reductase)) dependantdependant •• Stored Stored inin tissuestissues forfor latterlatter useuse •• Insoluble Insoluble inin plasmaplasma (a(a typetype ofof lipid)lipid) –– Must Must havehave transporttransport mechanismmechanism LipoproteinsLipoproteinsLipoproteins

•• Lipids Lipids areare surroundedsurrounded byby proteinprotein coatcoat toto ‘hide’‘hide’ hydrophobichydrophobic fattyfatty core.core. •• Lipoproteins Lipoproteins describeddescribed byby densitydensity –– VLDL, VLDL, LDL,LDL, IDL,IDL, HDL,HDL, VHDLVHDL •• LDL LDL containcontain mostmost cholesterolcholesterol inin bodybody –– Transport Transport cholesterol cholesterol from from liver liver to to tissues tissues for for use use (“Bad”)(“Bad”) •• HDL HDL movemove cholesterolcholesterol backback toto liverliver –– “Good” “Good” b/c b/c remove remove cholesterol cholesterol from from circulation circulation WhyWhyWhy WeWeWe FearFearFear CholesterolCholesterolCholesterol

•• Risk Risk ofof CADCAD linkedlinked toto LDLLDL levelslevels •• LDLs LDLs are are depositeddeposited underunder endothelialendothelial surfacesurface andand oxidizedoxidized wherewhere they:they: –– Attracts Attracts monocytes monocytes -> -> macrophages macrophages –– Macrophages Macrophages engulf engulf oxidized oxidized LDL LDL •• Vacuolation Vacuolation into into ‘foam ‘foam cells’ cells’ –– Foam Foam cells cells protrude protrude against against intimal intimal lining lining •• Eventually Eventually a a tough tough cap cap is is formed formed –– Vascular Vascular diameter diameter & & blood blood flow flow decreased decreased WhyWhyWhy WeWeWe FearFearFear CholesterolCholesterolCholesterol

•• Plaque Plaque capcap cancan rupturerupture •• Collagen Collagen exposedexposed •• Clotting Clotting cascadecascade activatedactivated •• Platelet Platelet adhesionadhesion •• Thrombus Thrombus formationformation •• Embolus Embolus formationformation possiblepossible •• Occlusion Occlusion causescauses ischemiaischemia LipidLipidLipid DepositionDepositionDeposition ThrombusThrombusThrombus FormationFormationFormation PlateletPlateletPlatelet AdhesionAdhesionAdhesion EmbolusEmbolusEmbolus FormationFormationFormation OcclusionOcclusionOcclusion CausesCausesCauses InfarctionInfarctionInfarction AntihyperlipidemicAntihyperlipidemicAntihyperlipidemicAgentsAgents Agents

•• Goal: Goal: DecreaseDecrease LDLLDL •• lovastatin lovastatin (Mevacor (Mevacor®®)) –– Inhibition Inhibition ofof LDLLDL •• pravastatin pravastatin (Pravachol (Pravachol®®)) synthesissynthesis •• simvastatin simvastatin (Zocor (Zocor®®)) –– Increase Increase LDLLDL ®® receptorsreceptors inin liverliver •• atorvastatin atorvastatin (Lipitor (Lipitor )) •• Target: Target: << 200200 mg/dlmg/dl •• StatinsStatinsareare HMGHMG CoACoA reductase reductase inhibitorsinhibitors ThankThankThank You!You!You!

•• To To TempleTemple CollegeCollege EMSEMS ProfessionsProfessions forfor permissionpermission toto useuse theirtheir materialsmaterials