(精品)心血管治疗药物DrugsthatAffecttheCardiovascularSystem.ppt

PharmacologyDrugs that Affect the Cardiovascular SystemTopicsElectrophysiologyVaughn-Williams classificationAntihypertensivesHemostatic agentsCardiac FunctionDependent uponAdequate amounts of ATPAdequate amounts of Ca+Coordinated electrical stimulusAdequate Amounts of ATPNeeded to:Maintain electrochemical gradientsPropagate action potentialsPower muscle contractionAdequate Amounts of CalciumCalcium is glue that links electrical and mechanical events.Coordinated Electrical StimulationHeart capable of automaticityTwo types of myocardial tissueContractileConductiveImpulses travel through action potential superhighway.A.P.SuperHighwaySinoatrial nodeAtrioventricular nodeBundle of HisBundle BranchesFasciclesPurkinje NetworkElectrophysiologyTwo types of action potentialsFast potentialsFound in contractile tissueSlow potentialsFound in SA,AV node tissuesFast Potential-80-60-40-200+20RMP-80 to 90 mVPhase 1Phase 2Phase 3Phase 4controlled by Na+channels=“fast channels”Fast PotentialPhase 0:Na+influx“fast sodium channels”Phase 1:K+effluxPhase 2:(Plateau)K+efflux AND Ca+influxPhase 3:K+effluxPhase 4:Resting Membrane PotentialCardiac Conduction CycleSlow Potential-80-60-40-200Phase 4Phase 3dependent upon Ca+channels=“slow channels”Slow PotentialSelf-depolarizingResponsible for automaticityPhase 4 depolarizationslow sodium-calcium channelsleaky to sodiumPhase 3 repolarizationK+effluxCardiac Pacemaker DominanceIntrinsic firing rates:SA=60 100 AV=45 60Purkinje=15-45Cardiac PacemakersSA is primaryFaster depolarization rateFaster Ca+leakOthers are backupsGraduated depolarization rateGraduated Ca+leak ratePotential TermsAPDERPRRPrelative refractoryperiodeffective refractory periodaction potential durationDysrhythmia GenerationAbnormal genesisImbalance of ANS stimuliPathologic phase 4 depolarizationEctopic fociDysrhythmia GenerationAbnormal conductionAnalogies:One way valveBuggies stuck in muddy roadsReentrant CircuitsWarning!All antidysrhythmics have arrythmogenic propertiesIn other words,they all can CAUSE dysrhythmias too!AHA Recommendation ClassificationsDescribes weight of supporting evidence NOT mechanismClass IClass IIaClass IIb IndeterminantClass IIIView AHA definitionsVaughn-Williams ClassificationClass 1IaIbIcClass IIClass IIIClass IVMiscDescription of mechanism NOT evidenceClass I:Sodium Channel BlockersDecrease Na+movement in phases 0 and 4Decreases rate of propagation(conduction)via tissue with fast potential(Purkinje)Ignores those with slow potential(SA/AV)Indications:ventricular dysrhythmiasClass Ia AgentsSlow conduction through ventriclesDecrease repolarization rateWiden QRS and QT intervalsMay promote Torsades des Pointes!PDQ:procainamide(Pronestyl)disopyramide(Norpace)qunidine(Quinidex)Class Ib AgentsSlow conduction through ventriclesIncrease rate of repolarizationReduce automaticityEffective for ectopic fociMay have other usesLTMD:lidocaine(Xylocaine)tocainide(Tonocard)mexiletine(Mexitil)phenytoin(Dilantin)Class Ic AgentsSlow conduction through ventricles,atria&conduction systemDecrease repolarization rateDecrease contractilityRare last chance drugflecainide(Tambocor)propafenone(Rythmol)Class II:Beta BlockersBeta1 receptors in heart attached to Ca+channelsGradual Ca+influx responsible for automaticityBeta1 blockade decreases Ca+influxEffects similar to Class IV(Ca+channel blockers)Limited#approved for tachycardiasClass II:Beta Blockerspropranolol(Inderal)acebutolol(Sectral)esmolol(Brevibloc)Class III:Potassium Channel BlockersDecreases K+efflux during repolarizationProlongs repolarizationExtends effective refractory periodPrototype:bretyllium tosylate(Bretylol)Initial norepi discharge may cause temporary hypertension/tachycardiaSubsequent norepi depletion may cause hypotensionClass IV:Calcium Channel BlockersSimilar effect as blockersDecrease SA/AV automaticityDecrease AV conductivityUseful in breaking reentrant circuitPrime side effect:hypotension&bradycardiaverapamil(Calan)diltiazem(Cardizem)Note:nifedipine doesnt work on heartMisc.Agentsadenosine(Adenocard)Decreases Ca+influx&increases K+efflux via 2nd messenger pathwayHyperpolarization of membraneDecreased conduction velocity via slow potentialsNo effect on fast potentialsProfound side effects possible(but short-lived)Misc.AgentsCardiac Glycocidesdigoxin(Lanoxin)Inhibits NaKATP pumpIncreases intracellular Ca+via Na+-Ca+exchange pumpIncreases contractilityDecreases AV conduction velocityPharmacologyAntihypertensivesAntihypertensive Classesdiureticsbeta blockersangiotensin-converting enzyme(ACE)inhibitors calcium channel blockersvasodilatorsBlood Pressure=CO X PVRCardiac Output=SV x HRPVR=AfterloadBP=CO x PVRKey:CCB=calcium channel blockersCA Adrenergics=central-acting adrenergicsACEis=angiotensin-converting enzyme inhibitorscardiac factorscirculating volumeheart ratecontractility1.Beta Blockers2.CCBs3.C.A.AdrenergicssaltaldosteroneACEisDiureticsBP=CO x PVRHormones1.vasodilators2.ACEIs3.CCBs Central Nervous System1.CA AdrenergicsPeripheral SympatheticReceptorsalpha beta1.alpha blockers 2.beta blockersLocal Acting1.Peripheral-Acting AdrenergicsAlpha1 BlockersStimulate alpha1 receptors-hypertensionBlock alpha1 receptors-hypotensiondoxazosin(Cardura)prazosin(Minipress)terazosin(Hytrin)Central Acting AdrenergicsStimulate alpha2 receptors inhibit alpha1 stimulationhypotensionclonidine(Catapress)methyldopa(Aldomet)Peripheral Acting Adrenergicsreserpine(Serpalan)inhibits the release of NEdiminishes NE storesleads to hypotensionProminent side effect of depressionalso diminishes seratoninAdrenergic Side EffectsCommondry mouth,drowsiness,sedation&constipationorthostatic hypotensionLess commonheadache,sleep disturbances,nausea,rash&palpitationsAngiotensin IACEAngiotensin II1.1.potent vasoconstrictor-increases BP2.stimulates Aldosterone-Na+&H2OreabsorbtionACE Inhibitors.RAASRenin-Angiotensin Aldosterone SystemAngiotensin II =vasoconstrictorConstricts blood vessels&increases BPIncreases SVR or afterloadACE-I blocks these effects decreasing SVR&afterloadACE InhibitorsAldosterone secreted from adrenal glands cause sodium&water reabsorptionIncrease blood volumeIncrease preloadACE-I blocks this and decreases preloadAngiotensin Converting Enzyme Inhibitorscaptopril(Capoten)enalapril(Vasotec)lisinopril(Prinivil&Zestril)quinapril(Accupril)ramipril(Altace)benazepril(Lotensin)fosinopril(Monopril)Calcium Channel BlockersUsed for:AnginaTachycardiasHypertensionCCB Site of Actiondiltiazem&verapamilnifedipine(and otherdihydropyridines)CCB Actiondiltiazem&verapamildecrease automaticity&conduction in SA&AV nodesdecrease myocardial contractilitydecreased smooth muscle tonedecreased PVRnifedipinedecreased smooth muscle tonedecreased PVRSide Effects of CCBsCardiovascularhypotension,palpitations&tachycardiaGastrointestinalconstipation&nauseaOtherrash,flushing&peripheral edemaCalcium Channel Blockersdiltiazem(Cardizem)verapamil(Calan,Isoptin)nifedipine(Procardia,Adalat)Diuretic Site of Action.loop of HenleproximaltubuleDistal tubuleCollecting ductMechanismWater follows Na+20-25%of all Na+is reabsorbed into the blood stream in the loop of Henle5-10%in distal tubule&3%in collecting ductsIf it can not be absorbed it is excreted with the urine Blood volume=preload!Side Effects of Diureticselectrolyte losses Na+&K+fluid losses dehydrationmyalgiaN/V/DdizzinesshyperglycemiaDiureticsThiazides:chlorothiazide(Diuril)&hydrochlorothiazide(HCTZ,HydroDIURIL)Loop Diureticsfurosemide(Lasix),bumetanide(Bumex)Potassium Sparing Diureticsspironolactone(Aldactone)Mechanism of VasodilatorsDirectly relaxes arteriole smooth muscleDecrease SVR=decrease afterload Side Effects of Vasodilatorshydralazine(Apresoline)Reflex tachycardiasodium nitroprusside(Nipride)Cyanide toxicity in renal failureCNS toxicity=agitation,hallucinations,etc.Vasodilatorsdiazoxide Hyperstathydralazine Apresolineminoxidil Lonitensodium Nitroprusside NipridePharmacologyDrugs Affecting HemostasisHemostasisReproduce figure 11-9,page 359 Sherwood Platelet AdhesionCoagulation CascadeReproduce following components of cascade:Prothrombin-thrombin Fibrinogen-fibrinPlasminogen-plasminPlatelet InhibitorsInhibit the aggregation of plateletsIndicated in progressing MI,TIA/CVASide Effects:uncontrolled bleedingNo effect on existing thrombi AspirinInhibits COXArachidonic acid(COX)-TXA2(aggregation)GP IIB/IIIA InhibitorsGPGP IIIIb b/IIIIIIa aInhibitorsInhibitorsFibrinogenGPGP IIIIb b/IIIIIIa aReceptorReceptorGP IIB/IIIA Inhibitorsabciximab(ReoPro)eptifibitide(Integrilin)tirofiban(Aggrastat)AnticoagulantsInterrupt clotting cascade at various pointsNo effect on plateletsHeparin&LMW Heparin(Lovenox)warfarin(Coumadin)HeparinEndogenousReleased from mast cells/basophilsBinds with antithrombin IIIAntithrombin III binds with and inactivates excess thrombin to regionalize clotting activity.Most thrombin(80-95%)captured in fibrin mesh.Antithrombin-heparin complex 1000X as effective as antithrombin III aloneHeparinMeasured in Units,not milligramsIndications:MI,PE,DVT,ischemic CVAAntidote for heparin OD:protamine.MOA:heparin is strongly negatively charged.Protamine is strongly positively charged.warfarin(Coumadin)Factors II,VII,IX and X all vitamin K dependent enzymesWarfarin competes with vitamin K in the synthesis of these enzymes.Depletes the reserves of clotting factors.Delayed onset(12 hours)due to existing factorsThrombolyticsDirectly break up clotsPromote natural thrombolysisEnhance activation of plasminogenTime is Musclestreptokinase(Streptase)alteplase(tPA,Activase)anistreplase(Eminase)reteplase(Retevase)tenecteplase(TNKase)Occlusion MechanismtPA MechanismCholesterol MetabolismCholesterol important component in membranes and as hormone precursorSynthesized in liverHydroxymethylglutaryl coenzyme A reductase(HMG CoA reductase)dependantStored in tissues for latter useInsoluble in plasma(a type of lipid)Must have transport mechanismLipoproteinsLipids are surrounded by protein coat to hide hydrophobic fatty core.Lipoproteins described by densityVLDL,LDL,IDL,HDL,VHDLLDL contain most cholesterol in bodyTransport cholesterol from liver to tissues for use(“Bad”)HDL move cholesterol back to liver“Good”b/c remove cholesterol from circulationWhy We Fear CholesterolRisk of CAD linked to LDL levelsLDLs are deposited under endothelial surface and oxidized where they:Attracts monocytes-macrophagesMacrophages engulf oxidized LDLVacuolation into foam cellsFoam cells protrude against intimal liningEventually a tough cap is formedVascular diameter&blood flow decreasedWhy We Fear CholesterolPlaque cap can ruptureCollagen exposedClotting cascade activatedPlatelet adhesionThrombus formationEmbolus formation possibleOcclusion causes ischemiaLipid DepositionThrombus FormationPlatelet AdhesionEmbolus FormationOcclusion Causes InfarctionAntihyperlipidemic AgentsGoal:Decrease LDLInhibition of LDL synthesisIncrease LDL receptors in liverTarget:200 mg/dlStatins are HMG CoA reductase inhibitorslovastatin(Mevacor)pravastatin(Pravachol)simvastatin(Zocor)atorvastatin(Lipitor)