心血管治疗药物综述

nullPharmacologyPharmacologyDrugs that Affect the Cardiovascular SystemTopicsTopicsElectrophysiology Vaughn-Williams classification Antihypertensives Hemostatic agentsCardiac FunctionCardiac FunctionDependent upon Adequate amounts of ATP Adequate amounts of Ca++ Coordinated electrical stimulusAdequate Amounts of ATPAdequate Amounts of ATPNeeded to: Maintain electrochemical gradients Propagate action potentials Power muscle contractionAdequate Amounts of CalciumAdequate Amounts of CalciumCalcium is ‘glue’ that links electrical and mechanical events.Coordinated Electrical StimulationCoordinated Electrical StimulationHeart capable of automaticity Two types of myocardial tissue Contractile Conductive Impulses travel through ‘action potential superhighway’.A.P. SuperHighwayA.P. SuperHighwaySinoatrial node Atrioventricular node Bundle of His Bundle Branches Fascicles Purkinje NetworkElectrophysiologyElectrophysiologyTwo types of action potentials Fast potentials Found in contractile tissue Slow potentials Found in SA, AV node tissuesFast PotentialFast Potential-80-60-40-200+20RMP -80 to 90 mVPhase 1Phase 2Phase 3Phase 4controlled by Na+ channels = “fast channels”Fast PotentialFast PotentialPhase 0: Na+ influx “fast sodium channels” Phase 1: K + efflux Phase 2: (Plateau) K + efflux AND Ca + + influx Phase 3: K+ efflux Phase 4: Resting Membrane PotentialCardiac Conduction CycleCardiac Conduction CycleSlow PotentialSlow Potential-80-60-40-200Phase 4Phase 3dependent upon Ca++ channels = “slow channels”Slow PotentialSlow PotentialSelf-depolarizing Responsible for automaticity Phase 4 depolarization ‘slow sodium-calcium channels’ ‘leaky’ to sodium Phase 3 repolarization K+ effluxCardiac Pacemaker DominanceCardiac Pacemaker DominanceIntrinsic firing rates: SA = 60 – 100 AV = 45 – 60 Purkinje = 15 - 45Cardiac PacemakersCardiac PacemakersSA is primary Faster depolarization rate Faster Ca++ ‘leak’ Others are ‘backups’ Graduated depolarization rate Graduated Ca++ leak ratePotential TermsPotential TermsAPDERPRRPrelative refractory periodeffective refractory periodaction potential durationDysrhythmia GenerationDysrhythmia GenerationAbnormal genesis Imbalance of ANS stimuli Pathologic phase 4 depolarization Ectopic fociDysrhythmia GenerationDysrhythmia GenerationAbnormal conduction Analogies: One way valve Buggies stuck in muddy roadsReentrant CircuitsReentrant CircuitsWarning!Warning!All antidysrhythmics have arrythmogenic properties In other words, they all can CAUSE dysrhythmias too!AHA Recommendation ClassificationsAHA Recommendation ClassificationsDescribes weight of supporting evidence NOT mechanism Class I Class IIa Class IIb Indeterminant Class IIIView AHA definitionsVaughn-Williams ClassificationVaughn-Williams ClassificationClass 1 Ia Ib Ic Class II Class III Class IV MiscDescription of mechanism NOT evidenceClass I: Sodium Channel BlockersClass I: Sodium Channel BlockersDecrease Na+ movement in phases 0 and 4 Decreases rate of propagation (conduction) via tissue with fast potential (Purkinje) Ignores those with slow potential (SA/AV) Indications: ventricular dysrhythmiasClass Ia AgentsClass Ia AgentsSlow conduction through ventricles Decrease repolarization rate Widen QRS and QT intervals May promote Torsades des Pointes!PDQ: procainamide (Pronestyl®) disopyramide (Norpace®) qunidine (Quinidex®)Class Ib AgentsClass Ib AgentsSlow conduction through ventricles Increase rate of repolarization Reduce automaticity Effective for ectopic foci May have other usesLTMD: lidocaine (Xylocaine®) tocainide (Tonocard®) mexiletine (Mexitil®) phenytoin (Dilantin®)Class Ic AgentsClass Ic AgentsSlow conduction through ventricles, atria & conduction system Decrease repolarization rate Decrease contractility Rare last chance drugflecainide (Tambocor®) propafenone (Rythmol®)Class II: Beta BlockersClass II: Beta BlockersBeta1 receptors in heart attached to Ca++ channels Gradual Ca++ influx responsible for automaticity Beta1 blockade decreases Ca++ influx Effects similar to Class IV (Ca++ channel blockers) Limited # approved for tachycardiasClass II: Beta BlockersClass II: Beta Blockerspropranolol (Inderal®) acebutolol (Sectral®) esmolol (Brevibloc®)Class III: Potassium Channel BlockersClass III: Potassium Channel BlockersDecreases K+ efflux during repolarization Prolongs repolarization Extends effective refractory period Prototype: bretyllium tosylate (Bretylol®) Initial norepi discharge may cause temporary hypertension/tachycardia Subsequent norepi depletion may cause hypotensionClass IV: Calcium Channel BlockersClass IV: Calcium Channel BlockersSimilar effect as ß blockers Decrease SA/AV automaticity Decrease AV conductivity Useful in breaking reentrant circuit Prime side effect: hypotension & bradycardiaverapamil (Calan®) diltiazem (Cardizem®) Note: nifedipine doesn’t work on heartMisc. AgentsMisc. Agentsadenosine (Adenocard®) Decreases Ca++ influx & increases K+ efflux via 2nd messenger pathway Hyperpolarization of membrane Decreased conduction velocity via slow potentials No effect on fast potentials Profound side effects possible (but short-lived)Misc. AgentsMisc. AgentsCardiac Glycocides digoxin (Lanoxin®) Inhibits NaKATP pump Increases intracellular Ca++ via Na+-Ca++ exchange pump Increases contractility Decreases AV conduction velocityPharmacologyPharmacologyAntihypertensivesAntihypertensive ClassesAntihypertensive Classesdiuretics beta blockers angiotensin-converting enzyme (ACE) inhibitors calcium channel blockers vasodilatorsBlood Pressure = CO X PVRBlood Pressure = CO X PVRCardiac Output = SV x HR PVR = AfterloadBP = CO x PVRBP = CO x PVRKey:CCB = calcium channel blockers CA Adrenergics = central-acting adrenergics ACEi’s = angiotensin-converting enzyme inhibitorsnullBP = CO x PVRPeripheral Sympathetic Receptors alpha beta 1. alpha blockers 2. beta blockersLocal Acting 1. Peripheral-Acting AdrenergicsAlpha1 BlockersAlpha1 BlockersStimulate alpha1 receptors -> hypertension Block alpha1 receptors -> hypotensiondoxazosin (Cardura®) prazosin (Minipress®) terazosin (Hytrin®) Central Acting AdrenergicsCentral Acting AdrenergicsStimulate alpha2 receptors inhibit alpha1 stimulation hypotensionclonidine (Catapress®) methyldopa (Aldomet®) Peripheral Acting AdrenergicsPeripheral Acting Adrenergicsreserpine (Serpalan®) inhibits the release of NE diminishes NE stores leads to hypotension Prominent side effect of depression also diminishes seratoninAdrenergic Side EffectsAdrenergic Side EffectsCommon dry mouth, drowsiness, sedation & constipation orthostatic hypotension Less common headache, sleep disturbances, nausea, rash & palpitationsACE Inhibitors Angiotensin I ACE Angiotensin II 1. potent vasoconstrictor - increases BP 2. stimulates Aldosterone - Na+ & H2O reabsorbtion ACE Inhibitors .RAASRenin-Angiotensin Aldosterone SystemRenin-Angiotensin Aldosterone SystemAngiotensin II = vasoconstrictor Constricts blood vessels & increases BP Increases SVR or afterload ACE-I blocks these effects decreasing SVR & afterloadACE InhibitorsACE InhibitorsAldosterone secreted from adrenal glands cause sodium & water reabsorption Increase blood volume Increase preload ACE-I blocks this and decreases preloadAngiotensin Converting Enzyme InhibitorsAngiotensin Converting Enzyme Inhibitorscaptopril (Capoten®) enalapril (Vasotec®) lisinopril (Prinivil® & Zestril®) quinapril (Accupril®) ramipril (Altace®) benazepril (Lotensin®) fosinopril (Monopril®)Calcium Channel BlockersCalcium Channel BlockersUsed for: Angina Tachycardias HypertensionCCB Site of ActionCCB Site of Actiondiltiazem & verapamilnifedipine (and other dihydropyridines)CCB ActionCCB Actiondiltiazem & verapamil decrease automaticity & conduction in SA & AV nodes decrease myocardial contractility decreased smooth muscle tone decreased PVR nifedipine decreased smooth muscle tone decreased PVRSide Effects of CCBsSide Effects of CCBsCardiovascular hypotension, palpitations & tachycardia Gastrointestinal constipation & nausea Other rash, flushing & peripheral edemaCalcium Channel BlockersCalcium Channel Blockersdiltiazem (Cardizem®) verapamil (Calan®, Isoptin®) nifedipine (Procardia®, Adalat®)Diuretic Site of ActionDiuretic Site of Action.loop of Henleproximal tubuleDistal tubuleCollecting duct MechanismMechanismWater follows Na+ 20-25% of all Na+ is reabsorbed into the blood stream in the loop of Henle 5-10% in distal tubule & 3% in collecting ducts If it can not be absorbed it is excreted with the urine  Blood volume =  preload ! Side Effects of DiureticsSide Effects of Diureticselectrolyte losses [Na+ & K+ ] fluid losses [dehydration] myalgia N/V/D dizziness hyperglycemiaDiureticsDiureticsThiazides: chlorothiazide (Diuril®) & hydrochlorothiazide (HCTZ®, HydroDIURIL®) Loop Diuretics furosemide (Lasix®), bumetanide (Bumex®) Potassium Sparing Diuretics spironolactone (Aldactone®)Mechanism of VasodilatorsMechanism of VasodilatorsDirectly relaxes arteriole smooth muscle Decrease SVR = decrease afterload Side Effects of VasodilatorsSide Effects of Vasodilatorshydralazine (Apresoline®) Reflex tachycardia sodium nitroprusside (Nipride®) Cyanide toxicity in renal failure CNS toxicity = agitation, hallucinations, etc.VasodilatorsVasodilatorsdiazoxide [Hyperstat®] hydralazine [Apresoline®] minoxidil [Loniten®] sodium Nitroprusside [Nipride®]PharmacologyPharmacologyDrugs Affecting HemostasisHemostasisHemostasisReproduce figure 11-9, page 359 Sherwood Platelet AdhesionPlatelet AdhesionCoagulation CascadeCoagulation CascadeReproduce following components of cascade: Prothrombin -> thrombin Fibrinogen -> fibrin Plasminogen -> plasminPlatelet InhibitorsPlatelet InhibitorsInhibit the aggregation of platelets Indicated in progressing MI, TIA/CVA Side Effects: uncontrolled bleeding No effect on existing thrombi Aspirin AspirinInhibits COX Arachidonic acid (COX) -> TXA2 ( aggregation)GP IIB/IIIA InhibitorsGP IIB/IIIA InhibitorsGP IIb/IIIa InhibitorsFibrinogenGP IIb/IIIa ReceptorGP IIB/IIIA InhibitorsGP IIB/IIIA Inhibitorsabciximab (ReoPro®) eptifibitide (Integrilin®) tirofiban (Aggrastat®)AnticoagulantsAnticoagulantsInterrupt clotting cascade at various points No effect on platelets Heparin & LMW Heparin (Lovenox®) warfarin (Coumadin®)HeparinHeparinEndogenous Released from mast cells/basophils Binds with antithrombin III Antithrombin 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 aloneHeparinHeparinMeasured in Units, not milligrams Indications: MI, PE, DVT, ischemic CVA Antidote for heparin OD: protamine. MOA: heparin is strongly negatively charged. Protamine is strongly positively charged. warfarin (Coumadin®)warfarin (Coumadin®)Factors II, VII, IX and X all vitamin K dependent enzymes Warfarin competes with vitamin K in the synthesis of these enzymes. Depletes the reserves of clotting factors. Delayed onset (~12 hours) due to existing factorsThrombolyticsThrombolyticsDirectly break up clots Promote natural thrombolysis Enhance activation of plasminogen ‘Time is Muscle’streptokinase (Streptase®) alteplase (tPA®, Activase®) anistreplase (Eminase®) reteplase (Retevase®) tenecteplase (TNKase®)Occlusion MechanismOcclusion MechanismtPA MechanismtPA MechanismCholesterol MetabolismCholesterol MetabolismCholesterol important component in membranes and as hormone precursor Synthesized in liver Hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase) dependant Stored in tissues for latter use Insoluble in plasma (a type of lipid) Must have transport mechanismLipoproteinsLipoproteinsLipids are surrounded by protein coat to ‘hide’ hydrophobic fatty core. Lipoproteins described by density VLDL, LDL, IDL, HDL, VHDL LDL contain most cholesterol in body Transport cholesterol from liver to tissues for use (“Bad”) HDL move cholesterol back to liver “Good” b/c remove cholesterol from circulationWhy We Fear CholesterolWhy We Fear CholesterolRisk of CAD linked to LDL levels LDLs are deposited under endothelial surface and oxidized where they: Attracts monocytes -> macrophages Macrophages engulf oxidized LDL Vacuolation into ‘foam cells’ Foam cells protrude against intimal lining Eventually a tough cap is formed Vascular diameter & blood flow decreasedWhy We Fear CholesterolWhy We Fear CholesterolPlaque cap can rupture Collagen exposed Clotting cascade activated Platelet adhesion Thrombus formation Embolus formation possible Occlusion causes ischemiaLipid DepositionLipid DepositionThrombus FormationThrombus FormationPlatelet AdhesionPlatelet AdhesionEmbolus FormationEmbolus FormationOcclusion Causes InfarctionOcclusion Causes InfarctionAntihyperlipidemic AgentsAntihyperlipidemic AgentsGoal: Decrease LDL Inhibition of LDL synthesis Increase LDL receptors in liver Target: < 200 mg/dl Statins are HMG CoA reductase inhibitors lovastatin (Mevacor®) pravastatin (Pravachol®) simvastatin (Zocor®) atorvastatin (Lipitor®)