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1、Pharmacology,Drugs that Affect the Cardiovascular System,Topics,ElectrophysiologyVaughn-Williams classificationAntihypertensivesHemostatic agents,Cardiac Function,Dependent uponAdequate amounts of ATPAdequate amounts of Ca+Coordinated electrical stimulus,Adequate Amounts of ATP,Needed to:Maintain el
2、ectrochemical gradientsPropagate action potentialsPower muscle contraction,Adequate Amounts of Calcium,Calcium is glue that links electrical and mechanical events.,Coordinated Electrical Stimulation,Heart capable of automaticityTwo types of myocardial tissueContractileConductiveImpulses travel throu
3、gh action potential superhighway.,A.P.SuperHighway,Sinoatrial nodeAtrioventricular nodeBundle of HisBundle BranchesFasciclesPurkinje Network,Electrophysiology,Two types of action potentialsFast potentialsFound in contractile tissueSlow potentialsFound in SA,AV node tissues,Fast Potential,-80,-60,-40
4、,-20,0,+20,RMP-80 to 90 mV,Phase 1,Phase 2,Phase 3,Phase 4,controlled by Na+channels=“fast channels”,Fast Potential,Phase 0:Na+influx“fast sodium channels”Phase 1:K+effluxPhase 2:(Plateau)K+efflux AND Ca+influxPhase 3:K+effluxPhase 4:Resting Membrane Potential,Cardiac Conduction Cycle,Slow Potential
5、,-80,-60,-40,-20,0,Phase 4,Phase 3,dependent upon Ca+channels=“slow channels”,Slow Potential,Self-depolarizingResponsible for automaticityPhase 4 depolarizationslow sodium-calcium channelsleaky to sodiumPhase 3 repolarizationK+efflux,Cardiac Pacemaker Dominance,Intrinsic firing rates:SA=60 100 AV=45
6、 60Purkinje=15-45,Cardiac Pacemakers,SA is primaryFaster depolarization rateFaster Ca+leakOthers are backupsGraduated depolarization rateGraduated Ca+leak rate,Potential Terms,APD,ERP,RRP,relative refractoryperiod,effective refractory period,action potential duration,Dysrhythmia Generation,Abnormal
7、genesisImbalance of ANS stimuliPathologic phase 4 depolarizationEctopic foci,Dysrhythmia Generation,Abnormal conductionAnalogies:One way valveBuggies stuck in muddy roads,Reentrant Circuits,Warning!,All antidysrhythmics have arrythmogenic propertiesIn other words,they all can CAUSE dysrhythmias too!
8、,AHA Remendation Classifications,Describes weight of supporting evidence NOT mechanismClass IClass IIaClass IIb IndeterminantClass III,View AHA definitions,Vaughn-Williams Classification,Class 1IaIbIcClass IIClass IIIClass IVMisc,Description of mechanism NOT evidence,Class I:Sodium Channel Blockers,
9、Decrease 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 dysrhythmias,Class Ia Agents,Slow conduction through ventriclesDecrease repolarization rateWiden QRS and QT intervals
10、May promote Torsades des Pointes!,PDQ:procainamide(Pronestyl)disopyramide(Norpace)qunidine(Quinidex),Class Ib Agents,Slow conduction through ventriclesIncrease rate of repolarizationReduce automaticityEffective for ectopic fociMay have other uses,LTMD:lidocaine(Xylocaine)tocainide(Tonocard)mexiletin
11、e(Mexitil)phenytoin(Dilantin),Class Ic Agents,Slow conduction through ventricles,atria&conduction systemDecrease repolarization rateDecrease contractilityRare last chance drug,flecainide(Tambocor)propafenone(Rythmol),Class II:Beta Blockers,Beta1 receptors in heart attached to Ca+channelsGradual Ca+i
12、nflux responsible for automaticityBeta1 blockade decreases Ca+influxEffects similar to Class IV(Ca+channel blockers)Limited#approved for tachycardias,Class II:Beta Blockers,propranolol(Inderal)acebutolol(Sectral)esmolol(Brevibloc),Class III:Potassium Channel Blockers,Decreases K+efflux during repola
13、rizationProlongs repolarizationExtends effective refractory periodPrototype:bretyllium tosylate(Bretylol)Initial norepi discharge may cause temporary hypertension/tachycardiaSubsequent norepi depletion may cause hypotension,Class IV:Calcium Channel Blockers,Similar effect as blockersDecrease SA/AV a
14、utomaticityDecrease AV conductivityUseful in breaking reentrant circuitPrime side effect:hypotension&bradycardia,verapamil(Calan)diltiazem(Cardizem)Note:nifedipine doesnt work on heart,Misc.Agents,adenosine(Adenocard)Decreases Ca+influx&increases K+efflux via 2nd messenger pathwayHyperpolarization o
15、f membraneDecreased conduction velocity via slow potentialsNo effect on fast potentialsProfound side effects possible(but short-lived),Misc.Agents,Cardiac Glycocidesdigoxin(Lanoxin)Inhibits NaKATP pumpIncreases intracellular Ca+via Na+-Ca+exchange pumpIncreases contractilityDecreases AV conduction v
16、elocity,Pharmacology,Antihypertensives,Antihypertensive Classes,diureticsbeta blockersangiotensin-converting enzyme(ACE)inhibitors calcium channel blockersvasodilators,Blood Pressure=CO X PVR,Cardiac Output=SV x HRPVR=Afterload,BP=CO x PVR,Key:,CCB=calcium channel blockersCA Adrenergics=central-acti
17、ng adrenergicsACEis=angiotensin-converting enzyme inhibitors,BP=CO x PVR,Peripheral SympatheticReceptorsalpha beta1.alpha blockers 2.beta blockers,Local Acting1.Peripheral-Acting Adrenergics,Alpha1 Blockers,Stimulate alpha1 receptors-hypertensionBlock alpha1 receptors-hypotension,doxazosin(Cardura)p
18、razosin(Minipress)terazosin(Hytrin),Central Acting Adrenergics,Stimulate alpha2 receptors inhibit alpha1 stimulationhypotension,clonidine(Catapress)methyldopa(Aldomet),Peripheral Acting Adrenergics,reserpine(Serpalan)inhibits the release of NEdiminishes NE storesleads to hypotensionProminent side ef
19、fect of depressionalso diminishes seratonin,Adrenergic Side Effects,Commondry mouth,drowsiness,sedation&constipationorthostatic hypotensionLess monheadache,sleep disturbances,nausea,rash&palpitations,Angiotensin IACEAngiotensin II1.potent vasoconstrictor-increases BP2.stimulates Aldosterone-Na+&H2Or
20、eabsorbtion,ACE Inhibitors,.,RAAS,Renin-Angiotensin Aldosterone System,Angiotensin II=vasoconstrictorConstricts blood vessels&increases BPIncreases SVR or afterloadACE-I blocks these effects decreasing SVR&afterload,ACE Inhibitors,Aldosterone secreted from adrenal glands cause sodium&water reabsorpt
21、ionIncrease blood volumeIncrease preloadACE-I blocks this and decreases preload,Angiotensin Converting Enzyme Inhibitors,captopril(Capoten)enalapril(Vasotec)lisinopril(Prinivil&Zestril)quinapril(Accupril)ramipril(Altace)benazepril(Lotensin)fosinopril(Monopril),Calcium Channel Blockers,Used for:Angin
22、aTachycardiasHypertension,CCB Site of Action,diltiazem&verapamil,nifedipine(and otherdihydropyridines),CCB Action,diltiazem&verapamildecrease automaticity&conduction in SA&AV nodesdecrease myocardial contractilitydecreased smooth muscle tonedecreased PVRnifedipinedecreased smooth muscle tonedecrease
23、d PVR,Side Effects of CCBs,Cardiovascularhypotension,palpitations&tachycardiaGastrointestinalconstipation&nauseaOtherrash,flushing&peripheral edema,Calcium Channel Blockers,diltiazem(Cardizem)verapamil(Calan,Isoptin)nifedipine(Procardia,Adalat),Diuretic Site of Action,.,loop of Henle,proximaltubule,
24、Distal tubule,Collecting duct,Mechanism,Water 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 Diuretics,electrolyte losses Na+&K
25、+fluid losses dehydrationmyalgiaN/V/Ddizzinesshyperglycemia,Diuretics,Thiazides:chlorothiazide(Diuril)&hydrochlorothiazide(HCTZ,HydroDIURIL)Loop Diureticsfurosemide(Lasix),bumetanide(Bumex)Potassium Sparing Diureticsspironolactone(Aldactone),Mechanism of Vasodilators,Directly relaxes arteriole smoot
26、h muscleDecrease SVR=decrease afterload,Side Effects of Vasodilators,hydralazine(Apresoline)Reflex tachycardiasodium nitroprusside(Nipride)Cyanide toxicity in renal failureCNS toxicity=agitation,hallucinations,etc.,Vasodilators,diazoxide Hyperstathydralazine Apresolineminoxidil Lonitensodium Nitropr
27、usside Nipride,Pharmacology,Drugs Affecting Hemostasis,Hemostasis,Reproduce figure 11-9,page 359 Sherwood,Platelet Adhesion,Coagulation Cascade,Reproduce following ponents of cascade:Prothrombin-thrombin Fibrinogen-fibrinPlasminogen-plasmin,Platelet Inhibitors,Inhibit the aggregation of plateletsInd
28、icated in progressing MI,TIA/CVASide Effects:uncontrolled bleedingNo effect on existing thrombi,Aspirin,Inhibits COXArachidonic acid(COX)-TXA2(aggregation),GP IIB/IIIA Inhibitors,GP IIb/IIIaInhibitors,Fibrinogen,GP IIb/IIIaReceptor,GP IIB/IIIA Inhibitors,abciximab(ReoPro)eptifibitide(Integrilin)tiro
29、fiban(Aggrastat),Anticoagulants,Interrupt clotting cascade at various pointsNo effect on plateletsHeparin&LMW Heparin(Lovenox)warfarin(Coumadin),Heparin,EndogenousReleased from mast cells/basophilsBinds with antithrombin IIIAntithrombin III binds with and inactivates excess thrombin to regionalize c
30、lotting activity.Most thrombin(80-95%)captured in fibrin mesh.Antithrombin-heparin plex 1000X as effective as antithrombin III alone,Heparin,Measured in Units,not milligramsIndications:MI,PE,DVT,ischemic CVAAntidote for heparin OD:protamine.MOA:heparin is strongly negatively charged.Protamine is str
31、ongly positively charged.,warfarin(Coumadin),Factors II,VII,IX and X all vitamin K dependent enzymesWarfarin petes with vitamin K in the synthesis of these enzymes.Depletes the reserves of clotting factors.Delayed onset(12 hours)due to existing factors,Thrombolytics,Directly break up clotsPromote na
32、tural thrombolysisEnhance activation of plasminogenTime is Muscle,streptokinase(Streptase)alteplase(tPA,Activase)anistreplase(Eminase)reteplase(Retevase)tenecteplase(TNKase),Occlusion Mechanism,tPA Mechanism,Cholesterol Metabolism,Cholesterol important ponent in membranes and as hormone precursorSyn
33、thesized in liverHydroxymethylglutaryl coenzyme A reductase(HMG CoA reductase)dependantStored in tissues for latter useInsoluble in plasma(a type of lipid)Must have transport mechanism,Lipoproteins,Lipids are surrounded by protein coat to hide hydrophobic fatty core.Lipoproteins described by density
34、VLDL,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 circulation,Why We Fear Cholesterol,Risk of CAD linked to LDL levelsLDLs are deposited under endothelial surface and
35、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 decreased,Why We Fear Cholesterol,Plaque cap can ruptureCollagen exposedClotting cascade
36、activatedPlatelet adhesionThrombus formationEmbolus formation possibleOcclusion causes ischemia,Lipid Deposition,Thrombus Formation,Platelet Adhesion,Embolus Formation,Occlusion Causes Infarction,Antihyperlipidemic Agents,Goal:Decrease LDLInhibition of LDL synthesisIncrease LDL receptors in liverTarget:200 mg/dlStatins are HMG CoA reductase inhibitors,lovastatin(Mevacor)pravastatin(Pravachol)simvastatin(Zocor)atorvastatin(Lipitor),
