心血管治疗药物综述课件.ppt

1、Drugs that Affect the Cardiovascular System Electrophysiology Vaughn-Williams classification Antihypertensives Hemostatic agents Dependent upon Adequate amounts of ATP Adequate amounts of Ca+Coordinated electrical stimulus Needed to:Maintain electrochemical gradients Propagate action potentials Powe

2、r muscle contraction Calcium is glue that links electrical and mechanical events.Heart capable of automaticity Two types of myocardial tissue Contractile Conductive Impulses travel through action potential superhighway.Sinoatrial node Atrioventricular node Bundle of His Bundle Branches Fascicles Pur

3、kinje Network Two types of action potentials Fast potentials Found in contractile tissue Slow potentials Found in SA,AV node tissues-80-60-40-200+20RMP-80 to 90 mVPhase 1Phase 2Phase 3Phase 4controlled by Na+channels=“fast channels”Phase 0:Na+influx“fast sodium channels”Phase 1:K+efflux Phase 2:(Pla

4、teau)K+efflux AND Ca+influx Phase 3:K+efflux Phase 4:Resting Membrane Potential-80-60-40-200Phase 4Phase 3dependent upon Ca+channels=“slow channels”Self-depolarizing Responsible for automaticity Phase 4 depolarization slow sodium-calcium channels leaky to sodium Phase 3 repolarization K+efflux Intri

5、nsic firing rates:SA=60 100 AV=45 60 Purkinje=15-45 SA is primary Faster depolarization rate Faster Ca+leak Others are backups Graduated depolarization rate Graduated Ca+leak rateAPDERPRRPrelative refractoryperiodeffective refractory periodaction potential duration Abnormal genesis Imbalance of ANS

6、stimuli Pathologic phase 4 depolarization Ectopic foci Abnormal conduction Analogies:One way valve Buggies stuck in muddy roads All antidysrhythmics have arrythmogenic properties In other words,they all can CAUSE dysrhythmias too!Describes weight of supporting evidence NOT mechanism Class I Class II

7、a Class IIb Indeterminant Class III View AHA definitions Class 1 Ia Ib Ic Class II Class III Class IV Misc Description of mechanism NOT evidence Decrease Na+movement in phases 0 and 4 Decreases rate of propagation(conduction)via tissue with fast potential(Purkinje)Ignores those with slow potential(S

8、A/AV)Indications:ventricular dysrhythmias Slow conduction through ventricles Decrease repolarization rate Widen QRS and QT intervals May promote Torsades des Pointes!PDQ:procainamide(Pronestyl)disopyramide(Norpace)qunidine (Quinidex)Slow conduction through ventricles Increase rate of repolarization

9、Reduce automaticity Effective for ectopic foci May have other uses LTMD:lidocaine(Xylocaine)tocainide(Tonocard)mexiletine(Mexitil)phenytoin(Dilantin)Slow conduction through ventricles,atria&conduction system Decrease repolarization rate Decrease contractility Rare last chance drug flecainide(Tamboco

10、r)propafenone(Rythmol)Beta1 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 tachycardias propranolol(Inderal)acebutolol(Sectral)esmolol(Brevibloc)Decrease

11、s 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 hypotension Similar effect as blockers Decrease SA/AV automa

12、ticity Decrease AV conductivity Useful in breaking reentrant circuit Prime side effect:hypotension&bradycardia verapamil(Calan)diltiazem(Cardizem)Note:nifedipine doesnt work on heart adenosine(Adenocard)Decreases Ca+influx&increases K+efflux via 2nd messenger pathway Hyperpolarization of membrane De

13、creased conduction velocity via slow potentials No effect on fast potentials Profound side effects possible(but short-lived)Cardiac Glycocides digoxin(Lanoxin)Inhibits NaKATP pump Increases intracellular Ca+via Na+-Ca+exchange pump Increases contractility Decreases AV conduction velocityAntihyperten

14、sives diuretics beta blockers angiotensin-converting enzyme(ACE)inhibitors calcium channel blockers vasodilators Cardiac Output=SV x HR PVR=AfterloadKey:CCB=calcium channel blockersCA Adrenergics=central-acting adrenergicsACEis=angiotensin-converting enzyme inhibitorscardiac factorscirculating volum

15、eheart 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 AdrenergicsStimulat

16、e alpha1 receptors-hypertensionBlock alpha1 receptors-hypotension doxazosin(Cardura)prazosin(Minipress)terazosin(Hytrin)Stimulate alpha2 receptors inhibit alpha1 stimulation hypotension clonidine(Catapress)methyldopa(Aldomet)reserpine(Serpalan)inhibits the release of NE diminishes NE stores leads to

17、 hypotension Prominent side effect of depression also diminishes seratonin Common dry mouth,drowsiness,sedation&constipation orthostatic hypotension Less common headache,sleep disturbances,nausea,rash&palpitationsAngiotensin IACEAngiotensin II1.1.potent vasoconstrictor-increases BP2.stimulates Aldos

18、terone-Na+&H2Oreabsorbtion.RAAS Angiotensin II =vasoconstrictor Constricts blood vessels&increases BP Increases SVR or afterload ACE-I blocks these effects decreasing SVR&afterload Aldosterone secreted from adrenal glands cause sodium&water reabsorption Increase blood volume Increase preload ACE-I b

19、locks this and decreases preload captopril(Capoten)enalapril(Vasotec)lisinopril(Prinivil&Zestril)quinapril(Accupril)ramipril(Altace)benazepril(Lotensin)fosinopril(Monopril)Used for:Angina Tachycardias Hypertensiondiltiazem&verapamilnifedipine(and otherdihydropyridines)diltiazem&verapamil decrease au

20、tomaticity&conduction in SA&AV nodes decrease myocardial contractility decreased smooth muscle tone decreased PVR nifedipine decreased smooth muscle tone decreased PVR Cardiovascular hypotension,palpitations&tachycardia Gastrointestinal constipation&nausea Other rash,flushing&peripheral edema diltia

21、zem(Cardizem)verapamil(Calan,Isoptin)nifedipine(Procardia,Adalat).loop of HenleproximaltubuleDistal tubuleCollecting duct Water 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 wit

22、h the urine Blood volume=preload!electrolyte losses Na+&K+fluid losses dehydration myalgia N/V/D dizziness hyperglycemia Thiazides:chlorothiazide(Diuril)&hydrochlorothiazide(HCTZ,HydroDIURIL)Loop Diuretics furosemide(Lasix),bumetanide(Bumex)Potassium Sparing Diuretics spironolactone(Aldactone)Direct

23、ly relaxes arteriole smooth muscle Decrease SVR=decrease afterload hydralazine(Apresoline)Reflex tachycardia sodium nitroprusside(Nipride)Cyanide toxicity in renal failure CNS toxicity=agitation,hallucinations,etc.diazoxide Hyperstat hydralazine Apresoline minoxidil Loniten sodium Nitroprusside Nipr

24、ideDrugs Affecting Hemostasis Reproduce figure 11-9,page 359 Sherwood Reproduce following components of cascade:Prothrombin-thrombin Fibrinogen-fibrin Plasminogen-plasmin Inhibit the aggregation of platelets Indicated in progressing MI,TIA/CVA Side Effects:uncontrolled bleeding No effect on existing

25、 thrombi Inhibits COX Arachidonic acid(COX)-TXA2(aggregation)Fibrinogen abciximab(ReoPro)eptifibitide(Integrilin)tirofiban(Aggrastat)Interrupt clotting cascade at various points No effect on platelets Heparin&LMW Heparin(Lovenox)warfarin(Coumadin)Endogenous Released from mast cells/basophils Binds w

26、ith 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 alone Measured in Units,not milligrams Indications:MI,PE,DVT,ischemic CVA

27、 Antidote for heparin OD:protamine.MOA:heparin is strongly negatively charged.Protamine is strongly positively charged.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

28、 hours)due to existing factors Directly break up clots Promote natural thrombolysis Enhance activation of plasminogen Time is Muscle streptokinase(Streptase)alteplase(tPA,Activase)anistreplase(Eminase)reteplase(Retevase)tenecteplase(TNKase)Cholesterol important component in membranes and as hormone

29、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 mechanism Lipids are surrounded by protein coat to hide hydrophobic fatty core.Lipoproteins described by dens

30、ity 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 circulation Risk of CAD linked to LDL levels LDLs are deposited under endothelial surface and oxidized where th

31、ey: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 decreased Plaque cap can rupture Collagen exposed Clotting cascade activated Platelet adhesion Thrombus formation Embolus formation possible Occlusion causes ischemia Goal: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)