心血管治療藥物綜述ppt課件

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 Po

2、wer 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

3、 Purkinje 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

4、 Phase 2: (Plateau) 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 re

5、polarization K+ efflux Intrinsic 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 dura

6、tion Abnormal genesis Imbalance of ANS 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 supporti

7、ng evidence NOT mechanism Class I Class IIa 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

8、 (Purkinje) Ignores those with slow potential (SA/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 condu

9、ction through ventricles Increase rate of repolarization 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 repolariza

10、tion rate Decrease contractility Rare last chance drug flecainide (Tambocor) 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 # approv

11、ed for tachycardias propranolol (Inderal) acebutolol (Sectral) esmolol (Brevibloc) Decreases K+ efflux during repolarization Prolongs repolarization Extends effective refractory period Prototype: bretyllium tosylate (Bretylol) Initial norepi discharge may cause temporary hypertension/tachycardia Sub

12、sequent norepi depletion may cause hypotension Similar effect as blockers Decrease SA/AV automaticity Decrease AV conductivity Useful in breaking reentrant circuit Prime side effect: hypotension & bradycardia verapamil (Calan) diltiazem (Cardizem) Note: nifedipine doesnt work on heart adenosine

13、(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) Cardiac Glycocides digoxin (Lanoxin) Inhibits NaKATP pump

14、 Increases intracellular Ca+ via Na+-Ca+ exchange pump Increases contractility Decreases AV conduction velocityAntihypertensives diuretics beta blockers angiotensin-converting enzyme (ACE) inhibitors calcium channel blockers vasodilators Cardiac Output = SV x HR PVR = AfterloadKey:CCB = calcium chan

15、nel 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 Sy

16、stem1. CA AdrenergicsPeripheral SympatheticReceptorsalpha beta1. alpha blockers 2. beta blockersLocal Acting1. Peripheral-Acting AdrenergicsStimulate alpha1 receptors - hypertensionBlock alpha1 receptors - hypotension doxazosin (Cardura) prazosin (Minipress) terazosin (Hytrin) Stimulate alpha2 recep

17、tors inhibit alpha1 stimulation hypotension clonidine (Catapress) methyldopa (Aldomet) reserpine (Serpalan) inhibits the release of NE diminishes NE stores leads to hypotension Prominent side effect of depression also diminishes seratonin Common dry mouth, drowsiness, sedation & constipation ort

18、hostatic hypotension Less common headache, sleep disturbances, nausea, rash & palpitationsAngiotensin IACEAngiotensin II1. potent vasoconstrictor- increases BP2. stimulates Aldosterone- Na+ & H2Oreabsorbtion.RAAS Angiotensin II = vasoconstrictor Constricts blood vessels & increases BP In

19、creases 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 blocks this and decreases preload captopril (Capoten) enalapril (Vasotec) lisinopril (Prinivi

20、l & Zestril) quinapril (Accupril) ramipril (Altace) benazepril (Lotensin) fosinopril (Monopril) Used for: Angina Tachycardias Hypertensiondiltiazem & verapamilnifedipine (and otherdihydropyridines) diltiazem & verapamil decrease automaticity & conduction in SA & AV nodes decrease

21、 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 diltiazem (Cardizem) verapamil

22、(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 with the u

23、rine 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 spironolacto

24、ne (Aldactone) Directly 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 L

25、oniten sodium Nitroprusside NiprideDrugs 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: u

26、ncontrolled bleeding No effect on existing 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 (

27、Coumadin) Endogenous 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 alone

28、Measured 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. Factors II, VII, IX and X all vitamin K dependent enzymes Warfarin competes with vitamin K in the synthe

29、sis of these enzymes. Depletes the reserves of clotting factors. Delayed onset (12 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

30、 (Retevase) tenecteplase (TNKase) Cholesterol 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 mechanism Lipids