1、 Acute Heart Failure/Cardiogenic ShockApril 16,2004Darren M.Triller,PharmDThe plan Stick close to the text Review pharmacology and pathophysiology only to enhance understanding of the drug therapy Know the few drugs well Expectations for pharmacists in general hospital or home care practice Test que
2、stions will target these goalsWhy is this important?HF common diagnosis Hospitalizations are common Associated costs are astronomical Pharmacists will routinely be involved in preparing and dispensing to ICU/CCU Use of the drugs is frequently in urgent/emergent situationsAcute HF/Cardiogenic shockDe
3、athShockIII Heart FailureIIIIVHTNDrugsMIValve DzMIRelationships/Key Terms Cardiac output=HR x Stroke volume MAP=CO x SVR Preload Contractility Afterload Frank-Starling relationshipThe Big Picture in FailurePreloadContractilityNeed volume to increase stretch,Frank StarlingNeed contractility and rate
4、to maintain outputNeed constriction to maintain pressureAfterloadVeinsHeartArteriesAutoregulation The ability to maintain blood flow over wide range of perfusion pressures Cerebral and coronary arteries Ability declines at MAP 60mmHg Mediated by vasoconstrictors:epi,NE,AngII,TxA2,vasopressin vasodil
5、ators:PGI2,NO,adenosine,natriuretic peptidesNormal reflex mechanisms Increase preload:Na/H20 retention,RAAS Increased contractility:adrenergic outflow(NE)Increased afterload:norepi,AngII,endothelin,vasopressinIt is important to relax!Remember that coronary arteries fill during diastole Remember that
6、 filling during diastole contributes to stroke volume(Starling)Remember that increasing heart rate decreases ventricular and coronary filling,upsets calcium processing by SR,O2 demand increase Chronic HF patients have typically maxed out preload,and do not have the reserve that you do Contractility
7、Increased contractility will provide increased stroke volume/CO for a given level of preload and afterload Chronic HF patients have high circulating levels of catecholamines and are less responsive to adrenergic stimuli receptor downregulation Catecholamines cardiotoxic?Necrosis/apoptosis?Arrhythmia
8、s?Afterload is double edged sword Increased SVR is important for maintaining MAP Increased afterload will reduce stroke volume slams the screen door before all the kids get out Chronic HF patients are very succeptable to increases in afterloadApproach to patient Assess status:s/s,target organ damage
9、 Address alterable causes Drugs Diseases/conditions Assess fluid status-over or under hydrated?Assess severity and initiate pharmacotherapy Adjust moment by momentPatient monitoring Vital signs Acid/base Oxygenation Hydration Renal function Swan line PCWP Cardiac outputApproach by hemodynamic subset
10、PCWPCISTD treatment/monitoringMortality increases from set to set!See figure 13-7 in text.Subset One Patient symptomatic Warrant full work-up Address other cause Maximize oral therapy for chronic HF ACEI BB Diuretics Dig Misc.:vaccines,smoking cessation,diet,education,etc.Approach by hemodynamic sub
11、setPCWPCILower pcwp(preload)with nitrates,diureticsMortality increases from set to set!See figure 13-7 in text.Subset Two Patient perfusing at expense of higher pressure Gradually lower PAOP without causing adverse effects Avoid over-shooting or else!Avoid prompting reflex mechanisms Typically invol
12、ves diuretics,nitrates and(more recently)nesiritide.Nitroglycerine Preferred preload reducer Decreases PCWP,decreases pulmonary congestion Cheap,short T50,easily titrated Used in combination with inotropes in patients with pulmonary congestion and reduced LV function Coronary dilation at high doses:
13、useful in patients with ischemia Avoid if elevated intracranial pressure Tolerance in 12-72 hoursTypical Dosage/Administration Protect from light Stable in D5W or NS in GLASS or special container Special“nitro”tubing,avoid filters Check for infusion incompatabilities 5 to 10mcg/min initially Titrate
14、 up to about 200mcg/min as continuous IV infusionDiuretics Vasodilation:5-10min,prostaglandin mediated Diuresis:20+minutes Reduction in preload in patients with volume depletion or decreased diastolic function may be harmful Does not improve CI/CO in most patients(curve flat)Role:use carefully to re
15、duce symptoms of congestion without compromising cardiac outputLoop diuretics Furosemide(Lasix)IV(40mg/5ml),IM,PO Bioavailability poor/variable Stable in LR,D5W or LR Typically 40mg 80mg IVP over 1-2 min Repeat every 1-2 hours as needed Monitor hemodynamics Monitor I/O for measure of net fluid loss
16、Administer potassium as needed in fluids Ototoxicity,allergy possibleOther Diuretics Bumetanide(Bumex):1/40th dose of lasix Good bioavailability IV,IM,PO 0.5-1mg IVP over 1-2 minutes,repeat 1-2 hrs 0.25mg/ml solution;0.5mg,1mg,2mg tablet Lasix refractory or allergic patients Can cause musculoskeleta
17、l s/s Torsemide(Demadex)IV/PO Dose approximately half of lasix dose Good bioavailability Potential PK and electrolyte advantages over furosemideDiuretic resistance Afterload reduction“Renal dose”dopamine Increase bolus dose Continuous infusion Add thiazide Diuril(chlorothiazide)Continuous Infusions
18、Bumex 12mg in 500ml D5W 38ml/hr Furosemide Stability issues pH must remain above 7 or precipitatesNesiritide(Natrecor)Human B-type natriuretic peptide 32 AA sequence generated from E.coli Mechanism Binds guanylate cyclase receptors in smooth muscle,endothelium Increases c-GMP causing relaxation Caus
19、es dose-dependent reductions in PCWP and arterial pressureNesiritide PK T50 18 minutes Elimination Intracellular proteolysis Cleavage by circulating endopeptidases Renal filtration Dosing Bolus 2mcg/kg Infusion 0.01mcg/kg/minEfficacy of Nesiritide Safely and effectively lowers PCWP Onset 15 minutes
20、Peak effect at 3hrs Hypotension primary adverse effect Not arrhythmogenic Expensive!ICU trials difficult to control variablesEffects at 3 Hours Plac(n=62)Nitro(n=60)BNP(n=124)Pulmonary capillary wedge pressure(mm Hg)-2.0-3.8-5.8 Right atrial pressure(mm Hg)0.0-2.6-3.1 Cardiac index(L/min/M 2)0.0 0.2
21、 0.1 Mean pulmonary artery pressure(mm Hg)-1.1-2.5-5.4 Systemic vascular resistance(dynes*sec*cm-5)-44-105-144 Systolic blood pressure (mm Hg)-2.5-5.7 -5.6 pNEIsoprazocinVascular smooth muscleContraction GUContraction LiverGluconeogenesis HeartInotropy,arrhythmias GIRelaxation Alpha-2EpiNEIsoyohimbi
22、nePancreasDecreased insulin clonidine PlateletesAggregation Nerve terminalsDecreased NE release Vascular smooth muscleContraction Beta-1IsoEpi=NEmetoprololHeartInotrope,AV velocity Dobutamine JuxtaglomerulusIncreased renin Beta-2IsoEpeNE Smooth muscleRelaxation terbutaline(bronchial,GI,GU)Positive I
23、notropes Increase cAMP Beta agonists through receptor activation of adenyl cyclase Phosphodiesterase inhibitors-reduce cAMP breakdown Net effect:increased rate and extent of calcium influx during systole resulting increased contractility increased reuptake of calcium by endoplasmic reticulum during
24、diastole improves active relaxation(lusitropic)Adrenergic agonists:dopamine(Intropin),dobutamine(Dobutrex),norepinephrine(Levophed),epinephrine Phosphodiesterase inhibitors:amrinone(Inocor),milrinone(Primacor)Digoxin?Why not?Dopamine(Intropin)Intrinsic neurotransmitter plus a precursor to NE,direct
25、receptor action on D1 and D2 receptors,also increases NE release Multiple receptor affinities depending on dosage:Low(10):A1 kicks in,increase afterload,HR,O2 demand,ischemia and arrhythmogenic Can increase CI and also elevate BP if neededDopamine 200mg/5ml ampule Premixed 400mg/500mlIV bags Stable
26、in NS,D5W,LR 200mg in 500ml yields 0.4mg/ml or 400mcg/ml solution Increase concentration in patients with volume overload.Be able to calculate infusion rates!Dobutamine(Dobutrex)Synthetic catecholamine,B1,B2 and some A1 activity Doesnt cause NE release like DA does Net vascular effect is usually dil
27、ation(B2A1)B1=inotrope,a potent inotrope and vasodilator with modest effects on HR and BP Dose range and name similar to dopamine!Lack of effect on BP may be drawback in hypotensive patient Tachyphylaxis after 72 hrs-receptors down regulate?!Some studies show sustained symptomatic improvement,but al
28、so increased mortalityPhosphodiesterase inhibitors Amrinone and milrinone(theo,Trental,Pletal,Viagra,et al)Increase cAMP effects by reducing breakdown“Inodilator”:increase cardiac index while dilating veins and arteries,also aid diastole via enhanced Ca handling MAP stays stable,with venodilation of
29、fsetting increased contractility In combo with adrenergics if hypotensive Tachyphylaxis:receptor?Must be intracellular uncoupling of beta receptor from adenyl cyclase?Use if other agents fail,not tolerated,in combo with others Beta blocker over-rideComparison of Inotropes Hemodynamically similar Dob
30、utamine increases heart rate to greater degree PDEIs have T50 in hrs(longer than adrenergics)need loading dose to get early peak effect ADRs longer lived harder to titrate to effect Milrinone:renal clearance,dose adjust Thrombocytopenia with amrinone Cost?Subset Four Elevated wedge pressure AND hypo
31、perfusion Need to increase contractility and reduce pulmonary congestion simultaneously Increased mortality Increased adverse drug eventsNitroprusside Mixed areterial-venous dilator Works through enhanced NO production Although not a true inotrope,effects are similar to that of dobutamine(except wit
32、h more hypotension)Watch out for hypotension Rapid onset,short duration allow tight titration,taper off May be used in combo with DA/Dobut to maintain pressures Cyanide toxicity with high doses or extended useNorepinephrine/Epinephrine Utilized primarily if refractory hypotension Norepinephrine:Levo
33、phed a.k.a.“leave em dead”?Increases afterload,mostly A1 and B1,little B2 arrhythmogenic when used alone Epinephrine:usually not in HF,use short term post bypass,for BB overdose,etcShock Acute,severe circulatory failure Arterial hypotension Marked blood flow reduction to organs Impaired mentation Di
34、minished renal function Eventual cellular damage and deathStages I:Compensated hypotension blood flow shifted to vital organs brain and heart protected,others sacrificed II:Compensatory mechanisms overwhelmed,early renal,cerebral and myocardial s/s,excess sympathetic discharge III:Tissue damage(irre
35、versible)severe ischemia,tissue damage endothelial damage to kidneys,liver,lungs bacteria invade via GI tract(endotoxin,sepsis?)vascular permeability,transudation,hypotension,pulmonary congestion acidosis,toxin release,myocardial depressionEtiologies Sepsis:gram negative or overwhelming Hypovolemic:
36、hemorrhage,dehydration,burns Cardiogenic Misc:anaphylaxis,drug overdose,myxedema,neurogenic,hepatic or renal functionCardiogenic shock Condition of severly decreased CO(CI1.8L/min/m2)and hypotension(SBP80,MAP 60)Most often due to massive MI(5-10%)dead myocardium does not contract 40%loss of muscle m
37、ass or greater Other causes:arrhythmia,atrial myxoma,valvular/perivalvular lesions,severe HF,tamponade,massive PE,etc.High mortality unless rapid interventionVicious cycle Initial damage/event Cascade of inflammatory and other mediators-histamine,LTs,PAF,lactic acid,myocardial depressant factor Incr
38、eased oxygen demand,worsened coronary perfusion Damage begets more damagePresentation Acute MI typical presentation Tachycardia,cool clammy skin,hypotension,poor peripheral pulses,decreased urine output,MS changes JVD,pulmonary congestion Rule out surgically corrected causes-valves,papillary rupture
39、,tamponade Lab studies specific for underlying cause cardiac nz,CBC,lytes,coags,ABGs,etc.X-ray,echo,ekg,etcGeneral management ABCs:airway,breathing,circulation Oxygen Ventilation Vasopressors(volume expansion?)Central line placement Address cause revascularization,PTCA,stent,thrombolyticsDrug therap
40、y Nitrates,morphine reduce pain hypotension dangerous Dopamine,dobutamine Amrinone,milrinone Beta blockers when able BP,HR limitations Misc:diuretics,antiplatelet,LMWHs,etcOutcomes Very very poor 70%with medical management perhaps 30-50%with surgical/cath lab intervention Prevention Early identifica
41、tionDrug Therapy None are“clean”-all have multiple actions as well as reflex responses that need consideration Reflex action as important as drug action Need to be short acting Need to have rapid onset Need vigilant monitoring Personalize therapy-not“cook book”Must always consider ischemia and arrhythmias-can occur at any time As much art as science-a real specialtyTake away points Understand the basic relationships in HF Understand the effects of the agents and their associated reflex actions Dose and titration implications Pharm calc/rate calculations key!ADRs
