anusha inotropes 21

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    INOTROPES ANDINOTROPES AND

    VASOPRESSORSVASOPRESSORS

    PRESENTERS:Anusha.MPRESENTERS:Anusha.MDipinDipin

    MODERATOR:MODERATOR: Dr.SuhasDr.Suhas

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    1.Cardiac glycosides 6.Levosimendan1.Cardiac glycosides 6.Levosimendan

    2.Noradrenaline 7.Nesiritide2.Noradrenaline 7.Nesiritide

    3.Adrenaline 8.Phenylephrine3.Adrenaline 8.Phenylephrine

    4.Dopamine 9.PDE Inhibitors4.Dopamine 9.PDE Inhibitors

    5.Dobutamine5.Dobutamine

    Recent advances and uses of the above drugs.Recent advances and uses of the above drugs.

    OVERVIEWOVERVIEW

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    CARDIAC GLYCOSIDESCARDIAC GLYCOSIDES

    The first line ofThe first line of inotropesinotropes include all digitalisinclude all digitalis

    derivativesderivatives

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    usesuses

    MaintananceMaintanance dosedose--0.125 to 0.375mg/day.0.125 to 0.375mg/day.

    DRAW A SERUM DIGOXIN LEVEL ATDRAW A SERUM DIGOXIN LEVEL ATLEST SIX HOURS AFTER THE LASTLEST SIX HOURS AFTER THE LASTDOSE!DOSE!

    DIGOXIN

    Tablets Elixir Capsules

    OralAbsorption

    60% 80% 75 - 90%

    Time topeak (min)

    90 45 - 60 60 - 90

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    Digitoxin Digoxin

    Less polar and more lipid soluble More polar and less lipid soluble

    Easily crosses BBB Does not cross BBB

    Produces CNS symptom Does not produce CNS symptom life is 5 days life is 1 days

    Heart : plasma ratio is 7:1 Heart : plasma ratio is 30:1

    Mostly metabolized in the liver, so itsexcretion is independent of renal function

    More than 80% excreted unchanged viaurine, rest is removed by non-renal routes

    like biliary excretion and hepaticmetabolism

    Digitalization requires (4x5) 20 days Digitalization requires (4x1) 20 days

    S/EHeart block(33%),

    Bradycardia (24%),

    Junctional tachycardia (15%), a

    AF (12%).

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    At present, patients with preserved left ventricular systolic function probably shouldAt present, patients with preserved left ventricular systolic function probably should

    not be treated withnot be treated with digoxindigoxin. At present, the consensus is that. At present, the consensus is that digoxindigoxin therapy istherapy isprobably inappropriate in patients with preserved left ventricular systolic function.probably inappropriate in patients with preserved left ventricular systolic function.

    In addition,In addition, digoxindigoxin therapy may not be useful in patients with congestive hearttherapy may not be useful in patients with congestive heart

    failure and a high cardiac output syndrome such asfailure and a high cardiac output syndrome such as anemiaanemia oror thyrotoxicosisthyrotoxicosis ..

    Patients presenting with acute myocardial infarction should not be started onPatients presenting with acute myocardial infarction should not be started on digoxindigoxin

    therapy.therapy.

    NN EnglEngl J Med 1997;336:525J Med 1997;336:525--33.33.

    Use of lower dosages is particularly important in the elderly, because digitalis toxicityUse of lower dosages is particularly important in the elderly, because digitalis toxicity

    may be difficult to recognize in this patient population.may be difficult to recognize in this patient population.3232 It is generally agreed thatIt is generally agreed that

    digoxindigoxin should be given in a dosage of0.125 to 0.25 mg per day. Dosages highershould be given in a dosage of0.125 to 0.25 mg per day. Dosages higher

    than 0.25 mg per day are probably unwarranted.than 0.25 mg per day are probably unwarranted.

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    DIGOXIN AND ARYTHIMIASDIGOXIN AND ARYTHIMIAS

    DigoxinDigoxin has a limited, but useful, role, either alone or in combination with otherhas a limited, but useful, role, either alone or in combination with other

    agents such as agents such as --blockers,blockers, diltiazemdiltiazem oror verapamilverapamil, in achieving satisfactory resting, in achieving satisfactory resting

    ventricular rate control in patients with chronicventricular rate control in patients with chronic atrialatrial fibrillation.fibrillation.

    In patients who lead a predominantly sedentary lifestyle (perhaps particularly inIn patients who lead a predominantly sedentary lifestyle (perhaps particularly in

    those who are elderly),those who are elderly), digoxindigoxin alone may be the agent of choice. both alone may be the agent of choice. both --blockersblockers

    and calciumand calcium--channel blocking agents were effective as firstchannel blocking agents were effective as first--line agents in aboutline agents in about

    50%50%70% of patients, and that70% of patients, and that digoxindigoxin (which was allowed to be added as a(which was allowed to be added as a

    secondsecond--line agent) appeared to increase the rate control efficacy of these agentsline agent) appeared to increase the rate control efficacy of these agents

    modestlymodestly

    Circulation 2002; 106 (Circulation 2002; 106 (SupplSuppl II): IIII): II--633.633.

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    NORADRENALINENORADRENALINE

    1.Increase in SVR predominates1.Increase in SVR predominates ReflexReflex bradycardiabradycardia

    2.Decrease in Cardiac Output2.Decrease in Cardiac Output

    3.Cardiac Output may maintained by positive3.Cardiac Output may maintained by positive inotropicinotropic effecteffect

    4.Increase in heart rate4.Increase in heart rate limit the clinical effectivenesslimit the clinical effectiveness

    5.Increases SBP, DBP & MAP5.Increases SBP, DBP & MAP

    RECEPTOR EFFECT

    1

    2

    1

    2

    Dopaminergic

    ++++++

    +++

    +/++

    -

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    DOSE:DOSE:

    Initial doseInitial dose: 8 to 12 mcg/min: 8 to 12 mcg/min -- MaintenanceMaintenance: 2 to 4 mcg/min.: 2 to 4 mcg/min.

    HighdosesHighdoses-- 0.5 to 1.5 mcg/kg/min for 10.5 to 1.5 mcg/kg/min for 1--10days10dayshave been used in septic shock.have been used in septic shock.

    Range usedinclinical trialsRange usedinclinical trials: 0.01: 0.01--33mcg/kg/minute.mcg/kg/minute.

    ACLS dosagerangeACLS dosagerange: 0.5 to 30 mcg/minute.: 0.5 to 30 mcg/minute.

    CalculationofdriprateCalculationofdriprate

    8 mg/ 250 ml (ml/hr) = mcg/min x 1.875.8 mg/ 250 ml (ml/hr) = mcg/min x 1.875.

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    NorepinephrineNorepinephrine bitartratebitartrate 2 mg =2 mg = NorepinephrineNorepinephrine base 1 mg.base 1 mg.

    S/ES/E

    ArrhythmiasArrhythmias

    BradycardiaBradycardia

    Peripheral (digital) ischemiaPeripheral (digital) ischemia Hypertension .Hypertension .

    ExtravasationExtravasation tissue necrosistissue necrosis

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    ADRENALINEADRENALINE

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    epinephrine 1 2 1 2 Dopamine

    ++++ ++++ ++++ +++ -

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    DOSESDOSES

    RefractoryhypotensionRefractoryhypotension

    Continuous IV infusion: range: 1Continuous IV infusion: range: 1--10 mcg/minute .. Usual rate:10 mcg/minute .. Usual rate:1 to 4 mcg/min.1 to 4 mcg/min.

    SeverecardiacdysfunctionSeverecardiacdysfunction-- doses >10 mcg/minute (up todoses >10 mcg/minute (up to

    max of 20 mcg/min in a 70kg patient).max of 20 mcg/min in a 70kg patient).

    EndotrachealEndotracheal: Doses (2: Doses (2--2.5 x IV dose) should be diluted to2.5 x IV dose) should be diluted to

    10 ml with NS or distilled water prior to administration10 ml with NS or distilled water prior to administration..

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    AnaphylaxisAnaphylaxis (adult):(adult):

    1.0.3 mg IM (0.3 ml of a 1:1000 solution). repeat 10 to 151.0.3 mg IM (0.3 ml of a 1:1000 solution). repeat 10 to 15

    minutesminutes2. 0.1 to 0.25 mg IV (1:10,000) over 52. 0.1 to 0.25 mg IV (1:10,000) over 5--10min repeat 5 to 1510min repeat 5 to 15

    minutesminutes

    3.start continuous infusion: 1 to 4 mcg/min.3.start continuous infusion: 1 to 4 mcg/min.

    AsthmaAsthma::1. Inhalational form: start with 1 inhalation, then wait at least1. Inhalational form: start with 1 inhalation, then wait at least

    11 min.,PERSISTSmin.,PERSISTS-- Do not use again for at least 3 hr.Do not use again for at least 3 hr.

    2.subcutaneous (SC) form: 0.22.subcutaneous (SC) form: 0.2--0.5 mg (0.20.5 mg (0.2--0.5 ml of a0.5 ml of a

    1:1000 solution) SC every 2 hr as required.1:1000 solution) SC every 2 hr as required.

    3.In severe attacks, may repeat dose every 20 min for a3.In severe attacks, may repeat dose every 20 min for a

    maximum of 3 doses.maximum of 3 doses.

    CardiacarrestCardiacarrest::

    1 mg IV initially; may be repeated as necessary q 31 mg IV initially; may be repeated as necessary q 3--5 min.5 min.

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    DOPAMINEDOPAMINE

    Dopamine

    (g /kg/

    min)

    1 1 2 Dopamine

    05- 2 0 + + ++

    3 - 10 + ++ + ++

    > 10 ++(+) ++(++) +(+) ++

    Low dose (0.5-2) DA1 and DA2. Actions-Natriuresis

    Medium dose (3-10) (chronotropic andCO)

    High dose (10-20) (beneficial effects blunted). High dose = NE.

    VERY High dose( >20)overrides dopamine effects.reverses renal

    dilation and Natriuresis

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    DOSESDOSESRefractory CHFRefractory CHF: initial dose: 0.5 to 2 mcg/kg/min.: initial dose: 0.5 to 2 mcg/kg/min.

    Renal perfusionshockRenal perfusionshock: 1 to 5 mcg/kg/min.: 1 to 5 mcg/kg/min.

    Initially 5 mcg/kg/min, increase by 5 to 10 mcg/kg/min (10 toInitially 5 mcg/kg/min, increase by 5 to 10 mcg/kg/min (10 to

    30 min) up to max of 50 mcg/kg/min.30 min) up to max of 50 mcg/kg/min.

    Cardiac lifesupportCardiac lifesupport(initial): 2 to 5 mcg/kg/min(initial): 2 to 5 mcg/kg/min -- titrated totitrated to

    effect. Infusion may be increased by 1effect. Infusion may be increased by 1--4 mcg/kg/min at 10 to4 mcg/kg/min at 10 to

    30 min intervals until optimal response is obtained. If dosages30 min intervals until optimal response is obtained. If dosages

    >20>20--30 mcg/kg/min are needed, a more direct30 mcg/kg/min are needed, a more direct--actingacting pressorpressor

    may be more beneficial.may be more beneficial.Renal shutdown may occur at doses >50 mcg/kg/min.Renal shutdown may occur at doses >50 mcg/kg/min.

    CalculationofdriprateCalculationofdriprate (ml/hr) 400mg/250 ml: wt(kg) x(ml/hr) 400mg/250 ml: wt(kg) x

    mcg/min x 0.0375.mcg/min x 0.0375.

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    ExtravasationExtravasation intotissuesintotissues--

    The infusion should be immediately stopped.The infusion should be immediately stopped.

    Infiltrate with 0Infiltrate with 0--15ml 0.9% Sodium Chloride containing 515ml 0.9% Sodium Chloride containing 5--10mg10mg PhentolalminePhentolalmine..

    RegitineRegitine is then administered SQ in the four 90is then administered SQ in the four 90quadrantsquadrants

    around the site of extravasations.around the site of extravasations.

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    DOBUTAMINEDOBUTAMINE

    1.Increases Cardiac Output by positive1.Increases Cardiac Output by positive inotropicinotropic effecteffect2.Minimal increase in heart rate2.Minimal increase in heart rate

    3.No effect on SVR3.No effect on SVRStrongStrong InotropicInotropic,,

    weakweak chronotropicchronotropic..

    4.Increases automaticity, AV conduction.4.Increases automaticity, AV conduction.5.5.NoNo norepinephrinenorepinephrine releaserelease

    6.Effective in catecholamine depleted states6.Effective in catecholamine depleted states

    7.Tolerance after 3 days of treatment7.Tolerance after 3 days of treatment

    Dobutamine 1 1 2

    Dopamine

    V1

    + +++++ +++ O O

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    DOSESDOSES Adult (usual)Adult (usual): 2.5 to 20 mcg/kg/minute. Max: 2.5 to 20 mcg/kg/minute. Max-- 40 mcg/kg/min.40 mcg/kg/min.

    Drip rate (500mg/250 ml) ml/hr = wt(kg) x (mcg/min) x 0.03.Drip rate (500mg/250 ml) ml/hr = wt(kg) x (mcg/min) x 0.03.

    S/E:S/E:

    TachycardiaTachycardia

    Increased ventricular response rate in patients with atrialIncreased ventricular response rate in patients with atrial

    fibrillationfibrillation

    Ventricular arrhythmiasVentricular arrhythmias

    Cardiac ischemiaCardiac ischemia

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    PDE inhibitorsPDE inhibitors

    Arterial dilator: ++Arterial dilator: ++ InotropicInotropic effect: +++effect: +++ VenodilatorVenodilator: 0: 0

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    AmrinoneAmrinone-- CI, LV stroke volume, LVEF. in PCWP, PA CI, LV stroke volume, LVEF. in PCWP, PA

    pressure, RA pressure, SVR. Positivepressure, RA pressure, SVR. Positive inotropicinotropic and vasodilator.and vasodilator.DOSES:DOSES:

    CHF(short term):Initial: 0.75 mg/kg IV bolus over 2CHF(short term):Initial: 0.75 mg/kg IV bolus over 2--3 min,3 min,

    Repeat after 30minRepeat after 30min

    MaintanceMaintance: 5: 5--10 mcg/kg/min IV infusion., not >10 mg/kg.10 mcg/kg/min IV infusion., not >10 mg/kg.Renal failure:Renal failure: CrclCrcl

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    DOSESDOSES MilrinoneMilrinone--CHFCHF: Initial loading dose, 50 mcg/kg IV over: Initial loading dose, 50 mcg/kg IV over

    10min, then 0.375 to 0.75 mcg/kg/min IV (Usual: 0.510min, then 0.375 to 0.75 mcg/kg/min IV (Usual: 0.5

    mcg/kg/min).mcg/kg/min). CardiacsurgeryCardiacsurgery: 15min before separation from: 15min before separation from

    cardiopulmonary bypass, 50 mcg/kg IV over 20 minutescardiopulmonary bypass, 50 mcg/kg IV over 20 minutes

    followed by a continuous infusion of0.5 mcg/kg/min IV for afollowed by a continuous infusion of0.5 mcg/kg/min IV for a

    minimum of 4hminimum of 4h

    CalculationofdriprateCalculationofdriprate: 50 mg/250ml (ml/hr) = wt (kg) x 0.3 x: 50 mg/250ml (ml/hr) = wt (kg) x 0.3 x

    Rec

    ommended

    infusi

    on

    rates:

    renal

    insufficiency

    Creatinine Clearance

    (mL/min/1.73 m 2)

    Infusion Rate

    (mcg/kg/min)

    5 0.20

    10 0.23

    20 0.2830 0.33

    40 0.38

    50 0.43

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    Side effectsSide effects

    Arrhythmias, enhanced AV conduction (increased ventricularArrhythmias, enhanced AV conduction (increased ventricular

    response rate inresponse rate in atrialatrial fibrillation)fibrillation) HypotensionHypotension

    ThrombocytopeniaThrombocytopenia

    HepatotoxicityHepatotoxicity

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    CalciumCalcium--Sensitizing AgentsSensitizing Agents

    LevosimendanLevosimendan

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    11) Changes) Changes actinactin--myosin crossmyosin cross--bridge kinetics withoutbridge kinetics withoutincreasing the cycling rate of the crossincreasing the cycling rate of the cross--bridges or myocardialbridges or myocardial

    ATP consumption,ATP consumption,

    (2) the effects of calcium on cardiac(2) the effects of calcium on cardiac myofilamentsmyofilaments duringduringsystolesystole

    (3) Improves contraction at low energy cost and Ca(3) Improves contraction at low energy cost and Ca2+2+ sensitizersensitizer

    at lower concentrationsat lower concentrations-- CaCa2+2+ sensitizersensitizer

    High ConcentrationsHigh Concentrations --PDEPDE--III inhibitorIII inhibitor t1/2=1hrt1/2=1hr

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    STUDIESSTUDIES

    CHF CLASS 3/4, EF of 21% ,PCWP over 15 mmHg andCHF CLASS 3/4, EF of 21% ,PCWP over 15 mmHg and

    cardiac index less than 2.5 L/min/m2 were enrolled.cardiac index less than 2.5 L/min/m2 were enrolled.

    Drug infusion dose raised over 4 hours from 0.1Drug infusion dose raised over 4 hours from 0.1

    micrograms/kg/minute to0

    .4 mcg/kg/minute and maintainedmicrograms/kg/minute to0

    .4 mcg/kg/minute and maintainedfor 2 hours.for 2 hours.

    LevosimendanLevosimendan--pulmonary pressures,pulmonary pressures, right atrialright atrial

    pressure, andpressure, andblood pressure.blood pressure.

    The drug improved shortness of breath and fatigue, andThe drug improved shortness of breath and fatigue, and

    caused no significant side effects.caused no significant side effects.

    Eur J Pharmacol 2000 Sep 15;404(1Eur J Pharmacol 2000 Sep 15;404(1--2):1912):191--99

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    LevosimendanLevosimendan at a 10 minute dose of 6at a 10 minute dose of 6 -- 24 mcg/kg followed24 mcg/kg followed

    by IV at 0.05 to 0.2 mcg/kg/minby IV at 0.05 to 0.2 mcg/kg/min --good results in acute heartgood results in acute heartfailure episodesfailure episodes

    J AmJ Am CollColl CardiolCardiol 2000 Nov 15;36(6).2000 Nov 15;36(6).

    LevosimendanLevosimendan is a good drug to treat acute CHF in the shortis a good drug to treat acute CHF in the short--term. It improves heart output without making the heart workterm. It improves heart output without making the heart work

    harder, and it improves right ventricle efficiencyharder, and it improves right ventricle efficiency..ClinClin PharmacolPharmacol TherTher 2000 Nov;68(5):5222000 Nov;68(5):522--31.31.

    In LIDO trials,In LIDO trials, levosimendanlevosimendan reduced risk of worsening CHFreduced risk of worsening CHF

    or death compared toor death compared to dobutaminedobutamine and placebo in CHFand placebo in CHF

    improvedimproved survival.levosimendansurvival.levosimendan caused fewer serious adversecaused fewer serious adverse

    events thanevents than dobutaminedobutamine ..

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    DOSESDOSES

    The usual dosage of IVThe usual dosage of IV --6 to 24 mg/kg loading dose over 10 min6 to 24 mg/kg loading dose over 10 min

    continuous infusion. 0.05to 0.2 mg/kg/min.continuous infusion. 0.05to 0.2 mg/kg/min.

    HaemodynamicHaemodynamic responses are generally observed within 5 minutes ofresponses are generally observed within 5 minutes of

    commencement of infusion of the loading dose.commencement of infusion of the loading dose.

    Peak effects are observed within 10 to 30 minutes of infusion; the durationPeak effects are observed within 10 to 30 minutes of infusion; the duration

    of action ofof action of levosimendanlevosimendan is about 72is about 72--78 hrs to week.78 hrs to week.

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    BB--typetypenatriureticnatriuretic peptidepeptide

    NesiritideNesiritide

    RecombiinantRecombiinant human Bhuman B--typetypenatriiuretiicnatriiuretiic

    peptiidepeptiide

    IdentiicalIdentiical totointriinsiicintriinsiic ventriicullarventriicullar hormonehormone

    manufacturedfrom E. coli usingmanufacturedfrom E. coli usingrDNArDNA technologytechnology

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    When administered to patients with heart failure, it:When administered to patients with heart failure, it:

    decreases preload anddecreases preload and afterloadafterload

    decreases pulmonary vascular resistancedecreases pulmonary vascular resistance

    increases cardiac outputincreases cardiac output

    In some studies:In some studies:

    increased urine outputincreased urine output

    reduced diuretic requirementsreduced diuretic requirements

    suppression ofsuppression of aldosteronealdosterone,, endothelinendothelin,, norepinephrinenorepinephrine

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    Human BNP is cleared from the circulation via the followingHuman BNP is cleared from the circulation via the following

    three independent mechanisms, in order of decreasingthree independent mechanisms, in order of decreasing

    importance:importance:

    1) internalization and1) internalization and lysosomallysosomal proteolysis;proteolysis; 2)2) proteolyticproteolytic cleavage of the peptide bycleavage of the peptide by endopeptidasesendopeptidases

    lumenallumenal surface;surface;

    3) renal filtration3) renal filtration..

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    formulationformulation

    TheThe quantitativequantitative composition of the lyophilized drug per vialcomposition of the lyophilized drug per vial

    is:is: nesiritidenesiritide 1.58 mg,1.58 mg, mannitolmannitol 20.0 mg, citric acid20.0 mg, citric acid

    monohydrate 2.1 mg, andmonohydrate 2.1 mg, and sodiumsodium citratecitrate dihydratedihydrate 2.94 mg.2.94 mg.

    s/e:s/e: dizziness, chest pain, fast heart rate, or confusion shortly afterdizziness, chest pain, fast heart rate, or confusion shortly after

    you receiveyou receive nesiritidenesiritide;;

    feeling lightfeeling light--headed, fainting;headed, fainting;

    coughing up blood; orcoughing up blood; or fever, pale skin, easy bruising, unusual weakness.fever, pale skin, easy bruising, unusual weakness.

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    DOSESDOSES

    BolusVolumeBolusVolume ((mLmL) = Weight (kg) / 3) = Weight (kg) / 3 Volume Infusion Flow Rate (Volume Infusion Flow Rate (mLmL/hr) =Weight (kg) x 0.1/hr) =Weight (kg) x 0.1

    Initial dose:Initial dose: 0.01 mcg/kg/minute0.01 mcg/kg/minute

    Increments:Increments: 1 mcg/kg IV bolus over 1 minute 0.0051 mcg/kg IV bolus over 1 minute 0.005

    mcg/kg/minutemcg/kg/minute

    Maximumcontinuousdosage:Maximumcontinuousdosage: 0.03 mcg/kg/minute0.03 mcg/kg/minute

    Weight (kg)Infusion FlowRate (mL/hr)

    60 6

    70 7

    80 8

    90 9

    100 10

    Weight (kg)Volume of Bolus(mL = kg/3)

    60 20.070 23.3

    80 26.7

    90 30.0

    100 33.3

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    STUDIESSTUDIES

    In the absence of hypotension, IV NTG, sodiumIn the absence of hypotension, IV NTG, sodium nitroprussidenitroprussideoror nesiritidenesiritide may be considered as an addition to diureticmay be considered as an addition to diuretictherapy for rapid improvement of congestive symptoms intherapy for rapid improvement of congestive symptoms in

    patients admitted with ADHF.patients admitted with ADHF.

    Intravenous vasodilators, (Intravenous vasodilators, (nitroprussidenitroprusside, nitroglycerin or, nitroglycerin ornesiritidenesiritide) may be considered in patients with ADHF and) may be considered in patients with ADHF andadvanced HF who have persistent severe HF despiteadvanced HF who have persistent severe HF despiteaggressive treatment with diuretics and standard oral therapies.aggressive treatment with diuretics and standard oral therapies.

    J Cardiac FailureJ Cardiac Failure. 2006;12:10. 2006;12:103838

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    TRIALSTRIALS VMAC TrialVMAC Trial

    VasodilationVasodilation in the Management of Acute CHFin the Management of Acute CHF NesiritideNesiritide vsvs IVIVnitroglycerinnitroglycerin vsvs placebo. Effects start @ 15 min. Sustained toplacebo. Effects start @ 15 min. Sustained to

    24hrs.Nesiritide equal to NTG in24hrs.Nesiritide equal to NTG in dyspneadyspnea improvement @ 3improvement @ 3

    hr.hr.

    THE NAPA TRIAL:THE NAPA TRIAL:

    NNesiritideesiritide AAdministereddministered PPerieri--AAnesthesianesthesia

    in Patients Undergoing Cardiac Surgery To explore the effectsin Patients Undergoing Cardiac Surgery To explore the effects

    ofof perioperativeperioperative administration ofadministration of nesiritidenesiritide on clinicalon clinical

    outcomesoutcomes andand safetysafety in heart failure patients undergoingin heart failure patients undergoing

    cardiac surgery.cardiac surgery. PRECEDENT (Prospective Randomized Evaluation ofPRECEDENT (Prospective Randomized Evaluation of

    CardiacCardiac EctopyEctopy withwith DobutamineDobutamine oror NatrecorNatrecor ((nesiritidenesiritide))

    Therapy). 0.015 and 0.03 mcg/kg/min without an initial bolusTherapy). 0.015 and 0.03 mcg/kg/min without an initial bolus

    for 24 hours did not aggravatefor 24 hours did not aggravate preexistingpreexisting VT.VT.

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    EndothelinEndothelin receptorantagonistreceptorantagonist

    ETETAA receptor antagonistsreceptor antagonists --SITAXENTAN, AMBRISENTAN.SITAXENTAN, AMBRISENTAN.

    Dual antagonistsDual antagonists --BOSENTAN,TEZOSENTANBOSENTAN,TEZOSENTAN

    SitaxentanSitaxentan,, ambrisentanambrisentan andand bosentanbosentan are mainlyare mainlyused for the treatment of PAHused for the treatment of PAH

    whilewhile atrasentanatrasentan is an experimental antiis an experimental anti--caner drug.caner drug.

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    STUDIESSTUDIES

    EndothelinEndothelin receptor antagonist (ETreceptor antagonist (ETAA/ET/ETBB non selective)non selective)

    IndicationIndication WHO group IWHO group I -- functional class II, III, IVfunctional class II, III, IV

    DosageDosage 62.5 mg oral twice daily for 4 weeks then 125 mg62.5 mg oral twice daily for 4 weeks then 125 mg

    oral twice dailyoral twice daily EndothelinEndothelin receptor antagonist (ETreceptor antagonist (ETAA selective)selective)

    IndicationIndication WHO group IWHO group I -- functional class II, IIIfunctional class II, III

    DosageDosage 5 mg and 10 mg oral daily5 mg and 10 mg oral daily

    CirculationCirculation. 2008;117:3010. 2008;117:3010--99

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    VASSOPRESSINVASSOPRESSIN

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    Receptors Tissues Principal Effects

    V1R Vascularsmooth muscleKidney,

    platelets, spleen

    Vasoconstriction

    V2R Renalcollecting duct

    Endothelium

    Increasedpermeability to

    water

    Vasodilation

    V3R Pituitary Neurotransmitter

    ACTH release

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    RECEPTORSRECEPTORS

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    DOSESDOSESDiabetesDiabetesinsipidusinsipidus::

    55--10 units IM/SQ 210 units IM/SQ 2--4 times daily as needed(dosage range 54 times daily as needed(dosage range 5--60 units/day).60 units/day).

    GIGI hemorrhagehemorrhage: IV: Initial: 0.2: IV: Initial: 0.2--0.4 unit/minute. If bleeding stops,0.4 unit/minute. If bleeding stops,

    continue at same dose for 12 hours, taper off over 24continue at same dose for 12 hours, taper off over 24--48 hours.48 hours.

    Continuous IV infusion: 0.5Continuous IV infusion: 0.5 milliunitsmilliunits/kg/hour (0.0005 unit/kg/hour)./kg/hour (0.0005 unit/kg/hour).

    Double dosage as needed every 30 minutes to a maximum of 10Double dosage as needed every 30 minutes to a maximum of 10milliunitsmilliunits/kg/hour./kg/hour.

    OutOut--ofof--hospitalhospital asystoleasystole :40 units IV. Repeat if not restored in 3 minutes.:40 units IV. Repeat if not restored in 3 minutes.

    PulselessPulseless VT/VFVT/VF: 40 units IV (as a single dose only).: 40 units IV (as a single dose only).EndotrachealEndotracheal--administer 40 units diluted with NS (to a total volume of 10 ml)administer 40 units diluted with NS (to a total volume of 10 ml)

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    VVasodilatoryshock/septicshockasodilatoryshock/septicshock::

    The recommended infusion rate for vasopressin in theThe recommended infusion rate for vasopressin in the

    treatment of shock in adults is 0.01treatment of shock in adults is 0.01 0.04 units/min.0.04 units/min.This dosage range is reported to be effective in about 85%This dosage range is reported to be effective in about 85%

    of patients with norepinephrine resistant hypotension.of patients with norepinephrine resistant hypotension.

    Doses greater than 0.04 units/min may lead to cardiacDoses greater than 0.04 units/min may lead to cardiac

    arrest.arrest.

    S/ES/E

    1.1. rapid rebound hypotension when stoppedrapid rebound hypotension when stopped

    2.Infusion range2.Infusion range -- ischemic skin lesions to intestinalischemic skin lesions to intestinal

    ischemia.ischemia.

    3. Vasopressin therapy may also result in3. Vasopressin therapy may also result in cardiaccardiac

    output and hepatosplanchnic flowoutput and hepatosplanchnic flow..

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    DRUG FORMULATIONSDRUG FORMULATIONS

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    VASOPRESSIN AND SEPSISVASOPRESSIN AND SEPSIS

    Surviving Sepsis Campaign study currently only recommendsSurviving Sepsis Campaign study currently only recommends

    vasopressin (at a regimen of0.01vasopressin (at a regimen of0.01--0.04 U/min) as adjunctive0.04 U/min) as adjunctive

    therapy in patients with refractory shock despite adequate fluidtherapy in patients with refractory shock despite adequate fluid

    resuscitation and highresuscitation and high--dosedose conentionalconentional vasopressorsvasopressors..

    There is currently aThere is currently a multicentredmulticentred study powered to examinestudy powered to examine

    the effects of vasopressin on outcome in septic shock, Thethe effects of vasopressin on outcome in septic shock, The

    Vasopressin versusVasopressin versus NorepinephrineNorepinephrine in Septic Shock Studyin Septic Shock Study

    (VASST). The hypothesis is that treatment with vasopressin(VASST). The hypothesis is that treatment with vasopressin

    will reduce mortality from septic shock at 28 days.will reduce mortality from septic shock at 28 days.

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    TRIALSTRIALS

    The first (a trial of 24 patients who underwent a 4The first (a trial of 24 patients who underwent a 4--hourhourblinded study) showed a significant improvement in renalblinded study) showed a significant improvement in renal

    function in the vasopressin group.function in the vasopressin group.

    The second (randomising 48 patients to vasopressin andThe second (randomising 48 patients to vasopressin and

    noradrenalinenoradrenaline oror noradrenalinenoradrenaline alone for a 48alone for a 48--hour period, andhour period, and

    monitoring broadly similar variables), showed significantmonitoring broadly similar variables), showed significant

    improved cardiac indices, fewerimproved cardiac indices, fewer tachyarrhythmiastachyarrhythmias andand

    improved gastric mucosal carbon dioxide tensions in theimproved gastric mucosal carbon dioxide tensions in the

    vasopressin group.vasopressin group.

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    SUMMARYSUMMARY

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    RECENT ADVANCESRECENT ADVANCES

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    NorepinephrineNorepinephrine as the firstas the first--line agent additionalline agent additional

    agents should be considered in patients who remainagents should be considered in patients who remain hypotensivehypotensive

    display evidence of inadequate tissue or organdisplay evidence of inadequate tissue or organ

    perfusion despite doses ofperfusion despite doses of norepinephrinenorepinephrine up to0

    .2up to0

    .2 gg/kg//kg/followed byfollowed by dobutaminedobutamine or epinephrine in patients with poor leftor epinephrine in patients with poor left

    ventricular (LV) function and vasopressin (fixed dose of0.03ventricular (LV) function and vasopressin (fixed dose of0.03

    u/min) in patientsu/min) in patients withpreservedwithpreserved LV function and a low LV function and a low

    systemic vascular resistancesystemic vascular resistance

    Survival sepsis guidelines 2011Survival sepsis guidelines 2011

    MarikMarik Annals of Intensive Care 2011, 1:17Annals of Intensive Care 2011, 1:17

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    ROLE IN HEART FAILUREROLE IN HEART FAILURE

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    ROLE IN HYPOVOLUMICROLE IN HYPOVOLUMIC

    SHOCKSHOCKInotropicand Vasoactive Catecholamines

    Drug Dosage Hemodynamic Action

    Norepinephrine 4 mg/250 mL or 500 mL 5% D/Wcontinuous IV

    infusion at 812 g/min initially, then at 24 g/min asmaintenance, with wide variations

    -Adrenergic:

    asoconstriction-Adrenergic: Inotropi

    chronotropic effects*

    Dopamine 400 mg/500 mL 5% D/Wcontinuous IV infusion at

    0.31.25 mL (0.251 mg)/min210 g/kg/min for low dose

    20 g/kg/min for high dose

    -Adrenergic:

    asoconstriction

    -Adrenergic: Inotropi

    chronotropic effects a

    vasodilation

    onadrenergic: Renalsplanchnic vasodilatioDobutamine 250 mg/250 mL 5% D/Wcontinuous IV infusion at

    2.510 g/kg/min

    -Adrenergic: Inotropi

    effects

    *Effects are not apparent if arterial pres sure is elevated too much.Effects depend on dosage and underlying pathophysiology.

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    SummarySummary NorepinephrineNorepinephrine is considered the firstis considered the first--lineline vasopressorvasopressor inin

    vasodilatoryvasodilatory shock,shock, DobutamineDobutamine the firstthe first--lineline inotropeinotrope in shock associated within shock associated with

    decreased cardiac output,decreased cardiac output,

    Epinephrine is the firstEpinephrine is the first--line catecholamine inline catecholamine in

    cardiopulmonary resuscitation and also as second line in shockcardiopulmonary resuscitation and also as second line in shockthat is unresponsive to otherthat is unresponsive to other catecholaminescatecholamines..

    Vasopressin is emerging as a therapy in resistantVasopressin is emerging as a therapy in resistant vasodilatoryvasodilatory

    shock..shock..

    LevosimendanLevosimendan has been associated with an increasedhas been associated with an increasedproarrhythmicproarrhythmic risk. This may be prevented by cautious,risk. This may be prevented by cautious,

    concurrent blocker therapy, which inhibitsconcurrent blocker therapy, which inhibits levosimendanlevosimendan--

    induced sympatheticinduced sympathetic hyperreactivityhyperreactivity..

    CJASN March 2008 vol. 3 no. 2 546CJASN March 2008 vol. 3 no. 2 546--553553

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    NESIRITIDENESIRITIDE-- Severe hypotension andSevere hypotension and cardiogeniccardiogenic shock areshock are

    the major contraindications tothe major contraindications to nesiritidenesiritide use. It is a potentialuse. It is a potential

    secondsecond--line drug for the treatment of acutelyline drug for the treatment of acutely decompensateddecompensated

    chronic heart failure, although, in clinical practice, it is morechronic heart failure, although, in clinical practice, it is more

    liberally used.liberally used.

    PDE III InhibitorsPDE III Inhibitors-- PDE inhibitors improve cardiac output inPDE inhibitors improve cardiac output in

    cardiogeniccardiogenic shock and are used as secondshock and are used as second--line drugs for thisline drugs for this

    indication ,Because of their substantialindication ,Because of their substantial vasodilatoryvasodilatory action,action,

    PDE inhibitors frequently require the addition ofPDE inhibitors frequently require the addition of vasopressorsvasopressors..

    CJASN March 2008 vol. 3 no. 2 546CJASN March 2008 vol. 3 no. 2 546--553553

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    TerlipressinTerlipressin andand ornipressinornipressin both are synthetic vasopressinboth are synthetic vasopressin

    analogues with longer halfanalogues with longer half--life and duration of action. Thislife and duration of action. This

    may be disadvantageous in shock therapy, Inmay be disadvantageous in shock therapy, In noncontrollednoncontrolled,,

    smallsmall--sized septic shock studies, addition ofsized septic shock studies, addition of terlipressinterlipressin toto

    norepinephrinenorepinephrine increased MAP and visceral perfusion, butincreased MAP and visceral perfusion, butthese data are still preliminarythese data are still preliminary

    CJASN March 2008 vol. 3 no. 2 546CJASN March 2008 vol. 3 no. 2 546--553553

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    ReferencesReferences

    HarissonsHarissons principles of internal medicineprinciples of internal medicine-- 1616thth EditionEdition

    Millers AnesthesiaMillers Anesthesia 77thth EditionEdition

    Cardiovascular Drug Therapy .Cardiovascular Drug Therapy .Franz H.Franz H. MesserliMesserli MDMD--22ndnd EditionEdition

    Guytonand Hall TextbookofMedical Physiology 12theditionGuytonand Hall TextbookofMedical Physiology 12thedition

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    Thank YouThank You