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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..
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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..
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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
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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
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