INOTROPES AND VASOPRESSORS

PRESENTERS:Anusha.M Dipin MODERATOR: Dr.Suhas

OVERVIEW
1.Cardiac glycosides 2.Noradrenaline 3.Adrenaline 4.Dopamine 5.Dobutamine


6.Levosimendan 7.Nesiritide 8.Phenylephrine 9.PDE Inhibitors

Recent advances and uses of the above drugs.

CARDIAC GLYCOSIDES


The first line of inotropes include all digitalis derivatives

uses
Maintanance dosedose0.125 to 0.375mg/day.
DRAW A SERUM DIGOXIN LEVEL AT LEST SIX HOURS AFTER THE LAST DOSE!

DIGOXI N
Oral Absorption

Tablets

Elixir

Capsules

60%

80%

75 - 90%

Time to peak (min)

90

45 - 60

60 - 90

Digitoxin Less polar and more lipid soluble Easily crosses BBB Produces CNS symptom life is 5 days Heart : plasma ratio is 7:1

Digoxin More polar and less lipid soluble Does not cross BBB Does not produce CNS symptom life is 1 days Heart : plasma ratio is 30:1

Mostly metabolized in the liver, so its More than 80% excreted unchanged via excretion is independent of renal function urine, rest is removed by non-renal routes like biliary excretion and hepatic metabolism Digitalization requires (4x5) 20 days Digitalization requires (4x1) 20 days

S/E Heart block (33%), Bradycardia (24%), Junctional tachycardia (15%), a AF (12%).

At present, patients with preserved left ventricular systolic function probably should not be treated with digoxin. At present, the consensus is that digoxin therapy is digoxin. probably inappropriate in patients with preserved left ventricular systolic function. In addition, digoxin therapy may not be useful in patients with congestive heart failure and a high cardiac output syndrome such as anemia or thyrotoxicosis . Patients presenting with acute myocardial infarction should not be started on digoxin therapy.

N Engl J Med 1997;336:525-33. 1997;336:525Use of lower dosages is particularly important in the elderly, because digitalis toxicity may be difficult to recognize in this patient population.32 It is generally agreed that digoxin should be given in a dosage of 0.125 to 0.25 mg per day. Dosages higher than 0.25 mg per day are probably unwarranted.

DIGOXIN AND ARYTHIMIAS



Digoxin has a limited, but useful, role, either alone or in combination with other agents such as -blockers, diltiazem or verapamil, in achieving satisfactory resting verapamil, ventricular rate control in patients with chronic atrial fibrillation. In patients who lead a predominantly sedentary lifestyle (perhaps particularly in those who are elderly), digoxin alone may be the agent of choice. both -blockers and calcium-channel blocking agents were effective as first-line agents in about calciumfirst50% 50%70% of patients, and that digoxin (which was allowed to be added as a secondsecond-line agent) appeared to increase the rate control efficacy of these agents modestly Circulation 2002; 106 (Suppl II): II-633. (Suppl II-

NORADRENALINE
RECEPTOR EFFECT

1 2 1 2 Dopaminergic

+++ +++ +++ +/++ -

1.Increase in SVR predominates Reflex bradycardia 2.Decrease in Cardiac Output 3.Cardiac Output may maintained by positive inotropic effect 4.Increase in heart rate limit the clinical effectiveness 5.Increases SBP, DBP & MAP

DOSE:
    

Initial dose: 8 to 12 mcg/min dose: Maintenance: Maintenance: 2 to 4 mcg/min. High doses- 0.5 to 1.5 mcg/kg/min for 1-10days doses1have been used in septic shock. Range used in clinical trials: 0.01-3 trials: 0.01mcg/kg/minute. ACLS dosage range: 0.5 to 30 mcg/minute. range: Calculation of drip rate 8 mg/ 250 ml (ml/hr) = mcg/min x 1.875.

Norepinephrine bitartrate 2 mg = Norepinephrine base 1 mg. S/E Arrhythmias Bradycardia Peripheral (digital) ischemia Hypertension . Extravasation tissue necrosis

    

ADRENALINE

epinephrine

1 ++++

2 ++++

1 ++++

2 +++

Dopamine -

DOSES
Refractory hypotension Continuous IV infusion: range: 1-10 mcg/minute .. Usual rate: 11 to 4 mcg/min.  Severe cardiac dysfunction - doses >10 mcg/minute (up to max of 20 mcg/min in a 70kg patient).


Endotracheal: Endotracheal: Doses (2-2.5 x IV dose) should be diluted to (210 ml with NS or distilled water prior to administration.

Anaphylaxis (adult): 1.0.3 mg IM (0.3 ml of a 1:1000 solution). repeat 10 to 15 minutes 2. 0.1 to 0.25 mg IV (1:10,000) over 5-10min repeat 5 to 15 5minutes 3.start continuous infusion: 1 to 4 mcg/min. Asthma: Asthma: 1. Inhalational form: start with 1 inhalation, then wait at least 1 min.,PERSISTS- Do not use again for at least 3 hr. min.,PERSISTS2.subcutaneous (SC) form: 0.2-0.5 mg (0.2-0.5 ml of a 0.2(0.21:1000 solution) SC every 2 hr as required. 3.In severe attacks, may repeat dose every 20 min for a maximum of 3 doses. Cardiac arrest: arrest: 1 mg IV initially; may be repeated as necessary q 3-5 min. 3-

DOPAMINE
Dopamine (g /kg/ min) 05- 2 3 - 10 > 10 0 + ++(+) 1 1 2 Dopamine + ++ ++(++) + + +(+) ++ ++ ++

Low dose (0.5-2) DA1 and DA2. Actions-Natriuresis Medium dose (3-10) (chronotropic and CO) High dose (10-20) (beneficial effects blunted). High dose = NE. VERY High dose( >20) overrides dopamine effects.reverses renal dilation and Natriuresis

DOSES
Refractory CHF: initial dose: 0.5 to 2 mcg/kg/min. CHF: Renal perfusion shock: 1 to 5 mcg/kg/min. shock: Initially 5 mcg/kg/min, increase by 5 to 10 mcg/kg/min (10 to 30 min) up to max of 50 mcg/kg/min. Cardiac life support (initial): 2 to 5 mcg/kg/min - titrated to effect. Infusion may be increased by 1-4 mcg/kg/min at 10 to 130 min intervals until optimal response is obtained. If dosages >20>20-30 mcg/kg/min are needed, a more direct-acting pressor directmay be more beneficial. Renal shutdown may occur at doses >50 mcg/kg/min. Calculation of drip rate (ml/hr) 400mg/250 ml: wt(kg) x mcg/min x 0.0375.

Extravasation into tissuestissues The infusion should be immediately stopped.  Infiltrate with 0-15ml 0.9% Sodium Chloride containing 50510mg Phentolalmine. Phentolalmine.  Regitine is then administered SQ in the four 90quadrants 90 around the site of extravasations.

DOBUTAMINE
Dobutamine + 1 1 +++++ 2 +++ Dopamine O V1 O

1.Increases Cardiac Output by positive inotropic effect 2.Minimal increase in heart rate 3.No effect on SVRStrong Inotropic, SVRStrong Inotropic, weak chronotropic. chronotropic. 4.Increases automaticity, AV conduction. 5.No norepinephrine release 5.No 6.Effective in catecholamine depleted states 7.Tolerance after 3 days of treatment

DOSES
 

Adult (usual): 2.5 to 20 mcg/kg/minute. Max- 40 mcg/kg/min. (usual): MaxDrip rate (500mg/250 ml) ml/hr = wt(kg) x (mcg/min) x 0.03.

S/E:  Tachycardia  Increased ventricular response rate in patients with atrial fibrillation  Ventricular arrhythmias  Cardiac ischemia

PDE inhibitors
Arterial dilator: ++ Inotropic effect: +++ Venodilator: 0 Venodilator:

AmrinoneAmrinone- CI, LV stroke volume, LVEF. in PCWP, PA pressure, RA pressure, SVR. Positive inotropic and vasodilator. DOSES:  CHF(short term):Initial: 0.75 mg/kg IV bolus over 2-3 min, 2Repeat after 30min Maintance: 5Maintance: 5-10 mcg/kg/min IV infusion., not >10 mg/kg. Renal failure: Crcl<10 ml/min: Administer 50% to 75% of dose. Crcl<10


S/E:  Thrombocytopenia (most common)  Ventricular arrhythmias  Hypotension  Cardiac ischemia  Torsade des pointes

DOSES
 

Milrinone-CHF: Initial loading dose, 50 mcg/kg IV over Milrinone-CHF: 10min, then 0.375 to 0.75 mcg/kg/min IV (Usual: 0.5 mcg/kg/min). Cardiac surgery: 15min before separation from surgery: cardiopulmonary bypass, 50 mcg/kg IV over 20 minutes followed by a continuous infusion of 0.5 mcg/kg/min IV for a minimum of 4h infusion rates: renal insufficiency Recommended
Creatinine Clearance (mL/min/1.73 m 2 ) 5 10 20 30 40 50 Infusion Rate (mcg/kg/min) 0.20 0.23 0.28 0.33 0.38 0.43

Calculation of drip rate: 50 mg/250ml (ml/hr) = wt (kg) x 0.3 x rate: mcg/kg/min

Side effects  Arrhythmias, enhanced AV conduction (increased ventricular response rate in atrial fibrillation)  Hypotension  Thrombocytopenia  Hepatotoxicity

CalciumCalcium-Sensitizing Agents
Levosimendan

1) Changes actin-myosin cross-bridge kinetics actincross-

without increasing the cycling rate of the cross-bridges or myocardial crossATP consumption, (2) the effects of calcium on cardiac myofilaments during systole (3) Improves contraction at low energy cost and Ca2+ sensitizer at lower concentrations- Ca2+ sensitizer concentrationsHigh Concentrations -PDE-III inhibitor PDE t1/2=1hr

STUDIES
CHF CLASS 3/4, EF of 21% ,PCWP over 15 mmHg and cardiac index less than 2.5 L/min/m2 were enrolled.  Drug infusion dose raised over 4 hours from 0.1 micrograms/kg/minute to 0.4 mcg/kg/minute and maintained for 2 hours.  LevosimendanLevosimendan- pulmonary pressures, right atrial pressure, and blood pressure.  The drug improved shortness of breath and fatigue, and caused no significant side effects. Eur J Pharmacol 2000 Sep 15;404(1-2):191-9 15;404(1-2):191

Levosimendan at a 10 minute dose of 6 - 24 mcg/kg followed by IV at 0.05 to 0.2 mcg/kg/min -good results in acute heart failure episodes
J Am Coll Cardiol 2000 Nov 15;36(6).

Levosimendan is a good drug to treat acute CHF in the shortshortterm. It improves heart output without making the heart work harder, and it improves right ventricle efficiency.
Clin Pharmacol Ther 2000 Nov;68(5):522-31. Nov;68(5):522-

In LIDO trials, levosimendan reduced risk of worsening CHF or death compared to dobutamine and placebo in CHF improved survival.levosimendan caused fewer serious adverse events than dobutamine .

DOSES


The usual dosage of IV -6 to 24 mg/kg loading dose over 10 min continuous infusion. 0.05to 0.2 mg/kg/min.

Haemodynamic responses are generally observed within 5 minutes of commencement of infusion of the loading dose. Peak effects are observed within 10 to 30 minutes of infusion; the duration of action of levosimendan is about 72-78 hrs to week. 72-

B-type natriuretic peptide

Nesiritide  Recombiinant human B-type natriiuretiic B peptiide  Identiical to intriinsiic ventriicullar  hormone  manufactured from E. coli using rDNA technology

When administered to patients with heart failure, it:  decreases preload and afterload  decreases pulmonary vascular resistance  increases cardiac output In some studies:  increased urine output  reduced diuretic requirements  suppression of aldosterone, endothelin, norepinephrine aldosterone, endothelin,

 

Human BNP is cleared from the circulation via the following three independent mechanisms, in order of decreasing importance: 1) internalization and lysosomal proteolysis; 2) proteolytic cleavage of the peptide by endopeptidases lumenal surface; 3) renal filtration.

formulation


 

  

The quantitative composition of the lyophilized drug per vial is: nesiritide 1.58 mg, mannitol 20.0 mg, citric acid monohydrate 2.1 mg, and sodium citrate dihydrate 2.94 mg. s/e: dizziness, chest pain, fast heart rate, or confusion shortly after you receive nesiritide; nesiritide; feeling light-headed, fainting; lightcoughing up blood; or fever, pale skin, easy bruising, unusual weakness.

DOSES
 

BolusVolume (mL) = Weight (kg) / 3 mL) Volume Infusion Flow Rate (mL/hr) =Weight (kg) x 0.1 (mL/hr)
Weight (kg) Weight (kg) 60 70 80 90 100 Infusion Flow Rate (mL/hr) 6 7 8 9 10 60 70 80 90 100 Volume of Bolus (mL = kg/3) 20.0 23.3 26.7 30.0 33.3

 

Initial dose: 0.01 mcg/kg/minute Increments: 1 mcg/kg IV bolus over 1 minute 0.005 mcg/kg/minute Maximum continuous dosage: 0.03 mcg/kg/minute

STUDIES
In the absence of hypotension, IV NTG, sodium nitroprusside or nesiritide may be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms in patients admitted with ADHF.  Intravenous vasodilators, (nitroprusside, nitroglycerin or (nitroprusside, nesiritide) nesiritide) may be considered in patients with ADHF and advanced HF who have persistent severe HF despite aggressive treatment with diuretics and standard oral therapies. J Cardiac Failure. 2006;12:1038 Failure. 2006;12:10


TRIALS
VMAC Trial Vasodilation in the Management of Acute CHF Nesiritide vs IV nitroglycerin vs placebo. Effects start @ 15 min. Sustained to 24hrs.Nesiritide equal to NTG in dyspnea improvement @ 3 hr.  THE NAPA TRIAL: Nesiritide Administered Peri-Anesthesia eriin Patients Undergoing Cardiac Surgery To explore the effects of perioperative administration of nesiritide on clinical outcomes and safety in heart failure patients undergoing cardiac surgery.  PRECEDENT (Prospective Randomized Evaluation of Cardiac Ectopy with Dobutamine or Natrecor (nesiritide) nesiritide) Therapy). 0.015 and 0.03 mcg/kg/min without an initial bolus for 24 hours did not aggravate preexisting VT.


Endothelin receptor antagonist

ETA receptor antagonists -SITAXENTAN, AMBRISENTAN. Dual antagonists -BOSENTAN,TEZOSENTAN Sitaxentan, Sitaxentan, ambrisentan and bosentan are mainly used for the treatment of PAH while atrasentan is an experimental anti-caner drug. anti-

STUDIES


Endothelin receptor antagonist (ETA/ETB non selective) Indication WHO group I - functional class II, III, IV Dosage 62.5 mg oral twice daily for 4 weeks then 125 mg oral twice daily Endothelin receptor antagonist (ETA selective) Indication WHO group I - functional class II, III Dosage 5 mg and 10 mg oral daily

Circulation. 2008;117:3010Circulation. 2008;117:3010-9

VASSOPRESSIN

Receptors

Tissues

Principal Effects

V1R

Vascular Vasoconstriction smooth muscle Kidney, platelets, spleen

V2R

Renal Increased collecting duct permeability to Endothelium water Vasodilation Pituitary Neurotransmitter ACTH release

V3R

RECEPTORS

DOSES
Diabetes insipidus: insipidus: 5-10 units IM/SQ 2-4 times daily as needed(dosage range 5-60 units/day). 25GI hemorrhage: IV: Initial: 0.2-0.4 unit/minute. If bleeding stops, hemorrhage: 0.2continue at same dose for 12 hours, taper off over 24-48 hours. 24Continuous IV infusion: 0.5 milliunits/kg/hour (0.0005 unit/kg/hour). milliunits/kg/hour Double dosage as needed every 30 minutes to a maximum of 10 milliunits/kg/hour. milliunits/kg/hour. Out-ofOut-of-hospital asystole :40 units IV. Repeat if not restored in 3 minutes. Pulseless VT/VF: 40 units IV (as a single dose only). VT/VF: EndotrachealEndotracheal-administer 40 units diluted with NS (to a total volume of 10 ml)

Vasodilatory shock/septic shock: shock: The recommended infusion rate for vasopressin in the treatment of shock in adults is 0.01 0.04 units/min. 0.01 This dosage range is reported to be effective in about 85% of patients with norepinephrine resistant hypotension. Doses greater than 0.04 units/min may lead to cardiac arrest. S/E 1. rapid rebound hypotension when stopped 2.Infusion range - ischemic skin lesions to intestinal ischemia. 3. Vasopressin therapy may also result in cardiac output and hepatosplanchnic flow.

DRUG FORMULATIONS

VASOPRESSIN AND SEPSIS



Surviving Sepsis Campaign study currently only recommends vasopressin (at a regimen of 0.01-0.04 U/min) as adjunctive 0.01therapy in patients with refractory shock despite adequate fluid resuscitation and high-dose conentional vasopressors. highvasopressors. There is currently a multicentred study powered to examine the effects of vasopressin on outcome in septic shock, The Vasopressin versus Norepinephrine in Septic Shock Study (VASST). The hypothesis is that treatment with vasopressin will reduce mortality from septic shock at 28 days.

TRIALS


The first (a trial of 24 patients who underwent a 4-hour 4blinded study) showed a significant improvement in renal function in the vasopressin group. The second (randomising 48 patients to vasopressin and noradrenaline or noradrenaline alone for a 48-hour period, and 48monitoring broadly similar variables), showed significant improved cardiac indices, fewer tachyarrhythmias and improved gastric mucosal carbon dioxide tensions in the vasopressin group.

SUMMARY

RECENT ADVANCES

Norepinephrine as the first-line agent additional firstagents should be considered in patients who remain hypotensive display evidence of inadequate tissue or organ  perfusion despite doses of norepinephrine up to 0.2 g/kg/ g/kg/ followed by dobutamine or epinephrine in patients with poor left ventricular (LV) function and vasopressin (fixed dose of 0.03 u/min) in patients withpreserved LV function and a low withpreserved systemic vascular resistance Survival sepsis guidelines 2011 Marik Annals of Intensive Care 2011, 1:17


ROLE IN HEART FAILURE

ROLE IN HYPOVOLUMIC SHOCK

Inotropic and Vasoactive Catecholamines

Drug Norepinephrine

Dosage

Hemodynamic Actions

4 mg/250 mL or 500 mL 5% D/W continuous IV -Adrenergic: infusion at 812 g/min initially, then at 24 g/min as Vasoconstriction maintenance, with wide variations -Adrenergic: Inotropic chronotropic effects*

Dopamine

400 mg/500 mL 5% D/W continuous IV infusion at 0.31.25 mL (0.251 mg)/min 210 g/kg/min for low dose 20 g/kg/min for high dose

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

250 mg/250 mL 5% D/W continuous IV infusion at 2.510 g/kg/min

-Adrenergic: Vasoconstriction -Adrenergic: Inotropic chronotropic effects an vasodilation Nonadrenergic: Renal a splanchnic vasodilation -Adrenergic: Inotropic effects

Summary
 

Norepinephrine is considered the first-line vasopressor in firstvasodilatory shock, Dobutamine the first-line inotrope in shock associated with firstdecreased cardiac output, Epinephrine is the first-line catecholamine in firstcardiopulmonary resuscitation and also as second line in shock that is unresponsive to other catecholamines. catecholamines. Vasopressin is emerging as a therapy in resistant vasodilatory shock.. Levosimendan has been associated with an increased proarrhythmic risk. This may be prevented by cautious, concurrent blocker therapy, which inhibits levosimendanlevosimendaninduced sympathetic hyperreactivity. hyperreactivity.

CJASN March 2008 vol. 3 no. 2 546-553 546-

NESIRITIDE- Severe hypotension and cardiogenic shock are the major contraindications to nesiritide use. It is a potential secondsecond-line drug for the treatment of acutely decompensated chronic heart failure, although, in clinical practice, it is more liberally used. PDE III Inhibitors- PDE inhibitors improve cardiac output in Inhibitorscardiogenic shock and are used as second-line drugs for this secondindication ,Because of their substantial vasodilatory action, PDE inhibitors frequently require the addition of vasopressors. vasopressors.

CJASN March 2008 vol. 3 no. 2 546-553 546-

Terlipressin and ornipressin both are synthetic vasopressin analogues with longer half-life and duration of action. This halfmay be disadvantageous in shock therapy, In noncontrolled, noncontrolled, smallsmall-sized septic shock studies, addition of terlipressin to norepinephrine increased MAP and visceral perfusion, but these data are still preliminary

CJASN March 2008 vol. 3 no. 2 546-553 546-

References
   

Harissons principles of internal medicine- 16th Edition medicineMillers Anesthesia 7th Edition Cardiovascular Drug Therapy .Franz H. Messerli MD-2nd Edition .Franz MDGuyton and Hall Textbook of Medical Physiology 12th edition

Thank You