VASOACTIVE DRUGS

OVERVIEW

• Basic physiological principles

• Classification and basic pharmacology of Vasoactive drugs

• Common indications of their use

• Evidence based medicine

Vasoactive drugs Vasopressors Ionotropes

Increase the force of contraction of myocardial muscle

Positive ionotropism

Stimulates smooth muscle contraction of the capillaries & arteries

Vasoconstriction

Rise in Mean Blood Pressure

Improved tissue perfusion and oxygenation

BASIC PHYSIOLOGY

MAP = CO x SVR

~ 1

r4

HR x SV

PRELOADCONTRACTILITY

AFTERLOAD

VASOPRESSORS

↑MAP = CO x↑SVR

~ 1

↓r4

HR x SV

PRELOAD CONTRACTILITY

AFTERLOAD NORADRENALINE

VASOPRESSIN

IONOTROPES

↑MAP = ↑ CO xSVR

~ 1

r4

HR x ↑ SV

PRELOAD ↑ CONTRACTILITY

AFTERLOAD DOPAMINE

DOBUTAMINEADRENALINE

Vasoactive Receptors

• ALPHA (1 , 2)

• BETA ( 1, 2, 3 )

• VASOPRESSIN (V1 , V2)

• PHOSPHODIESTERASE ( PDE III)

• DOPAMINERGIC (D1, D2 ,D3, D4, D5)

ADRENOCEPTORS

RECEPTOR LOCATION ACTION on stimulation

1 • Vascular smooth muscle

• Myocardium

• Vasoconstriction

• Arrythmia

2 • CNS

•Vascular smooth muscle

• Platelets

• Reduced central sympathetic flow

•Vasoconstriction

• Platelet aggregation

1 • Myocardium • + ve Ionotropism

• + ve Chronotropism

2

• Bronchi

• Blood vessels

• Bronchodilation

• Vasodilation

RECEPTOR LOCATION ACTION on stimulation

V1 Vascular smooth muscle

• SKELETAL • MESENTRIC • CORONARY

• Vasoconstriction

PDE- III

• Myocardium

•Vascular smooth muscle

• + ve Ionotropism • + ve Chronotropism

•Vasodilatation

IONODILATION

D1 Vascular smooth muscle

• RENAL • MESENTRIC• CORONARY

• Vasodilatation

Vasoactive drugs in practice VASOPRESSORS/ PRESSORS –

DIRECT ACTING SYMPATHOMIMETIC

INDIRECT ACTING SYMPATHOMIMETIC

MIXED ACTINGSYMPATHOMIMETIC

OTHERS

NOR ADRENALINE

ADRENALINE @ high doses

PHENYLEPHRINE

ISOPRENALINE

METARAMINOL EPHEDRINE

MEPHENTERMINE

VASOPRESSIN

DOPAMINE @ VERY HIGH DOSES

IONOTROPES – Sympathomimetic drugs - • Dobutamine •Adrenaline @ low dose• Dopamine @ mod doses

Other mechanism of action – 1. PHOSPHODIESTERASE III INHIBITOR ( Ionodilators )

• Amrinone, Milrinone

2. CARDIAC GLYCOSIDES

• Digoxin

3. MYOFILAMENT CALCIUM SENSITISERS

• Levosimendan, pibomendan, sulmazole

4. GLUCAGON, CALCIUM

DRUG DOSE 1 1 2 CO SVR MAP HR ADRENALINE@ Low dose

@ High dose

0.1-0.5µg/kg/min

0.5-1µg/kg/Min

++

+++

+++

++

++

++

↑↑

↔↑

↓

↑↑

↑ ( SBP > DBP)

↑↑

↑

↑

NORAD 0.5- 30µg/min

+++ ++ 0 ↔↑ ↑↑ ↑↑ ( SBP ~ DBP)

↓

PHENYLEPHRINE

40–180 μg/min

+++ 0 0 ↔↑ ↑↑ ↑↑ ( SBP ~ DBP)

↓↓

ISOPRENALINE 2–10 μg/min

0 +++ +++ ↑ ↓ ↓ ( SBP >>>DBP↓↓ )

↑ ↑

DRUG 1 1 2 D1 EFFECTS

DOPAMINE

0.5 – 2 µg/kg/min

2- 5 µg/kg/min

5-10 µg/kg/min

10-20 µg/kg/min

0

0

+

++

+

+

++

++

0

0

0

0

++

++

++

++

RENAL, MESENTRIC VASODIL

CO ↔↑, VASODILATION

CO ↑

SVR ↑↑↑MAP↑ (SBP> DBP)HR ↔

DOBUTAMINE

2.5–20 μg/kg/min 0 +++ ++ 0

CO ↑SVR ↓MAP ↔↑ HR ↔

VASOPRESSIN-• V1 receptor stimulation• ↑ SVR• ↑MAP

PHOSPHODIESTERASE III INHIBITORs (Ionodilators ) – Amrinone, MilrinoneEnoximone , Piroximone (highly selective)• ↑↑CO • ↓SVR• ↓↔ MAP

DIGOXIN (↑ intracellular Ca++) –• ↑CO• ↓SVR• ↔ ↑MAP• ↔ HR

MYOFILAMENT CALCIUM SENSITISERS

Levosimendan, Pimobendan, Sulmazole

Enhance response of myofilament contractile element to Ca

without altering availability of this ion• ↑CO • ↓SVR• ↑MAP• ↔ HR

Adrenaline 1) DOC for cardiovascular resuscitation

1mg every 3 min

(Ionotropy + chronotropy + pressor action )

2) DOC for anaphylaxis

0.5 mg bolus f/b 1-10 µg/min infusion

0.5 mg bolus i.m. repeated every 5 min

(Mostly ‘coz of bronchodilator action)

3) Second-line agent in the management of septic shock

Reasons being considered second to Noradrenaline –1) Splanchnic and renal vasoconstriction at high doses2) Lactic acidosis3) Increased myocardial O2 demand and potential for inducing

myocardial ischemia 4) Tachyarrhythmias

However these observations not found to be significant in following trials -

EVIDENCE BASED MEDICINE (EBM)1) Anane et al ( Lancet, 2007 ) - no difference ADR Vs NA ± DOBUTAMINE 28 day mortality – 40 vs 34 %90 day mortality - 52 vs 50 %

2) Myburgh et al ( Intensive care medicine, 2008 ) ADR Vs NA with use of other drugs in either groupPrimary outcome – assess time to achieve MAP of 65(35.1 vs 40 hours) Secondary outcome - 28 day and 90 day mortality – same

But Adrenaline group had significant but transient lactic acidosis, tachyarrythmias and insulin requirements in both the studies.

NOR ADRENALINE 1) First line drug in hyperdynamic septic shock (0.5- 30 µg/min) (↑ C I , ↓ SVR, ↓ MAP )

PROS - 1) ↑ MAP – Better end organ perfusion 2) Efferent > afferent glomerular arteriolar constriction - imroved glomerular filtration 3) Potency > Dopamine 4) Preservation of Splanchnic circulation > Adrenaline 5) Cardiac index > Vasopressin

CONS - 1) Need very high dose (10 -30 µg/min ) due to alpha 1 receptor downregulation in sepsis 2) Consequent damage due to vasoconstriction

EBM1) Martin et al ( Chest 1993) DOPA vs NA Goal – maintain MAP > 80 or SVR > 1100 dyne or both 5 – improved with DOPA15 – improved with NA11 - who didn’t improve with high dose DOPA did improve with NA

2) Martin et al ( Critical care med 2000)

High-dose DOPA vs NA Use of norepinephrine was associated with improved survival

3) Bellomo R et al ( Critical care med 2001) NA improves renal blood flow and urine output

2) Can be used in spinal shock3) Cautious use in cardiogenic shockContraindicated in hypovolemic shockCostlier than dopamine and adrenaline

PHENYLEPHRINEUsed primarily in situations where severe vasodilatation has led to Hypotension -> shockEg- Anesthesia-induced hypotension

Utility of PNP in hyperdynamic septic shock is debatable

Limited trials available till date to support its use

EBM – use of PNP in septic shock

1) Gregory et al ( Critical Care Med 1991) very small sample size

Addition of phenylephrine to dobutamine or dopamine increased mean arterial pressure, systemic vascular resistance & urine output without a change in heart rate

2) Krejci V et al (Crit Care Med- 2006) Compared to epinephrine and norepinephrine, phenylephrine is less likely to decrease microcirculatory blood flow in the splanchnic circulation

Advantage of it being useful in situations where other vasopressors cant be used due to tachycardia/ tachyarrythmias

IsoproterenolTemporary treatment of hemodynamically significant bradycardia unresponsive to atropine till more definitive treatment with an external or transvenous pacemaker is made available

Temporary chronotropic and ionotropic support post cardiac transplantation.

Due to risk of - Tachycardia/ tachyarrythmiasIncreased myocardial O2 demand and ischemianot used routinely as an vasoactive drug

DOPAMINE 1) Hyperdynamic septic shock (when excessive vasodilation is the primary pathology) DOPA @ Mod to high doses cause increase CI > SVR NA preferred over it. May use as an add on to NA

2) Hypodynamic septic shock May be useful

3) Acute decompensated heart failure and hypotension In combination with venodilators, dobutamine

EBM1) Sakr et al ( Crit Care Med 2006)(SOAP study – Sepsis Outcome in critically ill Patients )Dopamine was associated with increased mortality

2) Provoa Et al (Crit Care Med. 2009)

SACiUCI trial – portugese population study28Day mortality NA a/w 3.5 x increase mortality , p= <0.001Dopamine a/w 0.7x lower mortality, p=0.049

3) Daniel de Backer et al ( NEJM 2010)Dopamine Vs NA in shock ( collective)with goal to maintain MAP allowing addition of other drugs to either group28 day mortality-Overall – same ( 52.5 vs 48.5 %)Septic shock- same Hypovolemic shock- same Cardiogenic shock - more with DopamineArrythmic events –More with DOPA group (24.1 vs 12.4 %)

4) Ruokonen E et al ( Crit Care Med 1993)DOPA vs NA Former was associated with splanchnic oxygen shuntingSplanchnic O2 delivery >>>>> O2 extraction

5) Marik PE et al (JAMA 1994)DOPA vs NA Former was associated with worser intragastic pH values

6) ANZICS (Lancet 2000)DOPA vs PLACEBONo renoprotective effect at lower doses in earlyrenal dysfunction as thought earlier.

Dobutamine 1) Acute and chronic decompensated heart failure (↑CO,↓SVR and PVR, ↓PCWP )

2) Concomitant septic shock and depressed cardiac function - Hypodynamic septic shock

@ 5 mics/kg /hr will cause ↑CO and improve (not restore) capillary perfusion

3) Doubtful utility in cardiogenic shock- may cause ↑ myocardial O2 demand - myocardial ischemia

Problems –• Down regulation of receptors after 72 hrs use –

tolerance may develop• Tachyarrytmias, myoischemia• Eosinophilic or hypersensitivity myocarditis with chronic

use

Ideal candidate – • Severly depressed LV function with low CO• Elevated LV filling pressure• Not associated with significant hypotension (MAP >70)

Vasopressin 1) Cathecolamine resistant septic shock/ refractory shock2) Dose reduction of cathecolamines with concomitant use

Rationale1) Relative deficiency of vasopressin in septic shock 2) In hypoxia and acidosis though alpha adrenergic effects of other

vasopressors is blunted, pressor effect of vasopressin seen.3) Diuresis in shock < 24 hrs ( septic, cardiogenic ) shock at low

doses as leads to NO and ANP release .

EBM1) Russel JA et al ( Crit Care Med 2007) Vasopressin vs NA as monotherapy in septic shock85% of those with vasopressin needed NA eventually to atttain desired MAP. None from NA group needed VASO

2) Russel JA et al ( NEJM 2008) VASST trial – Vasopressin And S eptic Shock Trial778 patients with septic shock who were receiving a minimum of 5 μg per minute of norepinephrine to receive either1) low-dose vasopressin (0.01 to 0.03 U per minute) or 2) norepinephrine (5 to 15 μg per minute) in addition to open-label

vasopressors.

28 days mortality rates – same Vasopressin Vs norepinephrine (35.4 Vs 39.3% )

Progression to renal failure – lesser with use of vasoVasopressin Vs norepinephrine (20.8 Vs 38.6% )

28 days mortality ratesIn patients with less severe sepsisPatients belonging to category R of RIFLE scoreLesser with use of vasopressin – Vasopressin Vs norepinephrine (30.8 Vs 54.7% )

Other use of vasopressin – Treatment of cardiac arrest unresponsive to epinephrine and defibrillation

EBM 1) Aung Ket al : Vasopressin as monotherapy for

cardiac arrest.( Arch Intern Med, 2005) 2) Gueugniaud PY, et al Vasopressin and Epinephrine vs. Epinephrine alone in

cardiopulmonary resuscitation( N Engl J Med 2008)

No benefit in mortality alone or with epinephrine

PDE-III inhibitors (Milrinone – ionodilators)

Used in acute decompensated heart failure

Loading dose (50 μg per kg),followed by a continuous infusion @ 0.25 to 0.75 μg / kg/ min.

Because it is a potent vasodilator, it should be avoided in the 1) patients with frank hypotension and is2) contraindicated in patients with severe aortic stenosis.

Levosimendan Used in acute decompensated heart failure

Mebazaa A, et al SURVIVE Trial (JAMA 2007)

1) Intravenous levosimendan showed no benefit compared to dobutamine in reducing all-cause mortality at 180 days (26% vs. 28% ) but

2) Increased the incidence of atrial fibrillation

Newer drugs

• Methylene blue• Glucagon• Cortisol• Hydrocortisone• Levothyroxine• Dotrecognin -alfa

Shock PCWP CO SVR Preferred agent

Hypovolemic /Low preload shock ↓ ↓ ↑ Fluids

Cardiogenic shock ↑ ↓ ↑ Ionotropes(Dopa > dobut)Ionodilators

Vasogenic /vasoplegic / Distributive shock•Hyperdynamic sepsis

•Sepsis with depressed cardiac function

•Anaesthetic induced

↑↔

↔

↔

↑

↓

↔

↓

↓

↔

N> D> A> V

D>N + Dobut

PNP, EPHEDRIN

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