1) Vasoactive drugs include vasopressors, ionotropes, and other drugs that act on vascular smooth muscle and cardiac muscle. 2) Norepinephrine is the first-line vasopressor for treating septic shock as it increases cardiac index and blood pressure while preserving organ perfusion. Dopamine can also be used but has greater risks. 3) Ionotropes like dobutamine are used to increase cardiac contractility in conditions with low cardiac output such as cardiogenic or hypodynamic septic shock.

1. VASOACTIVE DRUGS

2. OVERVIEW
• Basic physiological principles
• Classification and basic pharmacology of
Vasoactive drugs
• Common indications of their use
• Evidence based medicine

3. 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

4. BASIC PHYSIOLOGY
MAP = CO x SVR
~ 1
r4
HR x SV
PRELOAD
CONTRACTILITY
AFTERLOAD

5. VASOPRESSORS
↑MAP = CO x↑SVR
~ 1
↓r4
HR x SV
PRELOAD
CONTRACTILITY
AFTERLOAD
NORADRENALINE
VASOPRESSIN

6. IONOTROPES
↑MAP = ↑ CO xSVR
~ 1
r4
HR x ↑ SV
PRELOAD
↑ CONTRACTILITY
AFTERLOAD
DOPAMINE
DOBUTAMINE
ADRENALINE

7. Vasoactive Receptors
• ALPHA (α1 , α2)
• BETA ( β1, β2, β3 )
• VASOPRESSIN (V1 , V2)
• PHOSPHODIESTERASE ( PDE III)
• DOPAMINERGIC (D1, D2 ,D3,
D4, D5)
ADRENOCEPTORS

8. RECEPTOR LOCATION ACTION on stimulation
α1
• Vascular smooth muscle
• Myocardium
• Vasoconstriction
• Arrythmia
α2
• CNS
•Vascular smooth muscle
• Platelets
• Reduced central sympathetic flow
•Vasoconstriction
• Platelet aggregation
β1 • Myocardium
• + ve Ionotropism
• + ve Chronotropism
β2
• Bronchi
• Blood vessels
• Bronchodilation
• Vasodilation

9. 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

10. Vasoactive drugs in practice
VASOPRESSORS/ PRESSORS –
DIRECT ACTING
SYMPATHOMIMETIC
INDIRECT ACTING
SYMPATHOMIMETIC
MIXED ACTING
SYMPATHOMIMETI
C
OTHERS
NOR ADRENALINE
ADRENALINE
@ high doses
PHENYLEPHRINE
ISOPRENALINE
METARAMINOL EPHEDRINE
MEPHENTERMINE
VASOPRESSIN
DOPAMINE
@ VERY HIGH
DOSES

11. 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

12. DRUG DOSE α1 β1 β2
CO SVR MAP HR
ADRENALINE
@ Low dose
@ High dose
0.1-0.5
µg/kg/
min
0.5-1
µg/kg/
Min
++
+++
+++
++
++
++
↑↑
↔↑
↓
↑↑
↑
( SBP >
DBP)
↑↑
↑
↑
NORAD 0.5- 30
µg/min
+++ ++ 0 ↔↑ ↑↑ ↑↑ ( SBP ~
DBP)
↓
PHENYL
EPHRINE
40–180
μg/min
+++ 0 0 ↔↑ ↑↑ ↑↑ ( SBP
~ DBP)
↓↓
ISOPRENALINE 2–10
μg/min
0 +++ +++ ↑ ↓ ↓ ( SBP
>>>DBP↓↓ )
↑ ↑

13. DRUG α1 β1 β2
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 ↔

14. VASOPRESSIN-
• V1 receptor stimulation
• ↑ SVR
• ↑MAP
PHOSPHODIESTERASE III INHIBITORs (Ionodilators
) –
Amrinone, Milrinone
Enoximone , Piroximone (highly selective)
• ↑↑CO
• ↓SVR
• ↓↔ MAP

15. 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

16. 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)

17. 3) Second-line agent in the management of septic shock
Reasons being considered second to Noradrenaline –
1) Splanchnic and renal vasoconstriction at high doses
2) Lactic acidosis
3) Increased myocardial O2 demand and potential for inducing
myocardial ischemia
4) Tachyarrhythmias
However these observations not found to be significant in
following trials -

18. 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 group
Primary 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.

19. 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

20. EBM
1)Martin et al ( Chest 1993)
DOPA vs NA
Goal – maintain MAP > 80 or SVR > 1100 dyne or both
5 – improved with DOPA
15 – improved with NA
11 - 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

21. 2) Can be used in spinal shock
3) Cautious use in cardiogenic shock
Contraindicated in hypovolemic shock
Costlier than dopamine and adrenaline
PHENYLEPHRINE
Used primarily in situations where severe vasodilatation has led to
Hypotension -> shock
Eg- Anesthesia-induced hypotension
Utility of PNP in hyperdynamic septic shock is debatable
Limited trials available till date to support its use

22. 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

23. Isoproterenol
Temporary 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/ tachyarrythmias
Increased myocardial O2 demand and ischemia
not used routinely as an vasoactive drug

24. 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

25. EBM
1) 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 study
28Day mortality
NA a/w 3.5 x increase mortality , p= <0.001
Dopamine a/w 0.7x lower mortality, p=0.049

26. 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 group
28 day mortality-
Overall – same ( 52.5 vs 48.5 %)
Septic shock- same
Hypovolemic shock- same
Cardiogenic shock - more with Dopamine
Arrythmic events –
More with DOPA group (24.1 vs 12.4 %)

27. 4) Ruokonen E et al ( Crit Care Med 1993)
DOPA vs NA
Former was associated with splanchnic oxygen shunting
Splanchnic 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 PLACEBO
No renoprotective effect at lower doses in early
renal dysfunction as thought earlier.

28. 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

29. Problems –
• Down regulation of β 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)

30. Vasopressin
1) Cathecolamine resistant septic shock/ refractory shock
2) Dose reduction of cathecolamines with
concomitant use
Rationale
1) 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 .

31. EBM
1) Russel JA et al ( Crit Care Med 2007)
Vasopressin vs NA as monotherapy in septic shock
85% 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 Trial
778 patients with septic shock who were receiving a minimum of
5 μg per minute of norepinephrine to receive either
1) 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.

32. 28 days mortality rates – same
Vasopressin Vs norepinephrine (35.4 Vs 39.3% )
Progression to renal failure – lesser with use of vaso
Vasopressin Vs norepinephrine (20.8 Vs 38.6% )
28 days mortality rates
In patients with less severe sepsis
Patients belonging to category R of RIFLE score
Lesser with use of vasopressin –
Vasopressin Vs norepinephrine (30.8 Vs 54.7% )

33. 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

34. 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 is
2) contraindicated in patients with severe aortic stenosis.

35. 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

36. Newer drugs
• Methylene blue
• Glucagon
• Cortisol
• Hydrocortisone
• Levothyroxine
• Dotrecognin -alfa

37. 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

38. THANK YOU