أستاذنا الدكتور سمير الأنصاري

1. • VASOPRESSORS AND
INOTROPICS
SAMIR EL ANSARY
ICU PROFESSOR
AIN SHAMS
CAIRO

2. Myocardial Contraction
• Contractility increases over 1st months of life
along with:
– Sympathetic nerve fibers within myocardium
– Total concentration of endogenous
norepinephrine
• There is a greater dependence of CO on HR
than contractility during this time

3. Immature Heart
• Limited responsiveness to medications
–  noncontractile content
–  availability of releasable NE
– Less mature sympathetic system
– Underdeveloped intracellular calcium regulatory
mechanisms
–  functional reserve capacity

4. Ionized Calcium
• Plays central role in maintaining
myocardial contractility

5. Vascular Smooth Muscle
• Calcium dependent effects
– Agents that increase intracellular cAMP increase
intracellular calcium requirements for contraction,
thus encouraging smooth muscle relaxation and
vasodilation

6. Effects of Agents
• Pressors: increase systemic vascular resistance and
increase blood pressure
• Inotropes: affect myocardial contractility and
enhance stroke volume
• Chronotropic Agents: affect heart rate
• Lusotropic Agents: improve relaxation during
diastole and decrease EDP in the ventricles
• Dromotropic Agents: Affects conduction speed
through AV node; increases heart rate
• Bathmotropic Agents: affect degree of excitability

7. Alpha-Adrenergic Agents
–Alpha1-adrenergic effects:
• Vascular smooth muscle contraction
–Alpha2-adrenergic effects:
• Vascular smooth muscle relaxation

8. Beta-Adrenergic Agents
• Beta1-adrenergic effects:
– Direct cardiac effects
• Inotropy (improved cardiac contractility)
• Chronotropy (increased heart rate)
• Beta2-adrenergic effects:
• Vasodilation
• Bronchodilation

9. Dopaminergic Agents
• Dopaminergic Agents
– Several types of receptors located throughout
body (D1-D5)
– Certain (esp. D1-like & D2-like) dopaminergic
receptors increase renal and mesenteric blood
flow

10. Catecholamines
• Sympathomimetic amines that contain O-
dihydrobenzene
• Dopamine, epinephrine and norepinephrine are
endogenous
• Dobutamine and isoproterenol are synthetic
• Sustained use or antecedent CHF can lead to down-
regulation of β-receptors and decrease efficacy

11. Epinephrine
• Both an alpha- and beta-adrenergic agent 0.01
mcg/kg/min - 0.3 mcg/kg/min
– Low-dose infusion = β activation
• Increase HR, contractility, decrease SVR
– Higher doses =  activation
• Increased SVR and MAP
• Increased myocardial O2 demand

12. EPINEPHRINE
α1 predominantly
Vasoconstriction
↓ Renal BF
↓ Splanchnic BF
↑ Glucose
β1 predominantly
↑HR
↓ Duration of Systole
↑ Myocardial contract
Periph. arteriolar dil.
↑/ ↓ Renal BF
↑ Renin secretion
↑/ ↓ Splanchnic BF
↑ Glucose
Hypokalemia
Epinephrine
Low Dose
(<0.05-0.1 mcg/kg/min)
High Dose
(> 0.1 μg/kg/min)

13. Epinephrine
• Indications for its use as a continuous infusion are:
– low cardiac output state
• beta effects will improve cardiac function
• alpha effects may increase afterload and
decrease cardiac output
– septic shock
• useful for both inotropy and vasoconstriction

14. Epinephrine
• Adverse effects include:
– Anxiety, tremors,palpitations
– Tachycardia and tachyarrhythmias
– Increased myocardial oxygen requirements and
potential to cause ischemia
– Decreased splanchnic and hepatic circulation
(elevation of AST and ALT)
– Anti-Insulin effects: lactic acidosis,
hyperglycemia

15. Norepinephrine
• An epinephrine precursor that acts primarily on 
receptors
• Used primarily for alpha agonist effect - increases
SVR without significantly increasing C.O.
• Used in cases of low SVR and hypotension such as
profound “warm shock” with a normal or high C.O.
state- usually in combination with dopamine or
epinephrine
• Infusion rates titrated between 0.05 to 0.3
mcg/kg/min

16. Norepinephrine
• Differs from epinephrine in that the
vasoconstriction outweighs any increase in
cardiac output.
– i.e. norepinephrine usually increases blood
pressure and SVR, often without increasing
cardiac output.

17. Norepinephrine
• Adverse Effects:
– Similar to those of Epinephrine
– Can compromise perfusion in extremities and may
need to be combined with a vasodilator e.g.
Dobutamine or Nipride
– More profound effect on splanchnic circulation
and myocardial oxygen consumption

18. Vasopressin
• A peptide hormone released by the posterior
pituitary in response to rising plasma tonicity
or falling blood pressure
• Antidiuretic and vasopressor properties
• Deficiency of this hormone results in diabetes
insipidus

19. Vasopressin

20. Vasopressin
• Administration
– intravenous, intramuscular, or intranasal routes
– IV is route for vasopressor activity
– The half-life of circulating ADH is approximately 20
minutes, with renal and hepatic catabolism via
reduction of the disulfide bond and peptide
cleavage

21. Vasopressin
• Administration
– interacts with two types of receptors
• V1 receptors are found on vascular smooth
muscle cells and mediate vasoconstriction
• V2 receptors are found on renal tubule cells
and mediate antidiuresis through increased
water permeability and water resorption in
the collecting tubules
• Use in refractory septic shock with low SVRI in
pediatrics?

22. Dopamine
• Intermediate product in the enzymatic
pathway leading to the production of
norepinephrine; thus, it indirectly acts by
releasing norepinephrine.
• Directly has ,  and dopaminergic actions
which are dose-dependent.
• Indications are based on the adrenergic
actions desired.

23. Dopamine
•  renal perfusion 2-5 mcg/kg/min (dopaminergic
effects) by  sensitivity of vascular smooth muscle to
intracellular calcium
•  C.O. in Cardiogenic or Distributive Shock 5-
10mcg/kg/min ( adrenergic effects)
• Post-resuscitation stabilization in patients with
hypotension (with fluid therapy) 10-20 mcg/kg/min
( adrenergic effects) peripheral vasoconstriction, 
SVR, PVR, HR.

24. Dose Dependent effect of Dopamine
<5 mcg 5 - 10 mcg > 10 mcg
↑Contractility
Minimal change in
HR and SVR
↑ Renal BF
↑ Splanchnic BF
Modest ↑ CO
↑ Renal BF
↓Proximal Tub. Na
Absorbtion
↑ Splanchnic BF
↑ HR,
Vasoconstriction
↑/ ↓ Renal BF
↓/↑ Splanchnic BF

25. Dobutamine
• Synthetic catecholamine with 1 inotropic effect
(increases stroke volume) and 2 peripheral
vasodilation (decreases afterload)
• Positive chronotropic effect 1 (increases HR)
• Some lusotropic effect
• Overall, improves Cardiac Output by above beta-
agonist acitivity

26. Dobutamine
• Major metabolite is 3-O-methyldobutamine, a
potent inhibitor of alpha-adrenoceptors.
– Therefore, vasodilation is possible secondary to
this metabolite.
• Usual starting infusion rate is 5 mcg/kg/min,
with the dose being titrated to effect up to 20
mcg/kg/min.

27. DOBUTAMINE
D- isomer
Stimulates β1 and β2
L- isomer
Stimulates α1
Dobutamine

28. Dobutamine
• Used in low C.O. states and CHF e.g.
myocarditis, cardiomyopathy, myocardial
infarction
• If BP adequate, can be combined with
afterload reducer (Nipride or ACE inhibitor)
• In combination with Epi/Norepi in profound
shock states to improve Cardiac Output and
provide some peripheral vasodilatation

29. Isoproterenol
• Synthetic catecholamine
• Non-specific beta agonist with minimal alpha-
adrenergic effects.
• Causes inotropy, chronotropy, and systemic
and pulmonary vasodilatation.
• Indications: bradycardia, decreased cardiac
output, bronchospasm (bronchodilator).

30. Isoproterenol
• Occasionally used to maintain heart rate
following heart transplantation.
• Dose starts at 0.01 mcg/kg/min and is
increased to 2.0 mcg/kg/min for desired
effect.
• Avoid in patients with subaortic stenosis,
and hypertrophic cardiomyopathy or TOF
lesions because increases the outflow
gradient

31. Milrinone/Amrinone
• Belong to class of agents “Bipyridines”
• Non-receptor mediated activity based on
selective inhibition of Phosphodiesterase Type
III enzyme resulting in cAMP accumulation in
myocardium
• cAMP increases force of contraction and rate
and extent of relaxation of myocardium
• Inotropic, vasodilator and lusotropic effect

32. Milrinone/Amrinone
• Advantage over catecholamines:
–Independent action from -receptor
activation, particularly when these
receptors are downregulated
(CHF and chronic catecholamine use)

33. Milrinone
• Increases CO by improving contractility,
decreased SVR, PVR, lusotropic effect;
decreased preload due to vasodilatation
• Unique in beneficial effects on RV function
• Protein binding: 70%
• Half-life is 1-4 hours

34. Milrinone
• Elimination: primarily renally excreted
• Load with 50 mcg/kg over 30 mins
followed by 0.25 to 0.75 mcg/kg/min
• No increase in myocardial O2
requirement

35. PDE Inhibition
Aminophylline
Milrinone
Sildenefil
PDE PDE 3 PDE 5

36. Milrinone
Minimal ↑ HR
↑ CO
Minimal ↑ in
O2 demand ↓ SVR
↓ PVR
Diastolic
Relaxation

37. Other Vasoactive
Agents

38. BNP
{ Brain natriuretic peptide }
• Secreted by ventricles in response to ↑
wall stress and volume overload

39. NESRITIDE
{Recombinant Human BNP}
• Venous and arteriolar dilator, acts on
Guanylate cyclase
• It reduces RA pressure, PCWP and cardiac
index
• Dose: Infusion 0.01- 0.03 mcg/kg/min
• Hypotension

40. Nesiritide
• Nesiritide (recombinant human BNP) is a vasodilator
with other theoretical effects including:
– natriuresis, neurohormonal inhibition, and reverse
remodeling
– In the setting of Heart Failure, it has been shown
to reduce pulmonary capillary wedge pressure
and improve shortness of breath relative to
placebo
– Linked to possible renal failure and increased
mortality in some patient populations

41. Vasodilators
• Classified by site of action
• Venodilators: reduce preload - Nitroglycerin
• Arteriolar dilators: reduce afterload Minoxidil and
Hydralazine
• Combined: act on both arterial and venous beds and
reduce both pre- and afterload Sodium Nitroprusside
(Nipride)

42. Nitroprusside
• Vasodilator that acts directly on arterial and
venous vascular smooth muscle.
• Indicated in hypertension and low cardiac
output states with increased SVR.
• Also used in post-operative cardiac surgery to
decrease afterload on an injured heart.
• Action is immediate; half-life is short;
titratable action.

43. Nitroprusside
• Toxicity is with cyanide, one of the metabolites of the
breakdown of nipride.
• Severe, unexplained metabolic acidosis might
suggest cyanide toxicity.
• Dose starts at 0.5 mcg/kg/min and titrate to 5
mcg/kg/min to desired effect. May go higher (up to
10 mcg/kg/min) for short periods of time.

44. Nitroglycerine
• Direct vasodilator as well, but the major
effect is as a venodilator with lesser effect
on arterioles.
• Not as effective as nitroprusside in lowering
blood pressure.
• Another potential benefit is relaxation of
the coronary arteries, thus improving
myocardial regional blood flow and
myocardial oxygen demand.

45. Nitroglycerine
• Used to improve myocardial perfusion
following cardiac surgery
• Dose ranges from 0.5 to 8 mcg/kg/min.
Typical dose is 2 mcg/kg/min for 24 to 48
hours post-operatively
• Methemoglobinemia is potential side effect

46. Relative receptor activity of most
commonly used inotropes
α1 α2 β1 β2 DA
Norepinephrine +++ +++ + - -
Epinephrine +++ ++ +++ ++ -
Dopamine ++ + ++ +++ +++
Dobutamine + - +++ + -
Isoproterenol - - ++ ++ -

47. GOOD LUCK
SAMIR EL ANSARY
ICU PROFESSOR
AIN SHAMS
CAIRO