This document defines inotropes and vasopressors, and discusses their uses, mechanisms of action, and considerations for treatment of heart failure and cardiogenic shock. Inotropes such as dobutamine increase myocardial contractility, while vasopressors cause vasoconstriction. The most common inotropes recommended for refractory heart failure are dobutamine, dopamine, and milrinone, which aim to improve cardiac output and renal blood flow. Epinephrine can rapidly increase blood pressure to improve coronary perfusion. Vasopressors may be used with inotropes if blood pressure remains low. The rational use of vasopressors and inotropes is guided by their dose

1. INOTROPES
Dr. UDAYA
Army Hospital

3. Definition
•Inotropes increase myocardial contractility (inotropy)
e.g. adrenaline, dobutamine, isoprenaline
•Vasopressors cause vasoconstriction leading to increased
systemic and/or pulmonary vascular resistance (SVR, PVR)
e.g. , vasopressin, Phenylephrine

4. INOTROPES
Adrenergics Non-adrenergic
Catecholamines Non-catecholamines
PDE Inhibitors Ca -sensitizers
SyntheticNatural
•Adrenaline
•dopamine
•noradrnaline
•Ephedrine
•Dobutamine
• isoprenaline
•Dopexamine
•milrinone
•Levosimendan
MISC.
Myosin activator- Omecamtiv
SERCA activator -Istaroxime

5. CALCIUM
GLUCAGON

6. (sarcoplasmic Endo reticulum calcium ATPase)

7. HEART FAILURE

8. • Anrep effect
-sudden increase in afterload on the heart causes
an increase in ventricular inotropy.
(Russian physiologist Gleb von Anrep in 1912).
• Bowditch effect
-myocardial tension increases with an increase in
heart rate. Also known as the Treppe
phenomenon, Treppe effect or staircase effect.
( Henry Pickering Bowditch in 1871.)

10. PDE Inhibitors
Ca -sensitizers
•Milrinone /Milronone/Enoximone
•Levosimendan/Pimobendan

11. Aims of Inotropic Therapy
•Restore an effective cardiac output when optimum
fluid therapy alone has not
•Primary effect is to increase CO & not MAP
•No justification for routine elevation of CI to 4.5
l/min/m2
•Evidence of tissue under-perfusion with CI less
than 3 l/min/m2 after optimum fluid replacement
would suggest an inotrope
•Add vasopressor when CI > 4.0 l/min/m2 and MAP
still low

12. Heart rate
Conduction velocity
Contraction
Relaxation

14. vascular smooth muscle regulatory G protein
1,2-diacylglycerolPhosphatidyl-inositol
-4,5- biphosphate
Inositol 1,4,5-triphosphate

16. SERCA =Sarcoplasmic endoplasm reticulum calcium ATPase
Phospho-
lamban (PL)

18. Virus-mediated sarcoplasmic reticulum calcium pump gene transfer (AV-SERCA)

19. MOA of Inotropes
Activation of the β-receptors stimulates adenylyl cyclase
to produce cAMP, which activates protein kinase A (PKA)
to phosphorylate intracellular Ca-cycling proteins.
Phosphodiesterases (PDEs) degrade cAMP. (PDEs) are
inhibited by PDE inhibitors.
Digitalis inhibits transport of three Na-ions for two K-ions
through Na/K-ATPase.
Ca sensitizers increase the affinity of troponin C for Ca

22. Future inotropic compounds:
The ryanodine receptor (RyR) stabilizers(S44121)
reduce sarcoplasmic reticulum leak through and
reconstitute RyR channel function.
Istaroxime inhibits sodium-potassium-ATPase
and activates SERCA.

25. Istaroxime is a first-in-class luso-
inotropic agent
• inotropic (stimulation of myocardial
contractility during systole) and lusitropic
(improvement of diastolic relaxation) effects.
• It modulates calcium cycling through
inhibition of the Na+K+-ATPase and activation
of the sarcoplasmic reticulum Ca-ATPase,
SERCA2a.

26. Cardiac myosin activators
(Omecamtiv mecarbil)
transition of cross-bridges from the weakly to the
strongly bound force-producing state.
Energetic modulators
(Etomoxir, Pyruvate )
myocardial energetics through switching from
fatty acid to glucose oxidation or increase the cellular
phosphorylation potential.
Future inotropic compounds

28. Virus-mediated Sarcoplasmic Endoplasm Reticulum
Calcium ATPase pump gene transfer (AV-SERCA)
increases sarcoplasmic reticulum calcium uptake.
Nitroxyl (HNO) may increase sarcoplasmic reticulum
calcium uptake by modification of sarcoplasmic
reticulum calcium pump and/or phospholamban
(PL).
Future inotropic compounds

29. The most commonly recommended initial
inotropic therapies for refractory HF (dobutamine,
dopamine, and milrinone) are used to improve CO
and enhance diuresis by improving renal blood
flow and decreasing SVR without exacerbating
systemic hypotension.

30. Epinephrine, with its potent vasopressor and
inotropic properties, can rapidly increase diastolic
blood pressure to facilitate coronary perfusion
and help restore organized myocardial
contractility.

31. The best strategy seems to be
norepinephrine if hypotension is severe (SBP
<70torr), or dopamine or dobutamine (or
perhaps both, co-administered at lower doses of
each) if hypotension is moderate (SBP 70–
100torr)
CARDIOGENIC SHOCK FOLLOWING ACUTE
MYOCARDIAL INFARCTION

32. AHA Guidelines recommend
dobutamine if SBP is 70 to 100torr without shock,
dopamine if shock is present, and norepinephrine
if a second agent is needed
CARDIOGENIC SHOCK FOLLOWING ACUTE
MYOCARDIAL INFARCTION

33. ACUTE DECOMPENSATED HEART
FAILURE (ADHF)
Inotropic support to lower end-diastolic pressure
Improve diuresis
Allow typical regimens of angiotensin-converting
enzyme inhibitors,
Diuretics,
B-blockers to be reinstated gradually

34. Dobutamine or milrinone
Hypotensive ADHF and signs of decreased
peripheral perfusion or end-organ dysfunction, or
in patients unresponsive to or intolerant of IV
vasodilation.

38. The rational use of vasopressors and inotropes is
guided by three fundamental concepts:
• One drug, many receptors
• Dose-response curve
• Direct versus reflex actions

46. Vasopressors should only be initiated with/after
adequate resuscitation is provided with
crystalloids, colloids, and/or blood products
Low-dose dopamine should not be used for renal
protective effects.
Vasopressors and/or inotropes may be initiated
earlier in cardiogenic shock with clinical evidence
of volume overload.

47. Adrenal insufficiency of critical illness
(AICI) should be suspected in high-risk critically ill
patients with a random serum cortisol level < 20
mcg/dL.

48. Key Points
1) While increasing CO, Inotropes also typically
decrease ventricular filling pressures without
substantial effects on blood pressure
2) While increasing blood pressure, vasopressors
typically decrease CO and increase ventricular filling
pressures

49. 3) Vasodilators can have variable effects on CO
depending on whether or not venodilatation is
prominent but blood pressure and ventricular filling
pressures uniformly fall
4) Many have divergent hemodynamic effects
depending on the patient’s intravascular volume
5) Many agents have different cardiovascular
response profiles at different drug infusion rates
Key Points