Inotropes

Inotropes

1. INOTROPES Dr. UDAYA Army Hospital

2. Definition I notropes increase myocardial contractility ( inotropy ) e.g. adrenaline, dobutamine , isoprenaline V asopressors cause vasoconstriction leading to increased systemic and/or pulmonary vascular resistance (SVR, PVR) e.g. , vasopressin, Phenylephrine

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

4. CALCIUM GLUCAGON

5. ( sarcoplasmic Endo reticulum calcium ATPase )

6. HEART FAILURE

7. 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.)

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

9. 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/m 2 •Evidence of tissue under-perfusion with CI less than 3 l/min/m 2 after optimum fluid replacement would suggest an inotrope •Add vasopressor when CI > 4.0 l/min/m 2 and MAP still low

10. Heart rate Conduction velocity Contraction Relaxation

11. vascular smooth muscle regulatory G protein 1,2-diacylglycerol P hosphatidyl-inositol - 4,5- biphosphate Inositol 1,4,5-triphosphate

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

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

14. 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

15. 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.

16. 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.

17. 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

18. 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

19. 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 .

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

21. 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

22. 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

23. ACUTE DECOMPENSATED HEART FAILURE (ADHF) I notropic support to lower end-diastolic pressure Improve diuresis A llow typical regimens of angiotensin -converting enzyme inhibitors, Diuretics , B-blockers to be reinstated gradually

24. 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 .

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

26. 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.

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

28. Key Points 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

29. 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

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