1. PICU Resident Talk Stanford School of Medicine Pediatric Critical Care Medicine June 2014

2. Objectives Define inotropy, chronotropy, lusitropy, and vasopressor. List the determinants of BP and CO. Describe the receptor/ mechanism of action of epi, norepi, dopamine, dobutamine, milrinone, phenylephrine, and nitroprusside. List the major side effects of these medications.

3. Definitions Inotropy—the force of muscle contraction, most commonly cardiac muscle contraction Chronotropy—affecting the heart rate Lusitropy—relaxation function of cardiac muscle and chambers Vasopressor—producing a rise in blood pressure through vasoconstriction

4. Definitions Bonus ! Dromotropy Bathmotropy

5. Definitions Bonus ! Dromotropy ~ running; increase AV conduction Bathmotropy ~ threshold; increase excitability of cardiac cells

6. Determinants of Blood Pressure

8. Site of Action

9. Heart Vascular Smooth Muscle vasoconstriction Chronotropy Inotropy Adrenoreceptors vasodilation

10. Heart β1 receptors: Vascular Smooth Muscle α 1 receptors: vasoconstriction Chronotropy Inotropy Adrenoreceptors β 2 receptors: vasodilation

11. Heart Vascular Smooth Muscle NO & PDE Inhibitors PDE 3 Inhibitor: Vasodilation NO → guanalyl cyclase: vasodilation PDE 3 Inhibitor: Chronotropy Inotropy

14. PDE Inhibitors PDE 3 PDE 5

15. PDE Inhibitors PDE 3 PDE 5 Milrinone Sildenafil Tadalafil

16. Milrinone Increases CO Diastolic relaxationMinimal increase HR and O2 demand ↓ SVR ↓ PVR T1/2 2-4 hrs Further ↑ in renal impairment

17. The meds to choose from….

18. Dose: mcg/kg/minMechanism /Therapeutic EffectsAdverse Effects Epinephrine Norepinephrine Dopamine Dobutamine Milrinone Phenylephrine Nitroprusside β1  ↑ HR, ↑ inotropy β2  vasodilatation α1  vasoconstriction  ↑ SVR β1  ↑ HR, ↑ inotropy Min β 2 effects D1  diuresis, natriuresis, renal vasodilatation, (No proven benefit in preventing AKI or ↓ mortality) β1  ↑ HR, ↑ inotropy α1 effects  vasoconstriction  ↑ SVR β1  ↑ HR, ↑ inotropy Mild β2, α1 antagonist  vasodilation  ↓ PVR, SVR Phosphodiesterase Inhibitor (PDE 3 inhibitor): Myocardial : ↑ cAMP  ↑ contractility + lusiotropy Vasculature: ↑ cAMP  vasodilatation  ↓ SVR/PVR α1  vasoconstriction  ↑ SVR NO activates guanalyl cyclase (in vasc smooth muscle)  ↑ cGMP  vasodilation Arrhythmia ↑ myocardial O 2 demand Ischemic injury due to potent vasoconstriction ↑ After load Arrhythmia ↑ myocardial O 2 demand Arrhythmia, hypotension ↑ myocardial O 2 demand Hypotension, arrhythmia T1/2 ↑ in renal impairment Ischemic injury due to potent vasoconstriction ↑ afterload Cyanide toxicity ↑ V/Q mismatch 0.01- 1 < 5 5 -10 >10 5-20 0.25 -1 0.1-5 0.1-4

19. Dopamine Dobutamine Epinephrine Dopamine Dobutamine Epinephrine Norepinephrine Milrinone Increase SVR High dose Epi Norepinephrine High dose Dopa (>10) Phenylephrine Decrease SVR Low dose Epi, Nitroprusside Milrinone Dobutamine

20. Some interesting studies… Dopamine increases risk of infections - Inhibits anterior pituitary function & so ↓ prolactin, GH, TSH. 1-3 - Prolactin and growth hormone have immunestimulatory properties. 4 - Inhibits lymphocyte proliferation, immunoglobulin synthesis, cytokine production, and promote lymphocyte apoptosis. 5-8 - Chronotropic and inotropic effects  increases myocardial oxygen demand, may not be adequately met by coronaries  risk of tachycardia and tachy-arrhythmias. 9 - Beta adrenergic properties of dopamine predominate in sepsis 10

21. Some interesting studies… Septic patients treated with dopamine had a higher incidence of arrhythmias than those treated with norepinephrine. 1 Norepinephrine is a more potent vasopressor than dopamine, with norepinephrine being more effective in reversing the hypotension of septic shock. 2 In patients with sepsis, norepinephrine increases blood pressure, as well as cardiac output, renal, splanchnic, cerebral blood flow, and microvascular blood flow while minimally increasing heart rate. 1,3,4 By achieving these hemodynamic goals, norepinephrine may be better than dopamine in maintaining organ perfusion.

22. We did not talk… Ionized calcium Vasopressin Isoproterenol

23. Ionized Calcium Central role in maintaining myocardial contractility Effects mediated via intracellular concentration, calcium requirements of the muscle cell, sensitivity of the myofilaments to calcium Agents that increase intracellular cAMP increase intracellular calcium requirements for contraction, thus encouraging smooth muscle relaxation and vasodilation

24. Angiotensin II Hyperosmolarity Decreased atrial receptor firing sympethatic stimulation Vasopressin Vasoconstriction Renal fluid reabsorption Increased blood pressure

25. Isoproterenol Synthetic catacholamine. Non specific beta, no alpha. Causes inotropy, chronotropy, and systemic and pulmonary vasodilatation. Indications: bradycardia, decreased cardiac output, bronchospasm (bronchodilator).

26. THANK YOU !