Cardiovascular Medications

1. Cardiovascular Medications 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

7. Chronotropy HR x SV Volume Inotropy EDV - ESV Lusitropy Afterload BP = CO x SVR

8. Site of Action

9. Adrenoreceptors vasoconstriction Vascular Smooth Muscle Chronotropy Inotropy Heart vasodilation

10. Adrenoreceptors β1 receptors: α1 receptors: vasoconstriction Vascular Smooth Muscle Chronotropy Inotropy Heart β 2 receptors: vasodilation

11. NO & PDE Inhibitors PDE3 Inhibitor: NO → guanalylcyclase: vasodilation Vascular Smooth Muscle Chronotropy Inotropy Heart PDE3 Inhibitor: Vasodilation

14. PDE Inhibitors PDE 3 PDE 5

15. PDE Inhibitors PDE 3 PDE 5 Milrinone Sildenafil Tadalafil

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

17. The meds to choose from….

18. Dose: mcg/kg/min Mechanism /Therapeutic Effects Adverse Effects Epinephrine Norepinephrine Dopamine Dobutamine Milrinone Phenylephrine Nitroprusside 0.01- 1 β1  ↑ HR, ↑ inotropy β2  vasodilatation α1  vasoconstriction  ↑ SVR Arrhythmia ↑myocardial O2 demand Ischemic injury due to potent vasoconstriction ↑ After load 0.01- 1 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 < 5 5 -10 >10 Arrhythmia ↑myocardial O2 demand 5-20 β1  ↑ HR, ↑ inotropy Mild β2, α1 antagonist vasodilation  ↓ PVR, SVR Arrhythmia, hypotension ↑myocardial O2 demand 0.25 -1 Phosphodiesterase Inhibitor (PDE3 inhibitor): Myocardial : ↑ cAMP  ↑contractility + lusiotropy Vasculature: ↑ cAMP  vasodilatation  ↓ SVR/PVR Hypotension, arrhythmia T1/2 ↑ in renal impairment 0.1-5 α1  vasoconstriction  ↑ SVR Ischemic injury due to potent vasoconstriction ↑ afterload 0.1-4 Cyanide toxicity ↑ V/Q mismatch NO activates guanalylcyclase (in vasc smooth muscle)  ↑cGMP  vasodilation

19. Chronotropy HR x SV Volume Inotropy EDV - ESV Lusitropy Afterload Dopamine Dobutamine Epinephrine BP = CO x SVR Dopamine Dobutamine Epinephrine Norepinephrine Milrinone Decrease SVR Low dose Epi, Nitroprusside Milrinone Dobutamine Increase SVR High dose Epi Norepinephrine High dose Dopa (>10) Phenylephrine

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 sepsis10

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 !