Thank you Suanne Daves, MD Pharmacologic Management of Acute Circulatory Failure: Vasoactive Medications Thank you Suanne Daves, MD

What you will hear today A short review of Shock A look at how the intrinsic sympathetic nervous system & various drugs that can accelerate/enhance the excitation-contraction coupling phenomenon in myocytes (improve cardiac output).

Circulatory Failure / Shock What is it? Metabolic demand outstrips supply or the ability to extract The anaerobic state leads to accumulation of lactic acid. Energy dependent cellular processes cease Cellular edema, cellular disruption, cell death….. Organ failure 3

BP = CO x SVR Chronotropy HR x SV Volume Inotropy EDV - ESV Lusiotropy Afterload 4

BP = CO x SVR SVR = vascular tone

A digression to cell biology Cardiac Output and SVR are all about Calcium

all about Calcium PDE See chapter 2 page 13 of Heart Failure text – 3 G proteins, talk about coupling and specific actions PDE inhibitors raise intracellular cAMP. AMPactivates PK, etc. PK A leads to phosphorylation of phospholamban 2003;108;492-497 Circulation Lynne Warner Stevenson Forward?: Part II: Chronic Inotropic TherapyFigure 2. Effects of inotropic therapy on intracellular calcium handling in cardiac myocytes. Depolarization of membrane by action potential leads to opening of voltage-gated L-type calcium (Ca2+) channels, which allows entry of small amount of Ca2+ into cell. Through coupling mechanism between L-type Ca2+ channel and sarcoplasmic reticulum (SR) release channels (ryanodine receptors), larger amount of Ca2+ is released, which activates myofilaments, leading to contraction. During relaxation, Ca2+ is accumulated back into SR by SR Ca2+ ATPase pump (SERCA2a) and extruded extracellularly by sarcolemmal Na+/Ca2+ exchanger. Many sarcolemmal receptors affect calcium handling in cardiac myocytes. Agonists through G proteins increase adenyl cyclase (AC) activity, which results in cAMP production. This results in activation of protein kinase A (PKA), which leads to phosphorylation of L-type calcium channels, allowing increase in calcium entry, phosphorylation of phospholamban, increasing SERCA2a activity, and phosphorylation of troponin I, which decreases sensitivity of myofilaments to Ca2+. Phosphorylation effects of PKA induce greater release of calcium from SR and faster relaxation. Digoxin inhibits Na+/K+ ATPase pump, which increases intracellular Na+. This results in increase in intracellular Ca2+ via Na+/Ca2+ exchanger, which leads to enhanced Ca2+ loading of SR and increase in Ca2+ release. Phosphodiesterase inhibitors (PDEI) block breakdown of cAMP, which increases its intracellular level and activates PKA. Calcium sensitizers increase sensitivity of myofilaments to Ca2+, enhancing myofilament activation for any concentration of Ca2+. Vesnarinone prolongs action potential duration through modulation of K+ channels, thereby prolonging opening of L-type calcium channels and increasing Ca2+ entry. Through gene transfer of SERCA2a, 30 modified phospholamban (mPL), 31 or antisense phospholamban (asPL), 32 SR ATPase activity can be increased, which enhances SR Ca2+ content, inotropic and lusitropic state. At level of cardiomyocyte, several stimuli, including endothelin-1 (ET-1), phenylephrine, and angiotensin, are involved in development of hypertrophy through Gq-coupled receptors. They induce activation of phospholipase C (PLC) and diacylglycerol (DAG), which increases levels of inositol triphosphate (IP3). IP3 induces release of calcium from SR. Increased cytosolic calcium induces mitogen-activated protein kinases (MAPK) and activates calcineurin and caspases that contribute to apoptosis. Ang II indicates angiotensin II; NE, norepinephrine; PDE, phosphodiesterase; and PKC, protein kinase C. (Figure developed in collaboration with Roger Hajjar, MD, Cardiovascular Division, Massachusetts General Hospital, Boston, Mass.) PDE increase speed and force of not only cardiac contraction, but also relaxation. The relaxation of the myocardium is accelerated by reduction of cytosolic calcium (secondary to more efficient removal of calcium into the SR via the activated ATPase protein).

Back to something more familiar: Starling

The Body’s Neuronal Defense System

β1 β2 ά1 β2 ά1 β2 Vasopressin DA1-2 Vasopressin

Chang’s Heart Failure Looking at functional differences in signal transduction

Chang’s Heart Failure, chapter 2 We’re learning more about how these receptors produce a biologic effect through coupling of G proteints and activation of various protein kinases and the functional differences in these receptors.

Bohn (2006). Inotropic Agents in Heart Failure. Heart Failure in Children and Young Adults. Chang & Towbin.

PDE See chapter 2 page 13 of Heart Failure text – 3 G proteins, talk about coupling and specific actions PDE inhibitors raise intracellular cAMP. AMPactivates PK, etc. PK A leads to phosphorylation of phospholamban 2003;108;492-497 Circulation Lynne Warner Stevenson Forward?: Part II: Chronic Inotropic TherapyFigure 2. Effects of inotropic therapy on intracellular calcium handling in cardiac myocytes. Depolarization of membrane by action potential leads to opening of voltage-gated L-type calcium (Ca2+) channels, which allows entry of small amount of Ca2+ into cell. Through coupling mechanism between L-type Ca2+ channel and sarcoplasmic reticulum (SR) release channels (ryanodine receptors), larger amount of Ca2+ is released, which activates myofilaments, leading to contraction. During relaxation, Ca2+ is accumulated back into SR by SR Ca2+ ATPase pump (SERCA2a) and extruded extracellularly by sarcolemmal Na+/Ca2+ exchanger. Many sarcolemmal receptors affect calcium handling in cardiac myocytes. Agonists through G proteins increase adenyl cyclase (AC) activity, which results in cAMP production. This results in activation of protein kinase A (PKA), which leads to phosphorylation of L-type calcium channels, allowing increase in calcium entry, phosphorylation of phospholamban, increasing SERCA2a activity, and phosphorylation of troponin I, which decreases sensitivity of myofilaments to Ca2+. Phosphorylation effects of PKA induce greater release of calcium from SR and faster relaxation. Digoxin inhibits Na+/K+ ATPase pump, which increases intracellular Na+. This results in increase in intracellular Ca2+ via Na+/Ca2+ exchanger, which leads to enhanced Ca2+ loading of SR and increase in Ca2+ release. Phosphodiesterase inhibitors (PDEI) block breakdown of cAMP, which increases its intracellular level and activates PKA. Calcium sensitizers increase sensitivity of myofilaments to Ca2+, enhancing myofilament activation for any concentration of Ca2+. Vesnarinone prolongs action potential duration through modulation of K+ channels, thereby prolonging opening of L-type calcium channels and increasing Ca2+ entry. Through gene transfer of SERCA2a, 30 modified phospholamban (mPL), 31 or antisense phospholamban (asPL), 32 SR ATPase activity can be increased, which enhances SR Ca2+ content, inotropic and lusitropic state. At level of cardiomyocyte, several stimuli, including endothelin-1 (ET-1), phenylephrine, and angiotensin, are involved in development of hypertrophy through Gq-coupled receptors. They induce activation of phospholipase C (PLC) and diacylglycerol (DAG), which increases levels of inositol triphosphate (IP3). IP3 induces release of calcium from SR. Increased cytosolic calcium induces mitogen-activated protein kinases (MAPK) and activates calcineurin and caspases that contribute to apoptosis. Ang II indicates angiotensin II; NE, norepinephrine; PDE, phosphodiesterase; and PKC, protein kinase C. (Figure developed in collaboration with Roger Hajjar, MD, Cardiovascular Division, Massachusetts General Hospital, Boston, Mass.) PDE increase speed and force of not only cardiac contraction, but also relaxation. The relaxation of the myocardium is accelerated by reduction of cytosolic calcium (secondary to more efficient removal of calcium into the SR via the activated ATPase protein).

When you need to intervene: Vasoactive Medications: Goals of treatment Provide adequate tissue oxygenation. Maintain vital organ function. Restore systemic blood pressure. Tailor drugs to minimize adverse side effects.

Vasoactive Medications Catacholamines Vasopressin Phosphodiesterase inhibitors Calcium sensitizers

Catacholamines with inotropic properties Epinephrine Norepinephrine Isoproterenol Dopamine Dobutamine

Chang’s Heart Failure page 470 (Fig 33-1) Bohn (2006). Inotropic Agents in Heart Failure. Heart Failure in Children and Young Adults. Chang & Towbin.

Chang’s Heart Failure page 470 (Fig 33-1) Bohn (2006). Inotropic Agents in Heart Failure. Heart Failure in Children and Young Adults. Chang & Towbin.

Chang’s Heart Failure page 470 (Fig 33-1) Bohn (2006). Inotropic Agents in Heart Failure. Heart Failure in Children and Young Adults. Chang & Towbin.

Chang’s Heart Failure page 470 (Fig 33-1) Bohn (2006). Inotropic Agents in Heart Failure. Heart Failure in Children and Young Adults. Chang & Towbin.

Chang’s Heart Failure page 470 (Fig 33-1) Bohn (2006). Inotropic Agents in Heart Failure. Heart Failure in Children and Young Adults. Chang & Towbin.

Starling again Improved inotropy CO

Catacholamines with pressor properties Phenylephrine Epinephrine Norepinephrine Dopamine

More Starling… more preload = more CO Remember: too much afterload = CO

Other Vasoactive Options Milrinone PDE inhibitor Vasopressin Vasoconstriction Improves sensitivity to catachols Levosimendan Calcium sensitizing agent

Starling again Reduced afterload improved CO

The Downside of Vasoactive Agents (mostly true for catachols) Increased myocardial O2 demand Myocardial injury/cell death Tolerance/tachyphylaxis Arrhythmogenesis Peripheral vasoconstriction Elevates SVR Compromises splanchnic blood flow

Bedside Reality… A 4-mos-old infant presents to the ER with irritability, poor po intake, and tachypnea. The ER doc says the baby looks “shocky”. They have started an IV & given 20mL/kg NS.

Would you begin an inotrope/pressor? Which one? The infant is awake & quiet. HR: 170s-180s (sinus) RR: 70s BP: 90/68 He is cool peripherally. His pulses are ‘thready’ pH 7.29/pCO2 38/pO2 82/HCO3 18 Lactate 4.0 Would you begin an inotrope/pressor? Which one? Increased SVR is the hallmark of decompensated CHF. It is attributed to activation of the vasoconstrictor neurohormones, including Agn II, catecholamines, AVP, and ET, in an effort to maintain circulatory homeostasis in the face of diminishing systolic function.

Same infant………. HR: 180s (sinus) RR: 70s BP: 52/44

Key Concepts The predominant β-AR in the heart is the β1-AR (<75%). β2-ARs are largely found in vascular smooth muscle. Ά1-ARs predominate in vascular smooth muscle although they are present in the neonatal myocardium.

Key Concepts Catacholamines are good in the short term for hemodynamic support but most increase myocardial oxygen demand, increase diastolic pressures, and can lead to apoptosis PDE inhibitors, while increasing intracellular Ca+, are lusiotropic and inotropic agents that do not increase myocardial O2 demand and are not associated with tachyphylaxis.

Key Concepts A strategy of combining a PDE inhibitor with a catecholamine may be the best approach to support of the myocardium and circulation. Most inotropic agents to date have a common final intracellular pathway of increased intracellular Ca+, which may ultimately lead to cell (myocyte) death.

And we continue to look for something better A new generation of inotropic agents known as calcium-sensitizing agents achieve their positive inotropic effects without an increase in intracelluar Ca+ or myocardial O2 consumption. Unfortunately they early studies of the first of these drugs demonstrated less benefit than was anticipated Binds to calcium saturated troponin C complexes, and stabilizes the complex without affecting the initial calcium-binding capabilities of troponin C. This allows for a longer half-life and more effective use of calcium in the myocardium. The effect may last several days following a 24 hour infusion. Anti-inflammatory effect Available in oral form. Levosimendan

1 β2 β1 Chang Chapter33