Intensive Care Cardiovascular Pharmacology Toni Petrillo-Albarano, MD Director, Pediatric Transport Division of Critical Care Medicine

The “nervous system” is divided into the peripheral and central systems. Our discussion begins by directing our attention to the peripheral nervous system which is divided into the: autonomic system which controls cardiac and smooth muscle contraction and glandular secretion and somatic system supplying skeletal muscle and conducting sensory information such as pain and touch. The autonomic system is then further divided into the sympathetic system which is generally catabolic expending energy and the parasympathetic which is anabolic which conserves energy.

Cardiovascular Pharmacology Terminology Review Catecholamines Naturally occurring, biologically active amines Sympathomimetic Mimics stimulation of the sympathetic nervous system Catecholamines transmit most impulses to the sympathetic system Examples are norepinephrine and epinephrine which diffuse across the synaptic cleft and bind to post synaptic adrenergic receptors

Cardiovascular Pharmacology Terminology Review Adrenergic Refers to the sympathetic nervous system Cholinergic Refers to the parasympathetic nervous system Dopaminergic Dopamine receptors in renal, visceral, coronary, and cerebral areas Acetylcholine, hence cholinergic, transmits all parasympathetic signals to end organs (heart lungs etc) Adrenergic or adrenoreceptors are broken down into 2 subtypes alpha receptors and beta receptors

Cardiovascular Pharmacology Terminology Review Inotropic Influencing the force of contraction Chronotropic Influencing the rate of contraction

Cardiovascular Pharmacology Adrenoreceptors Six receptor subtypes: alpha 1 (postsynaptic) alpha 2 (presynaptic) beta 1 (cardiac) beta 2 (vascular/bronchial smooth muscle) DA 1 (postsynaptic) DA 2 (presynaptic) Alpha receptors are located on vascular smooth muscle presynaptic nerve terminals blood platelets fat cells brain cells two major types alpha 1 and alpha 2 Beta receptors are located on smooth muscle cardiac muscle some presynaptic nerve terminals lipocytes brain Dopaminergic receptors especially important in - renal - splanchnic - brain

Cardiovascular Pharmacology Adrenoreceptors ALPHA 1: Vasoconstriction Mydriasis Uterine contraction Bladder contraction Insulin inhibition Glucagon inhibition ALPHA 2: Inhibition of norepinephrine release

Cardiovascular Pharmacology Adrenoreceptors BETA 2: Vasodilation Bronchodilation Uterine relaxation Bladder relaxation Insulin release Glucagon release BETA 1: Inotropy Chronotropy Lipolysis

Cardiovascular Pharmacology Adrenoreceptors Desensitization: 2o to Chronic exposure Mechanisms uncoupling downregulation sequestration Uncoupling of the receptor from the G protein prevents signal transduction Downregulation: reduction in total number or density of beta receptors by increased receptor destruction or decreased receptor synthesis or both Sequestration involves the internalization of the receptor from the cell surface. Takes place over minutes to hours. in contrast to downregulation this permits recycling of the receptor back to the surface once beta exposure ceases. Steroid affect this by upregulation.

VASOMOTOR CENTER Sympathetic autonomic nervous system Parasympathetic autonomic nervous system Autonomic feedback loop Baroreceptors Peripheral vascular resistance Contractile force Venous tone Heart rate Mean arterial pressure Cardiac output Venous return feedback loop Hormonal Stroke volume Blood volume Aldosterone Renal blood flow/pressure Renin Angiotensin

Cardiac Output C.O.=Heart Rate x Stroke Volume Heart rate Preload- volume of blood in ventricle Afterload- resistance to contraction Contractility- force applied

Preload Afterload Contractility x Stroke Volume Heart Rate O2 Content Cardiac Output Resistance In order to understand the indications and effects of CV drugs that moderate volume, flow and pressure to ultimately improve O2 delivery we must understand the interactions that occur in the cardiovascular system. When one can identify the physiologic derangement treatment can be tailored to address the specific problem. Before reviewing individual drugs we will review the normal physiology and interactions of the CV system to maintain systemic O2 delivery O2 Delivery Arterial Pressure

Shock Inadequate tissue perfusion to meet the tissue demands a result of inadequate blood flow and/or inadequate oxygen delivery. Shock is defined as a state of circulation characterized by inadequate tissue perfusion and oxygen delivery. Although inadequate BP is used as a criteria for shock, inadequate regional perfusion may occur in the absence of a normal arterial BP - insert PALS graph

Mechanical Requirements for Adequate Tissue Perfusion Fluid Pump Vessels Flow

SHOCK Physiology of Shock Septic (Distributive) Cardiogenic Obstructive Hypovolemic Shock may be classified based on hemodynamic mechanisms SHOCK

Hypovolemic Shock: Inadequate Fluid Volume (decreased preload) Fluid depletion internal external Hemorrhage

Cardiogenic Shock: Pump Malfunction (decreased contractility) Electrical Failure Mechanical Failure cardiomyopathy metabolic anatomic hypoxia/ischemia

Distributive Shock Abnormal Vessel Tone (decreased afterload) Sepsis Anaphylaxis Neurogenesis (spinal) Drug intoxication (TCA, calcium channel blocker)

Pericardial tamponade Pulmonary embolism Pulmonary hypertension OBSTRUCTIVE SHOCK OBSTRUCTED FLOW Pericardial tamponade Pulmonary embolism Pulmonary hypertension

Hemodynamic Assessment of Shock

  ß Alpha-Beta Meter Dopamine Epinephrine Norepinephrine Dobutamine   ß Dopamine Epinephrine Dobutamine Norepinephrine Neosynephrine Isoproternol

Cardiovascular Pharmacology Dopamine Usage: activates multiple receptors DA1, DA2, beta, alpha receptors activated in dose related manner shown to increase at low doses: glomerular filtration rate renal plasma flow urinary Na+ excretion Dopamine is an intermediary product in the enzymatic pathway leading to the production of norepinephrine and ultimately epinephrine

Cardiovascular Pharmacology Dopamine Pharmacodynamics: 0.5 - 2.0 mcg/kg/min - dopaminergic 2.0 - 5.0 mcg/kg/min - beta 1 5.0 - 20 mcg/kg/min - alpha Little of any CV improvement with lower doses of dopamine but CI rises once dopamine infusion rates exceed 5 g/kg/min Tachycardia contributes to increased CI at infusion rates of 7.5 g/kg/min High dose dopamine elevates systemic arterial pressure in preterm infants with shock - achieved by increase SVR and increase HR LV contractility falls with the cause of this reduced inotropic response related to decreased norepinephrine stores

Cardiovascular Pharmacology Dopamine Indications: Low cardiac output Hypotension with SVR Risk of renal ischemia

Renal Dose Dopamine (RDD) Fact or Fiction? Summary of the Data In healthy humans and animal models, RDD augments: RBF, GFR, and natriuresis In experimental models of ischemia and nephrotoxic ARF, RDD augments: Denton et al, Kidney Int. 49:4-14,1996

Renal Dose Dopamine (RDD) Fact or Fiction? Summary of the Data Most human studies failed to demonstrate: RDD prevents ARF in high risk patients improves renal function or effects outcome in established ARF The “dark side” cardiovascular and metabolic complications Show side effect slide - as with everything we do there are positive and negative effects Denton et al, Kidney Int. 49:4-14,1996

Cardiovascular Pharmacology Dopamine Complications: activity with NE depletion PA pressure pulmonary vascular resistance dysrhythmias renal vasoconstriction tissue necrosis Dopamine activity can be decrease by as much as 50% when Ne stores are lacking. Ie Chronic CHF, immaturity Dark side complications CV - tachyarrythmias - increase R&R ventricular afterload - increased intrapulmonary shunting and worsening hypoxemia metabolic increase natriuresis at expense of tubular cell ischemia by blunting tubular glomerular filtration rate which protects tubular cells against ischemia.

Is Dopamine the Devil? Dopamine administration can reduce the release of a number of hormones from the anterior pituitary gland, including prolactin which can have important immunoprotective effects Dopamine administration was associated with ICU and hospital mortality rates 20% higher than in patients with shock who did not receive dopamine Critical Care Medicine - Volume 34, Issue 3 (March 2006)

Cardiovascular Pharmacology Dobutamine Synthetic catecholamine Direct beta1 weak alpha Indications: Low cardiac output in patients at risk for: Myocardial ischemia Pulmonary hypertension LV dysfunction (cardiomyopathy) Modified from isoproterenol More direct B1 agonist than isoproterenol which is non selective Actually has weak alpha1 agonism which can be unmasked by B blockade and manifest as severe HTN Strong inotropy weak vasodilator Dilates coronaries

Dobutamine Pharmacodynamics

Isoproterenol (Isuprel) Major indication bradycardia Pure beta Potent pulmonary/ bronchial vasodilator Increased cardiac output Widened pulse pressure Increased flow to noncritical tissue beds (skeletal muscle)

Isoproterenol (Isuprel) Drawbacks Tachycardia Dysrhythmias Peripheral vasodilation Increased myocardial consumption CPK indicating myocardial necrosis Decreased coronary O2 delivery “Splanchnic steal” by skeletal muscle

Epinephrine Indications Pressor of choice post-arrest Shock with bradycardia unresponsiveness to other vasopressors anaphylaxis Low cardiac output syndrome

Epinephrine Pharmacokinetics Limited data available in children Plasma concentration varies linearly with infusion rate Clearance 15.6-79.2 m/kg/min

Most potent catecholamine Direct acting Epinephrine Effects Most potent catecholamine Direct acting no catecholamine stores needed Prominent alpha and beta effects Increased diastolic pressures

Epinephrine Pharmacodynamics

Epinephrine Complications Renal ischemia Dysrhythmias Severe hypertension Myocardial necrosis Hyperglycemia Hypokalemia

Norepinephrine Levophed Leave ‘em Dead!

Norepinephrine (Levophed) Indications Sepsis with vasodilation unresponsive to volume expansion Hypotension unresponsive to therapy Dose: 0.05 - 1 mcg/kg/min t 1/2 = 2 - 2.5 min

Norepinephrine (Levophed) Effects Potent peripheral alpha agonist Little beta 1 effects Minimal to no beta 2 Produces vasoconstriction SVR, PVR increases systolic, MAP, diastolic BP Increased SVR may or may not alter CO depending on how much you increase the afterload. a little may improve CO too much may decrease CO

Norepinephrine (Levophed) Complications Renal vasoconstriction may be decreased with dopamine Possible cardiac function due to increased afterload Dysrhythmias Tissue necrosis 2 studies show benefit Martin et al CCM 24 patients with septic shock NE and titrated to maintain Nl SBP 20/24 pt return urine flow, decreased serum creatinine, increased creatinine clearance none got low dose dopa or lasix 4 patients remained oliguric 2/4 died 2/4 renal failure Hoogenburg et al low dose dopa + increasing doses norepi in healthy volunteers norepi caused decreased renal plasma flow but not GFR norepi + dopa prevented decreased renal plasma flow, increased sodium excretion attenuated HTN and renal vasoconstriction results of study sufficiently strong to recommend low dose dopamine in all critically ill patients requiring norepi.

Milrinone (Primacor) Mechanism of action Pharmacodynamics: Phosphodiesterase III inhibitor Pharmacodynamics: Almost pure inotrope CI Potent vasodilator SVR PVR Bolus: 50 mcg/kg Infusion: 0.375 - 0.75 mcg/kg/min

Milrinone (Primacor) Pharmacokinetics: Side effects: Advantages: t 1/2 = 90 min Side effects: Hypotension Thrombocytopenia Advantages: No precipitation Short t 1/2

Vasopressin ADH Analog Increases cyclic adenosine monophosphate (cAMP) which increases water permeability at the renal tubule resulting in decreased urine volume and increased osmolality direct vasoconstrictor (primarily of capillaries and small arterioles) through the V1 vascular receptors directly stimulates receptors in pituitary gland resulting in increased ACTH production; may restore catecholamine sensitivity

Vasopressin Vasodilatory shock with hypotension unresponsive to fluid resuscitation and exogenous catecholamines 0.0003-0.002 units/kg/minute (0.018-0.12 units/kg/hour); titrate to effect

A Rational Approach to Pressor Use in the PICU Shock / Hypotension Volume Resuscitation Signs of adequate circulation Adequate MAP NO pressors Yes NO

A Rational Approach to Pressor Use in the PICU Signs of adequate circulation Adequate MAP NO Dopamine?? Or perhaps now NE Inadequate MAP Norepi

A Rational Approach to Pressor Use in the PICU Milrinone or dobutamine norepinephrine adequate MAP Milrinone or dobutamine CO Inadequate MAP low C.O. Good C.O epinephrine Vasopressin

Questions ???