Inotropes & Vasopressors Sophie Young December 2006

Objectives Uses of inotropes Basic physiology Drug/receptor interactions Specific examples New developments

Definitions Inotrope Increases cardiac contractility Vasopressor Induces vasoconstriction elevation of mean arterial pressure

Use of inotropes & vasopressors To support the failing heart To support the failing peripheral vasculature To correct hypotension during anaesthesia (general or regional)

Physiology Sympathetic Nervous System Post synaptic NT = NA Exceptions: sweat glands (Ach, muscarinic) and adrenal medulla (Ach, nicotinic) Adrenergic receptors on post synaptic membrane Catecholamines= adrenergic agonists Adrenergic receptors G-protein coupled receptors, 7 transmembrane alpha segments Alpha and Beta receptors Structure-activity relationship of adrenergic drugs

Clinical Effects of Adrenergic Receptors Alpha1 Vasoconstriction Gut smooth muscle relaxation Increased saliva secretion Hepatic glycogenolysis Alpha2 Inhibit NA & Ach release Stimulate platelet aggregation Beta1 Chronotropy Inotropy Gut smooth muscle relaxation Lipolysis Beta2 Vasodilatation Bronchiole dilatation Visc smooth muscle relaxation Hepatic glycogenolysis Muscle tremor

Drug and Receptor Interactions Alpha1 Alpha2 Beta1 Beta2 Dopamine Epinephrine ++ +++ Norepinephrine + Dopexamine Phenylephrine

Epinephrine Alpha + beta agonist Clinical effects Inotrope + chronotrope + increased peripheral vascular resistance + proarrythmic + increased blood coagulability Bronchodilator, increased TV + RR Excitatory effects on CNS Decreased renal & increased splanchnic blood flow Increased blood glucose, increased renin activity Uses Administration Metabolism + Excretion

Norepinephrine Primarily alpha agonist – used for hypotension Clinical effects Increase SVR, coronary vasodilatation, decrease HR Bronchodilatation + increased MV (small effect) Decreased cerebral BF + oxygen consumption Decreased hepatic, splanchnic + renal BF Decreased insulin secretion Administration - infusion Metabolism + Excretion Cautions – MAOIs and TCAs

Dopamine Low dose – DA agonist, Higher dose – adrenergic stimulation (dose dep) Clinical effects Inotrope (low dose), vasoconstriction (high dose) Reduced resp response to hypoxia Exogenous - doesn’t cross BBB, nausea Decrease renal vasc resistance (low dose) Uses Metabolism + Excretion Caution - MAOIs

Dopexamine Dopamine & beta agonist, prevents NA reuptake Clinical uses Positive inotrope + chronotrope, arteriolar vasodil - decreased afterload, increased myocardial BF Bronchodilator Increased cerebral BF Increased renal & splanchnic BF Uses Metabolism + Excretion Caution – hypovolaemia, AS, phaeo, HCOM

Phenylephrine Pure alpha agonist Clinical effects Vasoconstriction, reflex bradycardia Used topically for nasal decongestion Caution with MAOIs, longer action than NA

Metaraminol Alpha > beta agonist (direct + indirect) Clinical effects Primarily- increased SVR, bradycardia, inotropy (min) Reduced cerebral BF Reduced renal BF Increased uterine tone Increased blood glucose Use Caution – may precipitate LVF/cardiac arrest

Ephedrine Alpha & beta agonist (direct + indirect – NorAd release) Clinical effects Positive inotrope + chronotrope, myocardial irritability, increased coronary BF Resp stimulant, bronchodilatation Stimulatory effect on CNS Constricts renal BF, decreases uterine tone Increased glycogenolysis Metabolism + Excretion Caution - tachyphylaxis

Potassium/Insulin/Glucose Infusion Acute MI Improves ischaemic cardiac dysfunction by: Insulin stimulates myocardial Na-K-ATPase reuptake of K stabilisation of cell membrane decrease in dysrrhythmias Insulin increase myocardial gluc uptake increase intracellular substrate Post CABG evidence: Cardiac index SVR Inotropic & Mechanical support No evidence for myocardial injury or mortality Monitor K+ for 24 hours post infusion

Phosphodiesterase III Inhibitors (I) Inhibit PDE III isoenzyme increase intracellular cAMP + cGMP in myocardial & sm. muscle cells cAMP phosphorylates cellular protein kinases Myocardium: Ca2+ influx more Ca2+ for contraction & improved Ca2+ reuptake improved relaxation Sm. Muscle: relaxation & 20 vasodilatation Clinical effects Increased cardiac contractility without increasing myocardial oxygen consumption Decreased preload and afterload Minimal chronotropic effect

Phosphodiesterase III Inhibitors (II) Clinical uses: Short term treatment for acute on chronic severe CCF Synergistic effect with beta agonists Role in cardiopulmonary bypass Enoximone Yellow, effect for 4-6 hours Loading dose then infusion Monitor for hypotension Hepatic metabolism, renal excretion

Levosimendan (I) Calcium sensitiser Action Clinical effects Stabilises interaction btn Ca2+ & Troponin C by binding Troponin C in Ca2+ dependent manner K+-ATP channel opener (PDE III inhib effect in vitro) Clinical effects Increased cardiac contractility – no increase in myocardial oxygen demand Vasodilatation resulting in decreased preload & afterload Not proarrythmogenic

Levosimendan (II) LIDO study Levosimendan vs dobutamine in low output cardiac failure 200 patients Haemodynamic performance assessed: Levosimendan - 28% increase Dobutamine – 5% increase (P=0.022) Mortality at 180 days Levosimendan – 26% Dobutamine – 38% (P=0.029)

Inotropic requirements & patient outcomes

Summary Inotropes and vasopressors have wide range of actions Basic knowledge of autonomic nervous system physiology essential to understand principles of inotropes and vasopressors Need to assess patient clinically and understand disease process to determine most appropriate drug to use

References General Rang, Dale and Ritter. Pharmacology Sasada and Smith. Drugs in Anaesthesia and Intensive Care Pinnock. Fundamentals of Anaesthesia PIG Gradinac S et al (1989) Annals of Thoracic Surgery 48:484-489 Broomhead CJ et al (2001) Heart 85:495-496 Quinn DW et al (2006) Journal of Thoracic and Cardiovascular Surgery 131:34-42 Levosimendan Nq TM (2004) Pharmacotherapy 24:1366-84 Follath F et al (2002) Lancet 360:196-202 www.abbott.com