1. Inotropes & Vasopressors
Sophie Young
December 2006

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

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

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

5. 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

6. 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

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

8. 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

9. 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

10. 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

11. 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

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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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)

20. Inotropic requirements & patient outcomes

21. 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

22. 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:
Broomhead CJ et al (2001) Heart 85:
Quinn DW et al (2006) Journal of Thoracic and Cardiovascular Surgery 131:34-42
Levosimendan
Nq TM (2004) Pharmacotherapy 24:
Follath F et al (2002) Lancet 360: