Transcript Inotropes & Vasopressors

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
arterial pressure
elevation of mean
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
Drug
Alpha1
Alpha2
Beta1
Beta2
Dopamine
++
++
+++
+++
0
+++
+++
++
+
0
Dopamine
+
0
++
++
+++
Dopexamine
0
0
+
+++
++
++
0
0
0
0
Epinephrine
Norepinephrine
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
1.
2.
Increased cardiac contractility without increasing
myocardial oxygen consumption
Decreased preload and afterload
3.
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
– 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
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