LES MEDICAMENTS

SYMPATHOMIMETIQUES

Cours DES ARMU

A1_15
Généralité

• L’inotrope : médicament qui améliore la

contraction myocardique
• Les (amines) presseurs : médicaments ou
produits chimiques qu’on les utilise pour
donner la vasoconstriction qui  PA 
• En pratique, les mots inotropes et les amines
presseuses sont interchangeable.
• Les inotropes (proprement dite):
– les inotropes positifs et
– les inotrope négatifs (qui diminue la contractilité du
myocarde)
LES DIFFERENTS GROUPES
D’INOTROPE
• Les catécholamines
• Le glycosides cardiaques
• Les inotropes non catécholamines et non
glycosidiques
• Le calcium
LES CATECHOLAMINES
(sympathomimétiques)
• Naturels
– Adrénaline (Epinephrine)
– Noradrénaline (Norepinephrine)
– Dopamine
• De synthèse (agonistes directs)
– Isoprotérénol
– Dobutamine
• De synthèse (agonistes indirects)
– Ephédrine
– Phenylephrine
Les inotropes non catécholamine-non
glycosidiques
• Les inhibiteurs sélectifs de
phosphodiestérase III
– Amrinone
– Milrinone
Les sympathomimétiques à l’action
pulmonaire
• Les bloquants sélectifs du récepteurs 2
– Albuterol
– Metaproterenol
– Terbutaline
Les chémorécepteurs sympathiques

• 1 adrénergique
– muscles lisses des Vx (artères et veines
cérébrales, rénale, dermique et le système gastro-
intestinale)
– stimulation  vasoconstriction
• 2 adrénergique
– pancréas et le tube gastro-intestinale
– stimulation 
• production d’insuline ,
• glucagon ,
• dans le SNC  libération noradrénaline pré-synaptique,
•  agrégation plaquettaire,
• constriction des sphincters GI
Les chémorécepteurs sympathiques

• 1 adrénergiques
– cœur
– stimulation 
• inotrope+,
• chronotrope+,
• dromotrope+,
• sécrétion rénine par appareil juxta glomérulaire,
• libération ghrelin gastrique  faim
• 3 adrénergique
– stimulation   lipolyse dans le tissu adipeux ou
graisse
Les chémorécepteurs sympathiques

• 2 adrénergiques
– bronches et bronchioles, système squelettique
– stimulation 
• bronchodilatation,
• génération osseux ou anabolisme,
• lipolyse,
• relaxation utérine,
• relaxation vésicale,
• dilatation des artères des squelettes,
• glycogènolyse,
• gluconéogenèse.
• sécrétion insuline 
• constriction des sphinctères GI
• salive est plus épaisse (visqueux)
• sécrétion rénine 
Les récepteurs couplés avec protéine G
G-Protein coupled Receptors

AC: adenyl cyclase, PDE: phosphodestherase, cAMP: AMP cyclique

 Les récepteurs couplés avec protéine G
G-Protein coupled Receptors

• G protein–coupled receptors consist of three

separate components:
– a receptor protein,
– three G proteins (α, β, and γ), and
– an effector mechanism
 Les récepteurs couplés avec protéine G
G-Protein coupled Receptors

• There are at least

– 16 Gα,
– 5 Gβ, and
– 11 Gγ proteins,
Stimulation du 2 récepteur
Les sympathomimétiques utilisés dans l’état de
choc ou/et la défaillance myocardique
ADRENALINE

• The relative balance of α1 and β2 receptors in

the vasculature of an organ determines
epinephrine’s overall effect on blood flow to
the organ.
• The net effect of these changes in peripheral
vascular tone is preferential distribution of
cardiac output to skeletal muscles and
increased systemic vascular resistance.
• Renal blood flow is substantially decreased
by epinephrine, even in the absence of
changes in systemic blood pressure.
ADRENALINE

• In general, β2 receptors are more sensitive to

lower epinephrine doses while effects
on α1 receptors predominate at higher doses.
• At high doses, the predominant α activity and
resultant vasoconstriction leads to increased
afterload, which may impede increases in
cardiac output.
ADRENALINE

• Epinephrine stimulates β1 receptors causing

– an increase in heart rate,
– an increase in myocardial contractility, and
– an increase in cardiac output.
• There may be a mild decrease in diastolic
blood pressure, reflecting vasodilation in
skeletal muscle vasculature due to
stimulation of β2 receptors.
ADRENALINE

• In usual therapeutic doses,

– no significant vasoconstrictive effect on cerebral arterioles.
– Coronary blood flow is enhanced even at doses that do not
alter systemic blood pressure.
• The hemodynamic effects of epinephrine are
attenuated and can be blocked by prior
administration of α- or β-adrenergic receptor
antagonists.
• Supra therapeutic doses of epinephrine may lead to
acute heart failure, pulmonary edema, arrhythmias,
hypertension, and myocardial ischemia.
 ADRENALINE

• Clinical uses of epinephrine

– treatment of life-threatening allergic reactions/anaphylaxis,
– treatment of severe asthma and bronchospasm,
– during cardiopulmonary resuscitation as a vital therapeutic drug,
– during periods of hemodynamic instability to promote myocardial
contractility and increase vascular resistance, and continuous
infusion for continuous support of myocardial contractility and
vascular resistance.
– to promote inotropy during weaning from cardiopulmonary
bypass.
– used as a vasoconstrictor to increase oxygen delivery and
increase cardiac output in sepsis.
– prolonging the duration of action of the anesthetic for regional
and local anesthesia.
ADRENALINE

• Absorption after subcutaneous injection is

slow because of local epinephrine–induced
vasoconstriction.
• Does not cross the blood-brain barrier;
crosses the placenta and enters breast milk.
• ½ vie élimination: 2min
• Duration of action: 20-30min (bronchodilator)
• Elimination: metabolism, uptake by nerve
endings
NORADRENALINE

• It is the immediate precursor of epinephrine.

• It stimulates β1- and α1-adrenergic receptors.
• Effect at β2 receptors is minima
• A potent α1 agonist producing intense arterial
and venous vasoconstriction in all vascular
beds except for the coronary arteries
• It increases MAP primarily by
vasoconstriction and to lesser degree by
increasing stroke volume and cardiac output.
 NORADRENALINE

NORADRENALINE ADRENALINE
Résistance Vasculaire ++ +
systémique 
Pression artérielle ++ +
diastolique 
Pression artérielle ++ +
moyenne 
Tachycardie + ++
NORADRENALINE

• Norepinephrine and epinephrine increase

total peripheral vascular resistance more than
dobutamine.
• Unlike epinephrine, norepinephrine has
minimal metabolic effects.
• Hyperglycemia is unlikely to occur as a result
of norepinephrine administration.
NORADRENALINE

• Peripheral vasoconstriction may decrease

tissue blood flow to the extent that metabolic
acidosis occurs
• Like epinephrine, norepinephrine dilates
coronary arteries.
• Dilute in D5%
• Usual dose for refractory hypotension:
2 -16 μg/min by continuous infusion
NORADRENALINE

• Clinical uses:
– a potent vasoconstrictor to increase total
peripheral vascular resistance and mean arterial
pressure.
– a first-line agent in the treatment of refractory
hypotension during severe sepsis.
– for patients with low systemic vascular resistance
after cardiopulmonary bypass.
– In patients with coronary artery disease, to
maintain perfusion pressure, it should be balanced
with the resultant increased afterload associated
with high doses.
NORADRENALINE

• Concentrates in sympathetic nervous tissue.

• Does not cross the blood-brain barrier but
readily crosses the placenta
• Elimination: by metabolism and re-uptake
• By IV route,
– onset of action: immediate,
– duration of action: 1-2min
DOPAMINE

• Low dose (0.5-3micg/kg/min),

– it stimulate D1, D2 receptors
• Dose of 3-10micg/kg/min,
– stimulation Beta1, and alpha receptor
– increased cardiac output by
• HR 
• Contractility 
• vasodilation and Afterload 
DOPAMINE

• Dose > 10micg/kg/min,

acts like a pure alpha1 agonist.
– Arterial and venous vasoconstriction,
– increased systemic vascular resistance,
– Increased blood pressure attenuating further
increases in cardiac output.
– Reflex bradycardia may also occur
DOPAMINE

• There are a wide range of clinical responses

depending on individual variability in
pharmacokinetics as well as other variables
• The effects of dopamine cannot be predicted
based on the dose, and the drug must be
titrated to effect.
• dopamine is less dysrhythmogenic than
epinephrine
• Dopamine increases myocardial oxygen
consumption.
DOPAMINE

• Dopamine should be dissolved in 5% glucose

in water for IV administration
• an elimination half-life of 1 to 2 minutes
• Approximately 25% is converted to
norepinephrine.
• metabolism
– in the liver with conjugation to sulfates and
glucuronides,
– pulmonary endothelium by catechol-O-
methyltransferase (COMT)
– excretion by the kidneys.
DOPAMINE

• Dopamine is used clinically to increase

cardiac output in patients with decreased
contractility, low systemic blood pressure, and
low urine output
• It is unique among the catecholamines in
being able to simultaneously increase
myocardial contractility, renal blood flow,
glomerular filtration rate, excretion of sodium,
and urine output
DOPAMINE

• Activation of arterial and venous α1 receptors

increases systemic vascular resistance,
preload, and left ventricular afterload.
• Dopamine increases pulmonary vascular
resistance,
• it may not be the preferred inotropic agents in
patients with pulmonary hypertension or right
ventricular dysfunction.
DOPAMINE

• The divergent pharmacologic effects of

dopamine and dobutamine make their use in
combination potentially useful.
• The objective of combination therapy is to
– increase coronary perfusion and cardiac output
– decreasing afterload
(similar to an intra-aortic balloon pump).
• Not only does low-dose dopamine not confer
any renal protective mechanism, it may in fact
be detrimental.
ISUPROTÉRÉNOL

• Isoproterenol is the most potent activator of

all the sympathomimetics with β1 and β2
receptor activity.
• It is 2-3 times more potent than Adrénaline
and at least 100 times more active than
Noradrénaline
• In clinical doses, isoproterenol does not have
α agonist effects and does not cause the
vasoconstriction associated with the naturally
occurring catecholamines.
ISUPROTÉRÉNOL

• continuous infusion (1 to 5 μg/min) 

– increases heart rate,
– increases myocardial contractility, and
– increases cardiac automaticity,
– decreases systemic vascular resistance (by
vasodilation in skeletal muscles)
• the MAP may decrease due to decreases in
systemic vascular resistance and associated
decreases in diastolic blood pressure.
ISUPROTÉRÉNOL

Pour une comparable DOBUTAMINE ISUPRENALINE

augmentation du DC
la Résistance - ---
vasculaire systémique
PA - /+ --
Tachycardie + +++
ISUPROTÉRÉNOL

• Isoproterenol is used to provide sustained

increases in heart rate before insertion of a
temporary or permanent cardiac pacemaker
in the treatment of brady-dysrhythmias.
• Isoproterenol’s ability to decrease pulmonary
vascular resistance may be useful in the
management of pulmonary hypertension and
right ventricular dysfunction
DOBUTAMINE

• Dobutamine has potent β1-adrenergic effects

with weaker β2-adrenergic activity. Its effect
on α receptors increases at higher doses.
• Dobutamine acts primarily as a positive
inotropic agent.
• Dobutamine leads to an increase in
intracellular cAMP, increasing calcium release
from the sarcoplasmic reticulum to increase
contractility.
DOBUTAMINE

• Dobutamine has weak effects on vascular

tone causing peripheral vasodilation
• Cardiac output is increased primarily by an
increase in stroke volume.
• Blood pressure usually is not significantly
affected
• it may be ineffective in patients who require
increased systemic vascular resistance rather
than augmentation of cardiac output to
increase systemic blood pressure.
DOBUTAMINE

• Chronotrope effect for a unit of increase CO:

Isuprenalin > Dopamin > Dobutamin > Adrenalin

• At low doses, increases in heart rate may be

minimal. However, high doses of dobutamine
(>10 μg/kg/min IV) may predispose the
patient to tachycardia and cardiac
dysrhythmias.
DOBUTAMINE

• Dobutamine increases myocardial oxygen

consumption by increasing tachycardia and
myocardial contractility.
• Myocardial oxygen consumption may also be
reduced with improved contractility,
decreased left ventricular end diastolic
pressure (LVEDP), and decreased wall
tension.
DOBUTAMINE

• Unlike dopamine, dobutamine does not act

indirectly by stimulating the release of
endogenous norepinephrine.
• Dobutamine does not activate dopaminergic
receptors to increase renal blood flow. Renal
blood flow, however, may improve as a result
of drug-induced increases in cardiac output.
• Dobutamine but not dopamine is a coronary
artery vasodilator.
DOBUTAMINE

• half-life of 2 minutes
• continuous infusion of 2 to 10 μg/kg/min to
maintain therapeutic plasma concentrations.
• Like dopamine, dobutamine should be
dissolved in D5
• biotransformation in the liver to
– inactive glucuronide conjugates and
– 3-0-methyldobutamine,
– most of which is excreted in the urine
EPHEDRINE

• Ephedrine is an indirect-acting synthetic

sympathomimetic that stimulates α- and β-
adrenergic receptors.
• The pharmacologic effects
– direct stimulation of adrenergic receptors and
– stimulation of release of endogenous
norepinephrine (indirect-acting).
• Oral route is available
EPHEDRINE

• The cardiovascular effects of ephedrine

resemble those of Adrénaline, but
– BP elevation less but last longer (10  longer)
– increases in systolic and diastolic blood pressure,
– increases heart rate, and
– increases cardiac output.
– Renal and splanchnic blood flows are decreased,
– coronary and skeletal muscle blood flows are
increased.
– Systemic vascular resistance may be altered
minimally.
EPHEDRINE

•  +/- hyperglycemia.
• Mydriasis accompanies the administration of
ephedrine, and CNS stimulation does occur, although
less than that produced by amphetamine

• Ephedrine, 5 to 10 mg IV administered to adults, is a

commonly selected sympathomimetic to increase
systemic blood pressure in the presence of
sympathetic nervous system blockade produced by
regional anesthesia or hypotension due to inhaled or
injected anesthetics
CARDIAC GLYCOSIDES

• Digoxin is used most often during the

perioperative period for the management of
supraventricular tachy-dysrhythmias
– paroxysmal atrial tachycardia,
– atrial fibrillation,
– atrial flutter
• it slows conduction of cardiac impulses
through the atrio-ventricular node
CARDIAC GLYCOSIDES

• Digoxin continues to have an important

therapeutic role in the treatment of chronic
congestive heart failure.
• Digoxin may not be of benefit in high-output
cardiac failure, such as that caused by
hyperthyroidism or thiamine deficiency.
CARDIAC GLYCOSIDES

• Cardiac glycosides selectively and reversibly

inhibit the Na+−K+ ATPase ion transport
system (sodium pump)  increase in
intercellular sodium  blocks the sodium–
calcium exchanger and increases intracellular
calcium
• cardiac glycosides enhance parasympathetic
nervous system activity, leading to delayed
conduction of cardiac impulses through the
atrioventricular node and decreases in heart
rate.
CARDIAC GLYCOSIDES

• The positive inotropic (increased stroke

volume, decreased heart size, and decreased
LVEDP) is associated with:
– left ventricular preload , afterload ,
– wall tension , and
–  oxygen consumption in the failing heart.
• Improved renal perfusion  diuresis that
often accompanies the administration of
cardiac glycosides to patients in cardiac
failure.
• Cardiac output is often unchanged or even
decreased when cardiac glycosides are
administered to patients with normal hearts.
• The electrophysiologic effects of therapeutic
plasma concentrations of cardiac glycosides
manifest on the ECG as
– (a) prolonged P-R intervals
– (b) shortened QTc intervals
– (c) ST segment depression
– (d) diminished amplitude or inversion of T waves.
the plasma and effect site time course of 0.5 mg
of digoxin, given either orally or intravenously
CARDIAC GLYCOSIDES

• In patient receiving cardiac glycosides

– β-adrenergic agonist may increase the likelihood
of cardiac dysrhythmias
– calcium IV, may precipitate cardiac dysrhythmias
– Any drug that facilitates hypokalemia  digitalis
toxicity.
– Fentanyl, enflurane, and, to a lesser extent,
isoflurane protect against digitalis-enhanced
cardiac automaticity
MILRINONE
(Corotrope 10mg/10ml)
• Selective inhibitors of phosphodiesterase
fraction III (PDE III) decrease the hydrolysis
of cAMP, leading to increased intracellular
concentrations of cAMP in the myocardium
and vascular smooth muscle.
• The overall effect of selective PDE III
inhibitors is to combine positive inotropic
effects with smooth muscle relaxation in both
arteriolar and venous beds. Hence, they have
been termed inodilators.
PDE III inhibitor

• Cardiac output improves both as a result of

increased inotropy as well as vascular
smooth muscle relaxation of peripheral and
pulmonary vessel.
• Dose-dependent increases in cardiac index
occur with minimal increases in myocardial
oxygen consumption.
PDE III inhibitor

• PDE III inhibitor effects:

– Decreases in LVEDP,
– Decreases mean arterial pressure,
– Decreases central venous pressure,
– Decreases pulmonary artery occlusion pressure,
– Decreases pulmonary vascular resistance, and
– Decreases systemic vascular resistance
– improvements in diastolic function
PDE III inhibitor

Milrinone Dobutamin
Pulmonary arterial  
pressure
Systemic vascular  
resistance
Blood pressure  

Tachycardia +/- +

MVO2 + ++
PDE III inhibitor

• Milrinone may be preferred in situations with

– high filling pressures,
– elevated pulmonary artery pressure,
– need for continued β blockade,
– decreased responsiveness to catecholamine
therapy, and
– increased risk for tachyarrhythmias.
• Dobutamine may be preferred in situations
with significant vasodilation or renal
dysfunction.
PDE III inhibitor

• Other effects:
– able to reverse vasospasm in arterial grafts.
– anti-inflammatory effects,
perioperative administration may dilate splanchnic
vasculature and attenuate systemic inflammation in
the acute phase response after cardiopulmonary
bypass.
PDE III inhibitor

• Dose: IV bolus of 50 μg/kg over 10 minutes

followed by a continuous infusion of 0.375 to
0.75 μg/kg/minute
• The maximum daily dose of milrinone should
not exceed 1.3 mg/kg/day.
• The elimination half-time is 2.7 hours
• The dose should be decreased in patients
with severe renal dysfunction.