INOTROPES

DR. MANISH SINGHAL

 Definition
 Classification
 Drug detail
 Newer Inotropes
 Role in AHF and Sepsis—
beliefs,controversies,recommendatio
ns
 Definition
 An inotrope is an agent which alters the
force or energy of muscular contraction.
Negatively inotropic agents weaken the
force of muscular contractions. Positively
inotropic agents increase the strength of
muscular contraction.
 Most commonly, the inotropic state is used
in reference to various drugs that affect
the myocardial contractility. However, it
can also refer to pathological conditions.
For example, ventricular hypertrophy can
increase inotropic state, while
myocardial infarction can decrease it.
 Classification

 Positive Inotropes

 Negative Inotropes.
 Both positive and negative inotropes are
used in the management of various
cardiovascular conditions.
 The choice of agent largely depends on
specific pharmacological effects of
individual agents with respect to the
condition.
 One of the most important factors
affecting inotropic state is the level of
calcium in the cytoplasm. Positive
inotropes usually increase the level, while
negative inotropes decrease it. However,
not all drugs involve calcium release, and
among those which do, the mechanism for
 Positive inotropic agents
 Positive inotropic agents increase myocardial contractility, and are
used to support cardiac function in conditions such as
decompensated congestive heart failure, cardiogenic shock,
septic shock, myocardial infarction, cardiomyopathy, etc.
Examples of positive inotropic agents include:
 Calcium
 Calcium sensitizers
 Levosimendan
 Cardiac glycosides
 Digoxin
 Catecholamines
 Dopamine
 Dobutamine
 Dopexamine
 Epinephrine (adrenaline)
 Isoprenaline (isoproterenol)
 Norepinephrine (noradrenaline)
 Eicosanoids
 Prostaglandins[1]
 Phosphodiesterase inhibitors
 Enoximone
 Milrinone
 Negative inotropic agents
 Negative inotropic agents decrease
myocardial contractility, and are used to
decrease cardiac workload in conditions
such as angina. While negative
inotropism may precipitate or
exacerbate heart failure, certain beta
blockers (e.g. carvedilol) have been
shown to reduce morbidity and mortality
in congestive heart failure.
Beta blockers
Diltiazem
 Catecholamines
 Naturally occuring
Adrenaline, Noradrenaline,
Dopamine
 Synthetic agents

Isoprenaline,Dobutamine,Dopexamin
e
CATECHOLAMINE
SYNTHESIS
 ADRENERGIC RECEPTORS

Action when
Receptor Subtype Location
stimulated
Vascular Vasoconstricti
Alpha (A) 1
smooth on
muscle
Thruout Sedation,
2
nervous analgesia
system
Heart +ive chrono
Beta (B) 1
and inotropic
Bronchi, Bronchodilatio
2
vascular n, vasodilation
Dopaminergi smooth ms.
Peripheral Vasodilation
c 1 of renal and
(D) mesentric
Peripheral beds
Inhibit
2 Noradrenaline
release
 ADRENALINE
(Epinephrine)
 Endogenous adrenaline is produced from
noradrenaline in the adrenal medulla.
 Non-selective adrenergic agonist.
Stimulates A1,A2,B1,B2 receptors.
 Degree of stimulation depends on it’s
circulating levels.
 Inotropic effect due to stimulation of B1
receptors.
 Inc myocardial contractility and also
increased oxygen demand.
 Half life: about 2 mins due to rapid
 NORADRENALINE
(norepinephrine)
 Stimulates mainly A1 but also B1
receptors, though to a lesser degree
than adrenaline.
 Causes peripheral vasoconstriction,
inc SBP and DBP, inc myocardial oxy
consumption.
 Short half life of about 2 mins due to
rapid metabolism. About 25% taken
up as it passes through the lungs.
 Dopamine
 Acts on Alpha, Beta and
Dopaminergic receptors.
 Degree of receptor stimulation
depends on the rate of infusion.
 B1 effects predominate at rates upto
10 mic/kg/min.
 Isoprenaline
 Acts on B1 and B2 receptors with no
Alpha effects.
 B1 effects increase contractility and
cardiac output.
 However due to it’s B2 effects of
vasodilation, the inc in cardiac output
may be insufficient to maintain BP.
 Tachycardia may decrease diastolic
coronary filling time.
 Dobutamine
 Synthetic derivative of isoprenaline
 Predominantly B1 effect, minimal B2.
 Inc contractility, Heart rate and
myocardial oxygen requirement.
 Limited fall in SVR due to B2 effect.
 Avoid in patients with cardiac outflow
obstruction eg Aortic stenosis.
 Dopexamine
 Synthetic analogue of Dopamine.
 Stimulates B2, D1 receptors and also
inhibits noradrenaline uptake. No
effect on Alpha receptors.
 Has positive inotropic
effects,improves cardiac output due
to B2 mediated reduced afterload.
 Produces no change in oxygen
extraction
 Ephedrine
 Has both direct and indirect
sympathomimetic actions.
 Increases CO,HR,BP,coronary flow
and Myocardial oxygen consumption.
 Extreme caution required in patients
taking MAOI.
 Prone to tachyphylaxis as
Noradrenaline stores become
depleted.
 Phosphodiestrase
inhibitors
 Aminophylline:
 Non-selective PDEi.

 Mild positive chronotropic and

inotropic effects.
 Increases arrythmogenic potential
esp with Halothane.
 Effective therapeutic concentration
10-20 mcg/ml
 Enoximone

 Selective PDE iii inhibitor.

 Acts by preventing cAMP degradation thereby

increasing the slow Ca++ current during the
cardiac action potential

 Termed as an “Inodilator” due to its positive

inotropic effects and vasodilator actions on the
vascular smooth muscle.

 In patients with IHD may aggravate ischaemia

due to a reduction in coronary filling pressure and
increased heart rate.

 Dose : 5-20 mcg/kg/min in plastic syringes.

It may take upto 30 mins to act.
 Milrinone
 Selective PDE iii inhibitor.
 Effects similar to enoximone.
 Safe in patients receiving Digoxin.
 May exacerbate atrial flutter and fibrillation due
to an increased ventricular response.
 Dose: 50 mcg/kg bolus followed by0.375
mcg/kg/min infusion

 Amrinone:
 Similar to Milrinone.
 Dose:0.75 mg/kg bolus over 15 mins followed by
5-10 mcg/kg/min infusion

BOTH THESE DRUGS HAVE BEEN USED IN CHRONIC CCF

BUT HAVE NOT SHOWN TO IMPROVE IN-HOSPITAL
MORBIDITY.
 Digoxin
 Has direct and indirect actions on the
heart.
 Inhibits Na/K ATPase increasing
intracellular Na which increases
availability of intracellular Ca
 Indirectly releases Ach at cardiac
muscarinic endings which slows
conduction.
 Has a low therapeutic index. Toxicity
at conc exceeding 2.5 mcg/ml.
 INFUSION
DRUG RECEPTORS
RATE
Adrenaline B2 1-2 mcg/min
B1 + B2 2-10 mcg/min
A1 > 10 mcg/min
Noradrenali A1 , B1>> B2 4-12 mcg/min
ne
Dopamine Dopaminergic 0-3
B mcg/kg/min
3-10
A mcg/kg/min
> 10
Dobutamine B1>>B2, A mcg/kg/min
2.5-
10mcg/kg/min
Isoprenaline B1>B2 0.5-10
mcg/min
 Newer Inotropes
 Levosimendan:
 Enhances cardiac contractility by “calcium
sensitisation”
 Levosimendan exerts its inotropic
effect by binding to cardiac troponin
C, thus stabilising calcium ion-induced
conformational changes in the
tropomyosin regulatory protein. As a
result, actin-myosin filament protein cross-bridge formation
is facilitated and prolonged. Cardiac performance and
contractility are improved without a significant increase in
total myocardial energy demand and oxygen consumption.
The potential for arrhythmias is also reduced as total
intracellular calcium levels are not raised.
 Pimobendan
 New PDE iii inhibitor.

 Increases calcium sensitization

 Promising results in the EPOCH Study

group, Circulation 2002; 66 (2): 149).
 Needs further evaluation.
 Other agents currently being
evaluated:
Denopamine ( B1 stimulant)
Xamoterol ( B1 partial agonist)
Ibopamine, Docarpamine
 Current place of Inotropes
in treatment of Acute Heart
Failure
 Inotropes continue to be widely used
despite evidence to the contrary.
 No role in patients with no evidence
of tissue hypoperfusion.
 Inotropic support has a clear role in short
term stabilization of patients with low
output states and definite end organ
hypoperfusion.
 Choice of agents will depend on the
clinical profile, blood pressure , renal
function.

Crit Care Med 2008 Vol 36 No. 1

 Role in Sepsis
 In patients with low cardiac output despite
adequate fluid resuscitation dobutamine
may be used. If used in the presence of
low blood pressure it should be combined
with vasopressor therapy viz.
Norepinephrine/Dopamine.( Grade E
evidence)
 A strategy of increasing cardiac index to
achieve an predefined elevated level is not
recommended. Goal should be to achieve
adequate oxygen delivery or avoid flow
dependent tissue hypoxia.
 Surviving Sepsis Campaign Crit Care Med
Thank you