Mecanismos de Accion Inotropicos

SYMPOSIUM: NEONATOLOGY
Mechanism of action of on the myocardial cells. An understanding of these adrenergic

receptors is therefore essential to fully appreciate the mode of
inotropes in neonates action of various inotropic medications.
What is an inotrope?
Rachel Morris Physiologically speaking, an inotrope is an agent/drug which has
Alok Sharma an effect on the strength of myocardial contractility; a positive
inotrope would augment and a negative inotrope would reduce
the myocardial contractility. A medication which has the sole
Abstract effect of altering the blood pressure is more correctly referred to
Whilst inotropes have been used in the neonatal intensive care unit as a vasoactive agent. However, most of the medications dis-
(NICU) for over 50 years, debate on the optimal management of cussed in this review have an overlapping effect on the heart and
neonatal hypotension continues. The complex biochemical processes the vasculature. As blood pressure is a dependent variable of
involved often mean these medications produce effects which seem to heart rate and stroke volume, a positive inotrope would increase
be contrary to expectations. The changing haemodynamics during the the blood pressure by virtue of increasing stroke volume.
transitional phase of the newborn period, along with the gestation Another term which often comes up during discussion of ino-
related structural and functional immaturity of the cardiovascular sys- tropes is "lusitropy". It refers to the rate of myocardial relaxation
tem, makes choosing an inotrope difficult. This review highlights the and all inotropes will also have a positive lusitropic effect; i.e.
main mechanism of action of the commonly used inotropes in the they increase the rate of cardiac and smooth muscle relaxation.
NICU. This knowledge should increase the probability that you pick For the purpose of this review, we will focus solely on the role
the best inotrope on the neonatal intensive care unit. of the adrenergic receptors which mediate the biological actions
of the endogenous catecholamines and similar exogenous agents.
Keywords adrenergic receptors; G protein coupled receptors;
inotropes; lusitropy; systemic vascular resistance
The adrenergic receptors
How do they function?
Introduction
The two main types of adrenergic receptors, the a receptors and
In the absence of any other easily measurable parameter, blood the b receptors are further subdivided into nine different sub-
pressure measurement is a surrogate for tissue blood flow. The types; (a-1A, a-1B, a-1D, a-2A, a-2B, a-2C, b-1, b-2 and b-3). These
systemic blood pressure is dependent on two independent vari- receptors belong to the family of G protein coupled receptors
ables; the cardiac output and systemic vascular resistance, and (GPCRs). The characteristic feature of the GPCR group of pro-
their relationship can be defined as: teins is the activation of a specific membrane bound enzyme
once a ligand has combined with its specific receptor. This goes
BP ¼ ½cardiac output ðCOÞ on to release a specific 2nd generation intracellular messenger
which drives further cytoplasmic reactions. The basic schema is
systemic vascular resistance ðSVRÞ
outlined in Figure 1.
The G protein refers to a member of the guanosine nucleotide
The cardiac output is determined by the intrinsic contractility of
binding protein family. The G proteins are hetreotrimeric; i.e. they
the heart, the venous return (preload) and the heart rate, as given
are composed of 3 sub units, a, b and g. In the resting state, GDP is
by the equation.
bound to the a sub-unit. A cascade of events is set into motion with
the binding of the specific catecholamine to its receptor. Firstly,
CO ¼ ½stroke volume ðSVÞ heart rate ðHRÞ
GDP leaves the a sub-unit and is replaced by GTP. This activates
the G protein which then causes the membrane bound enzyme
The SVR is determined largely by the tone of the smooth muscle
activation. This sequentially leads to generation of the 2nd gen-
cells lining the arterioles. A change in the diameter of these
eration messenger which act on downstream target molecules.
vessels by vasoconstriction or vasodilatation alters the SVR
The associated G proteins of the various receptor subtypes,
which in turn regulates the local tissue blood flow.
the target enzymes within the cell and the specific intracellular
The autonomic nervous system has a pivotal role in control-
messenger involved are outlined in Table 1.
ling the vascular tone of the smooth muscle cells lining the blood Figure 2 shows the sequence of events following activation of
vessels, besides also influencing myocardial function. This is a b-1 adrenergic receptor after its interaction with a catechol-
achieved via a complex interplay of adrenergic receptors located amine substrate like adrenaline. The activated Gsa -GTP unit
on the cell membranes of smooth muscles in the vasculature and activates the membrane bound adenyl cyclase which then cata-
lyzes the breakdown of ATP to cyclic AMP. cAMP phosphory-
lates an enzyme, protein kinase A (PKA) which then acts on
Rachel Morris MBBS MRCPCH is a Neonatal Grid Trainee, ST-6 in the several other cellular proteins. In this instance, it activates the L
Department of Neonatology, University Hospital of Wales, Cardiff, type Ca channel promoting entry of Ca 2þ into the cytoplasm.
UK. Conflicts of interest: none declared. The sequence of events following activation of an a adrenergic
Alok Sharma MBBS FRCPCH is a Consultant Neonatologist in the University receptor are similar; the G protein involved is Gq and the enzyme
Hospital of Wales, Cardiff, UK. Conflicts of interest: none declared. activated is phospholipase C (PLC). The intracellular messengers
PAEDIATRICS AND CHILD HEALTH xxx:xxx 1 Crown Copyright Ó 2019 Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Morris R, Sharma A, Mechanism of action of inotropes in neonates, Paediatrics and Child Health, https://doi.org/
10.1016/j.paed.2019.03.001
Figure 1 Basic schema of the G protein coupled receptor (GPCR) mediated production of 2nd generation intracellular messenger. The binding of a
ligand (L) to its receptor (R) leads to activation of the intracellular GTP binding protein (G). This produces activation of the membrane bound
enzyme (Enz) which catalyses production of the intracellular 2nd messenger (X).
generated are diacyl glycerol (DAG) and Inositol-tri phosphate Irrespective of the receptor or the intracellular messenger
(IP3). The IP3 allows the opening up of the IP-3 gated Ca2þ involved, the biochemical pathways appear to be geared towards
channels on the membrane of the sarcoplasmic reticulum leading altering the concentration of ionised calcium (Ca2þ) within the
to further Ca2þ release into the cytoplasm (Figure 3). cytoplasm. The raised levels of Ca2þ ions facilitate muscle contrac-
tion in the cardiac muscle as well as the smooth muscle cell. The role
Location, location, location of Ca2þ ions in this excitation contraction coupling is outlined in
Table 2 summarizes the location of the various adrenergic re- Figure 4. The importance of Ca2þ ions in the whole process can be
ceptors in the cardiovascular system and the effects of their understood from the use of drugs like verapamil, amlodipine and
stimulation. We will confine the discussion to the receptors nifedipine which specifically target the L type Ca channels to cause a
within the cardiovascular system although they are normally negative inotropic effect and induce vasodilatation.
present widely throughout the body tissues. In the case of
dopamine, we will elaborate briefly on the dopaminergic re- Deciding on the best inotrope
ceptors in the renal glomeruli and tubules as they have a sig-
nificant role in BP regulation. Three important concepts need to be remembered when
considering vasoactive drug use. Firstly, all of these agents can
act on multiple adrenergic receptor subtypes. This can often lead
Characteristics of the adrenergic receptor subtypes. PLC- to contradictory clinical effects. For example, adrenaline infusion
Phospholipase C; PLA- 2 -Phospholipase 2; AC-Adenyl will increase cardiac contractility through b-1 receptor action,
cyclase; DAG- Diacyl glycerol; IP-3-Inositol-triphosphate. causes vasoconstriction via a-1 receptors and vasodilatation via
PKA-Protein kinase A. The D symbol denotes activation b-2 receptor stimulation. The net effect on arterial blood pressure
and e symbol denotes inhibition of the enzyme. can be difficult to predict and can vary between patients.
Secondly, most of these medications exhibit a dose related
Receptor Associated G Principle target Intracellular second
response to the type of receptor activated. The classic example is
subtype protein enzyme messenger
dopamine which in "low" doses stimulates the dopaminergic
a-1A Gaq þ(PLC/PLA-2) [DAG, [IP-3 receptors, in intermediate doses, stimulates the b-1 receptors and
a-1B Gaq þ(PLC/PLA-2) [DAG, [IP-3 in higher doses stimulates the a-1 receptors.
a-1D Gaq þ(PLC/PLA-2) [DAG, [IP-3 Finally, these medications can affect the haemodynamic
a-2A Gai þ(PLC/PLA-2) Y cAMP indices indirectly via the central baroreceptor reflexes. Thus
Y PKA noradrenaline tends to increase blood pressure via the a-1
a-2B Gai e(AC) Y cAMP adrenergic receptor stimulation. The rise in blood pressure is
Y PKA detected by the carotid body baroreceptors which can mediate a
a-2C Gai e(AC) Y cAMP reflex slowing of the heart rate.
Y PKA Table 3 summarizes the target receptors and the chief hae-
b-1 Gas þ(AC) [cAMP modynamic effect mediated by some of the commonly used
b-2 Gas þ(AC) [cAMP vasoactive agents in the NICU. It is helpful to broadly classify the
b-3 Gas þ(AC) [cAMP vasoactive drugs in four groups as outlined in Box 1.
The Group I ino-constrictors comprise the three endogenous
Table 1 catecholamines; adrenaline, noradrenaline and dopamine.
10.1016/j.paed.2019.03.001
Figure 2 Schema of events following stimulation of a b-1 adrenergic receptor in a cardiac muscle cell (the glowing edges indicate the “activated
state” of the subunit/enzyme). The activated PKA phosphorylates a wide variety of intracellular proteins leading to their activation. The figure
demonstrates activation of the L-type Ca2þ channels (LTCC).
Figure 3 Schema of events following stimulation of a adrenergic receptor in a smooth muscle cell. PLC- Phospholipase C, PIP-2 -Phosphoinositol
biphosphate, IP3- Inositol tri phosphate, DAG- Diacylglycerol, SR Sarcoplasmic reticulum.
10.1016/j.paed.2019.03.001
Location and functional characteristics of the adrenergic receptors in the circulatory system
Receptor Tissue location Actions
a-1A B D Post synaptic in smooth muscle of arterioles Contraction of the vascular smooth muscle;
and major arteries; Vasoconstriction; Increase in vascular tone,
Also present in myocardium but lesser increase in afterload and hence BP increases.
compared to b receptors
a-2 A C Pre synaptic, on sympathetic neurons Regulation of Noradrenaline release from
a-2 Coronaries sympathetic nerve endings, can decrease
blood pressure
Mediates vasoconstriction
b-1 Myocardium and smooth muscle of blood Increase heart rate and contractility
vessels Positively chronotropic and inotropic
b-2 Smooth muscle of Blood vessels Vasodilatation
Table 2
Dopamine The DA1 receptors are found mainly in a post synaptic loca-
Dopamine is often a "first line" inotrope in most NICUs. It is a tion on the smooth muscle cells of blood vessels. They are most
precursor of noradrenaline and the metabolic pathway is out- abundant in the renal, mesenteric and coronary vessels and less
lined below. so in the pulmonary vascular bed. When stimulated, these DA1
receptors produce vasodilatation and concomitant increase in the
Phenylalanine / Tyrosine / L blood flow within that vascular bed. DA1 receptors are also
DOPA / Dopamine / Noradrenaline present in the juxta glomerular apparatus (JGA) cells and on the
renal tubular cells on both sides of the cell membrane (on the
In the central nervous system, dopamine is neurotransmitter basolateral side as well as the brush border on the luminal side).
acting via the specific dopaminergic receptors D1 and D2. The The role of the DA1 receptors in the kidney is complex and is
dopaminergic receptors in the peripheral vasculature are referred thought to mediate natriuresis and renin release by the JGA. The
to as DA1 and DA2 receptors. These peripheral dopaminergic DA2 receptors are located primarily at the adrenergic nerve
receptors also belong to the GPCR family and either stimulate or endings surrounding the splanchnic vessels in a pre-synaptic
inhibit the membrane bound adenyl cyclase enzyme thus location. Their stimulation leads to inhibition of release of
bringing a change in the cytosolic cAMP levels.
Figure 4 Role of Ca2þ ions in excitation-contraction coupling. Diagram showing Ca2þ entering the sarcoplasm from the T tubules via the voltage
gated channels on arrival of an impulse. This promotes further Ca2þ release from the sarcoplasmic reticulum (SR) via the RyR channels (ryanodine
receptor channels). The Ca2þ then interacts with the troponin complex which leads to formation of cross bridges between the myosin and actin
chains. This allows muscle contraction. In the smooth muscle, troponin is replaced by another protein, calmodulin. The Ca2þ within the sarcoplasm
form a complex with calmodulin and this complex activates an enzyme MLCK (myosin light chain kinase). This enzyme phosphorylates the myosin
light chains causing muscle contraction.
10.1016/j.paed.2019.03.001
Summary of main haemodynamic effects of commonly used vasoactive drugs. *Dopamine can have unpredictable effects
at the "low dose" infusions particularly in neonates. DA-1- Peripheral dopaminergic type 1 receptor. [ signifies an
increase in the variable, / signifies no change and Y signifies a decrease in the variable. Milrinone does not act on
membrane receptors, however the biochemical pathway promotes increased cAMP; thus the similarity with b receptor
action. PVR ePulmonary vascular resistance. Data from Journal of Cardiovascular Pharmacology and Therapeutics 2015;
20 (3): 249e260.
Medication Category Dose infusion rates (microgram/kg/min) Adrenergic receptor Principle haemodynamic effects
CO SVR MAP HR
Dopamine Inodilator* <2 DA1 [/Y// Y// Y// [

Inoconstrictor 2e10 b-1 [[ [ [ [[
>10 a-1 [ [[ [[ [
Dobutamine Inodilator 5e15 b-1 & b-2 [[[ //Y [///Y [[
>15 a-1 [ [// [// [
Adrenaline Inoconstrictor 0.02e0.1 b-1 [[[ [[ [[ [[
>0.1 b-2 [[ /Y / [
a-1 [ [[ [[ [[
Nor adrenaline Mainly vasoconstrictor, 0.02e1 a-1 [// [[[ [[[ [
þ/-inotropic b-1 Y/
Milrinone Inodilator 0.25e0.75 b like [[[ Y Y/ [
YYPVR
Table 3
noradrenaline which reduces vascular tone and thus mediates stimulate the b-1 receptor and doses >10 microgram/kg/min
vasodilatation. preferentially stimulate the a-1 adrenergic receptors. It should be
As mentioned earlier, dopamine is a classic prototype of a however remembered that these effects are probably more obvious
vasoactive agent which exhibits dose related receptor activation. in older children and adults and the response in neonates could be
At doses up to 2 microgram/kg/min, it acts mainly on the DA1 and unpredictable. This could be related to the developmental maturity
DA2 receptors to mediate vasodilatation in the splanchnic circu- of the receptors and different rates of metabolic clearance. A large
lation. Dose infusions of 2e6 microgram/kg/min predominantly fraction of infused dopamine is converted peripherally into
noradrenaline (up to 50%) which may explain the predominant a
effects at higher doses. Plasma dopamine is also cleared by uptake
Suggested classification for the vasoactive agents. Data in the liver and by renal excretion. It is therefore advisable to be
from Journal of Cardiovascular Pharmacology and Ther- cautious when using this drug in a sick neonate with compromised
apeutics 2015; 20 (3):249e260. liver or renal function.
Dopamine also stimulates the cardiovascular system indi-
rectly by mediating the release of noradrenaline from sympa-
Group I e The ino-constrictors thetic nerve endings in the myocardium. These stores are
relatively low in a neonate and this may explain the tachyphy-
C Positive inotropic and vasoconstrictor effects
laxis seen after prolonged use of dopamine infusions.
C E.g. adrenalin/dopamine/noradrenaline
Although it is a neurotransmitter, parenteral dopamine does
not cross the blood brain barrier in significant amounts. It does
Group II eThe pure vasoconstrictors however reach the anterior pituitary gland and some section of
the hypothalamus which lie outside the blood brain barrier. This
C No inotropic effects
explains the endocrine side effects of dopamine which include
C E.g. vasopressin, phenylephrine
inhibition of prolactin, thyrotropin (thyroid stimulating hormone
(TSH)), growth hormone and gonadotrophins. These effects are
Group III e The ino-dilators generally transient, however it is advised that thyroid function
testing should be held off until dopamine is discontinued.
C Positive inotropic and vasodilator effects
C E.g. dobutamine, milrinone
Noradrenaline
Noradrenaline is an endogenous catecholamine released from the
Group IV e The vasodilators sympathetic nerve endings. By virtue of its action on a1 re-
ceptors, it increases systemic vascular resistance to increase
C No inotropic effect
mean arterial blood pressure. It also acts on b1 receptors (effect
C E.g. nitroglycerin, nitroprusside
equipotent to adrenaline) and theoretically has an inotropic ef-
Box 1 fect. This is largely counteracted by the compensatory
10.1016/j.paed.2019.03.001
baroreflexes, which will slow the heart and lead to a reduction in requiring inotropic support may well have relative adrenal
cardiac output. The effect on pulmonary vascular bed is generally insufficiency, and even a normal cortisol level in the face of
that of a rise in the mean pressure although less so compared to illness may be indicative of adrenal insufficiency and benefit
adrenaline. Noradrenaline has virtually no effect on b2 receptors from hydrocortisone therapy.
which further distinguishes it from adrenaline. It is generally
used in adults and older children with septic shock where it will Vasoactive agents and developmental maturity-related
help to overcome the endotoxin mediated loss of vascular tone. issues
Adrenaline Children are not just small adults and neonates are not just small
Adrenaline is an endogenous catecholamine that stimulates almost children. Structurally, the preterm heart has poorly developed
all of the adrenergic receptor subtypes. The cardiovascular effects of contractile elements and relatively sparse sarcoplasmic reticulum.
adrenaline therefore reflect a net effect of stimulation of all of these From the discussion above, we know that this tubular network is
receptors; the crucial determinant being the type of receptor in a vital for the intracellular delivery of Ca2þ ions. The myocardium
particular tissue, the receptor density and the dosage used (Table 3). has limited reserve to increase its contractility and may fail to in-
Adrenaline causes a significant increase in systolic blood crease the SV in the face of a rise in SVR with use of inotropes.
pressure via b-1 receptor mediated positive inotropic ([ SV) and There are relatively sparse a-1-receptors in the heart tissues at
chronotropic effect ([HR). The a-1 agonist action causes marked birth; functionally they may exhibit “denervation hypersensitiv-
vasoconstriction in the cutaneous blood vessels and renal vessels. ity”, whereby small concentrations of catecholamine will cause
This causes a steep increase in the SVR further augmenting the maximal stimulation. The b-1 adrenergic receptors seem to be in
blood pressure. The mean pressure in pulmonary blood vessels is adequate numbers in a full term neonate.
also increased. The b-2 receptors mediate an increase in blood There is also a direct association between gestational maturity
flow to the skeletal muscles and to the splanchnic circulation with and expression of adrenergic receptors with their related intra
some increase in cerebral blood flow as well. The b-2 mediated cellular signalling pathways. Endogenous cortisol secretion
vasodilatation can potentially lower the diastolic blood pressure. primes the receptors in the cardiovascular system to make them
The vasoconstriction in the skin vessels can cause local ischemia more responsive to circulating catecholamines. This could be
and gangrene if the drug extravasates in the tissues. Excessive compromised in the sick preterm baby as they will not be able to
stimulation of the b2 receptors in the liver can cause lactic acidosis mount an appropriate stress glucocorticoid response. A
and hyperglycaemia which is often seen with this drug infusion.
FURTHER READING
Dobutamine Goodman L, Gilman A, Brunton L, Hilal-Dandan R, Knollmann B.
Dobutamine is a synthetic catecholamine which has predominant Goodman & Gilman’s the pharmacological basis of therapeutics.
effects on b receptors. Unlike dopamine, it does not cause any New York: McGraw-Hill Education, 2018 [i 11 pozosta1ych].
release of noradrenaline. Istvan S. Cardiovascular, renal, and endocrine actions of dopamine in
The b-1 receptor agonist action brings about improved SV and neonates and children. J Pediatr 1995; 126: 333e44.
CO. The b-2 receptor agonism causes peripheral vasodilatation. Jentzer J, Coons J, Link C, Schmidhofer M. Pharmacotherapy update
This combination makes it an ideal agent for a neonate with on the use of vasopressors and inotropes in the intensive care unit.
compromised myocardial function following a hypoxic ischaemic J Cardiovasc Pharmacol Ther 2015; 20: 249e60.
insult or in an extremely premature baby. Due to its potential for Khosrow Tayebati SF, Lokhandwala M, Amenta F. Dopamine and
lowering the SVR, it may need to be used in combination with a vascular dynamics control: present status and future perspectives.
vasopressor such as noradrenaline or dopamine to maintain Curr Neurovascular Res 2011; 8: 246e57.
adequate blood pressure. Lehninger A, Nelson D, Cox M. Principles of biochemistry. New York:
W.H. Freeman, 2013.
Milrinone
Milrinone is an inhibitor of the enzyme phosphodiesterase-3,
which promotes degradation of the intracellular cAMP. Thus it Practice points
promotes positive inotropic action analogus to the adrenergic
receptors. Its other prominent biological effect is a lowering of C Adrenergic receptors are G protein coupled receptors.
the SVR and pulmonary vascular resistance. It is therefore often C Multiple biochemical pathways exist to increase intracellular cal-
used as an adjunct in a scenario of neonatal persistent pulmonary cium which allows muscle contraction.
hypertension in combination with other vasoactive agents. C Most vasoactive agents have a dose dependent effect on the
adrenergic receptor sub types.
Hydrocortisone C The effect on haemodynamic indices is dynamic and can vary
Hydrocortisone, the synthetic form of the hormone cortisol, is
depending upon the predominant receptor stimulated and the
strictly speaking not a vasoactive agent. However it is increas-
compensatory changes in the body.
ingly used as a second line agent in the treatment of refractory C Gestational maturity can influence expression of the adrenergic
hypotension alongside inotropes and vasopressors. It has been
receptors and their related intra cellular signalling pathways.
shown to decrease the breakdown of catecholamines; increase C Premature babies are relatively deficient in endogenous cortisol
calcium levels in myocardial cells and upregulate the adren-
which may impair the pressor response to catecholamines
ergic receptors. Neonates and especially pre-term neonates
10.1016/j.paed.2019.03.001
Self assessment questions

1. An infusion of noradrenaline is expected to produce all of the following physiological changes except
a) Increase in heart rate
b) Increase in systolic blood pressure
c) Marked increase in stroke volume
d) Increase in diastolic blood pressure
e) Increase in pulmonary vascular resistance
2. With regards to dopamine, the following statements are all false except
a) It acts via the a-1, a2, b-1, b2 and the specific dopaminergic receptors
b) Stimulation of the D1 receptors produces consistent vasodilatation in the renal vascular bed.
c) The effect on b-1 receptors is as potent as epinephrine
d) The endocrine effects of systemically administered dopamine could produce transient decrease in prolactin, growth hormone and
thyroxine levels.
e) Systemically administered dopamine crosses the blood brain barrier in significant amounts.
3. Which of the following is not true regarding use of dobutamine as an inotropic agent?
a) It could lower the systemic vascular resistance
b) It may be a useful inotrope for a “warm shock” scenario
c) The maximum affinity is for the b-1 adrenergic receptor
d) It has a positive lusitropic effect
e) It is a (synthetic) catecholamine
4. The following combination of adrenoreceptors, the target enzyme in the cell membrane and the intracellular messenger released are all correct
except
a) b-1 receptor, adenyl cyclase and cAMP
b) a-1 receptor, phospholipase C and IP-3
c) a-2 receptor, phospholipase C and IP-3
d) b-2 receptor, phospholipase C and cAMP
e) D1 receptor, adenyl cyclase and cAMP
5. All of the following are true about milrinone except that it

a) Is a pulmonary vasodilator
b) Is an inhibitor of PDE-5
c) Has good lusitropic action
d) Has positive inotropic action
e) Is a systemic vasodilator
Answers
1. Correct answer is c.
Noradrenaline has primarily a adrenergic effect. Therefore the blood pressure is expected to rise due to an increase in the systemic vascular
resistance (afterload). This will reflect in both systolic and diastolic readings. The pressure in the pulmonary vascular bed is also elevated. There is a
variable effect on heart rate; theoretically the heart rate could decrease due to a reflex rise in BP. However in most instances, a rise in heart rate
would be seen. There would be an effect on cardiac contractility mediated by b agonist action. However this is unlikely to improve stroke volume
significantly.
2. Correct answer is d.
In practical terms, Dopamine exerts its inotropic action predominantly via the a-1, a2 and to some extent via the peripheral dopaminergic (D-1)
receptors. It has virtually no effect on the b2 receptors and a very weak effect on the b-1 receptor compared to adrenaline.
Dopamine can cross the blood brain barrier though not in significant amounts. It must be remembered that elements of the hypothalamus and
anterior pituitary lie outside the barrier and hence potential endocrine effects occur. The most common are inhibition of Prolactin, suppression of
Growth hormone pulses and decrease in levels of TSH and thyroxine.
Vasodilatation of the renal blood vessels by stimulation of D1 receptors has been described in several studies including in adult animal models. Their
applicability to neonatal population is limited particularly because the maturation pattern of these receptors in regional vasculature is not well
known. In piglet models, selective stimulation of these receptors did not produce any appreciable vasodilatation. This is felt to be most likely due to
10.1016/j.paed.2019.03.001
incomplete linkage of post receptor events to the intra cellular G-protein. For this reason, it is probably not correct to assume that Dopamine
stimulates receptors in a dose dependent manner as is often described in textbooks at least in the neonatal population.
3. The correct answer is b.
Dobutamine will not be a suitable inotrope in a situation of warm shock. In this situation, the cardiac output is relatively preserved and there is a low
SVR. Using Dobutamine will either make no difference or lower the SVR further as it is primarily a b receptor agonist with maximum affinity for b-1
adrenergic receptor. It would need a very high dose of Dobutamine to stimulate the a-1 adrenergic receptor to increase the blood pressure. All
inotropic medications will increase the rate of relaxation by pumping Ca2þ back into the sarcoplasmic reticulum through special channels called
Phospholombans. These channels are also cAMP dependent and are phosphorylated by the activated PKA.
4. The correct answer is d.
b-2 receptors activate the membrane bound adenyl cyclise. The intracellular messenger is cAMP (Table 1).
5. The correct answer is b.
Milrinone has good inotropic and vasodilator properties for both peripheral and pulmonary vascular beds. It also has positive lusitropic effect. It
works by inhibiting the enzyme PDE-3 (phosphodiesterase 3) which breaks down cAMP. The PDE5 inhibitor is sildenafil.
10.1016/j.paed.2019.03.001

Mecanismos de Accion Inotropicos

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SYMPOSIUM: NEONATOLOGY

Mechanism of action of on the myocardial cells. An understanding of these adrenergic

inotropes in neonates action of various inotropic medications.

Dopamine Inodilator* <2 DA1 [/Y// Y// Y// [

Self assessment questions

5. All of the following are true about milrinone except that it

3. The correct answer is b.

4. The correct answer is d.

5. The correct answer is b.

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