This document discusses inotropes, which are drugs that increase the force of myocardial contraction. It defines inotropes and discusses their physiological effects and classification. Various endogenous and exogenous inotropic agents are described in detail, including their mechanisms of action, indications, dosages, pharmacokinetics and side effects. Sympathomimetic drugs like epinephrine, norepinephrine and dopamine are discussed as conventional positive inotropic agents.

1. INOTROPES AND NEWER AGENTS
Dr Kiran Rajagopal DA DNB.
Anaesthesiologist

2. OBJECTIVES
• Define the term Inotrope
• Discuss basic physiological principles
• Discuss drug classification and pharmacology
• Inotropes ,anaesthesiologists and intensivists
• Newer agents

3. INOTROPES
• Drugs that affect the force
of contraction of myocardial
muscle,independent of
changes in heart rate and
loading conditions
• Positive or negative
• Term “inotrope”
generally used to
describe positive effect

4. GOOD VS EVIL
• Intravenous positive inotropic drugs are indicated
when patients with acute systolic heart failure
exhibit signs or symptoms of end-organ dysfunction
due to hypoperfusion.
• The use of positive inotropic drugs has concerns
regarding increased morbidity and mortality.

5. • Problems include increased arrhythmia,Induced
myocardial ischemia, and in some cases,hypotension
• The largest database demonstrating increased
mortality with inotropes is the ADHERE (Acute
Decompensated Heart Failure National Registry),
where short-term inotropic therapy was associated
with increased in-hospital mortality.

6. WHAT DEFINES AN INOTROPIC
INTERVENTION
•Inotropic interventions comprise all means that
increase contractile force of the myocardium

7. PHYSIOLOGY
• can be explained at the level of the smallest force-
producing unit, the actin-myosin cross-bridge using a
simplified two-stage cross-bridge model
• During a cross-bridge cycle, the myosin head
attaches to actin, rotates to produce force, which is
maintained during the so-called on-time.
• Thereafter, the cross-bridge detaches again to enter
its non-force-producing state for the duration of the
off-time

8. EXCITATION CONTRACTION COUPLING
• contractile force depends on the number of
crossbridges attached per unit of time
• The cross-bridges are activated by calcium binding to
troponin C with the subsequent conformational
changes of tropomyosin and troponin I to facilitate
actomyosin interaction.
• The muscle relaxes when calcium is pumped back into the
sarcoplasmic reticulum (SR) by the sarcoplasmic reticulum
calcium pump (SERCA) and eliminated outside the cell by the
sodium–calcium exchanger (NCX)

10. Inotropy, i.e. the number of cross-bridges activated,
depends upon:
(i) amount of calcium available to bind to troponin C,
(ii) the calcium affinity of troponin C,
(iii) alterations at the level of the cross-bridge
(iv) the ability of attached cross-bridges to increase
calcium affinity of troponin C and activate
neighbouring crossbridges (i.e. co-operativity)

11. • It is assumed that one molecule of ATP is hydrolysed
during one individual cross-bridge cycle.
• Accordingly, the most efficient way to increase
contractile force would be to prolong cross-bridge
attachment time

12. EXCITATION CONTRACTION COUPLING

13. Endogenous inotropic mechanisms include
• length-dependent activation of cross-bridges,
• contraction frequency-dependent activation of
contractile force, and
• catecholamine-mediated inotropy.
The most important mechanism is length-dependent
activation of cross-bridges by increasing the length of the
individual sarcomere (Frank-Starling mechanism)
HOW DOES THE HEART REGULATE ITS INOTROPIC
STATE?

14. • length-dependent activation occurs without an
increase in calcium release
• Frequency-dependent up-regulation of contractile
force is calcium dependent.
With increasing heart rate, more calcium enters the
cardiomyocyte, is accumulated into the SR, and is
available for release during the next contraction

15. • Catecholamines increase contractile force by the β-
adrenoceptor-adenylyl cyclase system or by
stimulation of α-receptors
• Through protein kinase A, the β-adrenoceptor
system phosphorylates L-type calcium channels to
increase calcium influx and ryanodine receptors
(RyRs) to increase SR calcium release resulting in
activation of cross-bridges

16. • In addition, phosphorylation of phospholamban
accelerates SR accumulation of calcium
• relaxation by phosphorylation of troponin I due to
reduced calcium sensitivity of troponin C (positive
lusitropy)
• At the cross-bridge level, cyclic AMP (cAMP)-
mediated increase in contractility reduce the
attachment time of the individual crossbridge.
• Consequently, cAMP-mediated inotropy increases
the rate of force development and rate of relaxation
at the expense of a reduced economy of contraction

17. ALTERATIONS IN HEART FAILURE
In heart failure, excitation–contraction coupling is
significantly altered, largely by abnormal calcium
accumulation of the SR
• SR calcium uptake is abnormal due to SR calcium leak
through RyR
• decreased re-uptake of calcium secondary to
decreased SERCA protein levels
• increased calcium elimination outside the cell due to
increased levels of the NCX.

18. • In the failing myocardium frequency-dependent up-
regulation of SR calcium load is absent, which is
associated with a decline of contractile force at
higher heart rates

19. CONVENTIONAL INOTROPIC AGENTS
•Sympathetic amines
•Phosphodiesterase inhibitors
•Cardiac glycosides
•Calcium sensitizers

20. SYMPATHOMIMETICS
• Epinephrine
• Norepinephrine
• Dopamine
Naturally occuring •Dobutamine
•Dopexamine
•Phenylephrine
•Metaraminol
•Ephedrine
Synthetic

21. SYMPATHOMIMETICS
• Epinephrine
• Norepinephrine
• Dopamine
Naturally occuring •Dobutamine
•Dopexamine
Synthetic

22. ADRENORECEPTORS
•  receptors
– 1
• Located in vascular smooth muscle
• Mediate vasoconstriction
Alpha1 receptor effects are mediated primarily by the
coupling protein Gq. When Gq is activated, the alpha
moiety of this protein activates the enzyme phospholipase
C, resulting in the release of inositol-1,4,5-trisphosphate
(IP3) and diacylglycerol (DAG) from membrane lipids.

23. Calcium is released from stores in
smooth muscle cells by IP3, and
protein kinase is activated by DAG.
Direct gating of calcium channels
may also play a role in increasing
intracellular calcium concentration

24. α2 RECEPTOR
•2
--Located throughout the CNS, platelets
–Mediate sedation, analgesia & platelet
aggregation
Alpha2 receptor activation results in inhibition of adenylyl
cyclase via the coupling protein Gi.

25. β ADRENOCEPTOR
•  receptors
– 1
• Located in the heart
• Mediate increased contractility & HR
– ---3
In fat cells.mediate lipolysis

26. – 2
• Located mainly in the smooth muscle of bronchi and
blood vessals Mediate bronchodilatation &
vasodilatation
β2-receptor population in human cardiac tissue accounts
for 15% of β receptors in the ventricles and 30% to 40% in the
atria
β2 Receptors may help compensate for disease by
maintaining response to catecholamine stimulation when β1
receptors are down-regulated during chronic catecholamine
stimulation and in CHF
• In addition to positive inotropic effects, β2 receptors in the
human atria participate in regulation of the heart rate.

27. β ADRENOCEPTOR
Beta receptors (β1, β2, and β3)
stimulate adenylyl cyclase via the
coupling protein Gs, which leads
to an increase in cyclic adenosine
monophosphate (cAMP)
concentration in the cell

28. DOPAMINERGIC RECEPTORS
DA1
• Renal and splanchinic,mesentric ,coronary blood
vessals
• Mediate vasodilatation
• Vasodilatory effects maximum in renal
Dopamine DA 1 receptors are post synaptic ,activate
adenylyl cyclase via Gs and increase cAMP in
neurons and vascular smooth muscle

29. DA 2 RECEPTORS
• Found in presynaptic receptors in nerve terminals
• These receptors reduce the synthesis of cAMP via Gi
and inhibit release of norepinephrine
• central DA2 receptors may mediate nausea and
vomiting

30. ADRENORECEPTORS

31. EPINEPHRINE
G - Protein Adenyl cyclase
ATP cAMP
Increased heart
muscle
contractility
Adrenaline

32. • Prototype drug among sympathomimetics
• Endogenous catecholamine produced in the adrenal
medulla.
• α 1 + α 2, β 1+ β 2 agonism . Weak β 3 action
• Natural function includes
• Regulation of
Myocardial contractility
Heart rate
Vascular& bronchial muscle tone
Glandular secretion
Glycogenolysis & lipolysis

33. INDICATIONS
• Cardiac arrest efficacy due to increased
coronary perfusion pressure
• Anaphylaxis
• Cardiogenic shock
• Bronchospasm
• Low output after CPB
• Hypotension with spinal/epidural can be
treated with 1-4µg/min
• Added to local anaesthetics to prolong action

34. DOSAGE
• Shock/hypotension
0.03-0.2 µg/kg bolus iv
0.03-0.015 µg/kg/min
0.05-0.5 µg/kg/min in children
• Cardiac arrest
0.5-1 mg iv bolus
0.01mg/kg iv in Pediatrics
• Anaphylaxis/bronchospasm
10 µg/kg sc(max 400 µg)/300µg every20 min. 3 dose
• Inhalation max daily dose -10-20 MDI

35. ABSORPTION
• Most potent activator of alpha adrenergic receptor
2-10 times > norepinephrine
100 times > isoproterenol
• Orally not effective as it is rapidly metabolized in gi
mucosa and liver.
• Slower after im and sc
• Effectively absorbed from tracheal mucosa

36. CARDIOVASCULAR EFFECTS
• Results from stimulation of α and β receptors
1-2µg/min iv stimulate β2 receptors
2-10 µg /mt stimulate β1 receptors
10-20 µg /mt stimulate both α+β receptors
• Positive inotrope ,chronotrope
• Increases heart rate by accelerating the rate of phase 4
depolarization
• Heart rate initially increases and later decrease due to vagal
reflex
• Increase cardiac out put and MVO2
• Improves coronary blood flow

38. CVS
as iv bolus
• increase SVR ,systolic bloodpressure
• minimal increase in diastolic blood pressure increases
coronary blood flow in arrest
Net effect is increase in pulse pressure and minimal change in
MAP.
as iv infusion
• SVR and DBP decrease( β2)

39. RESPIRATORY SYSTEM
• Respiratory stimulant
• Increase both tidal volume and respiratory
rate
• Potent bronchodilator
• Decrease the release of antigen induced
bronchospastic subastances from mast cells
• Increases the viscosity of bronchial secretions

40. CNS
• Limited penetration due to poor lipid solubility
• No effect on cerebral blood flow

41. AUTONOMIC SYSTEM
• Decreases the intestinal tone and secretions
• Splanchnic flow is increased

42. GIT
• Decrease renal blood flow by 40%
• GFR is unaltered
• Bladder tone decreased spinchter tone
increased

43. METABOLIC
• Decrease insulin secretion
• Increase glucagon and glycogenolysis
• Elevated blood sugar
• Initial increae in k+ de to release from liver f/b
decrease due to skeletol muscle uptake

44. METABOLISM
• COMT in liver to meta adrenaline ,nor meta
adrenaline
• MAO within adrenergic neurons
• EXCRETION in urine as inactive metabolites

45. ADVANTAGES
• Direct acting.not dependent on the release of
nor epinephrine
• Potent α+β gives maximum effects
• Powerful inotrope with variable α effect
• If BP rises tachycardia diminishes due to vagal
effect
• bronchodilator

46. DIASDVANTAGES
• Initial tachycardia ,arrythmias
• Organ ischemia esp kidney.U/O has to be monitored
• Pumonary vasoconstriction may occur  pHTN and
RV failure..a vasodilator may be added
• Risk of myocardial ischemia
• Extravasation from a peripheral line cause
necrosis.so central line prefered
• Elevation of plasma glucose

47. SPECIAL POINTS
• Dose of adrenaline should be limited to
1micrograms/kg/30 min in presence of halothane
3 micrograms/kg/30 min in presence of isoflurane to prevent
ventricular arrythmias
• . In adults, the epinephrine dose required to produce three
premature ventricular contractions in 50% of patients (ED50)
at 1.25 minimum alveolar concentration (MAC) was
2.1 μg/kg for halothane, 6.7 μg/kg for isoflurane, and 10.9
μg/kg for enflurane.
• Children tolerate larger doses than do adults
• Hypocapnia potentiates this drug interaction.

48. SPECIAL POINTS
• Halothane-epinephrine–induced arrhythmias are
attenuated by pretreatment with sodium thiopental
• The doses of epinephrine required to produce
ventricular arrhythmias during desflurane or
sevoflurane anesthesia are similar to, but
significantly less than, those observed during
administration of isoflurane and halothane.

49. SPECIAL POINTS
• Preexisting α1 blockade can cause the paradoxical
phenomenon of epinephrine reversal (a hypotensive
and tachycardic response) as the β2-vasodilating
effects are unmasked
• Patients receiving nonselective β-blockers may
demonstrate unopposed α responses.
Cardioselective (β1) blockade does not have this
• Infiltration of ADR containing solutions should be
avoided in regions supplied by end arteries

50. NOR EPINEPHRINE
• Endogenous neurotransmitter in post ganglionic
sympathetic nerve endings
• α1+α2+β1 limited β2
• Predominant at α receptors

51. DOSAGE
• short half-life of 2.5 minutes, continuous infusion is
preferred
• starting infusion doses
0.015-0.030 µg/kg/min
usual range
0.01-0.1 µg/kg/min

52. CVS
• Increase in SVR decreases
venous return to heart.
• decreased venous return
combined with baroreceptor
mediated reflex decreases in
heart rate due to marked
increase in MAP tend to
decrease CO despite β1
action of NE.

53. CVS
• Increase PVR  increase SBP ,DBP
• CO unchanged or decreases
• Bradycardia
• Increase coronary flow by coronary
vasodilatation

54. RESPIRATORY
• Slight increase in minute volume accompanied
by a degree of bronchodilation

55. CNS
• Decreases cerebral blood flow and oxygen
consumption
• Mydriasis

56. AUTONOMIC
• Decreased hepatic and splanchnic blood flow
• Decreased renal blood flow
• GFR is maintained
• Tone of bladder neck increased
GIT

57. METABOLIC
• Decrease insulin secretion  hyperglycemia

58. METABOLISM
• oxidative deamination by mitochondrial
MAO
• Methylation by cytoplasmic COMT
• EXCRETION by kidneys

59. INDICATIONS
• Refractory hypotension
• Sepsis
• for treating RV failure associated with cardiac
surgery.
simultaneous infusion of NE into left atrium by a left
atrial catheter plus inhaled NO/iv NTG.
NE first reaches systemic circulation,metabolized
peripherally before it reaches lung.if infused by a
central vein it would have incresed PVR

60. ADVANTAGES
• Equipotent to adrenaline at β1 receptors
• Redistributes blood flow to brain and heart as all
other vessals will be constricted
• Reduced organ perfusion
• Pulmonary vasoconstriction
• Arrhythmias
• Skin necrosis with extravasation
DISADVANTAGES

61. SPECIAL POINTS
• Mimimize the duration of use
• Monitor U/O , lactic acidosis
• Dose reduction with halothane
• Hypertensive crisis if co administered with
MAO Is or TCA
• Incompatabile with barbiturates and sodium
bicarbonate

62. DOPAMINE
• endogenous central neurotransmitter
• immediate precursor to norepinephrine in the
catecholamine synthetic pathway
Actions
• Direct: α1 , β1 ,DA1 agonistic action
• Indirect: induces release of stored neuronal
norepinephrine..
•

63. • At low doses (<3 mcg/kg/min)---
dopamine activates dopaminergic (DA1) receptors
vasodilation in various vascular beds, including the
coronary and renal arteries and mesenteric arteries.
• (3 to 10 mcg/kg/min)- activate β-adrenergic
receptors that cause increased inotropy and heart
rate and also promote release and inhibit reuptake
of norepinephrine in presynaptic sympathetic nerve
terminals
• (10 to 20 mcg/kg/min), dopamine acts primarily as
an α-adrenergic agonist resulting in peripheral
vasoconstriction

65. USES
• Increase cardiac output in patients with low systemic
BP ,increased atrial filling pressure,&decreased urine
output eg;CPB
• Increase myocardial contractility,renal blood flow, ,
excretion of Na,urine output
• Diuresis,natriuresis,independent of effect on renal
blood flow

66. RENAL DOSE OF DOPAMINE
• The benefits of “renal doses” of dopamine have
remained controversial. Estimated glomerular
filtration rate does not improve with use of low-dose
dopamine infusions, and there is no apparent renal
protective effect
• The ROSE AHF (Renal Optimization Strategies
Evaluation In Acute Heart Failure) trial recently found
that low-dose dopamine was not better than
placebo when added to standard care.

67. RENAL DOSE OF DOPAMINE
• No randomized control trials have demonstrated a
decrease in incidence of acute kidney injury when
dopamine is administered to patients considered to
be at risk for developing AKI.
• In patients receiving dopamine before renal insult
,there is clear diuretic effect but no evidence that the
creatinine clearance or need for HD is altered(Cottee
and Saul,1996)

68. CVS EFFECTS
• Increase cardiac out put (β1)
• Low doses may decrease SBP AND DBP(β2)
• increase in HR ,systolic BP,systemic vascular
resistance
• Positive inotropic effect partially due to release of
stored norepinephrine.
• Cardiac dysrrythmias may occur due to endogenous
norepinephrine release

69. RESP.SYSTEM
• Impairs the ventilatory response to arterial
hypoxemia.
• Depression of ventillation due to inhibitory action at
carotid bodies,so watch ABG

70. CNS
• Central neurotransmitter
• Exogenous dopamine doesnot cross BBB
except in its levo form
• Causes nausea due to direct action on
CTZ,which lies outside BBB

71. AUTONOMIC
• Vasodilatation of splanchnic circulation due to
action on dopaminergic receptors
• Decreases gastroduodenal motility in critically
ill

72. GIT
• Decrease hepatic blood flow with epidural is
reversed by dopamine 5mcg /kg/mt
• Increase splanchnic oxygen requirement (in septic
patients)
• Reduces the release of aldosterone

73. METABOLISM
• MAO ,COMT
• 25% of administered dopamine is converted
to noradrenaline within adrenergic nerve
terminals
• Renal excretion

74. ADVANTAGES
• Increased renal perfsion and urine output
• Blood flow shifts from skeletal muscles to
splanchnic circulation
• Easy to titrate

75. DISADVANTAGES
• Arrythmias
• Max inotropic effect less than epinephrine
• Renal vasodilator effects overrided by alpha
effects at high doses

76. SPECIAL POINTS
• Correction of hypovolemia as with all
inotropes
• Reduced dose in patients on MAOIs
• Inactivated by alkaline solutions

77. DOBUTAMINE
• Synthetic catecholamine
Actions
• Direct β1 agonist,limited α1 & β2 action.
• Positive inotropy via β1
.as dobutamine is metaboloised metabolite o methyl
dobutamine is α1 antagonist
any α1 agonist action of the drug diminishes over time.

78. CVS
• Increase contractility
• Sanode automaticity increasedchronotropic
• On blood vessals it cause minimal
vasodilation via β2
• Coronary blood flow may increase
• LVEDP decreases

79. • HR  increased
• Contractility increased
• CO  increased
• BP  increased or no change
• LVEDP  decreased
• LAP  decreased
• SVR decreased
• PVR decreased

80. CNS
• Stimulation at higher doses
• Urine output increases secondary to increase
in cardiac otput
GIT

81. METABOLIC
• Decreases blood glucose

82. METABOLISM
by redistribution
Rapid metabolism by COMT
Glucuronide conjugation in liver

83. INDICATION
• Low CO states especially with increase in
SVR ,PVR
• Cardiac stress testing

84. DOSAGE
2-20 µg/kg/min
• Diuresis function improves at 1-2 µg/kg/min.
• Patients on chronic infusions show tachyphylaxis
and need higher dose.
• Little benefit for doses above 10 µg/kg/min.other
therapies should be added or substituted when
doses approaching 15 µg/kg/min needed

85. ADVANTAGES
• At low doses,less tachycardia compared to
dopamine
• Increased CO with lesser increase in MVO2 and
higher coronary blood flow compared to dopamine
• After load reduction may improve RV and LV systolic
function.
• Renal blood flow may increase due to β2

86. DISADVANTAGES
• Tachycardia and arrhythmia are dose related
• Hypotension may occur,if reduction in SVR is not fully
offset by increase in CO.
• Tachyphylaxis > 72 hr use
• Should not be used in patients with cardiac outflow
obstruction

88. DOPEXAMINE
• Synthetic analogue of dobutamine.
• Activates β2 and dopaminergic receptors.
• Mild inotropic action via β2 and
• Potentiation of endogenous norepinephrine due to
blockade of reuptake.So indirect β1 action.
• In CHF there is down regulation of β1 but β2 is
preserved.Here dopexamine has a theoretical
advantage

89. ISOPROTERENOL
• Synthetic catecholamine
Actions
• β1+β2 agonist with no α action
• most potent activator of β1+β2

91. DOSAGE
• 20-500ng/kg/min
• 1-5 µg/min

92. DISADVANTAGES
• Not a pressor so hypotension while CO
increases
• Pro arrhythmia
• Tachycardia limits diastolic filing time
• Dilates all vascular bed –shifts blood away
from critical tissues
• Coronary steal

93. INDICATIONS
• Brady cardia unresponsive to atropine
• Low CO esp when tachycardia is not
detrimental
• Pulmonary hypertension or right heart failure
• Temporary therapy in AV block

95. ADRENOCEPTOR DYNAMICS
• Desensitisation / down-regulation
– Chronic heart failure
– Prolonged use of inotrope / vasopressor
– Sespis / acidosis

96. PHOSPHODIESTERASE INHIBITORS
• Phosphodiesterase is responsible for the hydrolysis
of cyclic 3,5 adenosine monophosphate (cAMP) and
3,5 cyclic guanosine monophosphate (cGMP)
• Both cAMP, and to a lesser extent cGMP, have an
important role in the regulation of inotropic
mechanisms in the human myocardium

97. • The inotropic effect is mediated through release of
calcium from the sarcoplasmic reticulum and other
sub-sarcolemmal sites, and the interaction between
released calcium ions and contractile proteins.
• cAMP causes an increase in protein kinase A (PKA)
activity which, in turn, promotes opening of the cell
membrane L-type calcium channel resulting in
calcium entry into the cell

98. • Calcium entry provides the stimulus for calcium
release via the ryanodine receptor in the
sarcoplasmic reticulum. This process has been called
calcium-induced calcium release (CICR).
• PKA may also increase contraction by promoting
calcium uptake into the sarcoplasmic reticulum as a
result of phosphorylation of the regulatory protein
phospholamban, and the Calcium binding protein
calmodulin.

99. Concentrations of cAMP can be increased by two
mechanisms
First, the concentration may be increased by active
conversion of adenosine triphosphate (ATP) to cAMP
via the enzyme adenylyl cyclase.
Following G protein coupled receptor activation,
stimulatory G-proteins activate adenyl cyclase
leading to an increase in myocardial 3,5 cAMP.eg
catecholamines via β receptors

100. • The breakdown of cAMP is under the control of the
enzyme phosphodiesterase, which catalyses the
hydrolysis of phosphodiester bonds in cAMP leading
to the production of a monophosphate and a free
hydroxyl group
• Currently, drugs which are available in clinical
practice for improving cardiac performance are
inhibitors of either phosphodiesterase III or IV.
These compounds are the biguanides amrinone and
milrinone, and the imidazolone derivative
enoximone.

102. MILRINONE
• Milrinone largely replaced amrinone in the 1980s.
Amrinone is no longer widely available worldwide
Actions
• Inotropic action: inhibits phosphodiesterase 111 in
heart and blood vessals.increased cAMP causes
positive inotropy,lusitropy,chronotropy,
dromotropy,and automaticity
• Vasodilator: in vascular smooth muscles increased
cAMP causes vasodilation

103. • Elimination half life is 2.5 hrs.Physiologic half life = 6
hrs.

104. DOSE
• frequently used without bolus to avoid rapid initial
effects
• loading dose:50µg/kg over 1-10 min f/b 0.375-0.75
µg/kg/min
• infusion can be started from 0.01µg/kg/min and
titrated to a maximum 0.75µg/kg/min
• oral form for chronic therapy
• Excretion: Renal . Dose reduction in renal
dysfunction which is common in CCF

105. ADVANTAGES
• When used as a single agent ,it has favourable effects
on myocardial oxygen supply-balance,due to
reduction of preload,afterload & minimal
tachycardia.
• No tachyphylaxis
• Retains efficacy in CCF where β1 receptor coupling is
impaired.

106. • When compared to dobutamine at equipotent
doses,milrinone produce greater decrease in
PVR,greater augmentation of RV ejection
fraction,less tachycardia ,fewer arrhythmias and
lower MVO2
• Synergistic action with those which increase cAMP
production(catecholamines)

107. DISADVANTAGES
• Hypotension with bolus doses.
• Arrhythmias
• When milrinone is discontinued after several days,its
physiologic half life may exceed 12-18 hrs.so monitor
the fluid balance and perfusion for atleast 48hrs after
stopping.

108. INDICATIONS
• Low CO syndrome, especially with increased LVEDP,
pulmonary hypertension ,RV failure
• To supplement /potentiate β agonists.
• As a bridge to cardiac transplantation.

109. INAMRINONE
• Bipyridine derivative
• Same pharmacology as milrinone
• Disadvantages
Prolonged use ( > 24hrs) causes thrombocytopenia
Produces photosensitivity
Less potent than milrinone
• Loading Dose: 0.75-1.5 mg/kg
• Infusion Dose: 5-20 µg/kg/min

110. ENOXIMONE
• A substituted imidazolone derivative .It acts by
competitive inhibition of the sub-type PDE IV and
possibly PDE III.
loading infusion of 0.5–1.0 mg /kg over 10–30 min,
followed by a maintenance infusion of 5–20
mcg /kg/ min.

111. CLINICAL PEARLS
• Before staring a PDEI, hypovolemia must be
corrected to prevent a further significant fall in blood
pressure.. Volume loading should be undertaken
with care in patients recently weaned from
cardiopulmonary bypass since left ventricular
compliance is usually abnormal, and rapid
transfusion resulting in excessive left ventricular
volume may cause a precipitate rise in left ventricular
pressure, subendocardial compression, and
myocardial ischaemia.

112. CLINICAL PEARLS
• Vasopressors may be needed and should be
prepared for use at the same time as PDEI
administration. A norepinephrine infusion is
commonly used; vasopressin has been described as
an alternative. For those patients already on a
vasopressor, an increase in dosage requirements
should be expected.
•

113. COMPARISON WITH CATECHOLAMINES
• Catecholamines show a greater increase in heart rate
and MAP, whereas the PDEI show a greater reduction
in PCWP ,greater increase in stroke volume and
hypotension .
• In clinical practice, PDEI and catecholamines are
frequently combined in order to maximize the
inotropic effect, while at the same time limiting the
vasodilator effects of PDI

114. LEVOSIMENDAN
• Levosimendan is a pyridazinone-dinitrile derivative
Calcium sensitizer that increases the affinity of
troponin C (TnC) for calcium.
Actions
• binds to the N-terminal domain of cardiac TnC in a
Ca2+ concentration-dependent manner, stabilizing
the TnC-Ca 2+ complex
• thereby accelerates the actin-myosin crossbridge
formation rate.

115. • Its effects are maximum during systole when ca
concentration is maximum and least during diastole
when calcium concentration is minimum
• Activates ATP-sensitive K+ channels in the vascular
smooth muscle sarcolemma, leading to cell
hyperpolarization and vasodilation and reducing
peripheral vascular resistance.
• Levosimendan relaxes both arterial and venous
smooth muscle cells leading to decrease in preload
and after load.

116. • It may protect the myocardium from ischemia as it dilates the
coronary arteries and improves O2 supply.
• It also opens myocardial mitochondrial ATPsensitive K+
channels, thereby protecting cardiomyocytes against
apoptosis, ischemia-reperfusion injury and oxidative stress
• Levosimendan selectively inhibits phosphodiesterase type 3,
thus increasing intracellular cyclic adenosine monophosphate
(cAMP) and ca, but these effects are minor at usual doses

118. ADVANTAGES
• Doesnot increase intracellular calcium
• Doesnot work via cAMP so no interaction with
β agonists or PDIs
• Renal blood flow and glomerular filtration rate are
improved both acutely and chronically by
levosimendan more than by dobutamine.
• Levosimendan is renoprotective through activation
of ATP-sensitive K + and potent vasodilation, which
leads to increased renal perfusion

119. DISADVANTAGES
• long-term effects on cardiac remodeling and
cardiovascular mortality remain largely unknown.
• Hypokalemia and Hypotension. The mechanism
underlying hypokalemia is still unknown.
Hypotension due to vasodilation and increased
diuresis is more pronounced when a bolus is
administered, and the new ESC guidelines on acute
and chronic HF do not recommend bolus
administration

120. LIDO /SURVIVE TRIAL
• In the Levosimendan Infusion versus dobutamine
(LIDO) trial, levosimendan led to greater
improvement in hemodynamics and in secondary
and post-hoc analyses it was associated with a lower
risk of death at 31 and 180 days
• In the SURVIVE trial no difference between
levosimendan and dobutamine groups was found for
survival during longterm follow-up despite evidence
for an early reduction in plasma BNP levels with
levosimendan

121. DOSE
• 8-24 µg/kg/min iv
Effects of levosimendan in cardiac surgery
Most studies on levosimendan in cardiac surgery
show a cardioprotective effect, with a decrease in
the incidence of low CO syndromes and reduced
cardiac troponin release and may reduce
postoperative mortality

122. DIGOXIN
NaK
ATPase
Na/Ca
X-ch
K
N
aN
a
Ca
Inhibits (slows)
NA/K ATPase
Reduced Na
gradient slows Ca
removal
K
Na
A cardiac glycoside derived from foxglove plant
(digitalis purpura)

123. ACTIONS
• Positive inotropism --> Inhibit Na K ATPase=>increase Na
conc=>increase--- increased intracellular ca---increased ca
release from ER =>positive inotropism
• Decrease automaticity by decreasing transmembrane
potential
• Decrease the sympathetic activation of heart---due to
sensitization of high pressure baroreceptors which reduces
sympathetic outflow

124. It remains uncertain whether the sympatholytic or
positive inotropic effects are responsible for relief of
symptoms in heart failure
• Contractility ---increased
• Av conduction—decreased
• Ventricular automaticity—inc rate of phase 4
depolarisation
• Refractory period—decreasd in atria and ventricles
,increased in av node

125. ADVANTAGES
• Supraventricular antiarrythmic actions
• Reduced ventricular rate in atrial fibrillation/flutter.
• Improves symptoms in CHF and reduce hospital stay

126. DISADVANTAGES
• Low therapeutic index
• Increased mvo2 and svr occur in patients withoutCHF
• Long half life
• Can cause any arrhythmia

127. INDICATIONS
• CHF
• Supraventricular arrhythmias

128. DOSAGE
loading dose iv and im 0.25-0.5 mg increments (total
of 1 to 1.25mg or 10-15 ug/kg)
maintenance dose,0.125 to 0.250 mg/day

129. FACTORS POTENTIATING TOXICITY
• Hypokalemia
• Hypomagnesemia
• Hypercalcemia
• Alkalosis
• Acidosis
• Renal Insufficiency
• Quinidine Therapy
• Hypothyroidism

130. CAUTION
• Administering calcium salts to digitalized
patients.Malignant ventricular arrythmias may
occur,even if the patient is off digoxin for more than
24 hrs

131. TREATMENT OF DIGOXIN TOXICITY
• Increase serum potassium to upper limit of normal
• Treat ventricular /atrial arrhythmias
• Beta blockers are effective for digoxin induced
arrhythmias, ventricular pacing if AV block develops
• Beware of cardioversion—VF refractory to
countershock may be induced.use low energy
synchronized cardioversion and slowely increase the
energy levels
•

132. SERUM DIGOXIN LEVELS
Digoxin levels >1.2 ng/ml may be harmful
levels in the range of 0.5 to 0.9 ng/ml may be
optimal.
In general, digoxin levels below 1.0 ng/ml are safer
and may even be more effective

133. DIG TRIAL
Digoxin was once widely used to treat patients with
systolic heart failure. However, in 1997, results from
the DIG (Digitalis Investigation Group) study
indicated that digoxin had a neutral effect on
mortality, although reductions were seen in overall
rates of hospitalization and heart failure progression

134. THE NEED FOR INOTROPIC DRUGS IN ANESTHESIOLOGY
AND INTENSIVE CARE
Perioperative heart failure is a major clinical problem,
and perioperative cardiac morbidity is the leading
cause of death following surgery and anesthesia. The
number of Patients with extensive cardiovascular
disease presenting for both cardiac and Noncardiac
surgery has dramatically grown. An increasing
number of sicker and older patients with ventricular
dysfunction are now undergoing Cardiac surgery .

135. INOTROPIC DRUGS IN NONCARDIAC
SURGERY
• atrioventricular or sinoatrial blocks- use of
chronotropic drugs (isoproterenol), when pacing not
available or feasible
• urgency/emergency surgery, or elective major
surgery (hepatic, vascular), in patients with
hemodynamic derangements determining an insult
to a heart with an unknown reduced coronary
reserve, or with preexisting valvular disease

136. • elective or urgent major vascular surgery (thoracic or
abdominal aortic surgery) in patients with known
chronic heart failure, in which aortic clamping
procedures may pose an excessive afterload to the
failing heart.
• myocardial dysfunction in septic shock patients
• perioperative pulmonary thromboembolic
complications

137. ANAESTHETIC GOAL
For Patients with reduced/depressed systolic heart
function anesthetic goals are
• monitoring of cardiac function
• avoid sympathetic responses
• optimisation of preload, afterload,
• monitoring and maintaining heart rate and rhythm,
• inotropic drugs
• Postoperative management will also require
monitoring in an intensive care unit.
•

138. INOTROPIC DRUGS IN CARDIAC SURGERY
POSTOPERATIVE MYOCARDIAL DYSFUNCTION
• significant impairment in ventricular performance
commonly occurs after cardiac surgery.
• Both right and left ventricular ejection fractions (EF)
may diminish to 35 to 75 percent of their pre-CPB
levels, along with decreased cardiac index

139. • Postoperative ventricular dysfunction following
cardiac surgery is similar to myocardial stunning:
a myocardial dysfunction following a brief ischemic
event, unassociated with morphologic injury
(necrosis), and thus reversible after a period of
convalescence.
• The heart undergoing this type of surgery is
subjected to ischemic and reperfusion injury
resulting in various degrees of cytosolic calcium
accumulation, free oxygen radicals generation, and
myocytes and myocardial edema

140. • postsurgical stunning may involve both right and left
ventricles
• Weaning from CPB represents a critical phase in
which the eventual ventricular dysfunction may fully
appear, and inotropic drugs support may be required
• A biphasic pattern of myocardial depression occurs -
recovery from the initial compromise after separating
from CPB is followed by a second period of low
myocardial performance which reaches its nadir 3 to
6 hours after separation from CPB.

141. • The time to full recovery is usually 8 to 24 hours
• return to baseline function is often delayed in
patients with worse preoperative ventricular function
• Postoperative ventricular dysfunction affects systolic
and Diastolic function

142. PREDICTORS OF INOTROPIC NEED

143. Four main factors must anyway be taken into account
when considering the use of an inotrope
Prolonged, unappropriate or excessive treatment with inotropic medication
may augment perioperative ischemic injury and adversely affect
myocardial function and weaning from CPB.

144. WHEN TO USE AN INOTROPE

145. CHOICE OF THE INOTROPE
The ideal positive inotropic agent should
• enhance contractility (both right and left ventricular)
-without any significant increase in heart rate,
preaload, afterload, and myocardial oxygen
consumption.
• enhance diastolic function
-maintain diastolic coronary perfusion pressure and
thus an adequate myocardial blood flow
• have rapid onset, short half life and titrability

146. INDICATIONS IN SPECIFIC SETTINGS

147. CABG
• During CABG surgery, inotropes may be needed in
case of preexisting ventricular dysfunction or
unsuccessful revascularization if intra aortic balloon
pump (IABP) alone is not enough.
• In emergency revascularization of acute myocardial
infarction, dobutamine and PDI may be the most
beneficial inotropes, as they may better affect the
oxygen delivery/consumption balance

148. CABG
• If inotropic support is anticipated to be
necessary for termination of CPB, it should be
started five minutes before termination of
CPB.
• Starting the infusion of inotropic agents too soon
increases myocardial oxygen consumption while the
heart is being reperfused on CPB. This compromises
the replenishmentof energy stores and serves no
useful purpose.

149. CHRONIC HEART FAILURE
myocardium presents unique features due to chronic
catecholamine hyperstimulation:
• β1 receptor downregulation with reduction in receptor
density (proportional to the severity of systolic dysfunction),
• a shift in proportion of β1 versus β2 receptors (from the
• normal 80:20 to 60:40)
• low intracellular levels of c AMP
• acute changes in β-adrenergic receptors function can also
occur during cardiac surgery .

150. • Catecholamine stimulation alone is submaximal, reaching a
plateau effect on adenylyl cyclase and response to PDI alone
could also be blunted (by a reduced intracellular AMPc pool)
• Combination therapy (i.e. a PDI administered along with a β-
adrenergic inotrope, dobutamine or epinephrine) may
therefore be the treatment of choice .It minimizes side
effects of the single drug
• As depletion of myocardial stores of norepinephrine also
occurs in chronic dysfunctional myocardium, indirect β-
adrenergic agents (dopamine, dopexamine) would be poorly
effective

151. • Choice of an inotropic agent, must take the problem
of diastolic dysfunction into account.
• When marked ventricular hypertrophy is present
(severe aortic stenosis, hypertrophic obstructive
cardiomyopathy) the use of β-adrenergic agents may
worsen diastolic function with decrease in cardiac
output.
• No inotropes at all (or inotropes with a better effect
on ventricular relaxation, such as PDI ) should be
used.
• Maintenance of adequate preload and perfusion
pressures is also essential.

152. VALVULAR SURGERY
• Aortic stenosis- the afterload has been markedly
reduced, but left ventricular hypertrophy and
diastolic dysfunction remain , inotropic support is
rarely needed
• Chronic aortic insufficiency-- ventricular dilation and
dysfunction persist, requiring adequate preload and
inotropes.

153. • Mitral stenosis, chronic mitral regurgitation,
treatment with inotropes should be warranted
• Acute aortic and mitral regurgitation both pose a
great risk of severe ventricular dysfunction after
surgical correction, requiring inotropic support, even
preoperatively.
• Tricuspid regurgitation is almost always associated
with right ventricular dysfunction needing inotropic
support.

154. HEART TRANSPLANTATION
Transplanted heart has normal contractile function
but it lacks the normal autonomic control of
chronotropy and inotropy because of the
interruption of autonomic innervation
Routine inotropic support after ortothopic cardiac
transplantation includes
isoproterenol (to increase automaticity, inotropism
and pulmonary vasodilation) and
dopamine (to add further support with preservation
of systemic perfusion pressures)

155. • The most frequent problems derive from sudden
exposure of the unconditioned donor right ventricle
to excessive afterload stress imposed by elevated
pulmonary vascular resistance, with right heart
failure ; prolonged graft ischemia or
inadequate myocardial protection(excessive pre
harvesting cathecolamine exposure)
Both these situations require aggressive inotropic
support and management of right ventricular failure

156. LUNG TRANSPLANTATION
Several critical stages pose the usually hypertrophied
right ventricle at high risk of failure
• induction of anesthesia (hypotension),
• commencement of positive-pressure ventilation (increase in
RV afterload, hyperinflation with circulatory collapse),
• institution of one lung ventilation (severe hypoxia),
• clamping of the pulmonary artery (sudden increase in
afterload),
• unclamping of the pulmonary artery (profound hypotension)

157. • Norepinephrine, in addition to low dose epinephrine
(or dobutamine) and cautious fluid loading, is the
management

158. INOTROPIC DRUGS IN THE INTENSIVE
CARE SETTING

159. Cardiogenic Shock Complicating Acute
Myocardial Infarction
• Inotropes increase myocardial oxygen consumption
and can cause ventricular arrhythmias, contraction
band necrosis, and infarct expansion
• Critical hypotension itself compromises myocardial
perfusion, leading to elevated left ventricular (LV)
filling pressures, increased myocardial oxygen
requirements, and further reduction in the coronary
perfusion gradient

160. • hemodynamic benefits usually outweigh specific
risks of inotropic therapy when used as a bridge to
more definitive treatment measures.
• Inotropic agents may improve mitochondrial function
in noninfarcted myocardium that has become
deranged during AMI complicated by shock.
• However, free cytosolic Calcium, which is significantly
elevated in post ischemic cardiac myocytes, is further
increased with the administration of inotropes, which leads to
activation of proteolytic enzymes, proapoptotic signal
cascades, mitochondrial damage, and eventual membrane
disruption and necrosis

161. • lowest possible doses of inotropic agents should be
used to adequately support vital tissue perfusion
while limiting adverse consequences.
• The American College of Cardiology/American Heart
Association guidelines for management of
hypotension complicating AMI suggest
dobutamine as a first-line agent if systolic blood
pressure ranges between 70 and 100 mm Hg in the
absence of signs and symptoms of shock.
Dopamine in patients who have the same systolic
blood pressure in the presence of symptoms of
shock.

162. • When response to a medium dose of dopamine or
dopamine/ dobutamine in combination is
inadequate, or the patient’s presenting systolic blood
pressure is <70 mm Hg, the use of norepinephrine
has been recommended

163. HEART FAILURE
• The use of positive inotropes in chronic HF has been
consistently demonstrated to increase mortality
• A proposed central mechanism involves a chronic
increase in intracellular Ca2, which contributes to
altered gene expression and apoptosis and an
increased likelihood of malignant ventricular
arrhythmias.

164. • As a result, the current American College of
Cardiology/ American Heart Association guidelines
for diagnosis and management of chronic HF in the
adult do not recommend the routine use of
intravenous inotropic agents for patients with
refractory end-stage HF but do state that they may
be considered for palliation of symptoms in these
patients

165. • Most commonly recommended initial inotropic
therapies for refractory HF are--
Dobutamine, dopamine, and milrinone
Used to improve CO and enhance diuresis by
improving renal blood flow and decreasing SVR
without exacerbating systemic hypotension
• β-adrenergic receptor responses are often blunted in
the failing human heart
• PDIs such as milrinone, acting through a non–β adrenergic
mechanism, are not associated with diminished efficacy or
tolerance with prolonged use

166. • Several major clinical trials have evaluated the safety
and efficacy of levosimendan in HF syndromes.
(RUSSLAN [Randomized Study on Safety and
Effectiveness of Levosimendan in Patients With Left
Ventricular Failure due to an Acute Myocardial
Infarct]
• LIDO [Levosimendan Infusion versus Dobutamine in
Severe Low-Output Heart Failure
• Both demonstrated mortality benefit

167. • In some patients, complete inotropic dependence
manifested by symptomatic hypotension, recurrent
congestive symptoms, or worsening renal function
may develop after discontinuation of parenteral
therapy.
• Inotropic support may become necessary until
cardiac transplantation or implantation of an LV
assist device can be instituted. Inotrope-dependent
HF patients who do not go on to definitive therapy
have a poor prognosis, with 1-year mortality ranging
from 79% to 94%.

168. • Long-term inotropic therapy is associated with an
increased risk of line sepsis, arrhythmias, accelerated
functional decline due to worsening nutritional
status, and direct acceleration of end organ
dysfunction

169. INOTROPES IN SEPSIS

170. NOR AD VS DOPAMINE

171. • Dobutamine is the first choice inotrope for patients with
measured or suspected low cardiac output in the presence of
adequate left ventricular filling pressure (or clinical
assessment of adequate fluid resuscitation) and adequate
MAP
• If evidence of tissue hypoperfusion persists despite
adequate intravascular volume and adequate MAP, a
viable alternative (other than reversing underlying
insult) is to add inotropic therapy.
Surviving Sepsis Campaign: International Guidelines for Management of
Severe Sepsis and Septic Shock: 2012

172. INOTROPES IN PREGNANCY
• Indications and use of digoxin is not altered
• Same dose of digoxin will yield lower maternal
values during pregnancy than in non pregnant
• Fetal levels approximate those in mother
• When iv inotropes are required the standard
agents dopamine,dobutamine
,norepinephrine can be used

173. • Fetus is jeopardized as all agents increase
resistance to uterine blood flow and can
stimulate uterine contractions
• Little information about efficacy of PDIs

174. FUTURE INOTROPES

175. ISTAROXIME
• Istaroxime
[(E,Z)-3-((2aminoethoxy)imino)androstane-6,17-dione]
• newer inotropic agents acting at the Na+/K+ -ATPase
• Istaroxime does not have a glycoside-like structure
• in addition to its inhibitory effects on
Na+/K+ -ATPase, it has been suggested to stimulate
SERCA

176. • Inhibition of Na+/K+ -ATPase increases intracellular
sodium, which reduces the driving force for the NCX,
decreasing calcium elimination outside the cell.
• increased sodium may stimulate the NCX to function
in the reverse mode of transporting calcium
intracellularly
• Calcium influx into the cytosol may, be harmful in
the failing heart with reduced SERCA activity and
elevated diastolic calcium levels

177. CARDIAC MYOSIN ACTIVATORS
• Directly influence the cross-bridge cycle.
• These molecules accelerate the rate of actin-
dependent phosphate release of the weakly bound
actin-myosin cross-bridge
• This promotes transition to the force producing on-state of
the cross-bridge, more cross-bridges enter the force-
producing state,more cross-bridges are activated per unit of
time, and contractile force increases

178. OMECAMTIV MECARBIL
Omecamtiv mecarbil has been under study.
It is found to increase stroke volume and cardiac
output, and decreased LV end-diastolic pressure and
heart rate without increased myocardial oxygen
consumption

179. GENE THERAPY
• to increase sarcoplasmic reticulum calcium pump
activity—by stimulating the calcium pumps
• Most approaches are related to reduced SR calcium
uptake, however, abnormal SR leak has also been
considered
• It has been shown in isolated myocytes that overexpression of
the RyR-regulatory protein FKBP12.6 increases SR
calcium content and fractional shortening

180. NITROXYL(HNO)
• Nitric oxide s one-electron-reduced and protonated
sibling.
• HNO and NO are both gaseous signalling molecules
and can be potent vasodilators,
• HNO appears to have additional unique signalling
pathways and mechanisms independent of NO.
• HNO is a potent arterio- and venodilator in intact
animal studies

181. • Mediated by
guanylate cyclase
increased circulating neuropeptide calcitonin gene
related peptide levels and
activation of vascular smooth muscle potassium
channels
• One characteristic that clearly differentiates HNO
from traditional nitrovasodilators is the potential
absence of tolerance or Tachyphylaxis.

182. • Early in vitro experiments suggested positive
inotropic and lusitropic properties of HNO.
• The mechanisms of these beneficial inotropic and
lusitropic effects continue to be elucidated,
• They appear to be independent of cAMP/protein
kinase A (PKA) and cGMP/PKG signalling, with no
modification of L-type calcium channel activity,
• related to modification of specific cysteine residues
on either phospholamban and/or SERCA2a, resulting
in augmented SR calcium transients.

183. RYANODINE RECEPTOR STABILIZERS
• Calcium leak through ryrs significantly contributes to
abnormal calcium cycling in human heart failure.
• A leak of calcium from the sr may not only decrease
sr calcium load and availability for systolic
contraction, but it may also promote diastolic
dysfunction due to diastolic activation of contractile
proteins.

184. • Jtv519, a 1,4-benzothiazepine, was one of the first
compounds that restored abnormal RYR function and
preserved contractile performance in heart failure
models
• jtv519 has inhibitor properties on l-type calcium
channels, potassium channels, and possibly other
transporters
• Molecules that may specifically act on cardiac ryrs
have been developed, including s44121.

185. ENERGETIC MODULATORS
• Disturbed energetic metabolism is considered to play
a major role in human heart failure
• Administration of the glycolytic substrate pyruvate
may result in profound inotropic effects under
experimental conditions as well as in patients with
heart failure

186. PYRUVATE
• Pyruvate has numerous molecular effects that may
contribute to its inotropic action. These include:
an increase in phosphorylation potential,
a reduction of inorganic phosphate,
a decrease in hydrogen ion concentration, and
a modulation of the cytosolic redox state.
• The most important mechanism for its inotropic
action may be an increase in the phosphorylation
potential

187. • In isolated muscle strip preparations from patients
with end-stage heart failure, pyruvate resulted in a
concentration-dependent increase in developed
force and a decrease in diastolic force.
• When pyruvate was injected into the coronary
circulation of patients with dilated cardiomyopathy, it
exhibited a profile of an ideal inotropic agent with an
increase in cardiac index and stroke volume index, a
decrease in PCWP and heart rate. Mean aortic
pressure and system vascular resistance did not
change.

188. REFERENCES
MILLERS ANAESTHESIA 8TH EDITION
STOELTING S PHARMACOLOGY
KAPLANS CARDIAC ANAESTHESIA
DINARDO CARDIAC ANAESTHESIA 3rd
CRAWFORDS CARDIOLOGY 3RD
BRAUNWALDS CARDIOLOGY
HURSTS THE HEART
JOURNALS