inotropes and their choice

1. Inotropes and their choice
Moderator: Speaker:
Dr. R. K. Verma Dr. Dharmraj Singh

2. Inotropes
 Drugs that affect the strength of contraction of heart
muscle (myocardial contractility).
 Positively inotropic agents ↑strength of muscular
contraction.
 Negatively inotropic agents weaken the force of
muscular contractions.
 Term “inotrope” generally used to describe positive
effect

3. Contd…
 Both positive and negative inotropes are used in the
management of various cardiovascular conditions.
 The choice of agent depends largely on specific
pharmacological effects of individual agents with
respect to the condition.
 One of the most important factor affecting inotropic
state is the level of calcium in the cytoplasm of the
muscle cell.
 Positive inotropes usually increase this level, while
negative inotropes decrease it.

4. Positive inotropic agents:
 ↑Myocardial contractility
 Used to support cardiac function in conditions such as:
a) Decompensated CHF,
b) Cardiogenic shock,
c) Septic shock,
d) Myocardial infarction,
e) Cardiomyopathy, etc.

5. Contd…
Positive inotropic agents include:
1) Calcium
2) Calcium sensitizers: Levosimendan
3) Cardiac myosin activators: Omecamtiv
4) Catecholamines:
• Dopamine
• Dobutamine
• Dopexamine
• Epinephrine (adrenaline)
• Isoprenaline (isoproterenol)
• Norepinephrine (noradrenaline)

6. Contd…
5) Cardiac glycosides: Digoxin
6) Phosphodiesterase (PDEIII) inhibitors:
• Enoximone, Piroximone
• Milrinone
• Amrinone
7) Prostaglandins: PGE₂
8) Glucagon

7. Negative inotropic agents
 ↓Myocardial contractility, and are used to ↓cardiac
workload in conditions such as angina.
 While negative inotropism may precipitate or
exacerbate heart failure,
 Certain beta blockers (e.g. carvedilol, bisoprolol and
metoprolol) have been believed to reduce morbidity
and mortality in congestive heart failure.

8. Contd…
1) Beta blockers
2) Calcium channel blockers:
 Diltiazem
 Verapamil
 Clevidipine
3) Class IA antiarrhythmics such as:
 Quinidine
 Procainamide
 Disopyramide
4) Class IC antiarrhythmics such as:
 Flecainide

9. Adrenergic Agents
 Alpha1-adrenergic effects:
• Vascular smooth muscle contraction
 Alpha2-adrenergic effects:
• Vascular smooth muscle relaxation

10. Beta-Adrenergic Agents
 Beta1-adrenergic effects:
o Direct cardiac effects
• Inotropy (improved cardiac contractility)
• Chronotropy (increased heart rate)
 Beta2-adrenergic effects:
• Vasodilation
• Bronchodilation

11. Dopaminergic Agents
 Dopaminergic Agents classified as D1 &D2
• D1-receptors mediates vasodilation in kidney,
intestine, & heart
• D2-antiemetic action of droperidol

12. Recepter selectivity of adrenergic agonists.1
Drugs α₁ α₂ β₁ β₂ DA₁ DA₂
Epinephrine 2 ++ ++ +++ ++ 0 0
Ephedrine 3 ++ ? ++ + 0 0
Norepinephrine2 ++ ++ ++ 0 0 0
Dopamine2 ++ ++ ++ + ++ +++
Dopexamine 0 0 +++ ++ ++ +++
Dobutamine 0/+ 0 +++ + 0 0
1 0,no effect; +, agonist effect (mild, moderate, marked)
2 the α₁- effects of epi, norepi, & dopamine became more prominent at higher dose
3 primary MOA of ephedrine is indirect stimulation

13. Effect of adrenergic agonists on organs sysyems.1
Drugs HR MAP CO PVR Bronchodilation RBF
Epinephrine ↑↑ ↑ ↑↑ ↑/↓ ↑↑ ↓↓
Ephedrine ↑↑ ↑↑ ↑↑ ↑ ↑↑ ↓↓
Norepinephrine ↓ ↑↑↑ ↓/↑ ↑↑↑ 0 ↓↓↓
Dopamine ↑/↑↑ ↑ ↑↑↑ ↑ 0 ↑↑↑
Dopexamine ↑/↑↑ ↓/↑ ↑↑ ↑ 0 ↑
Isoproterenol ↑↑↑ ↓ ↑↑↑ ↓↓ ↑↑↑ ↓/↑
Dobutamine ↑ ↑ ↑↑↑ ↓ 0 ↑
1 0, no effect; ↑,(mild, moderate marked); ↓, (mild, moderate marked);
↓/↑, variable effect; ↑/↑↑mild-to-moderate increase.

14. Effects of Agents
 Pressors: ↑SVR & ↑BP
 Inotropes: affect myocardial contractility and
enhance stroke volume
 Chronotropic agents: affect heart rate
 Lusotropic agents: improve relaxation during diastole
and ↓EDP in the ventricles
 Dromotropic agents: Affects conduction speed
through AV node; ↑HR
 Bathmotropic agents: affect degree of excitability

15. calcium
 When injected IV, produce intense positive inotropic
effect lasting 10-20 minutes & manifesting as ↑SV &
LVEDP, ↓HR & SVR
 Inotropic effects of Ca are enhanced in presence of
preexisting hypocalcaemia
 Risk of cardiac dysrhythmias when Ca is administered
IV to patients receiving digitalis should be
considered, especially if hypokalemia is also present.
Dose: CaCl₂, 5-10 mg/kg to adults, may administered to
improve myocardial contractility & SV at the
conclusion of CPB

16. Contd…
 Myocardial contractility at conclusion of CPB may be
↓by hypocalcemia because of
a) Use of K+ containing cardioplegia solutions
b) Administration of citrated stored whole blood
c) T/t of metabolic acidosis with NaHCO₃
 10% solution of CaCl₂ contains more Ca than Ca
gluconate solution

17. calcium sensitizers
 Pimobendan sulmazole, levosimendan are positive
inotropic drugs that improve myocardial contractility
independent of ↑in intracellular cAMP or Ca
concentration
 As a results, interaction b/w actin & myosin filaments is
prolonged, & ↑myocardial contractility occurs.

18. Contd…
 Desensitization of myofilaments to activating effects
of Ca may occur during myocardial ischemia &
stunning & these drugs may be particularly useful in
these circumstances.
 The PDE III inhibiting properties of myofilament Ca
sensitizers produces arterial & venous dilation that
likely also contribute to the positive inotropic effects
of these drugs.

19. Levosimendan
 Pyridazone-dinitrile derivative Calcium channel
sensitizer
Mode of action:
 ↑the sensitivity of the heart to Ca, thus ↑cardiac
contractility without a rise in intracellular Ca.
 Positive inotropic effect by ↑Ca sensitivity of
myocytes by binding to cardiac troponin C in a Ca-dependent
manner.
 Vasodilatory effect, by opening ATP-sensitive K
channels in vascular smooth muscle to cause smooth
muscle relaxation.

20. Contd…
 Combined inotropic and vasodilatory actions result in
an ↑force of contraction, ↓preload & afterload.
 By opening mitochondrial (ATP)-sensitive K-channels
in cardiomyocytes, the drug exerts a cardioprotective
effect.
 ↑Myocardial contractility without ↑myocardial O₂
demand, and as a consequence appears to be free of
serious arrhythmogenic effects in patients with
cardiac failure.

21. Mechanism of action of levosimendan on cardiovascular functions
Bollen Pinto et al., Current Opinion in Anesthesiology 2008, 21:168–177

22. Contd…
Loading dose: 6 to 12 μg/kg iv over 10 min F/B
Continuous infusion: 0.05-0.2 μg/kg /min for 24 hours
 Hemodynamic responses are generally observed
within 5 minutes of commencement of infusion of
the loading dose.
 Peak effects are observed within 10 to 30 minutes of
infusion; the duration of action is about 75-78 hours
to 1 week.
 No dosage adjustments required with mild to
moderate renal failure.
 Loading doses do not require adjustment with mild
to moderate hepatic impairment

23. Contd…
 Indicated for inotropic support in acutely
decompensated severe CHF, refractory cardiac
failure, refractory pulmonary hypertension and
dilated cardiomyopathy..
 Contraindicated in patients with:
a. Moderate-to-severe renal impairment,
b. Severe hepatic impairment,
c. Severe ventricular filling or outflow obstruction,
d. Severe hypotension and tachycardia,
e. History of torsades de pointes.

24. Contd…
Adverse effects: Common adverse drug reactions (≥1%
of patients) include:
 Headache,
 Hypotension,
 Arrhythmias (AF, extrasystoles, atrial tachycardia, VT),
 Myocardial ischaemia,
 Hypokalaemia,
 Nausea.

25. Contd…
CLINICAL BENEFITS:
 Enhances cardiac contractility without ↑myocardial
oxygen demand, and causes vasodilation
 Significantly reduces the incidence of worsening CHF
or death in patients with decompensated CHF
 No evidence of arrhythmogenesis to date
POTENTIAL LIMITATIONS :
 Vasodilatory properties can cause adverse effects
(headache, hypotension)
 Must be administered intravenously
 Limited clinical experience at present

26. Catecholamines
 Dopamine, epinephrine and norepinephrine are
endogenous
 Dobutamine and isoproterenol are synthetic
 Sustained use or antecedent CHF can lead to down-regulation
of β-receptors and decrease efficacy

27. Relative receptor activity of most commonly
used inotropes
α1 α2 β1 β2 DA
Norepinephrine +++ +++ + - -
Epinephrine +++ ++ +++ ++ -
Dopamine ++ + ++ +++ +++
Dobutamine + - +++ + -
Isoproterenol - - ++ ++ -

28. Dopamine(DA)
 Endogenous nonselective direct and indirect
adrenergic and dopaminergic agonist
 Clinical effects vary markedly with the dose.
1) Low dose: 0.5-3μg/kg/min
 Activates dopaminergic receptors(specifically DA₁)
 Vasodilation of renal vasculature and promotes
diuresis and natriuresis
 Use of this “renal dose” does not impart any
beneficial effect on renal function.

29. Contd…
2) Moderate dose: 3-10 μg/kg/min
 β₁ - stimulation ↑ myocardial contractility, HR, SBP,
and CO
 Myocardial O₂ demand typiaclly↑ more than supply
3) High dose: 10-20 μg/kg/min
 α₁ - effects became prominent
 ↑PVR & ↓renal blood flow(RBF)
 Indirect effects of DA are due to release of
norepinephrine from postsynaptic sympathetic
nerve ganglion.

30. Dose Dependent effect of Dopamine
<3 mcg 3 - 10 mcg > 10 mcg
↑Contractility
Minimal change in
HR and SVR
↑ Renal BF
↑ Splanchnic BF
Modest ↑ CO
↑ Renal BF
↓Proximal Tub. Na
Absorbtion
↑ Splanchnic BF
↑ HR,
Vasoconstriction
↑/ ↓ Renal BF
↓/↑ Splanchnic BF

31. Contd…
Uses:
 T/t of shock to improve CO, BP, & maintain renal
function
 Often used in combination with a vaodilator (eg.
Nitroglycerin or nitroprusside), which reduce
afterload & further improve CO
Chronotropic & proarrhythmic effects of DA limit its
usefulness in some patients.

32. Contd…
Dosing & Packing:
 Continuous infusion 1-20 μg/kg/min
 Most commonly supplied in 5 ml (40mg/ml) ampules
containing 200 mg of DA

33. Dobutamine
 Racemic mixture of two isomers with affinity for both
β₁ & β₂ receptors, with relatively higher selectivity for
β₁ receptors
 Primary cardiovascular effect - ↑CO as a result of
↑myocardial contractility
 ↓ PVR caused due to β₂- activation usually prevents
much of ↑arterial BP
 ↓LV filling pressure, whereas ↑coronary blood
flow(CBF)

34. Contd…
 Favorable effects on myocardial O₂ balance are
believed to make dobutamine a choice for patients
with the combination of CHF & CAD, particularly if
PVR is elevated.
 It has been shown to ↑myocardial O₂ consumption,
such as during stress testing (rationale for its use in
perfusion imaging), some concern remain regarding
its use in patients with myocardial ischaemia.
 Its should not be routinely used without specific
indications to facilitate separation from CPB

35. Contd…
 Used in low CO states and CHF e.g. myocarditis,
cardiomyopathy, MI
 If BP adequate, can be combined with afterload
reducer (Nitroprusside or ACE inhibitor)
 In combination with Epinephrine/Norepinephrine in
profound shock states to improve CO and provide
some peripheral vasodilatation
Dosing & Packing:
 Infusion @ 2-20 μg/kg/min
 Supplied in 5-ml (50 mg/ml) ampules containing 250
mg

36. Dopexamine
 Structural analogue of DA
 Potentail advantage over DA because it has less β₁-
adrenergic(arrhythmogenic) & α- adrenergic effects
 Because of ↓β-adrenergic effects & its specific
effects on renal perfusion, it may advantage over
dobutamine
 Clinically avialable in many country since 1990, but it
has not gained widespread acceptance in practice

37. Contd…
Dosing & Packing:
 Infusion should be started @0.5μg/kg/min, ↑ to
1μg/kg/min at interval of 10-15 min to maximum
infusion rate 6μg/kg/min.

38. Epinephrine(adrenaline)
 Endogenous catecholamine synthesized in the
adrenal medulla
 Direct stimulation of β₁- receptors of the myocardium
cause ↑BP, CO & myocardial O₂ demand by
↑contractility & HR
 α₁- stimultion ↓splanchnic & RBF but ↑coronary
perfusion pressure(CPP) by ↑aortic DP
 SBP rises, although β₂- mediated vasodilation in
skeletal muscle may ↓DP
 β₂- stimulation also relaxes bronchial smooth muscle

39. EPINEPHRINE
α1 predominantly
Vasoconstriction
↓ Renal BF
↓ Splanchnic BF
↑ Glucose
β1 predominantly
↑HR
↓ Duration of Systole
↑ Myocardial contract
Periph. arteriolar dil.
↑/ ↓ Renal BF
↑ Renin secretion
↑/ ↓ Splanchnic BF
↑ Glucose
Hypokalemia
Epinephrine
Low Dose
(<0.05-0.1 mcg/kg/min)
High Dose
(> 0.1 μg/kg/min)

40. Contd…
Uses:
 T/t for anaphylaxis & ventricular fibrillation
Complications:
 Cerebral hemorrhage
 Coronary ischaemia
 Ventricular dysrhythmias
 Volatile anesthetics, particularly halothane,
potentiate the dysrhthmic effects of
epinephrine(10μg/kg)

41. Contd…
Dosing & Packing:
 Emergency situation (eg, cardiac arrest & shock), iv
bolus 0.05-1 mg, depending on the severity of
cardiovascular compromise
 Major anaphylactic reactions 100-500μg (repeated, if
necessary) followed by infusion
 To improve myocardial contractility or HR, a
continuous infusion is prepared (1 mg in 250 ml
[4μg/ml]) & run @ 2-20μg/min

42. Contd…
 Reduce bleeding from operative sites
 Local anesthetics solutions containing 1:200,000
(5μg/ml) or 1:400,000 (2.5μg/ml)- less systemic
absorption & longer duration of action
 Epinephrine is available in vials & prefilled syringes
containing:
a) 1:1000 (1mg/ml)
b) 1:10,000 (0.1mg/ml [100μg/ml])
c) 1:100,000 (10μg/ml)- for pediatric use

43. Contd…
Common contraindication:
 Hypertension.
 Pheochromocytoma.
 Caution with heart failure angina and
hyperthyroidism.

44. Isoprenaline (Isoproterenol)
 Synthetic catecholamine
 Non-specific pure β- agonist with minimal alpha-adrenergic
effects.
 β₁- effects ↑HR, contractility , CO
 SBP may ↑ or remain unchanged, but β₂- stimulation
↓PVR & DBP
 ↑Myocardial O₂ demand while ↓O₂ supply, making
isoproterenol or any pure β- agonist a poor inotropic
choice in most situations

45. Contd…
 Causes inotropy, chronotropy, and systemic and
pulmonary vasodilatation.
 Indications: bradycardia, decreased CO,
bronchospasm (bronchodilator).

46. Contd…
Dosing & Packing:
 Occasionally used to maintain HR following heart
transplantation.
 Dose starts at 0.01 mcg/kg/min and is increased to
2.0 mcg/kg/min for desired effect.
 Avoid in patients with subaortic stenosis, and
hypertrophic cardiomyopathy or TOF lesions because
increases the outflow gradient
 Supplied in 1-ml (2 mg/ml) ampules containing 2 mg

47. Norepinephrine (Noradrenaline)
 Direct α₁- stimulation with little β₂- activity induces
intense vasoconstriction of arterial & venous vessels
 ↑Myocardial contractility from β₁- effects, along with
peripheral vasoconstriction contributes to ↑arterial
BP
 ↑SBP & DBP both, but ↑afterload & reflex
bradycardia prevent any ↑CO
 ↓Renal & splanchnic blood flow & ↑myocardial O₂
requirements limit the outcome benefits of
norepinephrine in management of refractory shock.

48. Contd…
 Norepinephrine has been used with an α- blocker (eg,
phentolamine) in an attempt to take advantage of its
β- activity without the profound vasoconstriction
caused by α- stimulation
 Extravasation of norepinephrine at the site of IV
administration can cause tissue necrosis
Dosing & Packing:
 Bolus 0.1μg/kg or
 Continuous infusion @ 2-20μg/kg/min (due to its
short half life)
 Ampules contain 2 mg of norepinephrine in 4 ml

49. prostaglandins
 The effects of prostaglandins on cardiac function are
complex & depend on direct inotropic effects, the
activity of the SNS relative to PNS, & the metabolic
status of heart
 PGE₂ produces an ↑in HR & myocardial contractility
by direct inotropic effects as well as by ↑reflex SNS
activity
 PGE₂(Dinoprostone) produces ↑ in HR &CO

50. CADIAC GLYCOSIDES
 Purified cardiac glycoside (clinically useful; Digoxin,
digitoxin, & ouabain) extracted from the foxglove plant,
Digitalis lanata.
 Widely used in the treatment of various heart conditions,
namely AF, atrial flutter and sometimes heart failure that
cannot be controlled by other medication.
Mechanism of Action:
Positive inotropic effect include direct on heart that modify
its electrical & mechanical activity & indirect effects
evoked by reflex alteration in ANS

51. CONTD…
 Selectively & reversibly inhibit Na-K ATP ion transport
system (Na pump) located in the sarcolemma of cardiac
cell membranes→
 ↑Na+ concentration in the cardiac cells leads to
↓extrusion of Ca2+ by Na+ pump mechanism
 ↑intracellular concentration of Ca2+ is responsible for
positive inotropic effect of cardiac glycosides
 Positive inotropic effects produced by cardiac glycosides
occur without change in HR & associated with ↓LV
preload, afterload, wall tension, & O₂ consumption in the
failing heart.

52. Contd…
• ↑PNS activity due to sensitization of arterial
baroreceptors (carotid sinus) & activation of vagal
nuclei & nodose ganglion in the CNS
• ↓activity of SA node & prolongs the effective
refractory period, & thus the time for conduction of
cardiac cardiac impuse through AV node
• Slowed HR especially in presence of AF

53. Digoxin Digitoxin
Avg digitalization dose
Oral 0.75-1.50 mg 0.8-1.2 mg
Intravenous 0.5-1.0 mg 0.8-1.2 mg
Avg daily maintenance dose
Oral 0.125-0.500 mg 0.05-0.20 mg
Intravenous 0.25 mg 0.1 mg
Onset of effect
Oral 1.5-6.0 hrs 3-6 hrs
Intravenous 50-30 mins 30-120 mins
Absorption from the GIT 75% 90-100%
Plasma protein binding 25% 95%
Route of elimination Renal Hepatic
Enterohepatic circulation Minimal Marked
Elimination half-time 31-33 hrs 5-7 days
Therapeutic plasma
0.5-2.0 ng/ml 10-35 ng/ml
concentration

54. Ouabain
Dose:
1.5-3.0 mcg/kg iv to provide rapid increases in
myocardial contractility or to decrease the heart
ratein rapid ventricular response AF

55. Selective Phosphodiesterase
inhibitors
(noncatecholamine, nonglycoside cardiac inotropic agents)
Selective PDE exert competitive inhibitory action on
an isoenzyme fraction of PDE (PDE III)
↓hydrolysis of cAMP & cGMP
↑intracellular concnof cAMP & cGMP in myocardium &
vascular smooth muscle
Stimulation of protein kinases C
Phosphorylate substance & inward movement of Ca2+

56. Contd…
 Positive inotropic effect with vascular & airway
smooth muscle relaxation
 Positive inotropic effect due to inhibition of cardiac
PDE III, leading to ↑myocardial cAMP
 Selective PDE inhibitors act independently of β-
adrenergic receptors & ↑myocardial contractility in
patients with myocardial depression from β-receptor
blockade & those who have become refractory to
catecholamine therapy

57. Contd…
 Selective PDE III inhibitors exceeds cardiac glycosides
& is complementary & synergistic to the action of
catecholamines.
 These drugs can be used in conjuction with digitalis
without provoking digitalis toxicity
 Mx of Ac cardiac failure (as after MI) in Pts who
would benefit from combined inotropic & vasodilator
therapy
 Amrinone, Milrinone, Enoximone, Piroximone

58. Amrinone
 Bipyridines derivative, selective PDE III inhibitor &
produces dose dependent positive inotropic &
vasodilator effects
 Non-receptor mediated activity based on selective
inhibition of Phosphodiesterase Type III enzyme resulting
in cAMP accumulation in myocardium
 cAMP increases force of contraction and rate and extent
of relaxation of myocardium
 Inotropic, vasodilator and lusotropic effect
 ↑CO & ↓LVEDP,
 HR & SBP may↑

59. CONTD…
Advantage over catecholamines:
 Independent action from β-receptor activation,
particularly when these receptors are downregulated
(CHF and chronic catecholamine use)
 Oral/ IV
 Initial injection single dose: 0.5-1.5 mg/kg IV, ↑CO with
in 5 min, with detectable positive inotropic effect
persisting for approx 2 hrs
 Continuous infusion: after initial injection 2-10
μg/kg/min
 Recommended maximum daily dose 10 μg/kg including
the initial dose

60. Contd…
 Patients who have failed to respond to
catecholamine may respond to amrinone
 Vasodilating effects of amrinone can accelerate the
cooling rate of core temperature during deliberate
mild hypothermia for neurosurgical procedure.
Side effects:
 Occasional hypotension
 Thrombocytopenia

61. Milrinone
 Like amrinone positive inotropic & vasodilator effects
 Minimal effects on HR & myocardial O₂ consumption
 ↑CO by improving contractility, ↓SVR, PVR, lusotropic
effect; ↓preload due to vasodilatation
 Unique in beneficial effects on RV function
 Protein binding: 70%
 Half-life is 1-4 hours
 Elimination: primarily renally excreted
 Load with 50 μg/kg over 30 mins followed by 0.25 to 0.75
μg/kg/min

62. Milrinone
Minimal ↑ HR
↑ CO
Minimal ↑ in
O2 demand ↓ SVR
↓ PVR
Diastolic
Relaxation

63. Enoximone & piroximone
 Imidazole derivatives that act as highly selective PDE III
inhibition to ↑myocardial contractility
 Half-life 4.3 hrs
 Metabolized mainly by liver
Dose: 0.5 mg/kg IV f/b 5-20 μg/kg/min continuous
infusion

64. COMPARISON BETWEEN LEVOSIMENDAN,
MILRINONE AND DOBUTAMINE
Feature Levosimendan Milrinone Dobutamine
Class Calcium channel
sensitizer
Phosphodiesterase-III
inhibitor
Catecholamine(β-
adrenergic agent)
↑intracellular Ca
concentrations
No Yes Yes
Vasodilator Coronary and
systemic
Peripheral Mild peripheral
↑Myocardial O₂
demand
No No Yes
Arrhythmogenic
potential
Rare and may be due
to QTc prolongation
Ventricular and
supraventricular
arrhythmias
Ventricular ectopic
activity; less
arrhythmogenic than
milrinone
Adverse events Headache,
hypotension
Ventricular
irregularities,
hypotension, headache
Tachycardia and
increased SBP on
overdosage

65. glucagon
 Polypeptide hormone produced by α- cell of
pancreas
 Enhances formation of cAMP
 Evoke the release of catecholamine
Principal cardiac indication: to ↑myocardial
contractility & HR in the presence of β-adrenergic
blockade.
 Because glucagon is peptide, it must be administered
IV or IM

66. Contd…
Cardiovascular effects:
 Rapid injection (1-5 mg IV to adults) or a continuous
infusion (20 mg/hr), reliabily ↑SV & HR independent
of adrenergic stimulation
 Tachycardia may sufficienlty with augmented CO
 Abrupt ↑in HR can occur when administered to
patients in atrial fibrillation
 MAP may ↑modestly, whereas SVR is unchanged or
↓
 Enhance automaticity in the SA & AV nodes without
↑automaicity of ventricles

67. Contd…
Renal effect: similar to dopamine, but less potent
Chronic administration is not effective in evoking
sustained positive inotropic & chronotropic effects.
Side effects:
 Nausea & vominting
 Hyperglycemia & paradoxical hypoglycemia
 Hypokalemia
 Systemic hypertension in patients unrecognized
pheochromocytoma

68. Beta blockers
 β-Receptor blockers have variable degree of
selectivity for the β₁- receptors
 More selective β₁- receptor blockers has less
influence on bronchopulmonary & vascular β₂-
receptors.
 Theoretically, a selective β₁ -blockers would have less
of an inhibitory effect on β₂-receptors & therefore ,
might be preferred in patients with COPD or PVD

69. Pharmacology of β₁-blockers*
Selectivity
for β₁-
Receptors
ISA α-Blockade
Hepatic
Metabolism
T1/2
Atenolol + 0 0 0 6-7
Esmolol + 0 0 0 -1/4
Labetalol 0 + + 4
Metoprolol + 0 0 + 3-4
Propranolol 0 0 + 4-6
*IAS, Intrinsic sympathomimetic activity; +, mild effect; 0, no effect

70. Contd…
 Patients with PVD could potentially have a ↓in blood
flow if β₂-receptors, which dilate the arterioles, are
blocked.
 Many of β-blockers have some agonist activity;
although they would not produce effects similar to
full agonist(such as epinephrine)
 Β-blockers with ISA may not be beneficial as β-
blockers without ISA in treating patients with
cardiovascular disease.

71. Esmolol
 Ultrashort-acting selective β₁-antagonist that ↓HR,
& to a lesser extent, BP
 Successfully used to prevent tachycardia &
hypertension in response to perioperative stimuli,
such as intubation, surgical stimulation, &
emergence.
 For example, esmolol (0.5-1 mg/kg) attenuates the
rise in BP & HR that usually accompanies ECT without
significantly affecting seizure duration.

72. Contd…
 Although esmolol is considered to be cardioselective, at
higher doses it inhibits β₂-receptors in bronchial and
vascular smooth muscle.
 The short DOA is due to rapid redistribution (distribution
half-life 2 min) & hydrolysis by RBC esterase (elimination
half-life 9 min)
 S/E can be reversed with in minutes by discontinuing its
infusion
 As with all β₁-antagonist, esmolol should be avoided in
patients with sinus bradycardia, heart block >1⁰,
cardiogenic shock, overt heart failure.

73. Contd…
Dosing & Packing:
 Short term therapy: Bolus (0.2-0.5 mg/kg), such as
attenuating the cardiovascular response to
laryngoscopy & intubation.
 Long-term treatment: typically initiated with a
loading dose of 0.5mg/kg administered over 1 min
f/b a continuous infusion of 50μg/kg/min to
maintain therapeutic effect.

74. Contd…
 If this fail to produce sufficient response within 5 min,
the loading dose may be repeated and the infusion
↑by increments of 50μg/kg/min every 5 min to a
maximum 200μg/kg/min.
 Multidose vials for bolus administration containing 10
ml of drug (10mg/ml)
 Ampules for continuous infusion (2.5g in 10ml) also
available but must be diluted prior to administration to
a concentration of 10mg/ml.

75. Choice of inotrope
Guided :
 The expected need for inotropes
 clinical evidence of depressed myocardial function
 Empirical drug choice and titration, with careful
hemodynamic monitoring

76. Predictive factors of inotropic support, as
highlighted by several studies.
 Low ejection fraction (< 45%)
 History of congestive heart failure
 Cardiomegaly
 High LVEDP following ventriculogram
 MI within 30 days of operation*
 Older age (> 70 years)
 Longer duration of aortic cross-clamping
 Prolonged cardiopulmonary bypass*
 Urgent operation
 Re-operation*
 Female gender*
 Diabetes mellitus
LVEDP = left ventricular end-diastolic pressure; MI = myocardial infarction.
* statistical significance for coronary artery bypass surgery only.

77. Ideal positive inotrope
 Enhance contractility without any significant increase
in heart rate preload, afterload, and myocardial
oxygen consumption.
 Enhance the diastolic function
 Maintain the diastolic coronary perfusion pressure
and thus an adequate myocardial blood flow.
 It finally should have rapid titration times and onset
of action and a short half-life

78. Contd…
 Catecholamines are the mainstay of current inotropic
treatment
 they can be divided into
 more potent (epinephrine, isoproterenol,
noradrenaline) and
 milder (dopamine, dopexamine, dobutamine

79. Indications in specific settings
Coronary artery bypass graft surgery:
 In most cases, no or only mild inotrope requirement.
 Inotropes may be needed in case of preexisting
ventricular dysfunction or in case of unsuccessful
revascularization if the intra-aortic balloon pump
alone is not enough.
 Emergency revascularization of acute myocardial
infarction, dobutamine and PDE inhibitors.
 Off-pump coronary artery bypass graft surgery
(dopamine, dobutamine)

80. Contd…
Chronic heart failure:
 Combination therapy (i.e. a PDE inhibitor
administered along with a beta-adrenergic inotrope,
dobutamine or epinephrine) may therefore be the
treatment of choice in these patients
Diastolic dysfunction:
 No inotropes at all (or inotropes with a better effect
on ventricular relaxation, such as PDE inhibitors, if
systolic dysfunction coexists)

81. Contd…
Valvular surgery
 Moderately severe aortic stenosis- Inotropic support
is rarely needed
 Chronic aortic insufficiency- Requiring adequate
preload and inotropes
 Mitral stenosis, chronic mitral regurgitation-
Treatment with inotropes is warranted.
 Acute aortic and mitral regurgitation- require
aggressive inotropic support even preoperatively
 Tricuspid regurgitation-Inotropes are beneficial

82. Contd…
Orthotopic cardiac transplantation:
 Routine inotropic support includes isoproterenol (to
increase the automaticity, inotropism and pulmonary
vasodilation) and dopamine (to add further support
whilst maintaining the systemic perfusion pressures).
Right ventricular dysfunction:
 heart transplantation,
 lung transplantation
 pulmonary thromboendoarterectomy
 left ventricular assist device implantation,
 inadequate myocardial protection

83. Successful management
Right ventricular
afterload The contractile
strength
maintenance of
the aortic blood
pressure
Pulmonary
vasodilators
inotropes :
• dobutamine,
•isoproterenol,
• epinephrine,
•PDE inhibitors
Vasoconstrictors

84. Clinical Application
1st Line Agent 2nd Line Agent
Septic Shock Norepinephrine Vasopressin
Phenylephrine
Epinephrine
(Adrenalin)
Heart Failure Dopamine Milrinone
Dobutamine
Cardiogenic Shock Norepinephrine
Dobutamine
Anaphylactic Shock Epinephrine (Adrenalin) Vasopressin
Neurogenic Shock Phenylephrine
Hypotension
Anesthesia
-induced Phenylephrine
Following
CABG Epinephrine

85. Summary
 Understand appropriate clinical application of
vasopressors and inotropic agents.
 In hyperdynamic septic shock, norepinephrine or
phenylephrine is first-line agent. Vasopressin as
second-line agent to reduce need for other pressors.
 In cardiogenic shock, norepinephrine is preferred
initial agent. After establishing adequate perfusion,
Dobutamine added.

86. Contd…
 In anaphylactic shock, 1st line agent is Epinephrine
followed by Vasopressin as second line agent.
 Epinephrine is the 1st line agent in hypotension
after CABG.
 In both neurogenic shock and anesthesia-induced
hypotension, Phenylephrine is the 1st line agent.

87. Thank You