Inotropes and their choice
-
Upload
dharmraj-singh -
Category
Automotive
-
view
7.011 -
download
0
Transcript of Inotropes and their choice
![Page 1: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/1.jpg)
Inotropes and their choice
Moderator: Speaker:Dr. R. K. Verma Dr. Dharmraj Singh
![Page 2: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/2.jpg)
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
![Page 3: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/3.jpg)
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.
![Page 4: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/4.jpg)
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.
![Page 5: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/5.jpg)
Contd…Positive inotropic agents include:1) Calcium2) Calcium sensitizers: Levosimendan3) Cardiac myosin activators: Omecamtiv4) Catecholamines:
• Dopamine• Dobutamine• Dopexamine• Epinephrine (adrenaline)• Isoprenaline (isoproterenol)• Norepinephrine (noradrenaline)
![Page 6: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/6.jpg)
Contd…5) Cardiac glycosides: Digoxin6) Phosphodiesterase (PDEIII) inhibitors:
• Enoximone, Piroximone• Milrinone• Amrinone
7) Prostaglandins: PGE₂8) Glucagon
![Page 7: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/7.jpg)
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.
![Page 8: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/8.jpg)
Contd…1) Beta blockers2) Calcium channel blockers:
Diltiazem Verapamil Clevidipine
3) Class IA antiarrhythmics such as: Quinidine Procainamide Disopyramide
4) Class IC antiarrhythmics such as: Flecainide
![Page 9: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/9.jpg)
Adrenergic Agents Alpha1-adrenergic effects:• Vascular smooth muscle contraction
Alpha2-adrenergic effects:• Vascular smooth muscle relaxation
![Page 10: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/10.jpg)
Beta-Adrenergic Agents Beta1-adrenergic effects:
o Direct cardiac effects• Inotropy (improved cardiac contractility)• Chronotropy (increased heart rate)
Beta2-adrenergic effects:• Vasodilation• Bronchodilation
![Page 11: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/11.jpg)
Dopaminergic Agents Dopaminergic Agents classified as D1 & D2
• D1-receptors mediates vasodilation in kidney, intestine, & heart
• D2-antiemetic action of droperidol
![Page 12: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/12.jpg)
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 dose3 primary MOA of ephedrine is indirect stimulation
![Page 13: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/13.jpg)
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.
![Page 14: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/14.jpg)
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
![Page 15: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/15.jpg)
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
![Page 16: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/16.jpg)
Contd… Myocardial contractility at conclusion of CPB may be
↓by hypocalcemia because of a) Use of K+ containing cardioplegia solutionsb) Administration of citrated stored whole bloodc) T/t of metabolic acidosis with NaHCO₃
10% solution of CaCl₂ contains more Ca than Ca gluconate solution
![Page 17: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/17.jpg)
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.
![Page 18: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/18.jpg)
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.
![Page 19: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/19.jpg)
Levosimendan Pyridazone-dinitrile derivative Calcium channel
sensitizerMode 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.
![Page 20: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/20.jpg)
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.
![Page 21: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/21.jpg)
Bollen Pinto et al., Current Opinion in Anesthesiology 2008, 21:168–177
Mechanism of action of levosimendan on cardiovascular functions
![Page 22: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/22.jpg)
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
![Page 23: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/23.jpg)
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.
![Page 24: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/24.jpg)
Contd…Adverse effects: Common adverse drug reactions (≥1%
of patients) include: Headache, Hypotension, Arrhythmias (AF, extrasystoles, atrial tachycardia, VT), Myocardial ischaemia, Hypokalaemia, Nausea.
![Page 25: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/25.jpg)
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 datePOTENTIAL LIMITATIONS : Vasodilatory properties can cause adverse effects
(headache, hypotension) Must be administered intravenously Limited clinical experience at present
![Page 26: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/26.jpg)
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
![Page 27: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/27.jpg)
Relative receptor activity of most commonly used inotropes
α1 α2 β1 β2 DA
Norepinephrine +++ +++ + - -
Epinephrine +++ ++ +++ ++ -
Dopamine ++ + ++ +++ +++
Dobutamine + - +++ + -
Isoproterenol - - ++ ++ -
![Page 28: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/28.jpg)
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.
![Page 29: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/29.jpg)
Contd…2) Moderate dose: 3-10 µg/kg/min β₁ - stimulation ↑ myocardial contractility, HR, SBP, and
CO Myocardial O₂ demand typiaclly↑ more than supply3) 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.
![Page 30: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/30.jpg)
Dose Dependent effect of Dopamine
<3 mcg 3 - 10 mcg > 10 mcg
↑Contractility
Minimal change inHR and SVR
↑ Renal BF
↑ Splanchnic BF
Modest ↑ CO
↑ Renal BF
↓Proximal Tub. Na Absorbtion
↑ Splanchnic BF
↑ HR,
Vasoconstriction
↑/ ↓ Renal BF
↓/↑ Splanchnic BF
![Page 31: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/31.jpg)
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.
![Page 32: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/32.jpg)
Contd…Dosing & Packing: Continuous infusion 1-20 µg/kg/min Most commonly supplied in 5 ml (40mg/ml) ampules
containing 200 mg of DA
![Page 33: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/33.jpg)
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)
![Page 34: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/34.jpg)
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
![Page 35: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/35.jpg)
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
![Page 36: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/36.jpg)
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
![Page 37: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/37.jpg)
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.
![Page 38: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/38.jpg)
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
![Page 39: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/39.jpg)
EPINEPHRINE
α1 predominantlyVasoconstriction↓ Renal BF↓ Splanchnic BF ↑ Glucose
β1 predominantly↑HR↓ Duration of Systole ↑ Myocardial contractPeriph. arteriolar dil.↑/ ↓ Renal BF ↑ Renin secretion↑/ ↓ Splanchnic BF↑ Glucose Hypokalemia
EpinephrineLow Dose (<0.05-0.1 mcg/kg/min)
High Dose(> 0.1 μg/kg/min)
![Page 40: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/40.jpg)
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)
![Page 41: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/41.jpg)
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
![Page 42: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/42.jpg)
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
![Page 43: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/43.jpg)
Contd…Common contraindication: Hypertension. Pheochromocytoma. Caution with heart failure angina and
hyperthyroidism.
![Page 44: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/44.jpg)
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
![Page 45: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/45.jpg)
Contd… Causes inotropy, chronotropy, and systemic and
pulmonary vasodilatation. Indications: bradycardia, decreased CO,
bronchospasm (bronchodilator).
![Page 46: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/46.jpg)
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
![Page 47: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/47.jpg)
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.
![Page 48: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/48.jpg)
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
![Page 49: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/49.jpg)
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
![Page 50: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/50.jpg)
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
![Page 51: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/51.jpg)
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.
![Page 52: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/52.jpg)
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
![Page 53: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/53.jpg)
Digoxin DigitoxinAvg digitalization dose Oral 0.75-1.50 mg 0.8-1.2 mgIntravenous 0.5-1.0 mg 0.8-1.2 mgAvg daily maintenance doseOral 0.125-0.500 mg 0.05-0.20 mgIntravenous 0.25 mg 0.1 mgOnset of effectOral 1.5-6.0 hrs 3-6 hrsIntravenous 50-30 mins 30-120 minsAbsorption from the GIT 75% 90-100%Plasma protein binding 25% 95%Route of elimination Renal HepaticEnterohepatic circulation Minimal MarkedElimination half-time 31-33 hrs 5-7 daysTherapeutic plasma concentration
0.5-2.0 ng/ml 10-35 ng/ml
![Page 54: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/54.jpg)
OuabainDose: 1.5-3.0 mcg/kg iv to provide rapid increases in
myocardial contractility or to decrease the heart ratein rapid ventricular response AF
![Page 55: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/55.jpg)
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+
![Page 56: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/56.jpg)
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
![Page 57: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/57.jpg)
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
![Page 58: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/58.jpg)
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↑
![Page 59: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/59.jpg)
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
![Page 60: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/60.jpg)
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
![Page 61: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/61.jpg)
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
![Page 62: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/62.jpg)
Milrinone
Minimal ↑ HR
↑ CO
Minimal ↑ in O2 demand ↓ SVR
↓ PVR
Diastolic Relaxation
![Page 63: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/63.jpg)
Enoximone & piroximone Imidazole derivatives that act as highly selective PDE III
inhibition to ↑myocardial contractility Half-life 4.3 hrs Metabolized mainly by liverDose: 0.5 mg/kg IV f/b 5-20 µg/kg/min continuous
infusion
![Page 64: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/64.jpg)
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
![Page 65: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/65.jpg)
glucagon Polypeptide hormone produced by α- cell of
pancreas Enhances formation of cAMP Evoke the release of catecholaminePrincipal cardiac indication: to ↑myocardial
contractility & HR in the presence of β-adrenergic blockade.
Because glucagon is peptide, it must be administered IV or IM
![Page 66: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/66.jpg)
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
![Page 67: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/67.jpg)
Contd…Renal effect: similar to dopamine, but less potentChronic 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
![Page 68: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/68.jpg)
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
![Page 69: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/69.jpg)
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
![Page 70: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/70.jpg)
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.
![Page 71: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/71.jpg)
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.
![Page 72: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/72.jpg)
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.
![Page 73: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/73.jpg)
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.
![Page 74: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/74.jpg)
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.
![Page 75: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/75.jpg)
Choice of inotropeGuided : The expected need for inotropes clinical evidence of depressed myocardial function Empirical drug choice and titration, with careful
hemodynamic monitoring
![Page 76: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/76.jpg)
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 mellitusLVEDP = left ventricular end-diastolic pressure; MI = myocardial infarction.* statistical significance for coronary artery bypass surgery only.
![Page 77: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/77.jpg)
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
Ideal positive inotrope
![Page 78: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/78.jpg)
Contd… Catecholamines are the mainstay of current inotropic
treatment they can be divided into more potent (epinephrine, isoproterenol,
noradrenaline) and milder (dopamine, dopexamine, dobutamine
![Page 79: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/79.jpg)
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)
![Page 80: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/80.jpg)
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)
![Page 81: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/81.jpg)
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
![Page 82: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/82.jpg)
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
![Page 83: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/83.jpg)
Successful management
Right ventricular afterload The contractile
strength
maintenance of the aortic blood
pressure
Pulmonary vasodilators
inotropes :• dobutamine, •isoproterenol,• epinephrine, •PDE inhibitors
Vasoconstrictors
![Page 84: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/84.jpg)
Clinical Application 1st Line Agent 2nd Line Agent
Septic Shock Norepinephrine Vasopressin
PhenylephrineEpinephrine (Adrenalin)
Heart Failure Dopamine Milrinone
Dobutamine
Cardiogenic Shock Norepinephrine Dobutamine
Anaphylactic Shock Epinephrine (Adrenalin) Vasopressin
Neurogenic Shock Phenylephrine
HypotensionAnesthesia-induced Phenylephrine
Following CABG Epinephrine
![Page 85: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/85.jpg)
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.
![Page 86: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/86.jpg)
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.
![Page 87: Inotropes and their choice](https://reader031.fdocuments.in/reader031/viewer/2022030310/58f9a6af760da3da068b5261/html5/thumbnails/87.jpg)
Thank You