Inotropes and their choice

Inotropes and their choice

Moderator: Speaker:

Dr. R. K. Verma Dr. Dharmraj Singh

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

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 inotropicstate is the level of calcium in the cytoplasm of the muscle cell.

Positive inotropes usually increase this level, while negative inotropes decrease it.

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.

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)

Contd…

5) Cardiac glycosides: Digoxin

6) Phosphodiesterase (PDEIII) inhibitors:

• Enoximone, Piroximone

• Milrinone

• Amrinone

7) Prostaglandins: PGE₂

8) Glucagon

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.

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

Adrenergic Agents

Alpha1-adrenergic effects:

• Vascular smooth muscle contraction

Alpha2-adrenergic effects:

• Vascular smooth muscle relaxation

Beta-Adrenergic Agents

Beta1-adrenergic effects:

o Direct cardiac effects

• Inotropy (improved cardiac contractility)

• Chronotropy (increased heart rate)

Beta2-adrenergic effects:

• Vasodilation

• Bronchodilation

Dopaminergic Agents

Dopaminergic Agents classified as D1 & D2

• D1-receptors mediates vasodilation in kidney, intestine, & heart

• D2-antiemetic action of droperidol

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

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.

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

calcium

When injected IV, produce intense positive inotropiceffect 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

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

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.

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.

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.

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 cardioprotectiveeffect.

↑Myocardial contractility without ↑myocardial O₂ demand, and as a consequence appears to be free of serious arrhythmogenic effects in patients with cardiac failure.

Bollen Pinto et al., Current Opinion in Anesthesiology 2008, 21:168–177

Mechanism of action of levosimendan on cardiovascular functions

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

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.

Contd…

Adverse effects: Common adverse drug reactions (≥1% of patients) include:

Headache,

Hypotension,

Arrhythmias (AF, extrasystoles, atrial tachycardia, VT),

Myocardial ischaemia,

Hypokalaemia,

Nausea.

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

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

Relative receptor activity of most commonly

used inotropes

α1 α2 β1 β2 DA

Norepinephrine +++ +++ + - -

Epinephrine +++ ++ +++ ++ -

Dopamine ++ + ++ +++ +++

Dobutamine + - +++ + -

Isoproterenol - - ++ ++ -

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.

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.

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

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.

Contd…

Dosing & Packing:

Continuous infusion 1-20 µg/kg/min

Most commonly supplied in 5 ml (40mg/ml) ampulescontaining 200 mg of DA

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)

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

Contd…

Used in low CO states and CHF e.g. myocarditis, cardiomyopathy, MI

If BP adequate, can be combined with afterloadreducer (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

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

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.

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

EPINEPHRINE

α1 predominantlyVasoconstriction↓ Renal BF↓ Splanchnic BF ↑ Glucose

β1 predominantly↑HR↓ Duration of Systole ↑ Myocardial contractPeriph. arteriolar dil.

↑/ ↓ Renal BF↑ Renin secretion↑/ ↓ Splanchnic BF↑ GlucoseHypokalemia

EpinephrineLow Dose (<0.05-0.1 mcg/kg/min)

High Dose(> 0.1 μg/kg/min)

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)

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

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

Contd…

Common contraindication:

Hypertension.

Pheochromocytoma.

Caution with heart failure angina and hyperthyroidism.

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 inotropicchoice in most situations

Contd…

Causes inotropy, chronotropy, and systemic and pulmonary vasodilatation.

Indications: bradycardia, decreased CO, bronchospasm (bronchodilator).

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

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 O₂requirements limit the outcome benefits of norepinephrine in management of refractory shock.

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

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

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

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.

Contd…

• ↑PNS activity due to sensitization of arterial baroreceptors (carotid sinus) & activation of vagalnuclei & 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

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 concentration

0.5-2.0 ng/ml 10-35 ng/ml

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

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+

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

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

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↑

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

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

Milrinone

Like amrinone positive inotropic & vasodilator effects

Minimal effects on HR & myocardial O₂ consumption

↑CO by improving contractility, ↓SVR, PVR, lusotropiceffect; ↓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

Milrinone

Minimal ↑ HR

↑ CO

Minimal ↑ in O2 demand ↓ SVR

↓ PVR

Diastolic Relaxation

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

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

Arrhythmogenicpotential

Rare and may be due to QTc prolongation

Ventricular and supraventriculararrhythmias

Ventricular ectopic activity; less arrhythmogenic than milrinone

Adverse events Headache, hypotension

Ventricular irregularities, hypotension, headache

Tachycardia and increased SBP on overdosage

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

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

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

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

Pharmacology of β₁-blockers*

Selectivityfor β₁-

ReceptorsISA 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

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.

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.

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.

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.

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.

Choice of inotrope

Guided :

The expected need for inotropes

clinical evidence of depressed myocardial function

Empirical drug choice and titration, with careful hemodynamic monitoring

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.

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

Contd…

Catecholamines are the mainstay of current inotropictreatment

they can be divided into

more potent (epinephrine, isoproterenol, noradrenaline) and

milder (dopamine, dopexamine, dobutamine

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)

Contd…

Chronic heart failure:

Combination therapy (i.e. a PDE inhibitoradministered along with a beta-adrenergic inotrope,dobutamine or epinephrine) may therefore be thetreatment 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)

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

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

Successful management

Right ventricular afterload The contractile

strength

maintenance of the aortic blood

pressure

Pulmonary vasodilators

inotropes :• dobutamine, •isoproterenol,• epinephrine, •PDE inhibitors

Vasoconstrictors

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 PhenylephrineFollowing CABG Epinephrine

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.

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.

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