•VASOPRESSORS AND INOTROPICS

SAMIR EL ANSARYICU PROFESSOR

AIN SHAMSCAIRO

Myocardial Contraction

• Contractility increases over 1st months of life along with:

– Sympathetic nerve fibers within myocardium

– Total concentration of endogenous norepinephrine

• There is a greater dependence of CO on HR than contractility during this time

Immature Heart

• Limited responsiveness to medications

– noncontractile content

– availability of releasable NE

– Less mature sympathetic system

– Underdeveloped intracellular calcium regulatory mechanisms

– functional reserve capacity

Ionized Calcium

• Plays central role in maintaining myocardial contractility

Vascular Smooth Muscle

• Calcium dependent effects

– Agents that increase intracellular cAMP increase intracellular calcium requirements for contraction,

thus encouraging smooth muscle relaxation and vasodilation

Effects of Agents

• Pressors: increase systemic vascular resistance and increase blood pressure

• Inotropes: affect myocardial contractility and enhance stroke volume

• Chronotropic Agents: affect heart rate

• Lusotropic Agents: improve relaxation during diastole and decrease EDP in the ventricles

• Dromotropic Agents: Affects conduction speed through AV node; increases heart rate

• Bathmotropic Agents: affect degree of excitability

Alpha-Adrenergic Agents

–Alpha1-adrenergic effects:

•Vascular smooth muscle contraction

–Alpha2-adrenergic effects:

•Vascular smooth muscle relaxation

Beta-Adrenergic Agents

• Beta1-adrenergic effects:

– Direct cardiac effects

• Inotropy (improved cardiac contractility)

• Chronotropy (increased heart rate)

• Beta2-adrenergic effects:

• Vasodilation

• Bronchodilation

Dopaminergic Agents

• Dopaminergic Agents

– Several types of receptors located throughout body (D1-D5)

– Certain (esp. D1-like & D2-like) dopaminergic receptors increase renal and mesenteric blood

flow

Catecholamines

• Sympathomimetic amines that contain O-dihydrobenzene

• 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

Epinephrine

• Both an alpha- and beta-adrenergic agent 0.01 mcg/kg/min - 0.3 mcg/kg/min

– Low-dose infusion = β activation

• Increase HR, contractility, decrease SVR

– Higher doses = activation

• Increased SVR and MAP

• Increased myocardial O2 demand

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

Epinephrine

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

High Dose(> 0.1 μg/kg/min)

Epinephrine

• Indications for its use as a continuous infusion are:

– low cardiac output state

• beta effects will improve cardiac function

• alpha effects may increase afterload and decrease cardiac output

– septic shock

• useful for both inotropy and vasoconstriction

Epinephrine

• Adverse effects include:– Anxiety, tremors,palpitations

– Tachycardia and tachyarrhythmias

– Increased myocardial oxygen requirements and potential to cause ischemia

– Decreased splanchnic and hepatic circulation (elevation of AST and ALT)

– Anti-Insulin effects: lactic acidosis, hyperglycemia

Norepinephrine

• An epinephrine precursor that acts primarily on receptors

• Used primarily for alpha agonist effect - increases SVR without significantly increasing C.O.

• Used in cases of low SVR and hypotension such as profound “warm shock” with a normal or high C.O.

state- usually in combination with dopamine or epinephrine

• Infusion rates titrated between 0.05 to 0.3 mcg/kg/min

Norepinephrine

• Differs from epinephrine in that the vasoconstriction outweighs any increase in

cardiac output.

– i.e. norepinephrine usually increases blood pressure and SVR, often without increasing

cardiac output.

Norepinephrine

• Adverse Effects:– Similar to those of Epinephrine

– Can compromise perfusion in extremities and may need to be combined with a vasodilator e.g.

Dobutamine or Nipride

– More profound effect on splanchnic circulation and myocardial oxygen consumption

Vasopressin

• A peptide hormone released by the posterior pituitary in response to rising plasma tonicity

or falling blood pressure

• Antidiuretic and vasopressor properties

• Deficiency of this hormone results in diabetes insipidus

Vasopressin

Vasopressin

• Administration

– intravenous, intramuscular, or intranasal routes

– IV is route for vasopressor activity

– The half-life of circulating ADH is approximately 20 minutes, with renal and hepatic catabolism via

reduction of the disulfide bond and peptide cleavage

Vasopressin• Administration

– interacts with two types of receptors

• V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction

• V2 receptors are found on renal tubule cells and mediate antidiuresis through increased water permeability and water resorption in

the collecting tubules

• Use in refractory septic shock with low SVRI in pediatrics?

Dopamine

• Intermediate product in the enzymatic pathway leading to the production of

norepinephrine; thus, it indirectly acts by releasing norepinephrine.

• Directly has , and dopaminergic actions which are dose-dependent.

• Indications are based on the adrenergic actions desired.

Dopamine

• renal perfusion 2-5 mcg/kg/min (dopaminergic effects) by sensitivity of vascular smooth muscle to

intracellular calcium

• C.O. in Cardiogenic or Distributive Shock 5-10mcg/kg/min ( adrenergic effects)

• Post-resuscitation stabilization in patients with hypotension (with fluid therapy) 10-20 mcg/kg/min ( adrenergic effects) peripheral vasoconstriction,

SVR, PVR, HR.

Dose Dependent effect of Dopamine

<5 mcg 5 - 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

Dobutamine

• Synthetic catecholamine with 1 inotropic effect (increases stroke volume) and 2 peripheral

vasodilation (decreases afterload)

• Positive chronotropic effect 1 (increases HR)

• Some lusotropic effect

• Overall, improves Cardiac Output by above beta-agonist acitivity

Dobutamine

• Major metabolite is 3-O-methyldobutamine, a potent inhibitor of alpha-adrenoceptors.– Therefore, vasodilation is possible secondary to

this metabolite.

• Usual starting infusion rate is 5 mcg/kg/min, with the dose being titrated to effect up to 20

mcg/kg/min.

DOBUTAMINE

D- isomer

Stimulates β1 and β2

L- isomerStimulates α1

Dobutamine

Dobutamine

• Used in low C.O. states and CHF e.g. myocarditis, cardiomyopathy, myocardial

infarction

• If BP adequate, can be combined with afterload reducer (Nipride or ACE inhibitor)

• In combination with Epi/Norepi in profound shock states to improve Cardiac Output and

provide some peripheral vasodilatation

Isoproterenol

• Synthetic catecholamine

• Non-specific beta agonist with minimal alpha-adrenergic effects.

• Causes inotropy, chronotropy, and systemic and pulmonary vasodilatation.

• Indications: bradycardia, decreased cardiac output, bronchospasm (bronchodilator).

Isoproterenol

• Occasionally used to maintain heart rate 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

Milrinone/Amrinone

• Belong to class of agents “Bipyridines”

• 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

Milrinone/Amrinone

• Advantage over catecholamines:

–Independent action from -receptor activation, particularly when these

receptors are downregulated

(CHF and chronic catecholamine use)

Milrinone

• Increases CO by improving contractility, decreased SVR, PVR, lusotropic effect;

decreased preload due to vasodilatation

• Unique in beneficial effects on RV function

• Protein binding: 70%

• Half-life is 1-4 hours

Milrinone

• Elimination: primarily renally excreted

• Load with 50 mcg/kg over 30 minsfollowed by 0.25 to 0.75 mcg/kg/min

• No increase in myocardial O2 requirement

PDE Inhibition

Aminophylline

Milrinone

Sildenefil

PDE PDE 3 PDE 5

Milrinone

Minimal ↑ HR

↑ CO

Minimal ↑ in O2 demand ↓ SVR

↓ PVR

Diastolic Relaxation

Other Vasoactive Agents

BNP{ Brain natriuretic peptide }

• Secreted by ventricles in response to ↑ wall stress and volume overload

NESRITIDE{Recombinant Human BNP}

• Venous and arteriolar dilator, acts on Guanylate cyclase

• It reduces RA pressure, PCWP and cardiac index

• Dose: Infusion 0.01- 0.03 mcg/kg/min

• Hypotension

Nesiritide

• Nesiritide (recombinant human BNP) is a vasodilator with other theoretical effects including:

– natriuresis, neurohormonal inhibition, and reverse remodeling

– In the setting of Heart Failure, it has been shown to reduce pulmonary capillary wedge pressure

and improve shortness of breath relative to placebo

– Linked to possible renal failure and increased mortality in some patient populations

Vasodilators

• Classified by site of action

• Venodilators: reduce preload - Nitroglycerin

• Arteriolar dilators: reduce afterload Minoxidil and Hydralazine

• Combined: act on both arterial and venous beds and reduce both pre- and afterload Sodium Nitroprusside

(Nipride)

Nitroprusside

• Vasodilator that acts directly on arterial and venous vascular smooth muscle.

• Indicated in hypertension and low cardiac output states with increased SVR.

• Also used in post-operative cardiac surgery to decrease afterload on an injured heart.

• Action is immediate; half-life is short; titratable action.

Nitroprusside

• Toxicity is with cyanide, one of the metabolites of the breakdown of nipride.

• Severe, unexplained metabolic acidosis might suggest cyanide toxicity.

• Dose starts at 0.5 mcg/kg/min and titrate to 5 mcg/kg/min to desired effect. May go higher (up to

10 mcg/kg/min) for short periods of time.

Nitroglycerine

• Direct vasodilator as well, but the major effect is as a venodilator with lesser effect

on arterioles.

• Not as effective as nitroprusside in lowering blood pressure.

• Another potential benefit is relaxation of the coronary arteries, thus improving myocardial regional blood flow and

myocardial oxygen demand.

Nitroglycerine

• Used to improve myocardial perfusion following cardiac surgery

• Dose ranges from 0.5 to 8 mcg/kg/min. Typical dose is 2 mcg/kg/min for 24 to 48

hours post-operatively

• Methemoglobinemia is potential side effect

Relative receptor activity of most commonly used inotropes

α1 α2 β1 β2 DA

Norepinephrine +++ +++ + - -

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

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

Dobutamine + - +++ + -

Isoproterenol - - ++ ++ -

GOOD LUCK

SAMIR EL ANSARYICU PROFESSOR

AIN SHAMSCAIRO