Transcript CARDIOVASCULAR MEDICATIONS

Vasoactive Agents
in the PICU
PCCM Faculty
University of North Carolina
Pediatric Critical Care Medicine
Outline
Developmental physiology of
cardiovascular system
Basic terminology review
Description of most commonly used
agents by site and mechanism of action
What this will not teach you
Will not review specific algorithms (i.e.sepsis, low cardiac output syndrome,
anaphylaxis, etc) in detail
Developmental Physiology
Myocardial Contraction
Contractility increases over 1st months of
life along with:
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#’s of 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
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 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

Effects mediated via intracellular
concentration, calcium requirements of the
muscle cell, sensitivity of the myofilaments to
calcium
1
Vascular Smooth Muscle
Calcium dependent effects
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Agents that increase intracellular cAMP
increase intracellular calcium requirements for
contraction, thus encouraging smooth muscle
relaxation and vasodilation
Vascular Smooth Muscle
Calcium independent effects
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G protein mediated activation of
phospholipase C results in breakdown of
phosphatidylinositol bisphosphate into IP3 and
DAG.
IP3 releases calcium from the sarcoplasmic
reticulum initiating contraction and DAG
activates protein kinase C with
phosphorylation of intracellular proteins
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
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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 Odihydrobenzene
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
Low Dose
(<0.05-0.1 mcg/kg/min)
Epinephrine
β1 predominantly
↑HR
↓ Duration of Systole
↑ Myocardial contract
Periph. arteriolar dil.
↑/ ↓ Renal BF
↑ Renin secretion
↑/ ↓ Splanchnic BF
↑ Glucose
Hypokalemia
High Dose
(> 0.1 μg/kg/min)
α1 predominantly
Vasoconstriction
↓ Renal BF
↓ Splanchnic BF
↑ Glucose
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
possesses antidiuretic and vasopressor
properties
deficiency of this hormone results in
diabetes insipidus
Vasopressin
Vasopressin
Administration
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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
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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
Newer drug to ACLS for resuscitation
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 (? Effects on
UOP)
 C.O. in Cardiogenic or Distributive Shock 510mcg/kg/min ( adrenergic effects)
Post-resuscitation stabilization in patients with
hypotension (with fluid therapy) 1020mcg/kg/min ( adrenergic effects) peripheral
vasoconstriction,  SVR, PVR, HR, and BP—This
dose may be needed in preterm infants for medium dose
effects
Dose Dependent effect of
Dopamine
<5 mcg
5 - 10 mcg
> 10 mcg
Modest ↑ CO
↑Contractility
↑ HR,
↑ Renal BF
Minimal change in
HR and SVR
Vasoconstriction
↓Proximal Tub. Na
Absorbtion
↑ Renal BF
↑ Splanchnic BF
↑ Splanchnic BF
↑/ ↓ 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-Omethyldobutamine, 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
Dobutamine
L- isomer
Stimulates α1
D- isomer
Stimulates
β1 and β2
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
Advantage over catecholamines:
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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
Elimination: primarily renally excreted
Load with 50 mcg/kg over 30 mins followed by
0.25 to 0.75 mcg/kg/min
No increase in myocardial O2 requirement
PDE Inhibition
PDE
PDE 3
PDE 5
Aminophylline
Milrinone
Sildenefil
Milrinone
Minimal ↑ HR
↑ CO
Diastolic
Relaxation
Minimal ↑ in
O2 demand
↓ SVR
↓ PVR
Other Vasoactive Agents
NESRITIDE
Recombinant hBNP
Secreted by ventricles in response to ↑
wall stress and volume overload
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: Other Effects
Nesiritide (recombinant human BNP) is a
vasodilator with other theoretical effects
including:
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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
Summary
Relative receptor activity of most
commonly used inotropes
α1
α2
β1
β2
DA
Norepinephrine
+++
+++
+
-
-
Epinephrine
+++
++
+++
++
-
Dopamine
++
+
++
+++
+++
Dobutamine
+
-
+++
+
-
Isoproterenol
-
-
++
++
-
Receptor Activity (continued)