1. Intensive Care Cardiovascular Pharmacology
Toni Petrillo-Albarano, MD
Director, Pediatric Transport
Division of Critical Care Medicine

2. The “nervous system” is divided into the peripheral and central systems.
Our discussion begins by directing our attention to the peripheral nervous system which is divided into the:
autonomic system which controls cardiac and smooth muscle contraction and glandular secretion
and
somatic system supplying skeletal muscle and conducting sensory information such as pain and touch.
The autonomic system is then further divided into the sympathetic system which is generally catabolic expending energy and the parasympathetic which is anabolic which conserves energy.

3. Cardiovascular Pharmacology Terminology Review
Catecholamines
Naturally occurring, biologically active amines
Sympathomimetic
Mimics stimulation of the sympathetic nervous system
Catecholamines transmit most impulses to the sympathetic system
Examples are norepinephrine and epinephrine which diffuse across the synaptic cleft and bind to post synaptic adrenergic receptors

4. Cardiovascular Pharmacology Terminology Review
Adrenergic
Refers to the sympathetic nervous system
Cholinergic
Refers to the parasympathetic nervous system
Dopaminergic
Dopamine receptors in renal, visceral, coronary, and cerebral areas
Acetylcholine, hence cholinergic, transmits all parasympathetic signals to end organs (heart lungs etc)
Adrenergic or adrenoreceptors are broken down into 2 subtypes
alpha receptors and beta receptors

5. Cardiovascular Pharmacology Terminology Review
Inotropic
Influencing the force of contraction
Chronotropic
Influencing the rate of contraction

6. Cardiovascular Pharmacology Adrenoreceptors
Six receptor subtypes:
alpha 1 (postsynaptic)
alpha 2 (presynaptic)
beta 1 (cardiac)
beta 2 (vascular/bronchial smooth muscle)
DA 1 (postsynaptic)
DA 2 (presynaptic)
Alpha receptors are located on
vascular smooth muscle
presynaptic nerve terminals
blood platelets
fat cells
brain cells
two major types alpha 1 and alpha 2
Beta receptors are located on
smooth muscle
cardiac muscle
some presynaptic nerve terminals
lipocytes
brain
Dopaminergic receptors especially important in
- renal
- splanchnic
- brain

7. Cardiovascular Pharmacology Adrenoreceptors
ALPHA 1:
Vasoconstriction
Mydriasis
Uterine contraction
Bladder contraction
Insulin inhibition
Glucagon inhibition
ALPHA 2:
Inhibition of norepinephrine release

8. Cardiovascular Pharmacology Adrenoreceptors
BETA 2:
Vasodilation
Bronchodilation
Uterine relaxation
Bladder relaxation
Insulin release
Glucagon release
BETA 1:
Inotropy
Chronotropy
Lipolysis

9. Cardiovascular Pharmacology Adrenoreceptors
Desensitization:
2o to Chronic exposure
Mechanisms
uncoupling
downregulation
sequestration
Uncoupling of the receptor from the G protein prevents signal transduction
Downregulation: reduction in total number or density of beta receptors by increased receptor destruction or decreased receptor synthesis or both
Sequestration involves the internalization of the receptor from the cell surface. Takes place over minutes to hours. in contrast to downregulation this permits recycling of the receptor back to the surface once beta exposure ceases. Steroid affect this by upregulation.

10. VASOMOTOR CENTER
Sympathetic
autonomic
nervous
system
Parasympathetic
autonomic
nervous
system
Autonomic
feedback loop
Baroreceptors
Peripheral
vascular
resistance
Contractile
force
Venous
tone
Heart
rate
Mean
arterial
pressure
Cardiac
output
Venous
return
feedback loop
Hormonal
Stroke
volume
Blood
volume
Aldosterone
Renal blood
flow/pressure
Renin
Angiotensin

11. Cardiac Output C.O.=Heart Rate x Stroke Volume Heart rate
Preload- volume of blood in ventricle
Afterload- resistance to contraction
Contractility- force applied

12. Preload Afterload Contractility x Stroke Volume Heart Rate O2 Content
Cardiac Output
Resistance
In order to understand the indications and effects of CV drugs that moderate volume, flow and pressure to ultimately improve O2 delivery we must understand the interactions that occur in the cardiovascular system.
When one can identify the physiologic derangement treatment can be tailored to address the specific problem.
Before reviewing individual drugs we will review the normal physiology and interactions of the CV system to maintain systemic O2 delivery
O2 Delivery
Arterial Pressure

13. Shock Inadequate tissue perfusion to meet the tissue demands
a result of inadequate blood flow and/or inadequate oxygen delivery.
Shock is defined as a state of circulation characterized by inadequate tissue perfusion and oxygen delivery. Although inadequate BP is used as a criteria for shock, inadequate regional perfusion may occur in the absence of a normal arterial BP
- insert PALS graph

14. Mechanical Requirements for Adequate Tissue Perfusion
Fluid
Pump
Vessels
Flow

15. SHOCK Physiology of Shock Septic (Distributive) Cardiogenic
Obstructive
Hypovolemic
Shock may be classified based on hemodynamic mechanisms
SHOCK

16. Hypovolemic Shock: Inadequate Fluid Volume (decreased preload)
Fluid depletion
internal
external
Hemorrhage

17. Cardiogenic Shock: Pump Malfunction (decreased contractility)
Electrical Failure
Mechanical Failure
cardiomyopathy
metabolic
anatomic
hypoxia/ischemia

18. Distributive Shock Abnormal Vessel Tone (decreased afterload) Sepsis
Anaphylaxis
Neurogenesis (spinal)
Drug intoxication (TCA, calcium channel blocker)

19. Pericardial tamponade Pulmonary embolism Pulmonary hypertension
OBSTRUCTIVE SHOCK
OBSTRUCTED FLOW
Pericardial tamponade
Pulmonary embolism
Pulmonary hypertension

20. Hemodynamic Assessment of Shock

21.   ß Alpha-Beta Meter Dopamine Epinephrine Norepinephrine Dobutamine
  ß
Dopamine
Epinephrine
Dobutamine
Norepinephrine
Neosynephrine
Isoproternol

22. Cardiovascular Pharmacology Dopamine
Usage:
activates multiple receptors
DA1, DA2, beta, alpha
receptors activated in dose related manner
shown to increase at low doses:
glomerular filtration rate
renal plasma flow
urinary Na+ excretion
Dopamine is an intermediary product in the enzymatic pathway leading to the production of norepinephrine and ultimately epinephrine

23. Cardiovascular Pharmacology Dopamine
Pharmacodynamics:
mcg/kg/min dopaminergic
mcg/kg/min beta 1
mcg/kg/min alpha
Little of any CV improvement with lower doses of dopamine but CI rises once dopamine infusion rates exceed 5 g/kg/min
Tachycardia contributes to increased CI at infusion rates of 7.5 g/kg/min
High dose dopamine elevates systemic arterial pressure in preterm infants with shock
- achieved by increase SVR and increase HR
LV contractility falls with the cause of this reduced inotropic response related to decreased norepinephrine stores

24. Cardiovascular Pharmacology Dopamine
Indications:
Low cardiac output
Hypotension with SVR
Risk of renal ischemia

25. Renal Dose Dopamine (RDD) Fact or Fiction? Summary of the Data
In healthy humans and animal models, RDD augments:
RBF, GFR, and natriuresis
In experimental models of ischemia and nephrotoxic ARF, RDD augments:
Denton et al, Kidney Int. 49:4-14,1996

26. Renal Dose Dopamine (RDD) Fact or Fiction? Summary of the Data
Most human studies failed to demonstrate:
RDD prevents ARF in high risk patients
improves renal function or effects outcome in established ARF
The “dark side”
cardiovascular and metabolic complications
Show side effect slide - as with everything we do there are positive and negative effects
Denton et al, Kidney Int. 49:4-14,1996

27. Cardiovascular Pharmacology Dopamine
Complications:
activity with NE depletion
PA pressure
pulmonary vascular resistance
dysrhythmias
renal vasoconstriction
tissue necrosis
Dopamine activity can be decrease by as much as 50% when Ne stores are lacking. Ie Chronic CHF, immaturity
Dark side complications CV
- tachyarrythmias
- increase R&R ventricular afterload
- increased intrapulmonary shunting and worsening hypoxemia
metabolic
increase natriuresis at expense of tubular cell ischemia by blunting tubular glomerular filtration rate which protects tubular cells against ischemia.

28. Is Dopamine the Devil?
Dopamine administration can reduce the release of a number of hormones from the anterior pituitary gland, including prolactin which can have important immunoprotective effects
Dopamine administration was associated with ICU and hospital mortality rates 20% higher than in patients with shock who did not receive dopamine
Critical Care Medicine - Volume 34, Issue 3 (March 2006)

29. Cardiovascular Pharmacology Dobutamine
Synthetic catecholamine
Direct beta1 weak alpha
Indications:
Low cardiac output in patients at risk for:
Myocardial ischemia
Pulmonary hypertension
LV dysfunction (cardiomyopathy)
Modified from isoproterenol
More direct B1 agonist than isoproterenol which is non selective
Actually has weak alpha1 agonism which can be unmasked by B blockade and manifest as severe HTN
Strong inotropy weak vasodilator
Dilates coronaries

30. Dobutamine Pharmacodynamics

31. Isoproterenol (Isuprel)
Major indication
bradycardia
Pure beta
Potent pulmonary/ bronchial vasodilator
Increased cardiac output
Widened pulse pressure
Increased flow to noncritical tissue beds (skeletal muscle)

32. Isoproterenol (Isuprel) Drawbacks
Tachycardia
Dysrhythmias
Peripheral vasodilation
Increased myocardial consumption
CPK indicating myocardial necrosis
Decreased coronary O2 delivery
“Splanchnic steal” by skeletal muscle

33. Epinephrine Indications
Pressor of choice post-arrest
Shock
with bradycardia
unresponsiveness to other vasopressors
anaphylaxis
Low cardiac output syndrome

34. Epinephrine Pharmacokinetics
Limited data available in children
Plasma concentration varies linearly with infusion rate
Clearance
m/kg/min

35. Most potent catecholamine Direct acting
Epinephrine Effects
Most potent catecholamine
Direct acting
no catecholamine stores needed
Prominent alpha and beta effects
Increased diastolic pressures

36. Epinephrine Pharmacodynamics

37. Epinephrine Complications Renal ischemia Dysrhythmias
Severe hypertension
Myocardial necrosis
Hyperglycemia
Hypokalemia

38. Norepinephrine Levophed
Leave ‘em Dead!

39. Norepinephrine (Levophed) Indications
Sepsis with vasodilation unresponsive to volume expansion
Hypotension unresponsive to therapy
Dose:
mcg/kg/min
t 1/2 = min

40. Norepinephrine (Levophed) Effects
Potent peripheral alpha agonist
Little beta 1 effects
Minimal to no beta 2
Produces
vasoconstriction
SVR, PVR
increases systolic, MAP, diastolic BP
Increased SVR may or may not alter CO depending on how much you increase the afterload. a little may improve CO too much may decrease CO

41. Norepinephrine (Levophed) Complications
Renal vasoconstriction
may be decreased with dopamine
Possible cardiac function due to increased afterload
Dysrhythmias
Tissue necrosis
2 studies show benefit
Martin et al CCM
24 patients with septic shock
NE and titrated to maintain Nl SBP
20/24 pt return urine flow, decreased serum creatinine, increased creatinine clearance
none got low dose dopa or lasix
4 patients remained oliguric
2/4 died 2/4 renal failure
Hoogenburg et al
low dose dopa + increasing doses norepi in healthy volunteers
norepi caused decreased renal plasma flow but not GFR
norepi + dopa prevented decreased renal plasma flow, increased sodium excretion attenuated HTN and renal vasoconstriction
results of study sufficiently strong to recommend low dose dopamine in all critically ill patients requiring norepi.

42. Milrinone (Primacor) Mechanism of action Pharmacodynamics:
Phosphodiesterase III inhibitor
Pharmacodynamics:
Almost pure inotrope CI
Potent vasodilator
SVR
PVR
Bolus: 50 mcg/kg
Infusion: mcg/kg/min

43. Milrinone (Primacor) Pharmacokinetics: Side effects: Advantages:
t 1/2 = 90 min
Side effects:
Hypotension
Thrombocytopenia
Advantages:
No precipitation
Short t 1/2

44. Vasopressin ADH Analog
Increases cyclic adenosine monophosphate (cAMP) which increases water permeability at the renal tubule resulting in decreased urine volume and increased osmolality
direct vasoconstrictor (primarily of capillaries and small arterioles) through the V1 vascular receptors
directly stimulates receptors in pituitary gland resulting in increased ACTH production; may restore catecholamine sensitivity

45. Vasopressin
Vasodilatory shock with hypotension unresponsive to fluid resuscitation and exogenous catecholamines
units/kg/minute ( units/kg/hour); titrate to effect

46. A Rational Approach to Pressor Use in the PICU
Shock / Hypotension
Volume Resuscitation
Signs of adequate circulation
Adequate MAP
NO pressors
Yes NO

47. A Rational Approach to Pressor Use in the PICU
Signs of adequate circulation
Adequate MAP NO
Dopamine?? Or perhaps now NE
Inadequate MAP
Norepi

48. A Rational Approach to Pressor Use in the PICU Milrinone or dobutamine
norepinephrine
adequate MAP
Milrinone or dobutamine CO
Inadequate MAP
low C.O.
Good C.O
epinephrine
Vasopressin

49. Questions ???