NEW CONCEPTS IN
VASOACTIVE
THERAPY
Jerrold H Levy, MD
Professor of Anesthesiology
Deputy Chairman for Research
Emory University School of Medicine
Cardiothoracic Anesthesiology and Critical Care
Emory Healthcare
Atlanta, Georgia
VASOACTIVE THERAPY
Vasodilators
BP
=
SVR
X
Beta Blockers
Other agents
CO
(SV x HR)
Vasoconstrictors
Inotropes
PHARMACOLOGIC APPROACHES FOR
BIVENTRICULAR DYSFUNCTION
PERIOPERATIVELY AND IN THE ICU
• Vasodilator therapy • Pulmonary
vasodilators
• Inotropic agents
– PDE inhibitors
– Catecholamines
– Inhaled NO
– Phosphodiesterase
• Prostaglandin
inhibitors

s
– Digoxin, calcium ,

• New agents
T3
Nesiritide,
Levosimendan
Bailey JM, Levy JH: Cardiac surgical pharmacology. Edmunds H (ed), McGraw Hill, New York, pp.
225-254, 1997.
Levy JH: Milrinone. Ann Thorac Surg 2002;73:325-30.
Levy JH: Postoperative circulatory control. Cardiac Anesthesia, 1233-1258, 4th Edition, W.B.
Saunders, Philadelphia, 1998.
VASODILATORS(1)
•
•
•
•
•
•
•
ACE inhibitors
Adenosine
A-II antagonists
Alpha1 adrenergic antagonists
Alpha2 adrenergic agonists
BNP (nesiritide)
Beta2 adrenergic agonists
VASODILATORS(2)
•
•
•
•
•
•
•
Calcium channel blockers
Dopamine1 agonists
Hydralazine
Nitrovasodilators
Nitric oxide
Phosphodiesterase inhibitors
Prostaglandins
SELECTIVE
VASODILATORS
• Nitroglycerin: due to selective
metabolism to nitric oxide
• Inhaled nitric oxide: due to
optimizing ventilation/perfusion
ratios and minimizing
intrapulmonary shunting
Mechanisms of Nitrate Tolerance
•
•
•
•
•
Decreased bioconversion to nitric oxide1
Cellular depletion of sulfhydryl groups2,3
Neurohumoral adaptations4
Superoxide anion production5
Upregulation of endothelin 16
1.
2.
3.
4.
5.
6.
Münzel T. Am J Cardiol. 1996;77:24C-30C.
Parker JD, Parker JO. N Engl J Med. 1998;338:520-531.
Needleman P, Johnson EMJ. J Pharmacol Exp Ther. 1973;184:709-715.
Münzel T, et al. J Am Coll Cardiol. 1996;27:297-303.
Münzel T, et al. J Clin Invest. 1995;95:187-194.
Münzel T, et al. Proc Natl Acad Sci. 1995;92:5244-5248.
Nitrovasodilators
Sodium Nitroprusside
NO+
CN
CN
Na+
CN
Fe++
CN
Na+
CN
NITROPRUSSIDE THERAPY
• Potent venodilator/arterial
vasodilator
• Cardiac output is often affected
due to venodilation
• Volume replacement is often
required for venodilation
Limitations of Nitrovasodilators for Acute
Heart Failure
• Nitroglycerin
– Efficacy in CHF ±1
– Tachycardia2
– Tachyphylaxis3
– Neurohormonal
activation due to
reflexive sympathetic
activity4
1
2
3
4
5
• Nitroprusside
– Difficult titration
– Arterial line monitoring due
to excessive hypotension
risk3
– Tachycardia3
– Coronary steal3
– Pulmonary shunting3
– Thiocyanate toxicity3
– Neurohormonal activation
due to reflexive sympathetic
activity4,5
Publication Committee for the VMAC Investigators. JAMA 2002; 287 (12): 1531-40.
Robertson R, et al. ''Chapter 32: Drugs Used for the Treatment of Myocardial Ischemia'' in
Pharmacologic Basis of Therapeutics,Goodman and Gilman, Eds. 9th. Edition 1996, McGraw-Hill.
Kelly and T Smith, ‘‘Chapter 34: Pharmacologic Treatment of Heart Failure’‘, in The
Pharmacologic Basis of Therapeutics, 9th. Ed. Goodman and Gilman, eds. 1996 McGraw-Hill.
Abraham W. Natriuretic peptides in heart failure. Heart Failure 1996; 12:391-393.
J Oates, J. Chapter 33: Antihypertensive Agents and Drug Treatment of Hypertension’‘, in The
Pharmacologic Basis of Therapeutics, 9th. Ed. Goodman and Gilman, eds. 1996 McGraw-Hill.
MAINSTAY VASOACTIVE THERAPY
FOR ACUTE HEART FAILURE IN
CRITICALLY ILL PATIENTS
•
•
•
•
•
•
Diuretics
Dobutamine
Enalaprilat
Milrinone
Nesiritide
Nitrovasodilators
MAINSTAY IV THERAPY FOR
HYPERTENSION IN CRITICALLY
ILL PATIENTS
• Beta adrenergic blockers
• Dihydropyridine (DHP) calcium
channel blockers (Nicardipine IV)
• Enalaprilat
• Hydralazine
• Nitrovasodilators (nitroprusside
and nitroglycerin
IV DHP CALCIUM
CHANNEL BLOCKERS
• 1st generation: nifedipine
• 2nd generation:
nicardipine, isradipine
• 3rd generation: clevidipine
DHP CALCIUM CHANNEL
BLOCKERS:CLINICAL
APPLICATIONS
•
•
•
•
No effects on SA/AV node
No myocardial depression
Cerebral and coronary vasodilator
Important applications in the ICU and
perioperative management of neuro and
CV disease. Has also been reported for
pregnancy induced hypertension
• Nicardipine is the first IV drug of this
class available in the US (94)
HEMODYNAMIC EFFECTS
OF IV NICARDIPINE
HR
MAP
PAOP
MPAP
RAP
CI
LV
LVEF
Control
71 ± 13
107 ± 14
9±4
15 ± 3
8±3
2.2 ± 0.3
1509 ± 376
57 ± 9
Nicardipine
70 ± 14
80 ± 9
8±3
16 ± 4
8±2
2.8 ± 0.4
1680 ± 485
68 ± 7
Lambert CR: Am J Cardiol 1993;71:420
HEMODYNAMIC EFFECTS OF IV ISRADIPINE
Variable
SBP
DBP
Baseline
150 ± 20
75 ± 9
30 Minutes
-30 ± 30‡
-18 ± 8.0‡
MAP
HR
CI
101 ± 10
89 ± 12
2.7 ± 0.6
-23 ± 11.0‡
4 ± 12*
0.4 ± 0.6‡
SVR
SVI
PADP
PCW
470 ± 417
0.0310 ± 0.006
13.4 ± 3.9
11.7 ± 4.3
-478 ± 281‡
0.004 ± 0.006†
0.2 ± 3.2
-0.0 ± 3.0
PVR
1.25 ± 0.9
-0.05 ± 0.47
Leslie: Circulation. 1994 Nov;90(5 Pt 2):II256
Should a moratorium be
placed on sublingual
nifedipine capsules given
more hypertensive
emergencies and pseudo
emergencies?
Gross et al: JAMA
1996:276;1342-3
Nicardipine IV Dosing (PI)
•
•
Initiation: 5 mg/hr (50 ml/hr)
Titration for gradual BP reduction:
•
For more rapid BP reduction:
•
Maintenance: Following achievement of
BP goal, adjust infusion rate to 3 mg/hr,
(30 ml/hr)
 rate 2.5 mg/hr (25 ml/hr) q 15 min to a
maximum of 15 mg/hr (150 ml/hr) until
blood pressure reduction achieved
 rate 2.5 mg/hr (25 ml/hr) q 5 min to a
maximum of 15 mg/hr (150 ml/hr) until
blood pressure reduction achieved
Nicardipine IV Dosing (FRANCE)
• For hypertensive urgency, Rx should
be adapted so BP decrease is not >25%
in 1 hr to avoid myocardial, cerebral or
renal ischemia.
• Rapid effect: 1 mg/min to 10 mg
• Progressive effect: 8-15 mg/h to 30
min, then 2 to 4 mg/h maintenance
• Infant: 1 to 2 mg/m2 of body surface
in 5 minutes.
Ref: http://www.biam2.org/www/Spe4359.html#Voie
Clevidipine in CABG: a dose-finding
study. Bailey JM et al:Anesthesiology
2002;96:1086
• Clevidipine, an ultrashort acting agent,
decreased MAP and SVR, without changes
in heart rate, CVP, PAOP, or CI at
increasing doses.
• The early phase of drug disposition had a
half-life of 0.6 min. The context-sensitive
half-time <2 min for up to 12 h of
administration.
• CONCLUSION: Clevidipine is a
dihydropyridine CCB that lowers BP
without changing heart rate, CI, or cardiac
filling pressures.
Fenoldopam (Corlopam)
• Selective vascular DA1 agonist
• Produces arterial vasodilation,
increases renal perfusion, and
natruresis
• Short duration of action/half life
• Approved in June 1997
• Expense and potency are major
issues
NOVEL AGENTS:
Nesiritide
(Human B-type
Natriuretic
Peptide)
Natriuretic Peptides: The Heart as a Secretory Organ
•Secretory granules found on EM
of atria. Kisch, Exp Med Surg 1956
•Balloon catheter in atria of dogs
resulted in diuresis: Henry and
Pearce, J Exp Phys 1956
•Homogenized atrium injected IV
cuases natriuresis, diuresis. DeBold, Life Sciences, 1981
•ANP identified in 1984. Kangawa
•BNP identified in 1988 in porcine
brain. Nature, 1988
•Amino acid sequence and DNA
clones: Sudoh et al, 1988 and
Seilhamer et al, 1989
Natriuretic Peptides
NH 22N- Ser
H2N- Ser
Pro
ANP
Leu
Arg
Arg
Gly
Phe
Ser
Ser
Gly Arg
Asp
S
S
COOH-
Gin
Gly
Ser
IIe
Gly
Leu
Arg
Gly Ser
Gly
Phe
Arg Lys
Met
Asp
Gly Cys
Gly
Cys
Ser
Phe
BNP
Val
Arg
Cys
Asn
Lys
Met
Met
Ala
Gin
Arg
IIe
S
S
Tyr
Val
Ser
Cys
Lys Gly
Ser
Leu
Leu
Arg
Gly Ser
Ser
Arg
HOOC- His
Pro
Ala
Thr
Arg Ser
Urodilatin
Leu
Arg
Arg
Gly
Phe
Ser
NH
NH2
Ser
Cys
Gly Arg
Arg
IIe
S
S
Ser
Phe
Arg
HOOC- Tyr
Cys
Asn
Gly
H
H2N- Gly
Leu
Met
Asp
Gly
Ala
Leu
Gin
Gly Ser
CNP
Gly
Phe
Ser
Lys
Gly
Leu Lys
Leu
Asp
Arg
Cys
IIe
S
S
HOOC- Cys
Gly
Gly
Ser
Leu
Gly Ser
Met
hBNP for Rx
of decompensated heart failure
Nesiritide (h-BNP) is identical to the endogenous naturally
occurring hormone, with identical pharmacological profile
D
M
K
R
G
F
S P K M V Q G S
R I S S
C
G
S
S
S
S
G
L
H
G
R
C
R
K V L
32 amino acid sequence
Recombinant technology using E-coli
NOTE: hBNP affects assay for BNP, but can still use proBNP or one of the proANP assays
Physiology of Natriuretic Peptides
+
Cardiac
Wall
Stress
-
Urodilatin
ANP+BNP
Neutral
Endopeptidases
Clearance
CNP
NPR-A/NPR-B
NPR-B
?NPR-D
NPR-C
Decreased
Vascular Growth
Decreased
Blood Pressure
Increased
Na/H20 Excretion
Adapted from Wilkins MR. Redondo J. Brown LA. Lancet 1997;349:1307-1310
B-Type Natriuretic Peptide (BNP)
Physiologic Effects
• Systemic Hemodynamic
– Preload reduction1,5
– Afterload reduction1,5
– Increased CI1,5
– No tachycardia1,5
• Neurohormonal
• Coronary Arteries
– Vasodilates2,3
• Renal
– Diureses and natriuresis1
– Increased filtration fraction6
– GFR effect variable6
1Colucci
– Decrease endothelin-14
– Inhibit RAA axis1,5
– Decrease norepinephrine5
WS, et al. NEJM 2000; 343(4):246-253
Kato H. Yasue H. Yoshimura M.Tanaka H. Miyao Y. Okumura K. Am Heart J 1994; 128: 1098-1104
3 Okumura K, et al. J Am Coll Cardiol 1995 Feb;25(2):342-8.
4Aronson D, et al. J Am Coll Cardiol, February 2001. Abstract from Poster Session 1046
5Abraham WT, et al. J Card Failure 1998; 4(1): 37-44
6Jensen KT, et al. Clinic Sci 1999;96:5-15
2
Clearance Pathways
Vascular Smooth Muscle Cell
GC= Guanylate Cyclase
GC-A
GTP
G/C
cGMP
GC-B
Biological
Effects
G/C
hBNP
?
NP-C
NP=neutral
endopeptidase
Clearance
receptor
clearance pathway
Nakao et al Can J Physiol Pharmacol, 1991, 69: 1500-1506
Neurohumoral Activation in Heart
Failure
Myocardial injury
Fall in LV performance
Activation of RAAS, SNS, ET,
and others
Myocardial toxicity
-
ANP
BNP
Peripheral vasoconstriction
Hemodynamic alterations
Remodeling and
progressive
worsening of
LV function
Heart failure symptoms
Morbidity and mortality
The Natriuretic Peptide System is Overwhelmed
in Acute Decompensated Heart Failure
ANP BNP
Endothelin
Aldosterone
Angiotensin II
Epinephrine
Adapted from Burnett JC, J Hypertens 1999
Natriuretic Peptide System
Sympatho-inhibitory
ET inhibition
Vasodilation
ANP
BNP
ANP
ANP
BNP
CNP
ANP
BNP
Antiproliferation
effect
BNP
ANP
BNP
Anti-fibrotic
Lusitropic
Vasodilation
•veins
•arteries
•coronaries
•pulmonary
Aldosterone
inhibition
Natriuresis
Renin inhibition
Pharmacologic Actions of Human BNP
R I SS
D
S
M
S
K
G
R
L
G
H
G
F
R
C
C S S
K V LR
G
S PK M V Q GS
Cardiac
• lusitropic
• anti-fibrotic
• anti-remodeling
Hemodynamic
 veins
 arteries
 coronary arteries
Neurohumoral
aldosterone
endothelin-1
norepinephrine
Renal
 diuresis
 natriuresis
Nesiritide Reconstitution
and Standard Dosing
• 1.5 mg vial reconstituted with 5 mL NS, 1/2NS, 1/4NS, or D5W
• Add 5 mL from reconstituted vial into 250 mL bag for a final
concentration of 6 mg/mL
• Administration via peripheral IV or non-heparin coated central line
catheter
Standard Dosing:
2 mcg/kg bolus + 0.01 mcg/kg/min continuous infusion
• Bolus volume (ml): Patient weight (Kg) / 3
• Infusion (ml/hour): 0.1 x patient weight (Kg)
• Duration: Dependent on clinical need – NO maximum duration
NB: Most patients are expected to be managed without dose adjustment
Nesiritide Clinical Summary
• Nine clinical trials in CHF. Over 900 CHF patients studied.
• Trials included patients with ACS, renal disease, serious
arrhythmias
• Studied with a wide variety of concomitant medications
Summary of Trial Data:
• Improves hemodynamics and CHF symptoms such as
dyspnea
• Decreases diuretic need and/or increases urine output
• Suppresses neurohormones
• More effective than IV NTG
• No tachyphylaxis
• No tachycardic or proarrhythmic effects
• Can be used safely with b-blockers
• Hypotension is the major side effect
NOVEL AGENTS:
Levosimendan
Calcium Sensitisation by
Levosimendan
• Enhanced contractility of myocardial cell
by amplifying trigger for contraction with
no change in total intracellular Ca2+
Effects of Opening
ATP-Sensitive Potassium
Channels
• Reduces preload and afterload
• Increased coronary blood flow
(Lilleberg et al. Eur Heart J. 1998;19:660-668.)
• Anti-ischemic effect
(Kersten et al. Anesth Analg.
2000;90:5-11;Kaheinen et al.
J Cardiovasc Pharmacol.
2001;37:367-374.)
Opening of ATP-Sensitive
Potassium Channels
•Activation of KATP channels in
coronary vascular smooth muscle
(Kaheinen J Cardiovasc Pharmacol. 2001;37:367374.)
•Results in venous, arterial, and
systemic vasodilation
Pharmacokinetic
Profile
• Active drug (t1/2= 1h)
– Rapid onset of action
– Titratability
• Active metabolite (t1/2= ~80h)
– Sustained hemodynamic
response
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