new concepts in vasoactive therapy l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
NEW CONCEPTS IN VASOACTIVE THERAPY PowerPoint Presentation
Download Presentation
NEW CONCEPTS IN VASOACTIVE THERAPY

Loading in 2 Seconds...

play fullscreen
1 / 40

NEW CONCEPTS IN VASOACTIVE THERAPY - PowerPoint PPT Presentation


  • 281 Views
  • Uploaded on

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. Beta Blockers

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'NEW CONCEPTS IN VASOACTIVE THERAPY' - elina


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
new concepts in vasoactive therapy
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
VASOACTIVE THERAPY

Vasodilators

Beta Blockers

Other agents

BP = SVR X CO

(SV x HR)

Inotropes

Vasoconstrictors

pharmacologic approaches for biventricular dysfunction perioperatively and in the icu
PHARMACOLOGIC APPROACHES FORBIVENTRICULAR DYSFUNCTION PERIOPERATIVELY AND IN THE ICU
  • Pulmonary vasodilators
    • PDE inhibitors
    • Inhaled NO
      • Prostaglandins
  • New agents Nesiritide, Levosimendan
  • Vasodilator therapy
  • Inotropic agents
    • Catecholamines
    • Phosphodiesterase inhibitors
    • Digoxin, calcium, T3

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
VASODILATORS(1)
  • ACE inhibitors
  • Adenosine
  • A-II antagonists
  • Alpha1 adrenergic antagonists
  • Alpha2 adrenergic agonists
  • BNP (nesiritide)
  • Beta2 adrenergic agonists
vasodilators 2
VASODILATORS(2)
  • Calcium channel blockers
  • Dopamine1 agonists
  • Hydralazine
  • Nitrovasodilators
  • Nitric oxide
  • Phosphodiesterase inhibitors
  • Prostaglandins
selective vasodilators
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
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. Münzel T. Am J Cardiol. 1996;77:24C-30C.

2. Parker JD, Parker JO. N Engl J Med. 1998;338:520-531.

3. Needleman P, Johnson EMJ. J Pharmacol Exp Ther. 1973;184:709-715.

4. Münzel T, et al. J Am Coll Cardiol. 1996;27:297-303.

5. Münzel T, et al. J Clin Invest. 1995;95:187-194.

6. Münzel T, et al. Proc Natl Acad Sci. 1995;92:5244-5248.

nitroprusside therapy
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

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

Limitations of Nitrovasodilators for Acute Heart Failure

1 Publication Committee for the VMAC Investigators. JAMA 2002; 287 (12): 1531-40.

2 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.

3 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.

4 Abraham W. Natriuretic peptides in heart failure. Heart Failure 1996; 12:391-393.

5 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
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
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
IV DHP CALCIUM CHANNEL BLOCKERS
  • 1st generation: nifedipine
  • 2nd generation: nicardipine, isradipine
  • 3rd generation: clevidipine
dhp calcium channel blockers clinical applications
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
HEMODYNAMIC EFFECTS OF IV NICARDIPINE

ControlNicardipine

HR 71 ± 13 70 ± 14

MAP 107 ± 14 80 ± 9

PAOP 9 ± 4 8 ± 3

MPAP 15 ± 3 16 ± 4

RAP 8 ± 3 8 ± 2

CI 2.2 ± 0.3 2.8 ± 0.4

LV 1509 ± 376 1680 ± 485

LVEF 57 ± 9 68 ± 7

Lambert CR: Am J Cardiol 1993;71:420

hemodynamic effects of iv isradipine
HEMODYNAMIC EFFECTS OF IV ISRADIPINE

Leslie: Circulation. 1994 Nov;90(5 Pt 2):II256

slide17

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
Nicardipine IV Dosing (PI)
  • Initiation: 5 mg/hr (50 ml/hr)
  • Titration for gradual BP reduction:

 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

  • For more rapid BP reduction:

 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

  • Maintenance: Following achievement of BP goal, adjust infusion rate to 3 mg/hr, (30 ml/hr)
nicardipine iv dosing france
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 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
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
natriuretic peptides the heart as a secretory organ
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. De- Bold, 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
slide25

I

S

R

S

D

S

M

S

K

G

R

L

G

H

G

F

R

C

R

S

S

C

L

K

V

G

K

P

M

S

S

V

Q

G

hBNP for Rx of decompensated heart failureNesiritide (h-BNP) is identical to the endogenous naturally occurring hormone, with identical pharmacological profile

  • 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

slide26

Physiology of Natriuretic Peptides

Cardiac

Wall

Stress

+

-

Urodilatin

ANP+BNP

Neutral

Endopeptidases

NPR-B

?NPR-D

Clearance

NPR-A/NPR-B

CNP

NPR-C

Decreased

Blood Pressure

Increased

Na/H20 Excretion

Decreased

Vascular Growth

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

Coronary Arteries

Vasodilates2,3

Neurohormonal

Decrease endothelin-14

Inhibit RAA axis1,5

Decrease norepinephrine5

Renal

Diureses and natriuresis1

Increased filtration fraction6

GFR effect variable6

B-Type Natriuretic Peptide (BNP) Physiologic Effects

1Colucci WS, et al. NEJM 2000; 343(4):246-253

2 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

slide28

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
Neurohumoral Activation in Heart Failure

Myocardial injury

Fall in LV performance

ANP

BNP

Activation of RAAS, SNS, ET,

and others

-

Peripheral vasoconstriction

Hemodynamic alterations

Myocardial toxicity

Remodeling and

progressive

worsening of

LV function

-

Heart failure symptoms

Morbidity and mortality

the natriuretic peptide system is overwhelmed in acute decompensated heart failure
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

slide31

Natriuretic Peptide System

Sympatho-inhibitory

ANP

BNP

  • Anti-fibrotic
  • Lusitropic
  • Vasodilation
  • veins
  • arteries
  • coronaries
  • pulmonary

ET inhibition

Vasodilation

ANP

ANP

BNP

BNP

ANP

CNP

BNP

ANP

Aldosteroneinhibition

BNP

Antiproliferationeffect

Natriuresis

Renin inhibition

pharmacologic actions of human bnp

I

S

R

S

D

S

M

S

K

G

R

L

G

H

G

F

R

C

R

S

S

C

L

K

V

G

K

P

M

S

S

V

Q

G

Pharmacologic Actions of Human BNP

Hemodynamic

veins

 arteries

 coronary arteries

Neurohumoral

aldosterone

endothelin-1

norepinephrine

  • Cardiac
  • lusitropic
  • anti-fibrotic
  • anti-remodeling

Renal

diuresis

natriuresis

nesiritide reconstitution and standard dosing
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
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
calcium sensitisation by 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
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
Opening of ATP-Sensitive Potassium Channels
  • Activation of KATP channels in coronary vascular smooth muscle (Kaheinen J Cardiovasc Pharmacol. 2001;37:367-374.)
  • Results in venous, arterial, andsystemic vasodilation
pharmacokinetic profile
Pharmacokinetic Profile
  • Active drug (t1/2= 1h)
    • Rapid onset of action
    • Titratability
  • Active metabolite (t1/2= ~80h)
    • Sustained hemodynamic response