NEW CONCEPTS IN VASOACTIVE

THERAPY

Jerrold H Levy, MDProfessor of Anesthesiology

Deputy Chairman for ResearchEmory University School of Medicine

Cardiothoracic Anesthesiology and Critical CareEmory HealthcareAtlanta, Georgia

VASOACTIVE THERAPY

VasoconstrictorsVasoconstrictors

BPBP = = SVRSVR X X COCO

VasodilatorsVasodilators

(SV x HR)(SV x HR)

Inotropes

Beta BlockersOther agents

PHARMACOLOGIC APPROACHES FORBIVENTRICULAR DYSFUNCTION

PERIOPERATIVELY AND IN THE ICU• 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.

• Pulmonary vasodilators– PDE inhibitors– Inhaled NO

• Prostaglandins

• New agents Nesiritide, Levosimendan

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. 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.

NitrovasodilatorsSodium Nitroprusside

Na+

CN

NO+

CN

Fe++

CN

CN

CNNa+

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

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

• 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

Control NicardipineHR 71 ± 13 70 ± 14MAP 107 ± 14 80 ± 9PAOP 9 ± 4 8 ± 3MPAP 15 ± 3 16 ± 4RAP 8 ± 3 8 ± 2CI 2.2 ± 0.3 2.8 ± 0.4LV 1509 ± 376 1680 ± 485LVEF 57 ± 9 68 ± 7

Lambert CR: Am J Cardiol 1993;71:420

HEMODYNAMIC EFFECTS OF IV ISRADIPINE

Variable Baseline 30 Minutes

SBP 150 ± 20 -30 ± 30‡

DBP 75 ± 9 -18 ± 8.0‡

MAP 101 ± 10 -23 ± 11.0‡

HR 89 ± 12 4 ± 12*

CI 2.7 ± 0.6 0.4 ± 0.6‡

SVR 470 ± 417 -478 ± 281‡

SVI 0.0310 ± 0.006 0.004 ± 0.006†

PADP 13.4 ± 3.9 0.2 ± 3.2

PCW 11.7 ± 4.3 -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:

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)• 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 OrganNatriuretic 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

ANPNH 2N-

COOH-

NH2

HOOC-

Urodilatin

BNP

CNP

H2N-

H2N-

HOOC-

HOOC-

ANPNH 2N- SerLeu

ArgArg

SerSer Cys

Phe

Gly

Gly Arg

Cys

Gly

ArgTyr

Asn

PheSer

Gly

LeuSer Gin

Ala

Gly

IIe

Arg

AspMet

COOH-

SS

NH2

HOOC-

Thr

AlaPro

Arg SerLeu

ArgArg

TyrArg

PheSer

AsnCys

GlyLeu

Gly Ser Gin

Ala

Gly

IIe

Arg

AspMet

ArgGlyGly

Phe

Cys

SerSer

SS

Urodilatin

BNP

CNP

SS

SS

H2N-

H2N-

HOOC-

HOOC-

SerPro

LysMet

ValGin

Gly

CysGlySer Phe

GlyLeu

SerLys

GlyCys

Phe

HisArg

ArgLeu

ValLys

Cys

Gly

LeuGly Ser

GlyArg Lys

MetAsp

IIe

Ser

Ser

Ser

Cys

GlyLeu

Gly SerMet

Ser

Gly

IIe

Arg

AspLeu

LysLeuGly

Arg

Natriuretic Peptides

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

32 amino acid sequenceRecombinant technology using E-coli

DR I

MKRG

S SS

SGLG

FC

CS S

GSGQVM

K V L RR

H

KPS

NOTE: hBNP affects assay for BNP, but can still use proBNP or one of the proANP assays

Physiology of Natriuretic PeptidesPhysiology of Natriuretic PeptidesCardiac

WallStress

Urodilatin

IncreasedNa/H20 Excretion

ANP+BNP

DecreasedBlood Pressure

NeutralEndopeptidases

Clearance

NPR-C

DecreasedVascular Growth

CNP

Adapted from Wilkins MR. Redondo J. Brown LA. Lancet 1997;349:1307-1310

-+

NPR-A/NPR-B

NPR-B?NPR-D

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

1Colucci WS, et al. NEJM 2000; 343(4):246-2532 Kato H. Yasue H. Yoshimura M.Tanaka H. Miyao Y. Okumura K. Am Heart J 1994; 128: 1098-11043 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 10465Abraham WT, et al. J Card Failure 1998; 4(1): 37-446Jensen KT, et al. Clinic Sci 1999;96:5-15

hBNP

clearance pathway

GC-AGTP

cGMP

?

Biological Effects

GC-B

G/C

NP-C

Nakao et al Can J Physiol Pharmacol, 1991, 69: 1500-1506

Clearance Pathways

G/C

GC= Guanylate Cyclase

NP=neutral endopeptidase Clearance

receptor

Vascular Smooth Muscle Cell

Neurohumoral Activation in Heart Failure

Myocardial injuryMyocardial injury Fall in LV performanceFall in LV performance

Activation of RAAS, SNS, ET,Activation of RAAS, SNS, ET,and othersand others

Myocardial toxicityMyocardial toxicity Peripheral vasoconstrictionPeripheral vasoconstrictionHemodynamic alterationsHemodynamic alterations

Remodeling andRemodeling andprogressiveprogressive

worsening ofworsening ofLV functionLV function Heart failure symptomsHeart failure symptomsMorbidity and mortalityMorbidity and mortality

ANPANPBNPBNP

-

-

The Natriuretic Peptide System is Overwhelmed The Natriuretic Peptide System is Overwhelmed in Acute Decompensated Heart Failurein Acute Decompensated Heart Failure

Adapted from Burnett JC, J Hypertens 1999

Angiotensin II

Epinephrine

Endothelin

ANP BNP

Aldosterone

Sympatho-inhibitorySympatho-inhibitory

ANPANPBNPBNP

Anti-fibroticAnti-fibroticLusitropicLusitropicVasodilationVasodilation•veinsveins•arteriesarteries•coronariescoronaries•pulmonarypulmonary

BNPBNP

ANPANPBNPBNP

AldosteroneAldosteroneinhibitioninhibition

NatriuresisNatriuresisRenin inhibitionRenin inhibition

AntiproliferationAntiproliferationeffecteffect

ET inhibitionET inhibitionVasodilationVasodilation

ANPANPBNPBNP

CNPCNPANPANP

BNPBNP

ANPANP

Natriuretic Peptide SystemNatriuretic Peptide System

Pharmacologic Actions of Human BNP

Neurohumoralaldosteroneendothelin-1norepinephrine

Hemodynamic veins arteries coronary arteries

DR I

MKRG

SSSSGLG

FC CS SG

SGQVMK V L R

RH

KPS

Cardiac• lusitropic• anti-fibrotic• anti-remodeling

diuresisnatriuresis

Renal

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 g/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 medicationsSummary 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+

• 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;37:367-374.)

•Results in venous, arterial, andsystemic 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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