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Cardiac Pharmacology: Ideas For Advancing Your Clinical Practice

Roberta L. Hines, M.D. Nicholas M. Greene Professor

Chair, Department of Anesthesiology Yale University School of Medicine

New Haven, CT

WHY ADMINISTER

CARDIOTONIC AGENTS ?

KEY QUESTION

? Patient Outcome ?

RISK BENEFIT Cardiotonic

Agents

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CAN WE IDENTIFY PATIENTS WHO

MAY BENEFIT FROM CARDIOTONIC

AGENTS?

In Patients Chronically Treated

with Metoprol, the Demand of Inotropic Catecholamine Support After CABG is Determined by the

Arg 389 Alg-β1 Adrenoceptor polymorphism

Ach Pharmacol 375:303-309, 2007

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LECTURE OBJECTIVES

Natriuretic Peptides Biology/Actions Prognostic/Diagnostic Valve Clinical Applications

Pulmonary Vasodilators

Physiological Advantage (Inhaled) PDE-V Inhibitors

Vasopressin

Hemodynamic Effects Clinical Applications

LECTURE OBJECTIVES

Vasoplegic Syndrome Thyroid Hormone Emerging Drugs: Levosimendan Pharmacology Clinical Indications

NATRIURETIC PEPTIDE

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Natriuretic Peptides Site of Synthesis

Heart ANP – atria in response to stretch BNP (Brain/B-type) – ventricle

Clinical effects modulated via specific receptors cGMP is second messenger

Pre-proBNP1-134

proBNP1-108

Inactive components

Active components

proBNP1-108

BNP1-32

BNP3-32

BNP7-32

NT-proBNP

BNP CLINICAL APPLICATIONS

Diagnostic Modality (Bio marker) Treatment Modality

CHF (dyspnea) Noncardiac Surgery Cardiac Surgery CHF Cardiac Surgery

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BNP and Pro-B-Type Natriuretic

Peptide

Diagnostic Applications

BNP, Age and Heart failure

90%, young healthy, BNP ≤ 25pg/ml

NT-proBNP ≤ 75pg/ml

Daniels LB, Maisel AS: J Am Coll Cardiol: 2007;50:2357

Clinical Caveat

The Introduction of Beta Blockade Increase

Plasma BNP and NT-pro BNP Levels

J Cardiovasc Pharmacol Therap 12(2):85-89, 2007

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BNP Congestive Heart Failure

Diagnostic Estimate filling pressures

Prognosticate adverse outcomes (dyspnea)

Confirm diagnosis (BNP > 100 pg/ml)

Circulation 105: 2392-2397, 2002 N Engl J Med 345: 1014-1021, 2001

Does BNP Have a Role in Perioperative Risk Assessment?

Heart 2006;92;1645

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Prognostic Value of Brain Natriuretic Peptide in Noncardiac Surgery

(A Meta-Analysis)

Anesthesiology 111:311-9, 2009

Meta-Analysis Results

(n = 15 publications)

Preoperative ↑ BNP → ↑ MACE ↑ All Cause Mortality ↑ Cardiac Death Results revealed ↑ risk for both

short term (< 43 days) and long term (> 6 mos) complications

Anesthesiology 111:311-9, 2009

BNP and Postoperative Outcomes Possible Etiologies

↑ BNP identifies patient with impaired CV function

↑ BNP identifies patients with ↑ ischemic

burden Preoperative BNP level strongly

associated with short-term (major adverse cardiac events) MACE

Anesthesiology 111:311-9, 2009

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Nt-Pro BNP in Cardiac Surgery Patients

Is It Helpful?

Levels Associated Need for inotropic Agents IABP Insertion Renal Failure ICU Stay

Anaesth Scand 52:182-187, 2008

BNP Treatment

Applications

Brain Natriuretic Peptides

HEMODYNAMIC EFFECTS

Vasodilation (preferentially acts on the venous system)

↓ CVP ↓ PCWP ↓ SVR ↓ PVR

No direct inotropic effect

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Nesiritide Administration in Patients with Left

Ventricular Dysfunction Undergoing CABG

J Am Coll Cardiol 2007; 45:727-728

NAPA : Objectives

To explore the effects of perioperative administration of nesiritide on clinical outcomes

and safety in heart failure patients undergoing cardiac

surgery

NAPA Trial Design

• Multi-center (54 centers) • Randomized • Double-blind • Placebo-controlled

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NAPA Trial Design

•  LV dysfunction (EF < 40%) • NYHA Class II – IV • Undergoing CABG + MVS • Using cardiopulmonary

bypass

NAPA Findings

•  Improved survival at 180 days •  Improved Postop Renal Function

Greater improvement in patients with renal dysfunction at baseline

• Decreased LOS

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PULMONARY VASODILATORS

Selective Pulmonary Vasodilators

Inhaled Agents Nitric Oxide Nitroglycerin Prostacyclin/Prostaglandins PDE-III / PDE-V Inhibitors Oral Agents (PDE-V Inhibitors) Sildenafil Tadalafil

PULMONARY VASODILATORS CLINICAL INDICATIONS

(Inhaled)

Management of pulmonary hypertension (acute and chronic)

Rx of right ventricle dysfunction Challenges

Selectivity Matching ventilation / perfusion

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ORAL AGENTS

PDE-V INHIBITORS

PDE – V Inhibitors

Clinical Applications Primary pulmonary hypertension Secondary pulmonary hypertension Valvular disease PIH CHF Congenital heart disease

PDE – V Inhibitors

Half – Life

Sidenafil (4-5 hours)

Tadalafil (17.5 hours)

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COMBINATION THERAPY

cAMP + cGMP

Pulmonary Endothelial Cell

Guanylate Cyclase cGMP GTP

Relaxation

Vascular Smooth Muscle Cell

NO¯ SNP TNG

ACh A232877

Gq

Ca2+

Phospholipase C

Gi Adenylate Cyclase

Pertussis Toxin Θ

L-Arginine

L-Citrulline

EDRF/NO NO Synthase

UK 14304

+

+

+Bradykinin

Treatment of Pulmonary Hypertension

New Strategies

Inhalational Agents New Oral Agents (PDE-V) Combination Therapy (cAMP + cGMP)

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VASOPRESSIN

Dx

“Vasodilatory Shock”

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Vasodilatory Shock Components

MAP < 65 mmHg

SVR < 650 dynes/sec/cm-5 CI > 2.5 l/min/m2 Catecholamine resistance

Vasodilatory Shock Etiology

Levels of Endogenous AVP

AVP : Hemodynamic Effects

↑ BP ↑ SVR ↓ Catecholamine requirements + ↑ Urinary output Caveat Should not be used for Rx of ↓ BP/CO unless : ↓ SVR ↑ CI

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VASOPLEGIC SYNDROME

Preoperative Risk Factors and Clinical Outcomes Associated

with Vasoplegia in Recipients of Orthotopic Heart Transplantation

in the Contemporary Era

Patarroyo M, Simbaqueba C, Shrestha K, Starling RC, et al

J Heart Lung Transplant (2011)

Vasoplegic Syndrome

SVR (<800 dynes) Despite : > 2 pressors

Epinephrine > 4mcg/min Norepi > 4 mcg/min Dopamine > 5mcg/kg/min Vasopressin > 1 U/hr

Preserved CI > 2.5 L/min Time of onset 6-48 hrs after surgery Rx : Methylene Blue (Patarroyo et al: J Heart Lung Transplant, 2011)

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Results (n = 348 OHT’s)

11% developed vasoplegia Risk Factors (demonstrated in previous studies)

Unos Status 1A BSA, BMI Preop ASA Previous cardiac surgery Mechanical Support

(Patarroyo et al: J Heart Lung Transplant, 2011)

Newly Identified Risk Factors

Hypothyroidism ( TSH, T4 or Free T4 ) Additional New Findings:

Inotropic support with Milrinone (preop) Conferred protection against vasoplegia

(Patarroyo et al: J Heart Lung Transplant, 2011)

Thyroid Hormone

(CPB)

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Thyroid Hormone and Cardiac Surgery

Impact of CPB on Thyroid Function

“Low T3 Syndrome” Serum T3 Normal T4 and TSH rT3

•  Total serum and free T3 levels from 50-70% in post CPB period •  Decrease persists for 1-4 days

Low T3 Syndrome and CPB

Proposed Mechanisms:

Hypothermia Hemodilution Activation of inflammatory

mediators Peripheral conversion

of T4/ T3

Clinical Studies In High Risk Patients

Demonstrate : CO SVR

Incidence of atrial fibrillation

need for inotropic agents in post ischemic hearts

J Thorac Cardiovasc Surg 98:972-975, 1998 Engl J Med 333:1522-1527, 1995

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T3 Adult Cardiac Surgery

CABG : (conflicting evidence) May reduce need for inotropes in patients EF<40 May have a role as part of multi modal therapy for pts with EF

Anesth Analg 85:30-36, 1997; JAMA 275:687-692, 1996 J Thorac Cardio Vasc Surg 98:972-977, 1989

Role of Thyroid Hormone Administration in Potential

Organ Donors

Following BSD: Low T3 states Administration of T3 reverses hemo-dynamic derangements May donor pool (by vasopressor requirements)

Arch Surg 136:1377-1380, 2001

EMERGING DRUGS

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Emerging Drugs

Levosimendan

Levosimendan

Mechanisms of Action Inotrope/vasodilator (inodilator) Calcium sensitizing properties Increases sensitivity of contractile proteins to Ca

Binds calcium-dependently to cardiac troponin-C

No change in cytosolic Ca Opens KATP Channels

Levosimendan Hemodynamic Effects

CO (+ myocardial 02 consumption) Peripheral vasodilation Coronary artery dilation + Lusotrophic effect LV filling pressures No effect on PVR

Half Life – 1 hour

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Levosimendan

Early Clinical Applications Decompensated CHF Combination Therapy Worsening or refractory CHF Cardiac Surgery (EF<30%)

Eur Heart J 22:1527-1560, 2001

Anesth Analg 90:5-11, 2000 Lancet 360:196-202, 2002

Levosimendan in Cardiac Surgery: A Unique Drug for the Treatment of Perioperative Left Ventricular Dysfunction or Just Another Inodilator Searching for

a Clinical Application

Question:

Anesth Analg 164:766-773, 2007

Will it Result in Improved Outcomes?

SUMMARY Natriuretic Peptide

Pulmonary Vasodilators

Vasopressin

Thyroid Hormone

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SUMMARY Emerging Drugs:

Levosimendan

? Clinical Application ?

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