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Nesiritide
Presenter Dr. Md. Azizul Karim MD 3rd Part Student Moderator Dr. Salahuddin Assistant professor NICVD

Introduction

Nesiritide is a human B-type natriuretic peptide (BNP), manufactured from E. Coli using recombinant DNA technology . It approved by the Food and Drug Administration (FDA) in 2001. Systemic infusion of nesiritide in patients with congestive heart failure results in beneficial hemodynamic actions, including arterial and venous dilatation, enhanced sodium excretion, and suppression of the reninangiotensin aldosterone (RAAS)and sympathetic nervous systems(SNS).

Chemical structure

Nesiritide has a molecular weight of 3464 g/mol and an empirical formula of C143H244N50O42S4. It has the same 32 amino acid sequence as the endogenous peptide, which is produced by the ventricular myocardium .

Pharmacokinetics

Nesiritide administered intravenously by infusion or bolus exhibits biphasic disposition from the plasma. The mean terminal elimination half-life (t) is 18 minutes . Elimination via three mechanisms : 1) Lysosomal proteolysis 2) Proteolytic cleavage by endopeptidases 3) Renal filtration.

Mechanism of action

Nesiritide binds to the natriuretic peptide receptors A&B (NPR-A and NPR-B) of vascular smooth muscle and endothelial cells. Intracellular levels of cGMP are increased by receptor activation of guanylate cyclase. Thereby causing arterial and venous vasodilatation.

Thus, preload and after load are decreased.

Indication

Nesiritide is indicated: Intravenous treatment of acute decompensated heart failure (ADHF )due to ischemic, hypertensive, or idiopathic cardiomyopathy in patients who have dyspnoea at rest or with minimal exertion (New York Heart Association [NYHA] Classes III and IV)

ESC Guideline 2008

Nesiritide can be used in Acute HF with pulmonary edema and systolic BP> 90 mm Hg, as a vasodilator (Class 1, Level B)

Contraindication

Hypersensitive to any of its components. Cardiogenic shock or Systolic blood pressure < 90 mm Hg.

Dosage and Administration

The recommended dose is 2 microgm/kg i.v. bolus followed by infusion at 0.01microgm/kg/min, based on actual body weight, with no adjustment for renal failure. There is an option to titrate up by 0.005microgm/kg/min intervals every 3 h to a maximum infusion rate of 0.03 microgm/kg/min. There is limited experience with administering for longer than 48 hours.

Side effects
Nesiritide can produce side effects in multiple systems of the body:

Cardiovascular Hypotension Central nervous system Headache Insomnia Dizziness Other systems Nausea and vomiting

Drug Interactions

Coadministration of Neseritide with angiotensin converting enzyme inhibitor may cause unsafe droop in blood pressure Nesiritide can react physically with many other drugs .These changes its effectiveness or cause toxicity. Drugs that can interact physically with nesiritide include the following : Insulin, heparin.

In general, these drugs are not given at the same time as nesiritide.

Clinical trials on Nesiritide

Nesiritide compared to placebo

Colucci et al (2000) efficacy trial, compared nesiritide with placebo. 127 admitted ADHF patients were randomized.
The hemodynamic data for the nesiritide patients revealed statistically significant decreases in pulmonary capillary wedge pressure(PCWP) and systemic vasculer resistance( SVR) with significant increase in cardiac index( CI). Furthermore, nesiritide patients, experienced significant improvements in their assessment of their own global clinical status, dyspnea, and fatigue (p<0.001).

Nesiritide compared to placebo

Nesiritide compared to standerd therapy

Colucci et al (2000) comparitive trial randomly assigned 305 patients with ADHF to standard therapy or neseritide .
This trial suggested that nesiritides ability to improve symptomatology is at least equivalent to standard therapy, with a possible trend for symptomatic superiority early in the treatment phase.

Neseritide compared to nitroglycerin

The multicenter vasodilation in the Management of Acute CHF (VMAC) study 2002 compared the efficacy and safety of i.v. nesiritide, i.v. nitroglycerin, or placebo . The investigators randomized 489 patients in a double blind fashion . Nesiritide caused a significantly greater reduction in PCWP when compared to nitroglycerin and placebo .(p<o.o5) Headache occurred nitroglycerin, significantly more frequently with

THE EFFECT OF NESIRITIDE AND DOBUTAMINE ON VENTRICULAR ECTOCOPY

PRECEDENT(2002) was an RCT open-label study that compared ventricular dysrhythmias in 246 patients with ADHF receiving dobutamine or nesiritide.

Dobutamine significantly increased ventricular ectopy when compared to nesiritide

Nesiritide actually was associated with decreased ectopy and no reflex tachycardia.

Effects of perioperative Neseritide in pts with left ventriculer dysfunction undergoing cardiac surgery Napa trial

This prospective, double-blind randomly assigned patients with EF 40%who were undergoing CABG to receive either nesiritide or placebo.

Nesiritide was associated with a significantly attenuated peak increase in serum creatinine (p<0.001) and a smaller fall in glomerular filtration rate (p<0.001) during hospital stay . In addition, nesiritide treated patients had a shorter hospital stay (p<0.043) and lower 180-day mortality (p=0.046).

PROACTION STUDY
The Proaction (Prospective Randomized Outcomes study of

ADHF treated initially in outpatients with Neseritide)study .

The primary endpoint was safe discharge from the observation unit(OU )after therapy. Overall admission rate of 49% in the nesiritide group and 55% for the placebo group. Of the hospitalized patients, recidivism was lower in the nesiritide (10%) than in the placebo group (23%) (p=0.058).

The effect Nesiritide and Dobutamine on mortality

Silver et al. retrospectively evaluated a subset of hospitalized ADHF patients . Patients treated with dobutamine were compared with nesiritide. Decreased 6-month mortality rate when using nesiritide (18%) compared to dobutamine (31%) (p=0.04) But the result from two meta-analyses suggested that nesiritide use associated with increased risk of worsening renal function and mortality. However this has been discounted by two recent studies (2007)

Recommended use of Neseritide in the Emergency Department(ED)

First group: Pts with moderate respiratory distress with

ADHF.Due to its ability to quickly drop PCWP in the first 15 min , nesiritide could be administered with diuretics and NIV in the hope of avoiding intubation

Second group: when use of GTN is contraindicated, especially when the titration of i.v. GTN for blood pressure control is contraindicated , or when standard therapy not produced satisfactory result. Third group: ADHF with tachycardia, serious atrial or ventricular dysrhythmias, or ventricular irritability.

Conclusion

Nesiritide is a potent vasodilatator that reduces PCWP and improves cardiac output and symptomatology, as well as, or better than standard therapy in hospitalized patients with ADHF Current evidence supports consideration of its ED use as an acceptable alternative to nitroglycerin in selected patients, particularly those who are volume overloaded and at least moderately ill with unsatisfactory response to standard therapy, or have concomitant dysrhythmia or ectopy.

Preliminary prospective data, as well as the theoretical advantage over nitroglycerin of less need for titration, support consideration of employing nesiritide therapy over 1224 h in an OU setting.

references
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VMAC investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure. JAMA 2002;287:1531-1540. Silver MA, et al. effect of nesiritide versus dobutamine on short-term outcomes in the treatment of patients with acutely decompensated heart failure. J Am Coll Cardiol 2002;39:798-803. Sackner- Bernstein JD, et al. risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487-1491. Mentzer RMA Jr, et al. effects of perioperative nesiritidel in patients with left ventricular dysfunction undergoing cardiac surgery: the NAPA trial. J Am Coll Cardiol 2007;49:716-726. Witteless RM, et al. impact of nesiritide on renal function in patients with acute decompensated heart failure and pre-exiting renal dysfunction: a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol 2007;50:1835-1840. Mills RM, Lejemtel TH, Horton Dp, et al. sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure: a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol 1999;34:155-62. Colucci ws, Elkayam U, Horton dp, Lejemtel T, et al.. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated ngestive heart failure. N Engl j Med 2000;343:24653.