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Clinical Disorders: Therapeutic Classes: Mechanism Classes:
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Natriuretic Peptides
General Pharmacology
Natriuretic peptides are peptide hormones that are synthesized by the heart, brain and other organs. Atrial natriuretic peptide (ANP) is a 28 amino acid peptide that is synthesized, stored, and released by atrial myocytes in response to atrial distension, angiotensin II stimulation, endothelin, and sympathetic stimulation (beta-adrenoceptor mediated). Therefore, elevated levels of ANP are found during hypervolemic states (elevated blood volume) and congestive heart failure. Brain-type natriuretic peptide (BNP; 32 amino acids), although first identified in the brain, is primarily produced by ventricular tissue in the heart, and like ANP, there is enhanced synthesis and release of BNP during heart failure. Neutral endopeptidase (NEP) is a circulating enzyme that degrades natriuretic peptides. Therefore, inhibition of this enzyme increases circulating levels of natriuretic peptide and potentiates their effects.
Cardiovascular
and renal effects. Natriuretic peptides are involved in the
long-term regulation of sodium and water balance, blood volume and arterial
pressure. These peptide hormones decrease aldosterone release by the adrenal
cortex, increase glomerular filtration rate (GFR) and filtration fraction,
produce natriuresis and diuresis (potassium sparing), and decrease
renin
release, thereby decreasing circulating levels of
angiotensin II.
These actions contribute to a reduction in
blood volume
and therefore
central venous pressure (CVP),
pulmonary capillary wedge pressure,
cardiac output,
and arterial blood
pressure. Chronic elevations of ANP appear to decrease arterial blood
pressure primarily by decreasing systemic vascular resistance. The mechanism of
systemic vasodilation involve ANP receptor-mediated elevations in vascular
smooth muscle cGMP as well as by attenuating sympathetic vascular tone. This
latter mechanism may involve ANP acting upon sites within the central nervous
system as well as through inhibition of norepinephrine release by sympathetic
nerve terminals. To summarize, natriuretic peptides serve as a
counter-regulatory system for the renin-angiotensin-aldosterone system.
Therapeutic Uses
Heart failure. Heart failure leads to activation of the renin-angiotensin-aldosterone system, which causes increased sodium and water retention by the kidneys. This in turn increases blood volume and contributes to the elevated venous pressures associated with heart failure, which can lead to pulmonary and systemic edema. Increased angiotensin II also causes systemic vasoconstriction, which increases the afterload on the left ventricle.
The primary use for diuretics in heart failure is to reduce pulmonary and/or systemic congestion and edema, and associated clinical symptoms (e.g., shortness of breath - dyspnea). Long-term treatment with diuretics may also reduce the afterload on the heart by promoting systemic vasodilation, which can lead to improved ventricular ejection.
Specific Drugs
Recombinant human BNP, or nesiritide, is approved for use in the acute treatment of decompensated congestive heart failure caused by systolic dysfunction. As a peptide, nesiritide has poor bioavailability and therefore is only available for intravenous administration. With a short half-life of less than 20 minutes, it is administered as a continuous infusion following a bolus injection. This drug is very effective in reducing pulmonary capillary wedge pressure and improving dyspnea in this population of patients.
Adverse Side Effects and Contraindications
The most prevalent side effect of nesiritide is hypotension, which can be long-lasted. Therefore, it is important to monitor arterial pressure during drug administration. Azotemia (an elevated blood level of urea or other nitrogen containing compounds) can occur in patients with renal disease in which kidney function depends on the activated renin-angiotensin-aldosterone system. This drug should not be used in patients having cardiogenic shock or having systolic pressures less than 90 mmHg.
Revised 03/15/07