In a patient presenting with acute dyspnea, a brain natriuretic peptide level above 100 pg/mL substantially increases the probability of acute heart failure as the cause of symptoms, while a value below 50 pg/mL makes heart failure unlikely. Values between 50 and 100 pg/mL are a gray zone requiring clinical judgment and additional assessment. For NT-proBNP, the threshold supporting acute heart failure diagnosis is above 300 pg/mL in the acute setting; age-stratified higher thresholds are used in some guidelines for patients over 50 or 75 years, reflecting the normal age-related rise in NT-proBNP levels.

Beyond diagnosis, both peptides correlate with heart failure severity — higher levels reflect greater ventricular wall stress, higher filling pressures, and worse prognosis. Serial measurement is used to assess treatment response: a fall in brain natriuretic peptide or NT-proBNP with diuresis and heart failure therapy confirms hemodynamic improvement and predicts better outcomes at discharge. Rising levels during an admission or after discharge signal inadequate decongestion or clinical deterioration.

Two conditions commonly produce falsely elevated brain natriuretic peptide levels that do not reflect primary cardiac dysfunction. Renal impairment raises brain natriuretic peptide (and particularly NT-proBNP, which relies heavily on renal clearance) because the peptide accumulates as glomerular filtration rate declines; the diagnostic thresholds must be interpreted cautiously in patients with significant chronic kidney disease. Atrial fibrillation with rapid ventricular rate also elevates brain natriuretic peptide through increased atrial and ventricular wall stress independent of systolic dysfunction.

Two conditions produce falsely low brain natriuretic peptide values that can lead to underdiagnosis of heart failure. Obesity suppresses brain natriuretic peptide secretion and clearance through mechanisms not fully understood, but the effect is clinically significant — obese patients with heart failure may have brain natriuretic peptide levels in the normal range despite elevated filling pressures. Sacubitril-valsartan (neprilysin inhibition) raises brain natriuretic peptide by preventing its degradation, so brain natriuretic peptide values in these patients reflect drug effect rather than disease severity and cannot be used diagnostically. NT-proBNP is not a neprilysin substrate and remains interpretable in patients taking sacubitril-valsartan, making it the biomarker of choice in this population.

Nesiritide activates natriuretic peptide receptors on vascular smooth muscle, renal tubular cells, and cardiac fibroblasts, producing three simultaneous effects: venous and arterial vasodilation (reducing both preload and afterload), natriuresis and diuresis (reducing volume overload), and suppression of the renin-angiotensin-aldosterone system and sympathetic nervous system activity. These effects are mechanistically complementary to intravenous diuretics, which reduce volume but do not directly reduce vascular resistance. Nesiritide is given as an intravenous bolus followed by a continuous infusion, typically in an inpatient setting.

The ASCEND-HF trial enrolled over 7,000 patients with acute decompensated heart failure and compared nesiritide added to standard care versus standard care alone. Nesiritide produced a modest improvement in patient-reported dyspnea at 6 and 24 hours — the primary endpoint — but this improvement did not reach statistical significance. There was no reduction in 30-day mortality or rehospitalization rates. Nesiritide did not increase renal dysfunction compared to placebo in ASCEND-HF, resolving an earlier concern from smaller studies, but neither did it improve renal outcomes.

The clinical implication is that nesiritide is not a replacement for intravenous loop diuretics, which remain the first-line treatment for acute decompensated heart failure with volume overload. Nesiritide may have a role as an adjunct to diuretics in selected patients with predominantly vasodilatory hemodynamics (elevated filling pressures with low systemic vascular resistance) or in patients with diuretic resistance. Hypotension is the most common dose-limiting adverse effect and requires careful blood pressure monitoring and dose titration.

Substance P is an 11-amino-acid neuropeptide released from enteric neurons and sensory afferents in the gastrointestinal tract during chemotherapy-induced mucosal injury, and from brainstem neurons in response to circulating emetic signals reaching the area postrema. Substance P binds NK1 receptors in the area postrema (the chemoreceptor trigger zone) and in the nucleus tractus solitarius, activating the central pattern generator for vomiting. The delayed phase of chemotherapy-induced nausea — which begins approximately 24 hours after chemotherapy and peaks at 48 to 72 hours — is driven predominantly by substance P and NK1 receptor signaling rather than by serotonin, which mediates the acute phase (0 to 24 hours). This mechanistic distinction explains why serotonin type 3 receptor antagonists (ondansetron, granisetron) alone do not adequately control delayed nausea and why adding an NK1 antagonist significantly improves delayed nausea control in highly and moderately emetogenic chemotherapy regimens.

Aprepitant is an orally administered selective NK1 receptor antagonist that penetrates the central nervous system and blocks substance P binding at the area postrema and nucleus tractus solitarius. It is given on day 1 of chemotherapy (at a higher dose) and days 2 and 3 (at a lower dose) as part of a three-drug antiemetic regimen that also includes a serotonin type 3 receptor antagonist and dexamethasone. The three-drug combination addresses all three major emetic pathways: serotonin (acute phase), substance P (delayed phase), and the corticosteroid anti-inflammatory mechanism that reduces prostaglandin-mediated nausea.

Fosaprepitant is a water-soluble phosphate prodrug of aprepitant that can be administered as a single intravenous dose on day 1 of chemotherapy, replacing the three-day oral aprepitant course in patients who cannot take oral medications. After intravenous administration, fosaprepitant is rapidly converted to aprepitant by plasma phosphatases.

Aprepitant is a moderate inhibitor and an inducer of cytochrome P450 3A4, producing a biphasic interaction pattern: it initially inhibits cytochrome P450 3A4 (raising levels of substrates for 3 to 5 days) and then induces it (reducing levels of substrates over the following week). The most clinically consequential interaction is with dexamethasone — a cytochrome P450 3A4 substrate — which is co-administered in the antiemetic regimen. Aprepitant raises dexamethasone plasma levels by approximately 2-fold; standard antiemetic regimens account for this by prescribing reduced dexamethasone doses when aprepitant is included. Aprepitant also induces warfarin metabolism (reducing anticoagulant effect) and interacts with oral contraceptives; patients on warfarin require international normalized ratio monitoring in the week following aprepitant use.

Three principles apply across nearly all vasoactive peptide drug classes. First, blocking a peptide system that is pathologically overactivated is therapeutic, but blocking the same system in a context where it is providing compensatory support is harmful. The clearest example is angiotensin-converting enzyme inhibition in bilateral renal artery stenosis, where angiotensin II is maintaining glomerular filtration rate; the same mechanism that is protective in heart failure causes acute kidney injury when the compensatory role is removed. The same logic applies to vasopressin blockade (beneficial in syndrome of inappropriate antidiuretic hormone secretion, dangerous if vasopressin is maintaining blood pressure), endothelin antagonism (beneficial in pulmonary arterial hypertension, irrelevant or potentially harmful in acute hemodynamic instability), and calcitonin gene-related peptide antagonism (beneficial in migraine, uncertain in active myocardial ischemia).

Second, vasoactive peptide systems are counter-regulatory pairs. The renin-angiotensin-aldosterone system (vasoconstrictive, sodium-retaining) is physiologically opposed by the natriuretic peptide system (vasodilatory, natriuretic). Endothelin-1 (vasoconstrictive, proliferative) is opposed by endothelial nitric oxide and prostacyclin. Vasopressin V1 vasoconstriction (pressor) is opposed by V2-mediated natriuretic peptide release and by the aquaretic response itself. Understanding these pairs helps predict what happens when one side of the pair is pharmacologically amplified or blocked.

Third, most vasoactive peptide drug interactions are pharmacodynamic rather than pharmacokinetic. Adding an angiotensin-converting enzyme inhibitor to an angiotensin receptor blocker produces additive angiotensin II suppression, not altered drug levels (with the exception of sacubitril-valsartan, where the angioedema risk is mechanistic). Adding aprepitant to dexamethasone produces a pharmacokinetic interaction (cytochrome P450 3A4 inhibition), but the combination of a serotonin type 3 receptor antagonist with aprepitant produces pharmacodynamic complementarity rather than interaction.

The following matrix organizes the chapter's pharmacological targets by their primary clinical indications. It is organized to support rapid review for examination purposes.