*Drug Class 12: New CHF Drugs-Tolvaptan, Niseritide, Candoxatril and Omapatrilat

Drug Class 12: New Drugs For Congestive Heart Failure (Nesiritide, Tolvaptan, Candoxatril, Omapatrilat)

ALL THESE DRUGS ARE PREDOMINANTLY FOR SYMPTOMATIC MANAGEMENT (FATIGUE, PULMONARY EDEMA, DYSPNEA, CARDIOMEGALY etc)

12.1 Tolvaptan (ADH/Anti-diuretic hormone antagonist)

Image Tolvaptan structure

Image

-Vasopressin structure (ADH is another name: It prevents diuresis, thus reabsorbs water)

  • Mechanism of action:

*It is an anti-diuretic hormone/ADH antagonist (Promotes water loss without increasing Na+ excretion)

-Fluid overload in heart failure gives rise to hyponatremia (Defined as serum concentration <135 mmol/L)

*Recall the story where the woman drank too much water in a radio contest and died (Hyponatremia <135 mmol/L)

-Hyponatremia Occurs in chronic heart failure and liver cirrhosis as well.

*Promotes aquaresis (excretion of water without electrolyte excretion)——-VERY IMPORTANT!

-When water is lost via aquaresis, concentration of Na+ in serum increases (beneficial to hyponatremic patients)

***Beneficial drug for euvolemic or hypervolemic hyponatremia patients.

12.2 Nesiritide (Recombinant form of BNP)-BNP mimicking molecule

Image (32 amino acids)

BNP is not released by brain, but by cardiac myocytes in the ventricles of the heart in response to excessive stretching!!!

-recombinant form of the 32 amino acid human B-type (Brain) natriuretic peptide

-Structurally identical to BNP

-The release of BNP is modulated by calcium ions.

*Misnomer: BNP is named as such because it was originally identified in extracts of porcine/pigs brain, although in humans it is produced mainly in the cardiac ventricles.

-Note: BNP and ANP have similar functions. They are both released in response to

-Both BNP and NT-proBNP (N-terminal fragment-Biologically active) levels are found to be raised in left ventricular dysfunction.

  • Mechanism of action of Nesiritide:

Image (ANP and BNP physiological actions-Counteracts RAAS system)

1. It binds to natriuretic peptide receptors present in the heart, kidneys, vasculature and other organs. cGMP levels increase.

***2. Natriuretic peptides (both BNP and ANP) binds to guanylyl cyclase coupled membrane receptors. This increases cGMP which is similar to organic nitrates and NO. 

3. Mimicks the functions of ANP (ANP promotes Na+ excretion). Thus, this would lead to promotion of Na+ excretion. Leading to water lost as alongside Na+.

4. Dilation of afferent renal arterioles and constricting of the efferent arterioles occur. Thus, GFR increases and more sodium is lost.

5. Relaxation of vascular smooth muscle. Vasodilation occcurs.

6. Decreased release and actions of aldosterone, Angiotensin II, Endothelin and ADH.

7. Increase diuresis and natriuresis while maintaining renal blood flow.

8. May reduce ventricular remodelling (Animal studies)

-Exert an anti-fibrotic effect on cardiac fibroblasts

-Reduce deposition of collagen and fibronectin in extracellular matrix (Reduce Angiotensin II production which has a profound effect on cardiac remodelling)

-Reduction production of inflammatory mediators.

Overall Benefits: Improves dyspnea (shortness of breathness-exertional) and rapidly reduces pulmonary pressure in patients with decompensated HF. 

  • Nesiritide vs Dobutamine (B1 selective inotropic agent for CHF)

Both Improves symptoms in patients with acutely decompensated HF (symptomatic control) [Symptomatic control]

-Appears to be safer than dobutamine

-Nesiritide may increase mortality (increased risk of death) compared to common, conventional, non-inotropic drugs (e.g. ACE-inhibitors, Organic nitrates, Calcium channel blockers)

12.3 Candoxatril-Orally active Prodrug (Treats CHF in men-‘Sexist drug’)

Candoxatril (‘Can do sex trail’)

Image (Candoxatril structure)

Orally active prodrug of candoxatril

Image (Notice that the two rings at the side is cleaved off to form COOH)

Candoxatrilat: A Metabolite which is a potent neutral endopeptidase (NEP) inhibitor

What is neutral endopeptidase (NEP or Neprilysin)?

Background information: Neutral endopeptidase (NEP) (a.k.a Neprilysin) degrades vasoactive peptides, including the natriuretic peptides, angiotensin II, and endothelin-1

-particularly highly expressed in kidney and lung tissues

  •  Mechanism of action (Candoxatril): Neutral endopeptidase (NEP) inhibitor.

-Inhibits neprilysin/NEP’s activity against signalling peptides (e.g. Atrial natriuretic factor, Substance P, endothelin and enkephalins)

-Potentiates ANP activity in the heart, endothelin activity in blood vessels (constricts Blood pressure and increases blood pressure) and substance P activity in the brain (Neuromodulator)

-So this inhibition may have a beneficial effect against cardiac impairment.

*Chronic administration of NEP inhibitors reduces both cardiac mass and amount of fibrotic tissues in the left ventricle in spontaneously hypertensive rats 

–>Indicates that NEP inhibitors may regulate cardiac fibroblasts’ synthesis of collagen.

***Treats CHF IN MEN (not women)!!!

12.4 Omapatrilat (NEP inhibitor and ACE-inhibitor combined)

-New anti-hypertensive agent which combines ACE-inhibitor and NEP inhibitor

Image (Notice the Thiazepine ring and carboxylic acid portion-Belongs to ACE-inhibitors)

  • Mechanism of action:

-Combination of ACE-inhibitor effects (Inhibits production of Angiotensin II-Effects inhibited)

-Combination of NEP-inhibitor (Inhibits activity of NEP against signalling molecules)

*Dramatic effect on Blood pressure and improves HF symptoms. Possible pharmacogenetic issues.

  • Side effects/Adverse effects

1. Angioedema

-Pharmacogenetic issues

-Some races may experience more angioedema (especially African-American races)

-Smokers also more susceptible to angioedema

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