Congestive Heart Failure-Pharmacological Approach III

There are various stages of heart failure:

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1. Stage A: High risk with no symptoms (Risk factor reduction, patient and family education)

-Treat hypertension, diabetes, dyslipidemia, ACE-inhibitors or ARBs

2. Stage B: Structural heart disease, no symptoms

ACE-inhibitors or ARBs in all patients, B-blockers in selected patients

3. Stage C: Structural disease, previous or current symptoms

-ACE inhibitors and B-blockers in all patients

-Dietary Na+ restriction, diuretics and digoxin

-Cardiac resynchronisation if bundle branch block (BBB) present

Revascularisation, mitral-valve surgery

-Consider multidisciplinary team

*Aldosterone antagonist: Nesiritide

4. Stage D: Refractory symptoms requiring special intervention

-Inotropes (Digoxin, B-agonists, Dopaminergic Agonists)

5. Ventricular Arterial Disease: Transplantation

6. Hospice required

Part 1: B-adrenergic and Dopaminergic agonists

Dopamine and dobutamine used

-Both are positive inotropic agents most used for short term support of circulation in advanced heart failure.

Mechanism of action:

***These drugs act by stimulating either cardiac myocyte dopamine D1 or B1/B2 adrenergic receptors.

-Leads to stimulationof Gs cyclic AMP-PKA pathway, production of Ca2+ increases.

1.1 Dopamine (DA)

Mechanism of action: Provides inotropic support in acute cardiac failure and acute exacerbation of chronic heart failure.

However, D1 receptors has different effects on cardio-vascular system depending on its local concentration of receptors. 

Effects of Dopamine

1. At low doses (<2 microgram/kg lean body mass per minute), DA causes vasodilation by

(a) Stimulating dopaminergic receptors (D2) on smooth muscles

(b) This causes cAMP-dependent relaxation–>Vasodilation

-Stimulating pre-synaptic D2 receptors on sympathetic nerves in peripheral circulation (inhibits NAdr release) and reducing alpha adrenergicstimulation of vascular smooth muscle.

-These receptors are prominent in splanchnic and renal arterial beds.

(c) DA infusion at this rate may increase renal blood blood and help maintain GFR in patients refractory (unresponsive) to diuretics

-DA also has direct effects on renal tubular epithelial cells that promotes diuresis.

 

2. At intermediate infusion rates (2-5 microgram/kg/min), DA directly stimulates B-receptors on the heart and vascular sympathetic neurons.

-Enhances cardiac contractility and neural NAdr release.

3. At higher infusion rates (5-15 microgram/kg/min), peripheral arterial and venous constriction occur. This is mediated by alpha-adrenergic receptor stimulation.

-This may be useful in critically reduced arterial pressure where circulatory failure is a result of vasodilation (e.g. sepsis or anaphylaxis)

*Note: High dose infusion isn’t used to treat heart failure patients with primary contractile dysfunction

Why not?

-In this case, increased vasoconstriction will increase arteriolar resistance which makes afterload increase. Patients with a weakened heart faces more stress  (SV and CO decreases)

-Also tachycardia is more pronounced with Dopamine than Dobutamine (cause ischemia in patients with coronary artery disease)

 

*Definition of sepsis: deadly illness due to a severe response to bacteria or other germs

*Definition of anaphylaxis: serious allergic reaction that is rapid in onset and may cause death. It is associated with systemic vasodilation that causes low blood pressure which is by definition 30% lower than the person’s baseline or below standard values

 

 1.2 Dobutamine

-Preferred B-agonist for management of patients with end stage systolic dysfunction and CHF.

-Dobutamine is supplied as a racemic mixture that stimulates both B1 and B2 subtypes.

-(-) enantiomer is an agonist for a-adrenergic receptors whereas (+) is a weak partial agonist.

Mechanism of action;

1. Increase in stroke volume  due to positive inotropic effects. At infusion rates that have a positive inotropic effect in humans, the B1 adrenergic effect in the myocardium predominates.

2. In the vasculature, a-agonist effect of the (-) enantiomer appears to be negated by the partial agonism of the (+) enantiomer and vasodilatory effects of B2 stimulation.

(i.e. no net effect on vessels)

∴  Principle hemodynamic effect is the increase in stroke volume due to positive inotropic effect.

3. At doses that increase cardiac output (CO), there is relatively little increase in heart rate.

-Dobutamine infusion generally cause a modest decrease in systemic resistance and intracardiac filling pressures. Mainly Stroke volume that increases.

-Dobutamine does not activate Dopaminergic receptors

∴The increase in renal blood flow that occurs in assocation with dobutamine is proportional to the increase in cardiac output.

1.3 Adrenaline

-Sympathomimetic drug which acts on both alpha and beta receptors

-Major effects are: Increased systolic blood pressure, reduced diastolic pressure, tachycardia, hyperglycemia and hypokalemia.

-Indications: Used for inotropic support in acute heart failure (stimulates B1 in the heart). Also it is used for relieving chronic heart failure.

-It is a non-selective adrenergic agonist but the affinity of adrenaline for beta receptors is somewhat greater than its affinity for alpha receptors.

-Physiological effects:

(a) Positive inotrophy and chronotropy (via B1 receptors)

(b) Vasodilation at lower doses (via B2 receptors)

(c) Vasoconstriction at higher doses (via a1 receptors)

(d) Bronchial smooth muscle relaxation (via B2 receptors)

NOTE: VASODILATION OR VASOCONSTRICTION IS DOSE DEPENDENT.

Pharmacokinetics:

-Onset of action is rapid and of short duration (after IV infusion t1/2-5 to 10 mins)

-Adrenaline is rapidly distributed to the heart, spleen, several glandular tissues and adrenergic nerves.

-*Approximately 50% bound to plasma proteins

-Rapidly metabolised in the liver and tissues.

-Up to 90% of the IV dose is excreted as metabolites in the urine (via Catechol O-Methyl Transferase and Monoamine oxidases)

***It crosses the placenta and is excreted in breast milk (portend fetal risk)

***Noradrenaline is a potent vasoconstrictor (selective for a1 receptors) with minimal cardiac action.

Summary of dopamine, adrenaline and noradrenaline affinities and physiological effects:

Sympathomimetic Receptor activity Physiological effect
Drug Dose Alpha Beta1 Beta2 VD VC INT CHT
dobutamine (B1 selective) + +++ + ++ +++ +
dopamine low (B1 selective, B2 present) ++ + ++
intermediate (B1 selective, a1, b2 present) + ++ + + ++ ++ ++
high (A1, B2 selective) +++ ++ +++ ++ ++
adrenaline low (B1 selective, a1 and a2 present) + +++ ++ ++ +++ ++
high (a1 selective, b1 present) +++ ++ +++ ++ +
isoprenaline  (Highly B1 selective, B2 present) ++++ +++ +++ +++ +++
noradrenaline  (Highly A1 selective, B1 present) ++++ + ++++ + +
VD = vasodilation; VC = vasoconstriction; INT = positive inotropism; CHT = positive chronotropism
+ = agonistic effect; – = no agonistic effect

 

 

1.4 Newer drugs for complications of CHF-Tolvaptan, Nesiritide, Candoxatril and Omapatrilat

 

(a) Tolvaptan

-V2 vasopressin (ADH) receptor antagonist

-Vasopressin is an anti-diuretic hormone that increases the reabsorption of water in the renal tubule, as well as causing vasoconstriction.

-Fluid overload in heart failure gives rise to hyponatremia (Defined as sodium levels below 135mmol/L) 

Normal sodium levels-135-145mmol/L

 

Why would fluid overload in heart failure cause hyponatremia?

When there is fluid overload, there is an excess of both sodium ions and water present. This triggers baroreceptors which recognises this apparent decrease in arterial blood volume (perceives hypoperfusion). It secretes Arginine vasopressin (AVP) which retains water only, diluting blood plasma, resulting in decreased sodium concentration.

  • This is a predictor of death amongst patients with CHF and cirrhosis.

 

Tolvaptan: promotes aquaresis (excretion of water without loss of electrolytes)

Definition of aquaresis: Excretion of water without electrolyte loss (i.e. no Na+ or K+ loss)

-In clinical trials, patients with euvolumic (normal blood fluid levels) or hypervolemic (excess blood fluid) hyponatremia receives tolvaptan.

 

(b) Nesiritide (Recombinant BNP)

Recombinant form of human brain natriuretic peptide (BNP)

-It is structurally and biologically similar to the endogenously produced BNP

-Specialised cells in the atria have endocrine function: They secrete Atrial Natriuretic Peptide (ANP) in response to volume overload.

-This leads to increased sodium and water excretion by the kidneys.

 

Mechanism of Nesiritide:

1. Works to facilitate cardiovascular fluid homeostasis through counterregulation of the RAAS, decreased release and action of aldosterone, angiotensin II, endothelin and ADH.

2. Relaxes Vascular smooth muscles. Stimulates cGMP, leading to smooth muscle cell relaxation (similar to organic nitrates and NO)

***3. Dilates afferent renal arterioles and constricts efferent renal arterioles. This results in increased GFR.

4. (For animals and experiments only) Nesiritide may reduce ventricular remodelling.

-It has an anti-fibrotic effect on cardiac fibroblasts

-It reduces deposition of collagen and fibronectin in extracellular matrix

-It reduces production of inflammatory mediators.

 

-Nesiritide mimics biological effects of BNP by binding to GC receptors in heart, vasculature, kidneys and other organ systems (to increase levels of cGMP)

-Improves symptoms in patients with acutely decompensated heart failure compared with placebo

Unproven reports: Appears to be safer than dobutamine but contradicted by another study which claims nesiritide has a high risk of death.

 

Benefits of nesiritide: Significantly improves dyspnea and rapidly reduces pulmonary pressure in patients with decompensated CHF.

It has also been shown to increase diuresis and natriuresis while maintaining renal blood flow.

 

(c) Candoxatril (NEP inhibitor)

-Orally active prodrug of candoxatrilat

-Potent neutral endopeptidase (NEP) inhibitor used in the treatment of CHF in man.

 

What is NEP (Neutral endopeptidase/Neprilysin/Enkephalinase)?

-Zinc-dependent metalloprotease enzyme that degrades a number of small secreted peptides (notably amyloid beta peptide whose abnormal misfolding and aggregation in neural tissue has been implicated in Alzhemiers)

-It plays a role in breaking down Atrial Natriuretic Peptide (enkephalins)

-Also play a role in modulation of peptide actions in various organs, including not only kidney , lungs, GIT and heart.

 

Mechanism of Candoxatril:

-It inhibits NEP. This potentiates ANP activity in the heart which helps in cardiac failure.

Experimentally proven: Chronic (long-term) use of NEP-inhibitors reduces both cardiac mass and amount of fibrotic tissue in the left ventricle in spontaneously hypertensive rats (?).

-Increased ANP activity promotes natriuresisdiuresisvasodilation, and reductions in preload and ventricular remodeling.

-This suggests that it may regulate collagen synthesis in cardiac fibroblasts.

-It is currently being assesed in various experimental models.

 

(d) Omapatrilat (combined ACE-inhibitor and NEP inhibitor)

-Combined ACE-inhibitor and NEP inhibitor

-It has a dramatic effect on BP and improves heart failure symptoms.

-However, there may be certain pharmacogenic issues associated (e.g. certain races are more susceptible to prevalent angioedema)

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