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

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


12.1 Tolvaptan (ADH/Anti-diuretic hormone antagonist)

Image Tolvaptan structure


-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

Drug class 9: Cardiac glycoisides-Digoxin

Digoxin (Does not reduce mortality but reduces morbidity and hospitalisation for heart failure)

9.1 Mechanism of action:

1. ***Potent inhibitors of the active transport of Na+/K+ across cell membranes. 

-Reversible binding to subunit of Na+, K+ ATPase.

-Both sodium and calcium ions enter cardiac muscle cells during each depolarisation.

Normally, Calcium entry triggers contraction. It is then taken into the Sarcoplasmic reticulum via SERCA (S.R. calcium ATPase)

-It is also removed from the cell via Na+/Ca2+ exchanger (NCX) and sarcolemmal Ca2+ ATPase.

∴Inhibition of Na+/K+ ATPase by digoxin results in a reduction in rate of Na+ removal (dump out of cell). Na+ accumulates in cell.

-Reduces ability of NCX ability to remove Calcium ions during myocyte repolarisation.

-As Ca2+ accumulates (due to repeated entry of ions) and reduced efflux of Calcium ions, the calcium ion intake into the SR is increased.

Ultimately, the calcium present in the SR increases and more is released during the next ECC (excitation-contraction coupling). Increases myocardial contractility!!!

2. Increases force of myocardial contraction (Positive inotropic)

3. Decreases AV nodal conduction (predominantly by its vagotonic effect on the heart). Decreases automaticity.

4. Increases diastolic resting membrane potential in atrial and AV nodal tissues (Easier to reach threshold) ??? ASK JOE WOULDN’T THAT INCREASE AUTOMATICITY?

Vagontonic: hyperexcitability of the vagus nerve, producing bradycardia, decreased heart output, and faintness.

4. Modulates ANS (autonomic nervous system). This contributes to their efficacy in the management of CHF. Decreases sympathetic tone.

5. May increase excitability of cardiac muscle (particularly at higher doses)–>Atrial and Ventricular arrhythmias (AT HIGHER DOSES).

-This simultaneous non-uniform increase in automaticity and depression of conduction in Purkinje fibres and ventricular muscle fibres can cause serious ventricular arrhythmias.

9.2 Clinical Indications

(a) Atrial and AF flutter (Decrease heart rate)

(b) Heart Failure

9.3 Precautions

1. Hyperthyroidism and fever. Both of these conditions increase sympathetic tone thus making digoxin relatively ineffective (Since digoxin affects ANS too)

Solution: Treat underlying cause and use larger doses or another agent.

2. Hypothyroidism. May increase sensitivity to digoxin

Solution: Require smaller doses.

3. Hypokalemia, Hypomagnesemia, Hypercalcemia (i.e. lack of electrolytes) and Hypoxia (lack of oxygen)

-Increase risk of digoxin toxicity

-Increases risk of digoxin toxicity due to electrolyte imbalance and oxygen imbalance.

Solution: Correct electrolyte imbalance.

4. Cardiac Issues

-Contraindicated in second or third degree heart block (without pace-maker)–>Arrhythymias

-Contraindicated in SVT (sino-ventricular tachycardia) involving accessory pathway–>Wolff-Parkinson-White syndrome (Bundle of Kent affected)

*Second-degree heart block may result in the heart skipping a beat or beats. This type of heart block also can make you feel dizzy or faint.

*Third-degree heart block limits the heart’s ability to pump blood to the rest of the body. This type of heart block may cause fatigue (tiredness), dizziness, and fainting. Third-degree heart block requires prompt treatment because it can be fatal.

-Contraindicated in Ventricular tacycardia and filbrillation

-Contraindicated in Hypertrophic obstructive cardiomypopathy or cor pulmonale (acute and chronic)

*Cor Pulmonle-Enlargement of the right ventricle of the heart as a response to increased pressure in lungs (Pulmonary hypertension)

-Contraindicated in constrictive pericarditis

Use cautiously in the following cardiac conditions:

In acute MI, ischemic heart disease or myocarditis. Digoxin incresaes risk of arrhythmias.

-Sick Sinus Syndrome. Increases risk of severe bradycardia or sinoatrial block.

-Severe aortic stenosis. Digoxen may worsen cardiac function because it increases force of myocardial contraction (Positive inotropic)

5. Renal Issues (Impaired)

-Digoxin is mainly renal cleared (70%)

Solution: Reduce dose in renal impairment.

6. Elderly-Reduce dose.

7. Pregnancy-Safe to use, dose requirement is not predictable. Safe to use when breastfeeding.

Solution: Depending on circumstance, increased dose may be required. ***Used to treat fetal arrhythmias (CAT A-AUS)

9.4 Adverse effects/ Side effects

***Potential to worsen arrhythmia/Proarrhythmic effect


1. Effect on ECG. Digoxin results in prolonged PR interval, ST depression or T-wave inversion.

-Apart from the effect on PR interval, which is a sign of toxicity, these ECG changes do not necessarily mean digoxin toxicity or MI.

-In children, arrhythmias (including sinus bradycardia) are the earliest and most frequent indicator that digoxin dosage is too high.

2. Blurred vision (Xanthopsia Yellow)

3. Arrhythmias (mentioned above)

4. Nausea

5. Confusion

6. Depression

7. Psychosis (acute)


8. Vomitting, diarrhoea, anorexia, drowsiness, dizziness, nightmares, agitation

Infrequent side effects: Delirium, amnesia, shorterned QRS complex, atrial or ventricular extrasystoles, paroxysmal atrial tachycardia with AV block, ventricular tachycardia or filbrillation, heart block, Gynaecomastia (prolonged use)

Rare: Rash, thrombocytopenia, seizures

9.5 Pharmacokinetics

-t1/2 for digoxin is 36 hours in patients with normal renal function.

-Steady-state blood levels achieved in around 5 days-1 week after initiation of maintenance therapy

-Digoxin excreted via kidneys (mentioned previously) at a clearance proportional to GFR. This means that if anything that alters GFR (e.g. renal insufficiency/renal arterial stenosis will potentially affect clearance of digoxin.

-It is a CYP3A4 substrate [Note and remember all the CYP3A4 substrates]. Potential drug interactions.

9.6 Practice Points + Counselling


Adjust/Tailor dosage according to renal function, clinical response and therapeutic drug monitoring.

-Digitalisation with loading dose is needed only to treat arrhythmias and is usually not required for heart failure.

-IV administration is seldom required and offers little therapeutic advantage over oral dosage.

What is a loading dose?

-Loading dose is Maximum possible dose given at the start/initial part of treatment course before dropping down to a lower maintenance dose (to maintain steady levels)Loading doseSteady state levels

e.g. Adult loading dose, oral/IV 250-500 mcg/ every 4-6 hours. Max 1.5 mg

compared to

Maintenance dose, oral 125250 mcg/ once daily  (Rarely increased up to 500 mcg daily)

*The above dosages are from AMH 2012.


*Careful concentration monitoring is required!!!

-Take blood sample at least 6 hours after a dose to allow for redistribution.

-Steady state is reached in about 5 days if renal function is normal (half life is 36 hours). Renal impairment t1/2 increases.

-Manufacturers recommend a therapeutic range of 0.5-2 mcg/L (0.5-2 nanograms/ml). However, do note that toxic effects (e.g. anorexia, nausea, vomitting) occur at this range.

*Strike a balance between clinical benefit and the occurance of clinical side effects. Reduce dose if necessary.

-Remember that (look at precautions) that we said that the elderly, electrolyte imbalanced individual, hypoxia or hypothyroidism individuals are more susceptible to digoxin toxicity. 

-Interpret the results of concentration monitoring in relation to clinical condition (DON’T JUST ASSUME ONE SIZE FITS ALL e.g. PATIENT MAY APPEAR TO have normal levels but has hepatic impairment.


-Consider using lower concentrations of 0.5-0.8 micrograms/L for patients with Heart Failure who are in sinus rhythm (normal beating of the heart, as measured by an electrocardiogram (ECG)). 

-Higher concentrations of digoxin within the therapeutic range may be associated with increased rates of mortality and hospitalisation.


*Administration: Give IV over at least 5 mins, compatible fluids are sodium chloride 0.9%, glucose 5% and glucose/sodium chloride solution

*DO NOT GIVE INTRAMUSCULARLY (unpredictable absorption, local irritation)

*Counselling-Check if the patient is taking any OTC or herbal products.

*Practice points: 

-Always check the renal function and electrolyte concentration before starting digoxin

-OAA: 4-6 hours after initial dose

-Regularly assess patients for evidence of digoxin toxcitiy (including resting heart rate) , Routine measurement of pulse rate before giving next dose of digoxin is not needed.

-Assume that any arrhythmia that occurs in a child taking taking digoxin is due to the drug until proven otherwise. (GUILTY UNLESS PROVEN OTHERWISE)

-Stop Digoxin if patient reverts to sinus rhythm. *DOES NOT HAVE ANY PREVENTIVE ROLE IN PAROXYSMAL AF OR FLUTTER.

Paroxysmal-Sudden attack or incidence of symptoms

-If another arrhythmic agent (e.g. Verapamil, Diltiazem) is combined with digoxin, try to reduce and stop digoxin once patient is stable.

Therapeutic range of 0.5-2 mcg/L (0.5-2 nanograms/ml) [Manufacturer recommended]

Therapeutic range of 0.5-2 mcg/L (0.5-2 nanograms/ml)

Therapeutic range of 0.5-2 mcg/L (0.5-2 nanograms/ml)


9.7 Drug Interactions



2. Anti-arrhythmic agents used in combination (e.g. amiodarone)

3. Care with drugs that lower K+ levels (ARBs, ACE-inhibitors–>Refer to acronym…Captain Ace….)(Loop diuretics also will affect) or

4. Care with drugs that  lower Mg2+ levels


*Note: There are drugs out there that can reduce digoxin toxicity (e.g. DIGIBIND-Digoxin specific antibody/Fab fragments)


Congestive Heart Failure-Pharmacological Approach III

There are various stages of heart failure:


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)



-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)

Congestive Heart Failure-Pharmacological approach I (Cardiac Glycosides-Digoxin)

Drug classes that can be used to treat chronic heart failure:

1. ACE inhibitors

2. ARBs

3. Non-selective alpha antagonists

4. Selective alpha agonists

5. B-blockers

6. Calcium channel blockers

7. Diuretics (Loop diuretics and Spironolactone)

8. Digoxin (Cardiac Glycoside)

9. Direct K+ channel acting antagonists

10. Phosphodiesterase inhibitors

11. Nitric Oxides donors

12. Organic Nitrates

Part 1.1: Digoxin and Cardiac Glycosides

1.1 Mechanisms of Cardiac Glycosides in general:

1. Positive inotropic effect (increases force of contraction)

-Digoxin has a positive inotropic effect and thus helps the frail myocardium to pump by increasing contractility.

Mechanisms of action:

-Cardiac glycosides are potent inhibitors of active transport of sodium and potassium ions across the membrane.

-They reversibly bind to a subunit of the Na+/K+ ATPase.

-Both sodium and calcium ions enter the cardiac myocytes during each depolarisation.

-Calcium ion entry triggers contraction and the concentration within the cytoplasm increases.

-To restore original calcium concentrations, calcium ions are taken back into the sarcoplasmic reticulum via Ca2+ ATPase (SERCA-2).

-Also, it is removed from the cell by Na+/Ca2+ exchanger (NCX)

-Inhibition of Na+/K+ ATPase by cardiac glycosides results in a reduction in the rate of sodium extrusion and thus sodium ion conc. within cytoplasm increases.

-This leads to more Na+ removed via the NCX exchanger and Ca2+ is less effectively removed.

-With less Ca2+ efflux and repeated entry of calcium ions, calcium ions accumulate in the myocyte.

-This results in a few effects:

(a) Ca2+ uptake into the SR is increased via SERCA

(b) Increased Ca2+ is available for release from the SR during the next EC-coupling.

This leads to enhanced myocardial contractility.

2. Controls ventricular rate response to atrial filbrillation

-Atrial filbrillation (cardiac arrhythmia, associated with CHF). Indicated for atrial filbrilation and heart flutters.

3. Modulate nervous system activity

-This contributes to efficacy in managing heart failure.

4. Alters automaticity and diastolic RP of Digoxin (Electrophysiological actions)

-Decreases automaticity and increases diastolic resting membrane potential in atrial and AV nodal tissues.

-This is achieved by an increase in vagal tone (via m2 receptors) and a decrease in sympathetic nervous activity.

-This can cause sinus bradycardia and/or prolongation of AV conduction, higher-grade sinus arrest or AV block.

Definition of AV block: impairment of the conduction between the atria and ventricles of the heart 

Therpeutic Point and Take Note: At high concentrations, cardiac glycosides can directly increase automaticity in cardiac tissue, which contributes to atrial and ventricular arrhythmias.

-The simultaneous non-uniform increase in automaticity and depression of conduction in the Purkinje fibres and Ventricle muscle fibres can cause serious ventricular arrhythmias.

1.2 Pharmacokinetics

-t1/2 for digoxin is 36 hours in patients with normal renal function.

-Dosing issues: Loading doses (An initial higher dose of digoxin may be given at the beginning of a course of treatment before dropping to a lower maintenance dose)

Why use a loading dose?

-It is most useful for drugs that are eliminated from the body relatively slowly, i.e. have a long systemic half-life. Such drugs need only a low maintenance dose in order to keep the amount of the drug in the body at the appropriate therapeutic level (i.e. without an initial higher dose, it would take a long time for the amount of the drug in the body to reach that level)

*Definition of Maintenance dose: maintenance rate [mg/hr] of drug administration equal to the rate of elimination at steady state 

Steady state (in general occurs after 5-7 half-lives of drug):

Steady state levels

-This permits a once a day dosing (steady state blood levels are achieved one week after initiation of maintenance therapy).

-Excretion issues: The amount of digoxin excreted by kidney is denoted by clearance rate that is proportional to the glomerular filtration rate (GFR).

-Thus any issues with renal function (affecting GFR), will affect the half life in the body significantly (esp advanced renal insufficiency) [half life~3.5-5 days]

-The volume of distribution and clearance rate of the drug are decreased in the elderly.

1.3 Side effects/Adverse effects (Take extra caution in elderly or renal-impaired)

*Digoxin has a narrow therapeutic index/window (which means it is therapeutic dose and toxic dose is small).

Thus, digoxin MUST BE USED with caution in patients with renal insufficiency and in the elderly.

1. Blurred vision (with xanthopsia-yellow vision)

***2. Arrhythmias/Ventricular tachycardia or fibrillation

3. Nightmares

4. Confusion

5. Depression

6. Psychosis (abnormal condition of the mind)

1.4 Drug interactions

-Care with CYP3A4 inhibitors

-Other anti-arrhythmic drugs (e.g. amiodarone-sodium channel blocker)

-Many others (Check AMH 13 for complete list)

-Care with drugs that lower K+ levels in the blood (insufficient blood potassium to cause repolarisation) [e.g. loop diuretics-furosemide]  or lower Mg2+ levels (Affects Mg2+ dependent-ATPase)

-K+ and Mg2+ level changes will cause an increased risk of TOXICITY

***The advent/implementation of alternative therapies that palliate (lessen) the symptoms and improval of survival rates has led to more limited roles of cardiac glycosides for CHF treatment.

***Now only digoxin is widely used today

Congestive Heart Failure-Pharmacological approach II

-As mentioned in the pathophysiology lecture, renin-angiotensin-aldosterone system (RAAS) is highly activated in CHF.

-In CHF patients, plasma concentrations of plasma aldosterone can be as high as 20 times the normal level.

What is aldosterone?

-Main endogenous mineralocorticoid (steroid) with almost total sodium retention activity and minimal anti-inflammatory activity.

-It is produced in the zona-glomerulosa of the adrenal medulla

-Its main function is to INCREASE SODIUM REABSORPTION in the collecting tubules of the kidneys.


∴Overall effect is to increase fluid retention and increase blood pressure.

Two factors control the levels of aldosterone:

-The aldosterone secretion is dependent upon the electrolyte composition of plasma and the renin-angiotension system –

Decreased plasma sodium ions or increased potassium ions cause zona glomerulosa cells to release aldosterone.

-Since it is a steroid, it will bind to intracellular receptors

-Aldosterone specifically alters DNA regulatory regions to increase expression of genes for sodium channels as well as those for Na+/K+ ATPase molecules.

  • Potential roles of Aldosterone in CHF

1. Increased sodium and water retention                                                                     Edema, elevated cardiac filling pressures

2. K+ and Mg2+ loss                                                                                                              Arrhythmogenesis (generating arrhythmias) and risk of sudden cardiac death

3. Reduced myocardial NAdr uptake                                                                             Potentiation of NAdr effects, myocardial remodelling and arrhythmogenesis               4. Reduced Baroreceptor sensitivity                                                                               Reduced parasympathetic activity and risk of sudden cardiac death

5. Myocardial fibrosis, fibroblast proliferation.                                                           Remodelling and ventricular dysfunction 6. Alterations in sodium channel expression.                                                                                                                              Increased excitability and contractility of cardiac myocytes

*Aldosterone has biological effects beyond salt retention and antagonism of aldosterone’s action is beneficial in patients with heart failure. *These beneficial effects are additive to those of ACE inhibitors and B-Blockers.

-As a steroid, aldosterone binds intracellular receptors which specifically alters DNA regulatory regions to increase the expression of genes for sodium channels as well as those for Na+/K+ ATPase molecules.

-Increase in sodium channels present in the Collecting Tubule (CT) which facilitates sodium reabsorption.

1.1 Drug Class: Aldosterone Receptor Antagonists

1 (a) Spironolactone

-competitive antagonist of aldosterone, prevents aldosterone from binding, thus reducing no. of Na+ channels present in the DT. Na+ not reabsorbed, water loss.

Note: Since it is a renal drug (or any renal drug), caution must be taken when significant renal impairment is present.

Side effects:

1. Gynaecomastia (Spironolactone has cross-specificity with androgen and progesterone receptors, thus being able to stimulate secondary sex characteristics)

2. Impotence

*Other important clinical indications: Hirsutism (in females)

Mechanism of action (hirusutism): Inhibits binding of Dihydrotestosterone and the intracellular androgen receptor. It also inhibits ovarian steroidogenesis, resulting in lowered plasma levels of testosterone.

Dosage: Initiated at 12.5 or 25mg daily (Higher doses may lead to hyperkalemia-K+ sparing especially in patients receiving on an ACE inhibitor)

Note: Serum K+ levels and electrolytes should be checked after initiation (K+ sparing diuretic)

-Drug interactions and medical disorders may elevate serum K+ concentration (e.g. potassium supplements, ACE-inhibitors, worsened renal function


(b) Eplerenone

-more recent drug and reportedly lower impact on sex hormones.

Note: It is a substrate of CYP3A4, which potentially will be affected by drugs that inhibit or induce this system.


2. B-blockers (for CHF)

-As mentioned previously (in the pathophysiology notes), heart failure is characterized by sympathetic hyperactivation (heart pumps faster/harder to increase cardiac output etc)

-The body has these compensatory mechanisms to (a) enhance inotropy (b) Augment ventricular relaxation and filling (lusitropy-myocardial relaxation) (c) Increase rate (chronotropy) which worsens CHF


For many years (in the past), treatment of heart failure involved drugs that furthur stimulated responses (e.g. digoxin-positive inotrophy)

-The rationale for that was CHF main pathological cause was a drop in CO/SV as a result of myocardial dysfunction.

-However many of these sympathetic mimicking drugs increased mortality (death rate) in CHF patients whereas an unexpected decrease in mortality has been observed in administration of B-blockers.


-Now, it is accepted that sustained activation of sympathetic nerves in the myocardial injury contributes to progression of contractile dysfunction.

-This is supported by the adverse consequences of long-term sympathetic stimulation.

1.  Proliferation in the myocardium (Hyperplasia)

2. Direct Cardiomyocyte toxicity

3. Myocyte apoptosis

4. Increase in renin production (B1 receptors on JGA)


2.1 Mechanisms of action of B-Blockers

-Improve heart failure symptoms

-Improve exercise tolerance

-Improves ventricular function (over a peroid of several months in patients with CHF)

*However, a decrease in systolic pressure (afterload) would be expected immediately after administration of B-blocker in a CHF patient.

-Systolic function will recover and improve beyond baseline levels within the next 2-4 months.

-B-blockers ameliorate symptoms, reduce hospitalisation and decrease mortality in patients (mild to moderate cases of CHF)

Why does B-blockers decrase mortality?

1. This suggests a decrease in malignant ventricular arrhythmias (anti-arrhythmia benefits)

2. This might also suggest reduced hypokalemia following B-adrenergic blockade (renin-production inhibited, K+ reabsorbed into blood). 

-Sympathomimetic stimulation (via adrenaline) also results in hypokalemea, which may cause cardiac arrhythmias.

3. Could also be a direct consequence of the anti-ischemic effects of B-blockers

4. B-blockers also improve left ventricular structure and function by (a) decreasing chamber size (b) increase in ejection fraction (Due to reduced signalling for cardiac remodelling)



Caution! (Counter-productive effects)

*Note: We cannot assume that all B-blockers will exert similar effects.

1. Since B-blockers have the potential to worsen both ventricular function and symptoms in patients with CHF, they should be used cautiously in this disease.

They should be initiated at very low doses (generally less than 1/10th of the desired therapeutic dose)

-The doses should be increased slowly, over the course of weeks (until maximum dose is reachedunder careful supervision.

B-blockers:  Start low, Go slow,



2. Using B-blocker at doses used for hypertension or coronary artery disease may cause decompensation.

-Cardiac function is reduced is already reduced in hypertension or CAD.

-If sympathetic baroreceptor reflex is blocked as well, dyspnea, edema and venous pooling occurs.

-Even when therapy is initiated with low doses of B-blockers, there may be fluid retention requiring adjustments in diuretic regimen.


2.2 Side effects (Refer to anti-hypertensive notes): Worsen or futhur aggravates arrhythmias, Raynaud’s syndrome, Decreased sensitivity to hypoglycemia, Increased responsiveness upon abrupt cessation of B-blockers, depression.


3. Phosphodiesterase inhibitors


3.1Mechanism of action:

1. cAMP Phosphodiesterase (PDE) inhibitors reduce the degradation of cellular cAMP.

-This leads to elevated cAMP which leads to increase PKA levels which phosphorylate PRIDES (Increase calcium levels eventually)

*Positive inotrophy

2. Decreased arteriole resistance. 

-In the peripheral vasculature, the result is the dilation of vessels of arterioles and arteries, which increases supply Oxygen to organs.

-The vasculature can now respond to neuronal and humoral signals to regulate blood flow.

-Venous capacitance, capillary capacitance increases (esp. veins since majority of blood volume is located, regional blood volume modulated)

-Leads to reduction in afterload and preload.


*These combined effects on the myocardium and in the periphery underlie classification of these drugs as “inodilators (dilates arterioles and positive inotropic)


Drug examples: Milrinone

-Approved fo the short-term support circulation in advanced heart failure.

-It is a bi-pyridine derivative 

Mechanism of action:

  • Relatively selective inhibitor of Phosphodiesterase 3 which cGMP-inhibited cAMP phosphodiesterase
  • It causes direct stimulation of myocardial contractility  
  • Accelerates myocardial relaxation (reduce preload)
  • Causes balanced arterial and venous dilation with fall in systemic and pulmonary vascular resistance and left and right heart filling pressures (Decreased afterload and preload)

∴Cardiac output increases due to stimulation of myocardial contractility and decrease in left ventricular preload.











Congestive Heart Failure


Definitions of Congestive Heart Failure (CHF):

-The presence of heart failure symptoms, reversibility on treatment and objective evidence of cardiac dysfunction (European Society of Cardiology, 1995)

-Can be viewed as a consequence of disordered circulatory dynamics and pathologic cardiac remodelling.


Congestive Heart Failure occurs when the heart is unable to pump enough blood to meet the needs of the body.

-This reduces Cardiac Output, leading to hypoperfusion to tissues and Edema (explained below).

Cardiac Output=SV X HR                          Blood Pressure=TPR X Cardiac Output

-This stimulates various physiological responses (e.g. Increased sympathetic Nervous System-Baroreceptor Reflex, Increase in Renin-Angiotensin Aldosterone System and inflammation due to ischemia)

Why is the heart unable to pump sufficient blood in the first place?

-Due to decreased myocardial contractility (possibly due to myocardial infarction) (Results in Systolic Dysfunction)

-Cardiomyopathies (Deterioration of Myocardium which leads to inadequate pumping)-Could be due to hypertrophy which results in Systolic Dysfunction

-Long-standing hypertension (Results in Diastolic Failure)

-Severe mitral valvular regurgitation (Results in Systolic Failure)

-Arteriovenous fistulae (Abnormal passageway between an artery and vein)

Definition of fistulae: Abnormal connection or passageway between two epithelium lined organs or vessels that do not normally connect.

-Thiamine deficiency (Vitamin B1) –>Disease: Beriberi

-Severe anemia

-Alcohol (cardiotoxic in large quantities), Drugs (e.g. Beta-Blockers, Calcium channel blockers may depress myocardial contractility) (Chemotherapeutic agents such as doxorubicin may cause  myocardial damage).

-Persistent arrhythmias (Reduce cardiac efficiciency)

***Diastolic myocardial dysfunction-Impaired myocardial relaxation (due to increased ventricular wall stiffness and reduced compliance, results in impaired diastolic ventricular filling, decreasing preload). Could be due to:

(a) Ischemic myocardial fibrosis (Coronary artery disease)

(b) Left Ventricular Hypertension

(c) Hypertrophic cardiomyopathy

-Diastolic dysfunction often co-exists with systolic failure but may occur in isolation in 20-40% of patients presenting with heart failure.

-Diagnosis of diastolic dysfunction is via Doppler mitral diastolic flow velocity profile.

How does the heart deal with the lack of cardiac output and drop in BP?

Ans: Compensatory responses to maintain perfusion to vital organs

*Heart has to adapt to maintain sufficient cardiac output and blood pressure.

1. [Drop in Cardiac Output] Myocardial hypertrophy occurs  

-Attempts to increase myocardial contractility

-This increases the mass of contractile elements and improves systolic contraction

-Increase in Angiotensin II levels also induces myocardial hypertrophy.

-However it also increases ventricular wall stiffness which means it is less elastic and pumps less blood eventually.

2. [Drop in Blood Pressure and CO due to Reduced Renal perfusion] Renin Angiotensin Aldosterone system activated (Activation of neurohumoral system)

-Attempts to increase arterial tone.

-Stimulates the Renin-Angiotensin-Aldosterone System (RAAS) which increase levels of renin, levels of plasma angiotensin II and aldosterone.

-The drop in blood pressure also stimulates the baro-receptor reflex (sympathetic tone) which increases the release of catecholamines (NAdr) which stimulates more renin release.

-Aldosterone, Angiotensin II promotes Na+ and water retention and decreased excretion of K+.

3. [Drop in Blood Pressure and CO] Sympathetic nervous system is activated (Activation of neurohumoral systems)

-Baroreceptors are activated in CHF, resulting initially in enhanced myocardial contractility.

-Later on, it furthur activates the RAAS and the humoral system.

-Overall effect of this is an increased venous return (Increases cardiac preload)arterial tone (cardiac afterload–>Pressure to overcome arteriolar resistance), increased plasma concentration of NAdr, progressive retention of water and salt and edema.

-Chronic sympathetic stimulation results in down-regulation of cardiac B-receptors (Bark* enzyme decreases). Thus, it reduces responsiveness of heart to sympathetic stimulation.

4. [Drop in Blood Pressure] Regulatory Substances released 

(a) Atrial Natriuretic Peptide (ANP) is released from the cardiac atria in response to stretch, leading to natriuresis and vasodilation.

-ANP are physiological antagonists to the effects of AngT II on vascular tone, aldosterone secretion and renal sodium absorption.

(b) Endothelin is a potent vasoconstrictor peptide secreted by vascular endothelial cells which promotes the renal reabsorption of sodium.

-Constriction of systemic veins. Promoting sodium and water reabsorption increases atrial pressure (cardiac preload), sarcomeres lengthen and myofibril contraction is enhanced (Frank-Starling Mechanism).

-Beyond a certain stretch point, myocytes loses contractility, thus any increase in end-diastolic volume will not have an increase in stroke volume anymore,  stroke volume decreases (see heart failure region)

-Stroke Volume=End Diastolic Volume – End Systolic Volume

5. [Decrease in SV] Increasing left ventricular preload

Overall effect: Sustained cardiac output allows heart to operate at higher end-diastolic volume, leading to increased SV. Peripheral vasoconstriction attempts to allow for regional redistribution of cardiac output to vital organs. However, each of these compensatory responses promote disease progression.

–>Neurohumoral activation leads to arterial and venous constriction (Arterial constriction increases afterload, whereas venous constriction decreases preload)

Thus this decreases stroke volume

–>Secreted substances (NAdr and Angiotensin II) may act directly on myocardium to promote unfavourable remodelling.

∴ Thus, this increases wall stress and decrease myocardial contractility.

Pharamological aims:

1. Drugs reduce ventricular wall stress by inhibiting renin-angiotensin system (e.g. selected vasodilators, ACE-inbibitors, aldosterone antagonists)

-Preload Reduction, Afterload reduction.

2. Drugs may inhibit sympathetic nervous system. This decreases pathological ventricular remodelling, slows disease progression and decrease mortality  in patients with due systolic dysfunction (e.g. B-adrenergic antagonists)

– Afterload Reduction, Preload reduction

3. Enhancement of inotropic state

-These drugs are therefore vital in the long-term treatment of heart failure.

-Some drugs that slow progression provide immediate benefit on hemodynamic function and symptoms  (e.g. vasodilators and ACE inhibitors)

-Other drugs that slow disease progression can adversely affect hemodynamic function and worsen symptoms in the short term. Thus, they must be used with caution (e.g. B-blockers)

A vasodilator’s more prominent effect may be to reduce either preload or afterload. However most agents affect both.

Diagnosis of Congestive Heart Failure:

1. Echocardiogram which measures the Ejection fraction (Ef)

-Ef represents the volumetric fraction of blood pumped out of the ventricle (heart) with each heart beat

E_f = \frac{SV}{EDV} = \frac{EDV - ESV}{EDV}

2. Chest radiography 

-Will show Cardiomegaly (Cardiothoracic Ratio/CTR >50% abnormal)

Definition of Cardiothoracic ratio (CTR) which measures heart size= Cardiac Width : Thoracic Width

3. Electrocardiography (Abnormality in most patients). Abnormalities in Q waves, ST/T wave changes, Left Ventricle hypertrophy, conduction disturbance and arrhythmias.

4. Ambulatory ECG (detects arrhythmias)

5. Blood tests (For detection of anemia and renal function assessment)

-Thyroid dysfunction (hyperthyroidism)  may also cause heart failure so thyroid function tests are conducted as well.

6. Radionuclide imaging

-A method of assessing ventricular function and is useful when adequate Echocardiograms are hard to obtain.

7. Cardiac catheterisation 

-For rare cases of cardiomyopathy or myocarditis when myocardial biopsy is required

8. Exercise/Stress testing

-Assess the presence of myocardial ischemia and to measure maximum oxygen consumption (VO2)

Definition of VO2: Level beyond which oxygen consumption does not rise any further despite increasing levels of exertion (i.e. the limits of aerobic exercise tolerance and is considerably reduced in CHF)

Clinical Presentation/Symptoms of CHF

Depends on various factors:

1. Extent of cardiac damage

2. Extent of Hemodynamic overload

3. Secondary compensating mechanisms that arise as heart failure develops.

4. Rate of progression of the disease and whether secondary compensating mechanisms had time to develop (e.g. acute mitral valve regurgitation may be tolerated poorly compared to slow gradual development)

-Atrial filbrilation occurs in 10-50% of patients with established heart failure and the onset of AF may result in an acute deterioration.

-Ventricular arrhythmias (Ectopics, ventricular tachycardia) are also common.

-Symptoms (non-specific) presented during the early stages: Malaise, lethargy, fatigue, dyspnea, exercise intolerance

***Note: Heart failure may principally affect the left heart, right heart or both sides (biventricular). In practice, left heart is most commonly affected because it has to pump blood to the rest of the body.

  • Isolated Right Heart Failure may be due to major pulmonary embolism, pulmonary hypertension or pulmonary stenosis.
  • However, the ventricles share the interventricular spetum so dysfunction of either ventricle can potentially influence the function of the other

*Left Heart Failure

-Increase in left atrial pressure raises pulmonary venous pressure

-This results in pulmonary congestion and eventually alveolar edema, causing breathlessness, coughing, dyspnea and sometimes hemoptysis (expectoration of blood or of blood-stained sputum from the bronchi)

-Refer to drawing

-As Left Ventricular failure progresses (may occur at rest), orthopnea (breathlessness when lying down) and paroxysmal noctural dyspnea (Sudden acute breathlessness at night) precipitates.

-Symptoms include:

  • Cool and pale skin (indicating peripheral vasoconstriction)
  • Blood pressure may be high, low or normal as cardiac dysfunction worsens
  • Pulse may be low volume and rhythm may be normal or irregular due to ectpics or AF (pulsus alternans-alternative strong and weak beats may occur)
  • Resting sinus tachycardia may occur during severe heart failure or may be partially reflex due to drug-induced vasodilation.
  • Venous pressure is normal in isolated LHF

*Right Heart Failure

  • Symptoms: Minimal especially if diuretics already given.
  • Ankle swelling
  • Dyspnea
  • Reduced exercise capacity and angina pectoris occurs

The reduction in cardiac output in both LHF and RHF will result in low blood perfusion to the brain, kidneys and skeletal muscle. Thus, the general symptoms are mental confusion, tiredness and reduced exercise tolerance.

-The annual overall incidence of stroke or thromboembolism in CHF is 2%.