M3 L4 - Heart failure

What is Heart Failure?

Inability of the heart to pump sufficient quantities of blood to meet the requirements of the tissues

Causes of HF

• Cardiac

  • CAD

  • Hypertension

  • Heart valve lesions

  • Cardiomyopathy

• Extracardiac

  • Thyrotoxicosis

  • Anemia

Types of HF

• Left ventricular failure

• Right ventricular failure

• Biventricular failure

Manifestations of HF

• Exertional

  • dyspnea

  • fatigue

  • cough

• Dependent edema

• Enlarged heart (cardiomegaly)

Enlarged heart (cardiomegaly) signs

heart to thoracic cavity ratio is 50% or less of the width

Management of HF

• Nonpharmacologic treatment

• Pharmacotherapy

Nonpharmacologic Treatment of HF

• Modification of lifestyle

• Surgical treatment

Modification of lifestyle to treat HF

• Physical activity

  • Bed rest (during acute condition)

  • Gradual rehabilitation programs

Surgical treatment of HF

• Valve repair

• Coronary revascularization

• Cardiac transplantation

Pharmacotherapy

• Diuretics

• Inhibitors of RAAS:

  • ACEI

  • ARB

  • Aldosterone antagonists

• beta blockers

• Vasodilators

• Positive inotropic agents:

  • Cardiac glycosides (digitalis)

• Others

Cardiac Glycosides (Digitalis) Source

Derived from plant sources

Chemical structure of digitalis

• Glycoside: a molecule in which a sugar is bound to a non-carbohydrate moiety by a glycosidic bond

• Sugar (glycone)

• Non-sugar (aglycone steroid nucleus)

What does the sugar component of digitalis determine?

solubility

what does the aglycone steroid nucleus of digitalis determine?

determines pharmacological activity

Mechanism of action for digitalis

• Na+-K+-ATPase and Na+-Ca2+ exchanger

• increase vagal effect on the heart

Na+-K+-ATPase function

actively extrudes 3 sodium ions (Na⁺) out of the cardiomyocyte while importing 2 potassium ions (K⁺) in

• bring cell back to resting state

Na+-Ca2+ exchanger

an antiporter membrane protein that moves calcium ions out of cells in exchange for sodium ions

Effects of digitalis on Na+-K+-ATPase and Na+-Ca2+ exchanger

• Digoxin inhibits Na+-K+-ATPase, increasing Na concentration in the cell

• the increased Na in the cell causes the Na+-Ca2+ exchanger to send Ca in instead of out

• Digitalis directly decreased Na+-K+-ATPase pump in cardiomyocytes →

• increased intracellular Na+ →

• Na+-Ca2+ exchanger reversal →

• Instead of pumping Ca2+ out, the reversed exchanger brings more Ca2+ into the cell →

• increased intracellular Ca2+ →

• Enhanced myocardial contractility (Positive Inotropy)

Digitalis effects on vagus nerve

• stim PSNS to increase vagal effect on the heart →

  • decreased SA node firing rate (-ve chronotropy)

  • decreased conduction at AV node (-ve dromotropy)

• → decrease heart rate

Effect of Digitalis

• increased myocardial contractility:

  • decreased heart size

  • decreased venous congestion

  • decreased edema

  • increased renal perfusion

• decreased heart rate

Pharmacokinetics of Digoxin by oral ingestion

• Absorption: 70%

• Onset: 1–2 hours

• Peak: 6–8 hours

• Half-life: Approximately 40 hours

• Duration: 3 days

  • causes accumulation in the body

• Metabolism: Liver (14%)

• Elimination: Kidneys

Therapeutic Indications to Use Digitalis

• Congestive heart failure (CHF)

• Tachyarrhythmia:

  • Especially atrial flutter or fibrillation (AF)

Best indication to take digitalis?

Having Chronic Heart Failure and Atrial Fibrillation

Drug Interactions

• K+

• Hypercalcemia or IV Ca2+

• Quinidine and Varepamil

• Antibiotics

K+ drug interaction

• hyperkalemia: decreased digitalis activity (compete for Na+-K+- ATPase)

• hypokalemia: increased digitalis activity/toxicity

  • K+ losing diuretics: increased digitalis activity/toxicity (DDI type: altered physiology)

Hypercalcemia or IV Ca2+ drug interaction

increased risk of toxicity & dysrhythmia

Quinidine and Varepamil drug interaction

decreased renal clearance & Vd of digitalis → increased level & toxicity

Antibiotics drug interactions

inhibit intestinal flora that inactivate digoxin → increased level

Adverse effects of digitalis

• GI:

  • Anorexia, nausea, vomiting, diarrhea

• CVS:

  • Sinus bradycardia, AV block, ventricular dysrhythmia (e.g., VT)

• CNS:

  • Headache, fatigue, mental depression, confusion, hallucination, convulsions

• Visual disturbances:

  • yellow vision

• Gynecomastis

Digitalis Toxicity

Narrow therapeutic range & low therapeutic index

• Accumulates in the body

Digitalis Toxicity more common in which population

• old age

• renal impairment

• certain drug interactions

Early signs of Digitalis Toxicity

GI symptoms (N&V)

Dangerous signs of Digitalis Toxicity

VT and VF (VF fatal)

Treatment of Digitalis Toxicity

• Stop digitalis

• Digitalis antibody (digoxin immune fab [fragment antigen-binding])

Plasma Digoxin Level

• Therapeutic index: ≈2

• Therapeutic range: 0.5-2.0 ng/ml

• Toxic level: > 2.4 ng/ml

• Clinical importance:

  • Indicates if the patient received digoxin recently

  • Checks patient adherence to treatment

  • Helps when drug interaction is suspected (e.g., quinidine can raise digoxin blood level)

  • Helps when digitalis toxicity is suspected

Administration Route

oral or IV

Dose of digitalis

• Rapid:

  • Loading dose: 1-1.5 mg over first day

  • Maintenance dose: 0.125-0.5 mg/day

  • given for sever conditions

• Slow:

  • Start with maintenance dose

  • always oral

  • given to stable pt’s

Special consideration for dosing of digitalis

E.g., elderly – renal impairment

Preparations

tablets, capsules, elixir, ampoules

Other HF medications

• Recombinant B-natriuretic peptide

• Milrinone

• Vasopressin* receptor antagonists

• Neprilysin inhibitors (Sacubitril)

• Sodium/glucose cotransporter 2 inhibitors (SGLT inhibitors)

Recombinant B-natriuretic peptide

• increased Na & water loss

• given by IV

Milrinone

• PDE3 inhibitor – +ve inotropic effect on the heart

• Used for acute short-term NOT long-term treatment

• given via IV

Vasopressin* receptor antagonists

• Block the action of vasopressin at its receptors

• decreased water retention

• E.g., vaptans

• given orally or by IV

Neprilysin inhibitors (Sacubitril)

• Neprilysin inhibits natriuretic peptides (NP)

• Neprilysin inhibitors prevents the above effect → really increase NP

  • body releases these hormones to help protect the heart by widening blood vessels and signaling the kidneys to flush out extra salt and water

• Sacubitril/valsartan combination (angiotensin receptor- neprilysin inhibitor [ARNI])

Management of HF Pharmacologically

• ABCD

• ACEI – ARB – Aldosterone antagonists – ARNI

• Bed rest – beta blockers – B-natriuretic peptide

• Cardiac transplantation

• diet, digitalis, diuretics, dilators

Quadruple Medical Therapy of HF

1. Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

2. Beta blocker

3. Aldosterone antagonist (e.g., spironolactone)

4. Sodium/Glucose cotransporter 2 inhibitor (SGLT2 inhibitor)

combination is the best therapy