Pharmacology of Medicines Effective in Heart Failure

Comprehensive review flashcards covering the definitions, pathophysiology, hemodynamics, guideline-directed medical therapy, drug mechanisms, and acute management of heart failure.

What is the technical clinical definition of heart failure (HF)?

A complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood.

Why is there no single diagnostic test for heart failure?

Heart failure is largely a clinical diagnosis based on a careful history and physical examination.

What are the four components of holistic management in heart failure?

1. Surgical correction of underlying cause
2. Medical management of underlying disease
3. Treatment of aggravating factors
4. Treatment of heart failure per se (mostly irrespective of the underlying cause)

What are the three primary determinants of stroke volume (SV)?

1. Afterload
2. Preload
3. Contractility

What are the mathematical formulas for Stroke Volume (SV) and Cardiac Output (CO)?

$SV = EDV - ESV$$CO = HR \times SV$

How is preload defined in the context of cardiac hemodynamics?

The load on the heart created by the volume of blood received into the left ventricle from the left atrium at the end of diastole that it must eject with each contraction (volume overload).

How is afterload defined in the context of cardiac hemodynamics?

The load on the contracting ventricles created by the resistance to the blood projected by the ventricle into the arterial system (i.e., total peripheral resistance; pressure overload).

What are the three main categories of compensatory mechanisms activated in heart failure?

1. Cardiac compensation (increased HR, increased contractility, cardiac dilatation via the Frank-Starling mechanism, myocardial hypertrophy)
2. Systemic compensation (increased blood volume, redistribution of blood flow, increase of erythrocytes, increased tissue oxygen utilization)
3. Neurohormonal compensation (sympathetic nervous system, renin-angiotensin system, atrial natriuretic peptide, endothelin)

Why are compensatory neurohormonal feedbacks in heart failure characterized as "counter-regulatory"?

They ultimately make the condition worse rather than better because compensatory mechanisms cannot distinguish heart failure from severe blood loss or hemorrhage, releasing vasoconstrictors (such as angiotensin II) that worsen heart failure.

How do diuretics alter cardiac performance in heart failure based on the Starling curve?

They reduce congestion and symptoms of pulmonary venous congestion by decreasing filling pressure (preload), but lowering preload may also reduce cardiac output ($CO$), potentially worsening fatigue.

What are the two overarching therapeutic objectives of heart failure treatment?

1. To reduce morbidity (relief of symptoms, reduce severity, improve exercise tolerance, reduce acute exacerbations, avoid hospital admission)
2. To reduce mortality

What are the four core foundational medication classes in Guideline-Directed Medical Therapy for HFrEF ($\text{EF} < 40\%$)?

1. Renin-Angiotensin system inhibitors (ACEI, ARB) or Angiotensin receptor-Neprilysin inhibitors (ARNI)
2. $\beta$-receptor antagonists
3. Mineralocorticoid receptor antagonists (MRA)
4. Selective sodium-glucose cotransporter-2 (SGLT2) inhibitors

What is the mechanism of action of digoxin in cardiac myocytes?

Digoxin binds to and inhibits the sodium/potassium-ATPase ($\text{Na}^+/\text{K}^+\text{-ATPase}$ sodium pump) within the plasma membrane, increasing intracellular $\text{Na}^+$ and improving myocardial contractility (positive inotropic effect) independent of its negative chronotropic effect.

Why is digoxin the only positive inotropic drug suitable for treating chronic heart failure?

Digoxin effectively improves contractility in the dilated failing heart without increasing overall mortality or arrhythmias in heart failure, unlike other positive inotropes.

Which diuretic is specifically indicated for patients with mild heart failure and a GFR $> 30\,\text{mL/min/1.73m}^2$?

Hydrochlorothiazide

How do nitrates exert their therapeutic effect in chronic heart failure?

They dilate venous capacitance vessels (with negligible effect on arterioles in HF), increasing venous bed volume and reducing ventricular filling pressure and heart wall stretch, which reduces myocardial oxygen demand.

What unique advantage do ACE inhibitors have over other vasodilators regarding neurohormonal activation?

They are the only group of drugs that reduce peripheral resistance (afterload) without causing a reflex activation of the sympathetic nervous system.

How do ACE inhibitors reduce both preload and afterload in heart failure?

They reduce afterload by inhibiting ACE to decrease production of angiotensin II (a potent vasoconstrictor), and reduce preload by indirectly inhibiting aldosterone synthesis, thereby decreasing salt and water retention.

How do Angiotensin II receptor blockers (ARBs) differ from ACE inhibitors in their mechanism and side-effect profile?

ARBs competitively block angiotensin II type 1 ($\text{AT}_1$) receptors and do not increase bradykinin levels, resulting in lower rates of cough and angioedema, but possibly a higher rate of hypotensive symptoms.

Which three $\beta$-blockers have demonstrated a reduction in both mortality and hospitalization in heart failure?

Bisoprolol, carvedilol, and metoprolol.

How does the receptor selectivity of carvedilol differ from that of bisoprolol and metoprolol?

Bisoprolol and metoprolol are cardioselective $\beta_1$-adrenoceptor blockers, whereas carvedilol provides non-selective $\beta$-blockade plus $\alpha_1$-blockade, which provides additional vasodilation.

According to the British National Formulary (BNF), what comorbidities should not prevent the initiation of a $\beta$-blocker in heart failure?

Age, diabetes, chronic obstructive pulmonary disease (COPD), peripheral vascular disease, erectile dysfunction, or interstitial pulmonary disease.

What mechanisms explain the powerful therapeutic benefit of spironolactone in heart failure?

1. Anti-aldosterone effect (reducing preload by competitively blocking aldosterone receptors at the $\text{Na}^+/\text{K}^+$ exchange site in the collecting duct)
2. Improved potassium and magnesium conservation (antiarrhythmic effects)
3. Reversal of aldosterone-induced myocardial fibrosis

What two active agents comprise the ARNI combination drug, and what are their respective mechanisms?

Sacubitril (a prodrug that inhibits neprilysin, preventing breakdown of natriuretic peptides and activating the natriuretic peptide system) and valsartan (an angiotensin II receptor blocker).

Why must an ACE inhibitor never be combined with sacubitril?

Because neprilysin also degrades bradykinin; concurrent administration with an ACE inhibitor significantly increases bradykinin concentrations and elevates the risk of severe angioedema.

What drug class do enoximone and milrinone belong to, and what are their pharmacological properties?

Phosphodiesterase type-3 (PDE-3) inhibitors; they possess positive inotropic and vasodilator properties.

What are the pharmacological actions and secondary physiological effects of SGLT2 inhibitors (empagliflozin, dapagliflozin) in heart failure?

They inhibit the sodium-glucose cotransporter 2 in renal tubules, reducing water retention and preload. They also cause increased hematocrit, weight loss, and improved ventricular loading conditions.

How is Acute Heart Failure (AHF) defined?

A rapid or gradual onset of symptoms and/or signs of heart failure, severe enough for the patient to seek urgent medical attention, leading to an unplanned hospital admission or emergency department visit.

What are the four predominant clinical presentations of Acute Heart Failure (AHF)?

1. Acute decompensated heart failure
2. Acute pulmonary oedema
3. Isolated right ventricular failure
4. Cardiogenic shock

What are the seven standard therapeutic interventions used in the management of Acute Heart Failure (AHF)?

1. Oxygen therapy
2. Intravenous loop diuretics
3. Intravenous vasodilators (nitrates or nitroprusside)
4. Intravenous inotropes or vasopressors (dopamine, dobutamine, norepinephrine, epinephrine, enoximone, milrinone)
5. Intravenous morphine
6. Digoxin (if atrial fibrillation is present)
7. Thromboembolism prophylaxis (e.g., heparin)