drugs used for treatment of heart failure

Question 1

Stages of heart failure

Answer 1

compensatory phase = drugs need to decrease contractility to prevent over-exhaustion of muscles and progression to heart failure

heart failure = drugs not treating root cause anymore but increasing contractility to prolong patient’s life

Question 2

Beta-adrenoreceptor antagonists (beta-blockers)

Answer 2

Non-selective - blocks beta 1 and 2 = carvedilol
cardioselective - blocks beta 1 = bisoprolol, metoprolol
mixed = nebivolol

MOA: blocks adenylyl cyclase = decrease cAMP = decrease PKA = decrease opening of Ca2+ channel = decrease CICR and myosin-LC phosphorylation = decrease contractility

Question 3

Sacubitril-Valsartan

Answer 3

Sacubitril inhibits neprilysin = inhibits the breakdown of BNP, Ang II and bradykinin
a. BNP = promotes vasodilation, natriuresis and diuresis, antagonises RAAS
b. Ang II = activates RAAS, bad = use Valsartan (Ang II receptor blocker) to avoid negative effects
c. bradykinin = adverse effect of dry cough
thus Salcubitril-valsartan is an ARNi (angiotensin receptor/ neprilysin inhibitor) = fixed dose combi drug

clinical uses = chronic HF with rEF

Adverse effects = hypotension, hyperkalemia, renal failure, angioedema (due to Ang II)

Question 4

Hydralazine

Answer 4

MOA: direct arteriole vasodilator by inhibiting IP3-induced release of calcium = reduces peripheral resistance = compensatory release of epinephrine/ norepinephrine = increase venous return and cardiac output

Clinical uses
a.heart failure with rEF (tgt with isosorbide dinitrate)
b. essential hypertension (when 1st line medications are unsuitable, given orally)
c. acute-onset, severe peripartum or post-partum hypertension

adverse effects
a. baroreflex associated sympathetic activation
b. hydralazine-induced lupus syndrome (HILS)
- athralgia, myalgia, serositis, fever, dose-dependent, >6 months

contraindicated in coronary artery disease due to hydralazine’s stimulation of sympathetic N.S

Question 5

diuretics

Answer 5

a. Loop diuretics
b. K+- sparring diuretics

Question 6

Loop diuretics

Answer 6

Sulfonamide derivatives - furosemide, bumetanide, ethacrynic acid

MOA: inhibit luminal Na+/K+/2Cl- cotransporter = more Na+ in lumen = diuresis

note: Loop diuretics also increase Mg2+ and Ca2+ excretion and induce renal PG synthesis
- NSAIDs are contraindicated as they interfere with action by reducing PG synthesis

note: loop diuretics are rapidly absorbed = diuretic response extremely rapid

Clinical uses = acute pulmonary edema, hyperkalemia, acute renal failure, anion overdose

Adverse effects = hypokalemic, ototoxicity (avoid using tgt with aminoglycoside due to combined ototoxicity effects), hyperuricemia

Question 7

K+ sparring diuretics

Answer 7

Spironolactone, Eplerenone - blocks aldosterone receptor
Triamterene, amiloride - blocks Na+ channel
= reduce Na+ reabsorption
= reduce K+ secretion

note: Spironolactone has slow onset of action - needs several days for full therapeutic effect to be achieved

note: Triamterene is metabolised in the liver = shorter half-life = must be given more frequently than amiloride

clinical uses = diuretic, hyperaldosternism

adverse effects = hyperkalemia, metabolic acidosis, gynecomastia (only spironolactone due to inhibition of testosterone receptor), Acute renal failure (triamterene + indomethacin), kidney stones (only triamterene)

Question 8

Cardiac glycosides - heart failure drugs

Answer 8

Digoxin and digitoxin

MOA: inhibits Na+-K+ exchange = increase Na+ intracellularly = less Ca2+ efflux = more Ca2+ intracellularly to induce CICR = stronger systolic contractions

additional mechanical effects = reduce preload and afterload
additional electrical effects = QT, ST depression, inversion of T, increase in PR interval and decrease ventricular rate

note: increase intracellular Ca2+ may also induce toxic effects of automaticity, extrasystoles, tachycardia and fibrillation
note: K+ and digitalis inhibits each other’s actions of binding to Na+-K+ ATP-ase, thus hypokalemia will enhance action of digoxin = enhance toxicity (hypercalcemia, hypomagnesemia, furosemide and verapamil will also enhance toxicity)
Solution = discontinue therapy, correction of K+/Mg2+ deficiency, anti-arrhythmic drugs, digoxin antibody digibind

clinical uses = systolic dysfunction, atrial fibrillation

adverse effects = progressively more severe dysrhythmia, nausea, vomitting, headache

Question 9

Comparing digoxin and digitoxin

Answer 9

1. Digitoxin has more protein binding and thus a larger volume of distribution as compared to digoxin
2. digitoxin has a slower onset than digoxin
3. digitoxin has a longer half-life and thus needs less doses than digoxin
4. digitoxin is extensively metabolised by the liver, digoxin is not extensively metabolised by the liver
5. digitoxin is excreted in feces, digoxin is 2/3 excreted unchanged in kidney