52.4.2 Main Drug Classes Used in the Treatment of Heart Failure Flashcards
What is heart failure? What are the symptoms? Why are they present?
A fall in cardiac ouput which causes:
-exercise intolerance
-breathlessness due to venous congestion
-oedema due to fall in renal perfusion (retains water and sodium due to less blood)
-cardiac dilation
-acidaemia (due to impaired kidneys as less renal blood flow)
Why may ischaemic heart failure occur?
Left ventricle hypertrophies to try and increase cardiac output
Presses on coronary artery supplying heart
Increases oxygen demand which supply does not meet
What are the systemic consequences of heart failure?
-Increased sympathetic drive (from baroreceptor reflex activation)
-Activation of RAA axis (from reduced renal perfusion)
-Activaiton of ADH axis (from low blood pressure)
-Ventricular dilation and fibrosis (reduces contractility)
More fluid with adequate pressure to tissues
What are the main drug classes used to treat heart failure?
*Diuretics
*Vasodilators
*Cardio-stimulatory (Inotropic) drugs
*Cardio-inhibitory drugs
What are the different diuretics used?
Thiazide, loop, and potassium-sparring
What vasodilators are used?
*ACEi
*ARBs
*NO donors
*Natriuretic peptides
*Phosphodiesterase inhibitors
What cardio-stimulatory drugs are used?
*Digoxin
*Sympathetic drugs (Beta-agonists)
*Phosphodiesterase inhibitors
What cardio-inhibitory drugs are used?
Beta blockers
Ca2+ channel blockers
What is the mechanism of action of thiazide diuretics? What is their side effect?
Inhibit the action of NCC in the DCT (Na/Cl symporter)
More Na remains in the urine causing more water to remain and increase volume output
Potassium loss (proportional to increased sodium retained in the tubule)
What is the mechanism of action of loop diuretics?
e.g. Furosemide
Increase water loss which lowers blood volume through inhibiting the NKCC (NaK2Cl) transporter on the thick ascending limb of the loop of Henle resulting in sodium and thus water retention in the loop
Act as vasodilators (renal afferent dilate = GFR, vasa recta = washout, systemic arterioles = lower arterial blood pressure)
Name two potassium sparing diuretics
Aldosterone antagonist
ENaC inhibitor in collecting duct (amiloride)
How are diuretics useful in the treatment of cardiac failure?
Reduce oedema
Vasodilate (loop diuretics)
Increase CO by reducing the effective circulating volume to reduce workload on the heart
Reduce cardiac dilation
What are the downsides of diuretics in cardiac failure?
Reduce venous return which reduces cardiac output
Increases sympathetic tone which increases myocardial oxygen debt
Activates the renin axis and ADH
Name an ACE inhibitor
Captopril (ends in -pril)
How do angiotensin inhibitors (ACE and ARBS) treat cardiac failure?
Angiotensin constricts splanchnic and renal vasculature and decreases aldosterone production
Therefore the drugs:
-Diuretic effect (via stopping aldosterone which increases reabsorption of NaCl)
-Reduces sympathetic drive (angiotensin II)
-Vasodilates to decrease venous return
-Doesn’t increase oxygen demand on the heart
What are the bad aspects of angiotensin inhibitors?
Postural hypotension
Decreased renal blood flow resulting in electrolyte dysfunction
Name an angiotensin II receptor blocker
Losartan
How do nitric oxide donors work in the treatment of heart failure? Give an example
NO activates guanylate cyclase
cGMP causes relaxation of smooth muscle
Nitroprusside increases NO availability and results in vasodilation, reducing peripheral resistance and decreasing cardiac dilation
Name an aldosterone antagonist (potassium sparring diuretic). How is it used in the treatment of heart failure?
Spironolactone
Significant diuretic effect due to activation on renin axis during cardiac failure
Affects ventricular remodelling via reducing fibrosis and ischaemia
What is the mechanism of action of naturitic peptides? Give examples of drugs that promote this axis
ANP and BNP increase salt and water excretion and vasodilate
Neprilysin blocks the vascular endopeptidase which degrades ANP and BNP
Recombinant BNP (nesiritide)
Name an ARB
Angiotensin receptor blocker = valsartan
How are phsophodiesterase inhibitors useful in treating cardiac failure?
PDE breaks down cGMP which increases smooth muscle relaxation and vasodilation, reducing venous return and setting heart back onto starling curve
Give an example of a cardiac glycoside used to treat cardiac failure?
Digoxin
What is the mechanism of action of cardaic glycosides?
Na+K+ATPase inhibitors which increase the intracellular sodium levels and increase contractility:
Inhibit Na/K pump on plasma membrane
Increased intracellular sodium
Reduced action of NCX pump
Raises intracellular calcium
Increasing contractility
Why are cardiac glycosides such as digoxin particularly useful in treating heart failure?
Increase contracility with little increase in oxygen demand (passively increases Ca concentration)
At what dose can beta blockers be given to treat cardiac failure? Why?
LOW DOSE
Reduces rate and force of contraction to reduce oxygen debt
(reduce the effects of negative sympathetic drive without going into negative contracility)
Give an example of a beta blocker for the heart
Atenolol = beta 1 specific
Name a calcium channel blocker
Nifedipine = L type Ca on vascular smooth muscle
Verapamil (on the heart)
How do positive inotropes work in the treatment of heart failure?
Their use is relatively limited:
- Sympathomimetics (beta agonists) -> Increase contractility but also increase oxygen demand, so they are not widely used in chronic heart failure, only cardiogenic shock.
- Glycosides (Na+/K+-ATPase inhibitors) -> Increase contractility with little effect on oxygen demand, but they are highly toxic and clinical trials have shown mixed results.
- Calcium sensitizers -> None are used clinically yet but they show promise. Levosimendan is the drug closest to clinical use.
- Phosphodiesterase inhibitors -> Analogous to sympathomimetics.
Which is more effective in treating heart failure: diuretics or RAA axis inhibitors?
- RAA inhibitors are more effective because they also act as diuretics and vasodilators (via their inhibition of angiotensin and aldosterone), just like diuretics, but they have fewer side effects
- This is because they inhibit sympathetic tone (unlike the compensatory sympathetic stimulation in diuretic use), so they tend to reduce metabolic demand of the heart, rather than increase it
- However, RAA antagonists leave the kidney relatively under-perfused and can lead to electrolyte disturbances
