52.4.2 Main Drug Classes Used in the Treatment of Heart Failure

Question 1

What is heart failure? What are the symptoms? Why are they present?

Answer 1

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)

Question 2

Why may ischaemic heart failure occur?

Answer 2

Left ventricle hypertrophies to try and increase cardiac output
Presses on coronary artery supplying heart
Increases oxygen demand which supply does not meet

Question 4

What are the systemic consequences of heart failure?

Answer 4

-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

Question 5

What are the main drug classes used to treat heart failure?

Answer 5

*Diuretics
*Vasodilators
*Cardio-stimulatory (Inotropic) drugs
*Cardio-inhibitory drugs

Question 6

What are the different diuretics used?

Answer 6

Thiazide, loop, and potassium-sparring

Question 7

What vasodilators are used?

Answer 7

*ACEi
*ARBs
*NO donors
*Natriuretic peptides
*Phosphodiesterase inhibitors

Question 8

What cardio-stimulatory drugs are used?

Answer 8

*Digoxin
*Sympathetic drugs (Beta-agonists)
*Phosphodiesterase inhibitors

Question 9

What cardio-inhibitory drugs are used?

Answer 9

Beta blockers
Ca2+ channel blockers

Question 10

What is the mechanism of action of thiazide diuretics? What is their side effect?

Answer 10

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)

Question 11

What is the mechanism of action of loop diuretics?

Answer 11

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)

Question 12

Name two potassium sparing diuretics

Answer 12

Aldosterone antagonist
ENaC inhibitor in collecting duct (amiloride)

Question 13

How are diuretics useful in the treatment of cardiac failure?

Answer 13

Reduce oedema
Vasodilate (loop diuretics)
Increase CO by reducing the effective circulating volume to reduce workload on the heart
Reduce cardiac dilation

Question 14

What are the downsides of diuretics in cardiac failure?

Answer 14

Reduce venous return which reduces cardiac output
Increases sympathetic tone which increases myocardial oxygen debt
Activates the renin axis and ADH

Question 15

Name an ACE inhibitor

Answer 15

Captopril (ends in -pril)

Question 16

How do angiotensin inhibitors (ACE and ARBS) treat cardiac failure?

Answer 16

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

Question 17

What are the bad aspects of angiotensin inhibitors?

Answer 17

Postural hypotension
Decreased renal blood flow resulting in electrolyte dysfunction

Question 18

Name an angiotensin II receptor blocker

Answer 18

Losartan

Question 19

How do nitric oxide donors work in the treatment of heart failure? Give an example

Answer 19

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

Question 20

Name an aldosterone antagonist (potassium sparring diuretic). How is it used in the treatment of heart failure?

Answer 20

Spironolactone
Significant diuretic effect due to activation on renin axis during cardiac failure
Affects ventricular remodelling via reducing fibrosis and ischaemia

Question 21

What is the mechanism of action of naturitic peptides? Give examples of drugs that promote this axis

Answer 21

ANP and BNP increase salt and water excretion and vasodilate
Neprilysin blocks the vascular endopeptidase which degrades ANP and BNP
Recombinant BNP (nesiritide)

Question 22

Name an ARB

Answer 22

Angiotensin receptor blocker = valsartan

Question 23

How are phsophodiesterase inhibitors useful in treating cardiac failure?

Answer 23

PDE breaks down cGMP which increases smooth muscle relaxation and vasodilation, reducing venous return and setting heart back onto starling curve

Question 24

Give an example of a cardiac glycoside used to treat cardiac failure?

Answer 24

Digoxin

Question 25

What is the mechanism of action of cardaic glycosides?

Answer 25

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

Question 26

Why are cardiac glycosides such as digoxin particularly useful in treating heart failure?

Answer 26

Increase contracility with little increase in oxygen demand (passively increases Ca concentration)

Question 27

At what dose can beta blockers be given to treat cardiac failure? Why?

Answer 27

LOW DOSE
Reduces rate and force of contraction to reduce oxygen debt
(reduce the effects of negative sympathetic drive without going into negative contracility)

Question 28

Give an example of a beta blocker for the heart

Answer 28

Atenolol = beta 1 specific

Question 29

Name a calcium channel blocker

Answer 29

Nifedipine = L type Ca on vascular smooth muscle
Verapamil (on the heart)

Question 30

How do positive inotropes work in the treatment of heart failure?

Answer 30

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.

Question 31

Which is more effective in treating heart failure: diuretics or RAA axis inhibitors?

Answer 31

• 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