In this lecture we re gonna cover the pharmacology of drugs used in treatment of heart failure,
so let s get right into it.
Heart failure is simply defined as a chronic, progressive disorder in which the heart muscle
is unable to pump enough blood to meet the body's needs.
In a normal heart, the upper chambers called the atria and the lower chambers called the
ventricles squeeze and relax in turn to move blood through the body.
Now blood flows through the heart and lungs in four major steps.
First, the oxygen-poor blood that has already circulated through the body is received by
the right atrium, which in turn pumps it over to the right ventricle.
Secondly, the right ventricle pumps the blood through the pulmonary artery into the lungs,
where it picks up oxygen.
Thirdly, the pulmonary vein empties oxygen-rich blood, from the lungs into the left atrium,
which in turn pumps it to the left ventricle.
And finally the left ventricle pumps oxygenated blood through the aorta to the rest of the
body.
Now, the Frank-Starling law of the heart is a basic physiological principle that describes
how the heart is able to move blood through the body in a regulated way by pumping out
as much blood as it receives.
Specifically, this law states that increased filling of the ventricle results in greater
contraction force and thus a rise in the cardiac output.
In heart failure however this mechanism fails, as the ventricle is loaded with blood to the
point where heart muscle contraction becomes less efficient.
Now, depending on the primary cause, heart failure can manifest itself as either systolic
or diastolic dysfunction.
In systolic heart failure the heart muscle becomes weak and cannot squeeze as much blood
out.
Poor ventricular contractility leads to reduction in the amount of blood pumped out of the ventricle,
which we refer to as ejection fraction.
While the normal ejection fraction can range between 50 and 75%, heart failure due to systolic
dysfunction is typically associated with an ejection fraction of less than 40%.
For this reason the systolic heart failure is most commonly referred to as Heart Failure
with Reduced Ejection Fraction (HFrEF).
On the other hand, in diastolic heart failure the heart squeezes normally, but becomes stiff
and cannot adequately relax to allow for normal ventricular filling.
As a result, patients with diastolic heart failure have relatively normal ejection fraction
although stroke volume and cardiac output are reduced.
Because of this, diastolic failure is most commonly referred to as Heart Failure with
Preserved Ejection Fraction (HFpEF).
Now, in the presence of heart failure, in order to counteract the effect of falling
cardiac output and thus reduced perfusion to vital organs, the body will try to compensate
via two tightly regulated mechanisms.
The first one involves the increase in sympathetic nervous system activity.
In the face of a reduced cardiac output, the arterial baroreceptors located in the aortic
arch and carotid sinus will sense changes in blood pressure leading to the release of
norepinephrine that in turn stimulates beta-1 receptors located in the SA node, myocardium
and the ventricular conduction system.
Stimulation of these receptors increases heart rate and cardiac contractility leading to
greater stroke volume.
Because heart rate and stroke volume are components of cardiac output, which is simply equal to
the product of the two, when they both increase, cardiac output will also increase to maintain
adequate blood pressure and thereby perfusion to vital organs.
Moreover, increased sympathetic nerve traffic to the kidney also activates ?1-adrenergic
receptors located on juxtaglomerular cells causing them to release an enzyme responsible
for regulation of blood pressure and volume called renin.
And this brings us to the second major compensatory mechanism, which involves activation of the
renin angiotensin aldosterone system.
So, in addition to sympathetic nerves directly stimulating renin secretion via ?1 receptors,
the release of renin from the juxtaglomerular cells is also regulated by two other primary
mechanisms which are; the renal vascular baroreceptors that stimulate renin secretion in response
to low renal perfusion pressure, and the macula densa cells of the distal nephron that stimulate
renin secretion in response to fall in sodium chloride concentration.
Now once released into the blood, renin acts upon a circulating substrate that is primarily
supplied by the liver called angiotensinogen to produce angiotensin I.
On passing through the pulmonary circulation angiotensin I is converted into angiotensin
II by another enzyme, which is abundant in the lungs called angiotensin-converting enzyme
(ACE for short).
Now, circulating angiotensin II exerts its action by binding to various receptors throughout
the body with most of its effects being mediated via angiotensin II type 1 receptor (abbreviated
as AT1).
These include stimulation of AT1 receptors in the endothelium of systemic arterioles,
which leads to vasoconstriction; stimulation of angiotensin receptors in the brain, which
causes the pituitary to release antidiuretic hormone (ADH for short), which in turn binds
to specific vasopressin II receptors in the collecting ducts of the nehpron and promotes
reabsorption of water back into the circulation; and finally, angiotensin II also acts on the
angiotensin receptors in the adrenal cortex to stimulate the release of a steroid hormone
called aldosterone, which in turn binds to nuclear mineralocorticoid receptor within
the cells of the distal tubule and the collecting duct where it increases expression of genes
that encode epithelial sodium channels and the sodium/potassium pump (Na/K ATPase) thereby
promoting sodium and water reabsorption and potassium secretion causing increase in plasma
volume and blood pressure.
Furthermore, vasoconstriction and fluid retention elevates venous and capillary hydrostatic
pressures, forcing additional fluid out of the blood into the tissue leading to edema
particularly in the feet and legs.
The increased peripheral resistance and greater blood volume also place further strain on
the heart and accelerate the process of damage to the myocardium leading to structural cardiac
remodeling.
At this point, in the final attempt to maintain circulatory system homeostasis, the body will
try to counterbalance overstimulation of the renin angiotensin aldosterone system (RAAS)
and sympathetic nervous system by activating cardioprotective natriuretic peptides.
Specifically, in response to increased myocardial stretch and volume overload, atria begin to
secrete A-type natriuretic peptide (ANP) and ventricles begin to secrete B-type natriuretic
peptide (BNP), and in response to increased levels of pro-inflammatory mediators resulting
from cardiac injury, vascular endothelial cells begin to secrete C-type natriuretic
peptide (CNP).
Now the main role of these natriuretic peptides is to counter the effects of volume overload
and adrenergic activation by stimulating sodium and water excretion, promoting myocardial
relaxation, inhibiting cardiac hypertrophy and fibrosis, suppressing sympathetic outflow,
and stimulating vasodilation.
However, in the end, even this counter response is not enough to save the failing heart.
As heart failure advances, further activation of the renin angiotensin aldosterone system
and the sympathetic nervous system ultimately overcomes the short-lived beneficial effects
of the natriuretic peptides.
And this brings us to the second part of this lecture that is the treatment of heart failure.
Now the pharmacological management of patients with heart failure is complex and may require
the use of several classes of drugs.
So now let s discuss these one by one starting with beta-blockers.
So beta-blockers work by binding to beta-1 receptors in the heart and subsequently blocking
the action of norepinephrine thereby reducing heart rate and contractility which in turn
decreases cardiac output and blood pressure.
As a side note here, keep in mind that decreased heart rate allows more diastolic filling time
so the stroke volume is typically not reduced.
Now, similarly via blockade of the ?1 receptors of the renal juxtaglomerular complex, certain
beta-blockers may also reduce renin secretion, thereby reducing the severity of angiotensin
II-induced vasoconstriction as well as aldosterone-induced volume expansion.
It s important to remember that this however is not beta-blockers primary mechanism of
action.
Among several beta-blockers on the market, currently only three have proven to reduce
mortality in heart failure patients; these are Bisoprolol, Carvedilol, and Metoprolol.
Out of these three, Carvedilol has a unique pharmacological property in that it not only
blocks beta-1 receptors in the heart but also alpha-1 receptors located on the smooth muscles
of arteries and veins.
By preventing norepinephrine from activating the alpha-1 receptor, Carvedilol causes vessels
to dilate thereby reducing total peripheral resistance.
All right, moving on to the next class of drugs for heart failure that is angiotensin-converting
enzyme (ACE) inhibitors.
Drugs in this class selectively inhibit the angiotensin-converting enzyme, which in turn
reduces angiotensin II production and its effects on vasoconstriction as well as ADH
and aldosterone secretion.
In addition to this, inhibition of ACE, increases levels of a potent vasoactive peptide called
bradykinin.
Unlike angiotensin II, which is a vasoconstrictor, bradykinin is an endogenous vasodilator, which
is normally degraded by ACE.
So when ACE inhibition occurs, while angiotensin II levels drop, bradykinin levels rise.
As a result the blood vessels become dilated, total peripheral resistance is reduced and
blood pressure is lowered thereby reducing the effort needed to pump blood around the
body.
Drugs in this class include Captopril, Enalapril, Fosinopril, Lisinopril, Quinapril and Ramipril.
Another related class of drugs called angiotensin receptor blockers (ARBs) also works on the
same angiotensin pathway.
However instead of blocking the enzyme that drives angiotensin II production, ARBs work
by binding to AT1 receptors located on vascular smooth muscle as well as other tissues such
as heart directly blocking the actions of angiotensin II.
As a result, the effects are similar to ACE inhibitors that is less vasoconstriction and
less ADH and aldosterone secretion, which lowers blood pressure and ultimately prevents
damage to the heart and kidneys.
Also because ARBs do not inhibit ACE, they do not cause bradykinin levels to rise.
This makes ARBs a good alternative to ACE inhibitors as more bradykinin not only contributes
to the vasodilation but also contributes to some of the side effects of ACE inhibitors
such as cough and angioedema.
Drugs in this class include Candesartan, Losartan, Telmisartan, and Valsartan.
Now despite being treated with an ACE inhibitor or angiotensin receptor blocker many heart
failure patients continue to suffer from cardiovascular events.
As a result increasing the beneficial effects of natriuretic peptides has gained significant
interest as a therapeutic approach in the management of heart failure leading to development
of a new class of drugs called angiotensin receptor-neprilysin inhibitor.
Now, neprilysin is a circulating enzyme that degrades several endogenous vasoactive peptides,
including ANP, BNP, and CNP and thus terminates their positive actions.
Angiotensin receptor-neprilysin inhibitor simply combines angiotensin receptor blocker
and neprilysin inhibitor to simultaneously block angiotensin II receptor as well as inhibit
neprilysin enzyme thereby preventing it from breaking down natriuretic peptides.
This results in increased longevity of natriuretic peptides as well as enhancement of their beneficial
effects.
The example of drug that belongs to this class is Sacubitril/Valsartan.
Now, another shortfall of ACE inhibitors and angiotensin receptor blockers (ARBs) is that
in some cases they don t suppress the excessive formation of aldosterone sufficiently.
Therefore, select patients with moderate to severe heart failure can also benefit from
another class of drugs called aldosterone antagonists.
Aldosterone antagonists work by competitively blocking the binding of aldosterone to the
mineralocorticoid receptor thereby decreasing the reabsorption of sodium and water as well
as decreasing the excretion of potassium leading to cardioprotective effects.
For this reason we also refer to this class of drugs as Potassium-sparing diuretics.
The examples of drugs that belong to this class are Eplerenone and Spironolactone.
Now, although aldosterone antagonists have been shown to lower blood pressure and exert
some diuretic effect, in order to alleviate symptoms of volume overload, a more potent
class of drugs called loop diuretics is needed.
So the primary use of loop diuretics is to relieve symptoms associated with pulmonary
congestion and peripheral edema.
Loop diuretics achieve this by inhibiting the luminal sodium-potassium-chloride cotransporter
located in the thick ascending limb of the loop of Henle where about 20% to 30% of the
filtered sodium is managed.
As a result, in contrast to other diuretic agents, loop diuretics reduce reabsorption
of a much greater proportion of sodium.
This sodium is then excreted, along with the water that follows it, leading to significant
decrease in plasma volume, cardiac workload and oxygen demand thus relieving signs and
symptoms of volume excess.
Drugs that belong to this class include Bumetanide, Furosemide and Torsemide.
Now, in some cases when a patient is truly intolerant of ACE inhibitors or angiotensin
receptor blockers (ARBs), usually because of significant renal dysfunction, the blood
pressure can be controlled with another class of drugs referred to as vasodilators.
There are two drugs in this class that are typically used in treatment of heart failure.
The first one is Isosorbide dinitrate, which releases nitric oxide (NO) in the vascular
smooth muscle cell that subsequently activates guanylyl cyclase (GC), an enzyme that catalyzes
the formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP).
Increased intracellular cGMP in turn activates a series of reactions that cause decrease
in intracellular calcium concentrations.
And because calcium drives the contraction this decrease ultimately leads to smooth muscle
relaxation and thus vasodilation.
Now, in contrast to isosorbide, the second drug that is Hydralazine appears to have multiple
effects on the vascular smooth muscle, which include; stimulation of nitric oxide release
from the vascular endothelium stimulating cGMP production and decreasing calcium concentration,
opening of potassium channels, and inhibition of calcium release from the sarcoplasmic reticulum,
which altogether contribute to smooth muscle relaxation and subsequent vasodilation.
Finally, before we end, I wanted to briefly mention one more drug that can be used in
management of heart failure particularly in patients intolerant to ACE inhibitors or beta-blockers
that is Digoxin.
Now the mechanism of action of Digoxin is sort of the opposite of the vasodilators one,
in that it is used to increase cells' contractility, specifically the contractility of cardiac
muscle cells.
Digoxin accomplishes that by inhibiting the sodium potassium ATPase pump in cardiac muscle
cells, which is responsible for moving sodium ions out of the cell and bringing potassium
ions into the cell.
As a result of this inhibition, when sodium concentration in the cardiac cell increases,
another electrolyte mover known as sodium-calcium exchanger pushes the excess sodium ions out
while bringing additional calcium ions in.
This in turn causes an increase in the intracellular calcium, which is then available to the contractile
proteins.
The end result is increased force of contraction and thus increased cardiac output.
And with that I wanted to thank you for watching I hope you enjoyed this video and as always
stay tuned for more.