Pharmacology – HEART FAILURE (MADE EASY)
Pharmacology – HEART FAILURE (MADE EASY)
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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. 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. In diastolic heart failure the heart squeezes normally, but becomes stiff and cannot adequately relax to allow for normal ventricular filling. 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.\rThe first one involves the increase in sympathetic nervous system activity. The second one involves the activation of the renin–angiotensin–aldosterone system. This pharmacology lecture discusses mechanism of action of various drugs classes used in management of heart failure including beta-blockers, ACE inhibitors, angiotensin II receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors, aldosterone antagonists, loop diuretics, vasodilators, and cardiac glycosides.
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00:00 Heart \u0026 Circulatory System
01:40 Types of Heart Failure
02:50 Sympathetic activation
04:05 RAAS activation
06:40 Natriuretic peptides
08:17 Beta-blockers
09:43 ACE inhibitors
10:45 Angiotensin receptor blockers
11:48 ARB/Neprilysin inhibitor
12:56 Aldosterone antagonists
13:43 Loop diuretics
14:45 Vasodilators
16:11 Digoxin
Content
3.179 -> In this lecture we re gonna cover the pharmacology
of drugs used in treatment of heart failure,
8.51 -> so let s get right into it.
10.95 -> Heart failure is simply defined as a chronic,
progressive disorder in which the heart muscle
15.57 -> is unable to pump enough blood to meet the
body's needs.
19.5 -> In a normal heart, the upper chambers called
the atria and the lower chambers called the
23.84 -> ventricles squeeze and relax in turn to move
blood through the body.
29.42 -> Now blood flows through the heart and lungs
in four major steps.
33.77 -> First, the oxygen-poor blood that has already
circulated through the body is received by
39.34 -> the right atrium, which in turn pumps it over
to the right ventricle.
44.04 -> Secondly, the right ventricle pumps the blood
through the pulmonary artery into the lungs,
49.3 -> where it picks up oxygen.
51.61 -> Thirdly, the pulmonary vein empties oxygen-rich
blood, from the lungs into the left atrium,
58.329 -> which in turn pumps it to the left ventricle.
61.43 -> And finally the left ventricle pumps oxygenated
blood through the aorta to the rest of the
66.92 -> body.
67.92 -> Now, the Frank-Starling law of the heart is
a basic physiological principle that describes
73.13 -> how the heart is able to move blood through
the body in a regulated way by pumping out
77.97 -> as much blood as it receives.
80.65 -> Specifically, this law states that increased
filling of the ventricle results in greater
85.479 -> contraction force and thus a rise in the cardiac
output.
89.979 -> In heart failure however this mechanism fails,
as the ventricle is loaded with blood to the
95.27 -> point where heart muscle contraction becomes
less efficient.
99.02 -> Now, depending on the primary cause, heart
failure can manifest itself as either systolic
105.43 -> or diastolic dysfunction.
108.119 -> In systolic heart failure the heart muscle
becomes weak and cannot squeeze as much blood
113.42 -> out.
114.5 -> Poor ventricular contractility leads to reduction
in the amount of blood pumped out of the ventricle,
120.26 -> which we refer to as ejection fraction.
123.33 -> While the normal ejection fraction can range
between 50 and 75%, heart failure due to systolic
129.45 -> dysfunction is typically associated with an
ejection fraction of less than 40%.
136.019 -> For this reason the systolic heart failure
is most commonly referred to as Heart Failure
140.609 -> with Reduced Ejection Fraction (HFrEF).
144.4 -> On the other hand, in diastolic heart failure
the heart squeezes normally, but becomes stiff
149.709 -> and cannot adequately relax to allow for normal
ventricular filling.
154.139 -> As a result, patients with diastolic heart
failure have relatively normal ejection fraction
159.659 -> although stroke volume and cardiac output
are reduced.
163.56 -> Because of this, diastolic failure is most
commonly referred to as Heart Failure with
167.799 -> Preserved Ejection Fraction (HFpEF).
170.43 -> Now, in the presence of heart failure, in
order to counteract the effect of falling
175.09 -> cardiac output and thus reduced perfusion
to vital organs, the body will try to compensate
180.349 -> via two tightly regulated mechanisms.
183.569 -> The first one involves the increase in sympathetic
nervous system activity.
188.209 -> In the face of a reduced cardiac output, the
arterial baroreceptors located in the aortic
193.379 -> arch and carotid sinus will sense changes
in blood pressure leading to the release of
198.62 -> norepinephrine that in turn stimulates beta-1
receptors located in the SA node, myocardium
204.76 -> and the ventricular conduction system.
208.049 -> Stimulation of these receptors increases heart
rate and cardiac contractility leading to
212.68 -> greater stroke volume.
215.15 -> Because heart rate and stroke volume are components
of cardiac output, which is simply equal to
219.98 -> the product of the two, when they both increase,
cardiac output will also increase to maintain
225.109 -> adequate blood pressure and thereby perfusion
to vital organs.
229.549 -> Moreover, increased sympathetic nerve traffic
to the kidney also activates ?1-adrenergic
235.939 -> receptors located on juxtaglomerular cells
causing them to release an enzyme responsible
241.299 -> for regulation of blood pressure and volume
called renin.
245.579 -> And this brings us to the second major compensatory
mechanism, which involves activation of the
250.879 -> renin angiotensin aldosterone system.
253.219 -> So, in addition to sympathetic nerves directly
stimulating renin secretion via ?1 receptors,
259.829 -> the release of renin from the juxtaglomerular
cells is also regulated by two other primary
265.21 -> mechanisms which are; the renal vascular baroreceptors
that stimulate renin secretion in response
272.59 -> to low renal perfusion pressure, and the macula
densa cells of the distal nephron that stimulate
279.61 -> renin secretion in response to fall in sodium
chloride concentration.
285.539 -> Now once released into the blood, renin acts
upon a circulating substrate that is primarily
289.91 -> supplied by the liver called angiotensinogen
to produce angiotensin I.
294.9 -> On passing through the pulmonary circulation
angiotensin I is converted into angiotensin
299.87 -> II by another enzyme, which is abundant in
the lungs called angiotensin-converting enzyme
305.02 -> (ACE for short).
307.13 -> Now, circulating angiotensin II exerts its
action by binding to various receptors throughout
311.83 -> the body with most of its effects being mediated
via angiotensin II type 1 receptor (abbreviated
318.71 -> as AT1).
320.66 -> These include stimulation of AT1 receptors
in the endothelium of systemic arterioles,
325.75 -> which leads to vasoconstriction; stimulation
of angiotensin receptors in the brain, which
330.62 -> causes the pituitary to release antidiuretic
hormone (ADH for short), which in turn binds
336.36 -> to specific vasopressin II receptors in the
collecting ducts of the nehpron and promotes
341.36 -> reabsorption of water back into the circulation;
and finally, angiotensin II also acts on the
347.229 -> angiotensin receptors in the adrenal cortex
to stimulate the release of a steroid hormone
352.53 -> called aldosterone, which in turn binds to
nuclear mineralocorticoid receptor within
357.61 -> the cells of the distal tubule and the collecting
duct where it increases expression of genes
363.009 -> that encode epithelial sodium channels and
the sodium/potassium pump (Na/K ATPase) thereby
368.18 -> promoting sodium and water reabsorption and
potassium secretion causing increase in plasma
373.32 -> volume and blood pressure.
375.509 -> Furthermore, vasoconstriction and fluid retention
elevates venous and capillary hydrostatic
380.969 -> pressures, forcing additional fluid out of
the blood into the tissue leading to edema
385.849 -> particularly in the feet and legs.
388.83 -> The increased peripheral resistance and greater
blood volume also place further strain on
393.569 -> the heart and accelerate the process of damage
to the myocardium leading to structural cardiac
398.53 -> remodeling.
399.6 -> At this point, in the final attempt to maintain
circulatory system homeostasis, the body will
405.86 -> try to counterbalance overstimulation of the
renin angiotensin aldosterone system (RAAS)
410.41 -> and sympathetic nervous system by activating
cardioprotective natriuretic peptides.
417.12 -> Specifically, in response to increased myocardial
stretch and volume overload, atria begin to
423.039 -> secrete A-type natriuretic peptide (ANP) and
ventricles begin to secrete B-type natriuretic
430.779 -> peptide (BNP), and in response to increased
levels of pro-inflammatory mediators resulting
437.27 -> from cardiac injury, vascular endothelial
cells begin to secrete C-type natriuretic
443.469 -> peptide (CNP).
446.37 -> Now the main role of these natriuretic peptides
is to counter the effects of volume overload
451.3 -> and adrenergic activation by stimulating sodium
and water excretion, promoting myocardial
457.49 -> relaxation, inhibiting cardiac hypertrophy
and fibrosis, suppressing sympathetic outflow,
463.569 -> and stimulating vasodilation.
465.789 -> However, in the end, even this counter response
is not enough to save the failing heart.
471.199 -> As heart failure advances, further activation
of the renin angiotensin aldosterone system
476.12 -> and the sympathetic nervous system ultimately
overcomes the short-lived beneficial effects
481.09 -> of the natriuretic peptides.
484.479 -> And this brings us to the second part of this
lecture that is the treatment of heart failure.
489.689 -> Now the pharmacological management of patients
with heart failure is complex and may require
494.159 -> the use of several classes of drugs.
497.13 -> So now let s discuss these one by one starting
with beta-blockers.
501.669 -> So beta-blockers work by binding to beta-1
receptors in the heart and subsequently blocking
506.499 -> the action of norepinephrine thereby reducing
heart rate and contractility which in turn
511.509 -> decreases cardiac output and blood pressure.
514.89 -> As a side note here, keep in mind that decreased
heart rate allows more diastolic filling time
520.01 -> so the stroke volume is typically not reduced.
523.789 -> Now, similarly via blockade of the ?1 receptors
of the renal juxtaglomerular complex, certain
530.92 -> beta-blockers may also reduce renin secretion,
thereby reducing the severity of angiotensin
536.43 -> II-induced vasoconstriction as well as aldosterone-induced
volume expansion.
541.43 -> It s important to remember that this however
is not beta-blockers primary mechanism of
546.85 -> action.
548.639 -> Among several beta-blockers on the market,
currently only three have proven to reduce
552.529 -> mortality in heart failure patients; these
are Bisoprolol, Carvedilol, and Metoprolol.
560.17 -> Out of these three, Carvedilol has a unique
pharmacological property in that it not only
564.98 -> blocks beta-1 receptors in the heart but also
alpha-1 receptors located on the smooth muscles
570.589 -> of arteries and veins.
572.74 -> By preventing norepinephrine from activating
the alpha-1 receptor, Carvedilol causes vessels
578.38 -> to dilate thereby reducing total peripheral
resistance.
581.79 -> All right, moving on to the next class of
drugs for heart failure that is angiotensin-converting
587.73 -> enzyme (ACE) inhibitors.
590.04 -> Drugs in this class selectively inhibit the
angiotensin-converting enzyme, which in turn
594.58 -> reduces angiotensin II production and its
effects on vasoconstriction as well as ADH
599.93 -> and aldosterone secretion.
602.18 -> In addition to this, inhibition of ACE, increases
levels of a potent vasoactive peptide called
607.449 -> bradykinin.
609.11 -> Unlike angiotensin II, which is a vasoconstrictor,
bradykinin is an endogenous vasodilator, which
615.17 -> is normally degraded by ACE.
617.5 -> So when ACE inhibition occurs, while angiotensin
II levels drop, bradykinin levels rise.
625.25 -> As a result the blood vessels become dilated,
total peripheral resistance is reduced and
630.47 -> blood pressure is lowered thereby reducing
the effort needed to pump blood around the
635.06 -> body.
636.48 -> Drugs in this class include Captopril, Enalapril,
Fosinopril, Lisinopril, Quinapril and Ramipril.
645.69 -> Another related class of drugs called angiotensin
receptor blockers (ARBs) also works on the
652 -> same angiotensin pathway.
654.42 -> However instead of blocking the enzyme that
drives angiotensin II production, ARBs work
658.959 -> by binding to AT1 receptors located on vascular
smooth muscle as well as other tissues such
664.13 -> as heart directly blocking the actions of
angiotensin II.
668.6 -> As a result, the effects are similar to ACE
inhibitors that is less vasoconstriction and
673.88 -> less ADH and aldosterone secretion, which
lowers blood pressure and ultimately prevents
679.06 -> damage to the heart and kidneys.
681.949 -> Also because ARBs do not inhibit ACE, they
do not cause bradykinin levels to rise.
687.829 -> This makes ARBs a good alternative to ACE
inhibitors as more bradykinin not only contributes
693.35 -> to the vasodilation but also contributes to
some of the side effects of ACE inhibitors
698.35 -> such as cough and angioedema.
701.56 -> Drugs in this class include Candesartan, Losartan,
Telmisartan, and Valsartan.
708.82 -> Now despite being treated with an ACE inhibitor
or angiotensin receptor blocker many heart
713.54 -> failure patients continue to suffer from cardiovascular
events.
717.49 -> As a result increasing the beneficial effects
of natriuretic peptides has gained significant
722.66 -> interest as a therapeutic approach in the
management of heart failure leading to development
727.41 -> of a new class of drugs called angiotensin
receptor-neprilysin inhibitor.
732.829 -> Now, neprilysin is a circulating enzyme that
degrades several endogenous vasoactive peptides,
739.94 -> including ANP, BNP, and CNP and thus terminates
their positive actions.
746.84 -> Angiotensin receptor-neprilysin inhibitor
simply combines angiotensin receptor blocker
751.81 -> and neprilysin inhibitor to simultaneously
block angiotensin II receptor as well as inhibit
758.06 -> neprilysin enzyme thereby preventing it from
breaking down natriuretic peptides.
763.92 -> This results in increased longevity of natriuretic
peptides as well as enhancement of their beneficial
769.38 -> effects.
770.95 -> The example of drug that belongs to this class
is Sacubitril/Valsartan.
775.22 -> Now, another shortfall of ACE inhibitors and
angiotensin receptor blockers (ARBs) is that
781.329 -> in some cases they don t suppress the excessive
formation of aldosterone sufficiently.
786.529 -> Therefore, select patients with moderate to
severe heart failure can also benefit from
791.1 -> another class of drugs called aldosterone
antagonists.
794.449 -> Aldosterone antagonists work by competitively
blocking the binding of aldosterone to the
799.45 -> mineralocorticoid receptor thereby decreasing
the reabsorption of sodium and water as well
804.98 -> as decreasing the excretion of potassium leading
to cardioprotective effects.
810.72 -> For this reason we also refer to this class
of drugs as Potassium-sparing diuretics.
816.63 -> The examples of drugs that belong to this
class are Eplerenone and Spironolactone.
821.76 -> Now, although aldosterone antagonists have
been shown to lower blood pressure and exert
827.579 -> some diuretic effect, in order to alleviate
symptoms of volume overload, a more potent
833.259 -> class of drugs called loop diuretics is needed.
836.79 -> So the primary use of loop diuretics is to
relieve symptoms associated with pulmonary
841.199 -> congestion and peripheral edema.
844.11 -> Loop diuretics achieve this by inhibiting
the luminal sodium-potassium-chloride cotransporter
849.66 -> located in the thick ascending limb of the
loop of Henle where about 20% to 30% of the
854.99 -> filtered sodium is managed.
857.699 -> As a result, in contrast to other diuretic
agents, loop diuretics reduce reabsorption
862.74 -> of a much greater proportion of sodium.
865.91 -> This sodium is then excreted, along with the
water that follows it, leading to significant
870.9 -> decrease in plasma volume, cardiac workload
and oxygen demand thus relieving signs and
876.1 -> symptoms of volume excess.
879.06 -> Drugs that belong to this class include Bumetanide,
Furosemide and Torsemide.
884.63 -> Now, in some cases when a patient is truly
intolerant of ACE inhibitors or angiotensin
890.589 -> receptor blockers (ARBs), usually because
of significant renal dysfunction, the blood
895.449 -> pressure can be controlled with another class
of drugs referred to as vasodilators.
899.61 -> There are two drugs in this class that are
typically used in treatment of heart failure.
905.47 -> The first one is Isosorbide dinitrate, which
releases nitric oxide (NO) in the vascular
910.569 -> smooth muscle cell that subsequently activates
guanylyl cyclase (GC), an enzyme that catalyzes
916.74 -> the formation of cyclic guanosine monophosphate
(cGMP) from guanosine triphosphate (GTP).
924.77 -> Increased intracellular cGMP in turn activates
a series of reactions that cause decrease
929.85 -> in intracellular calcium concentrations.
932.98 -> And because calcium drives the contraction
this decrease ultimately leads to smooth muscle
937.99 -> relaxation and thus vasodilation.
941.13 -> Now, in contrast to isosorbide, the second
drug that is Hydralazine appears to have multiple
947.49 -> effects on the vascular smooth muscle, which
include; stimulation of nitric oxide release
952.91 -> from the vascular endothelium stimulating
cGMP production and decreasing calcium concentration,
959.11 -> opening of potassium channels, and inhibition
of calcium release from the sarcoplasmic reticulum,
965.06 -> which altogether contribute to smooth muscle
relaxation and subsequent vasodilation.
970.26 -> Finally, before we end, I wanted to briefly
mention one more drug that can be used in
974.96 -> management of heart failure particularly in
patients intolerant to ACE inhibitors or beta-blockers
980.569 -> that is Digoxin.
982.66 -> Now the mechanism of action of Digoxin is
sort of the opposite of the vasodilators one,
987.57 -> in that it is used to increase cells' contractility,
specifically the contractility of cardiac
992.66 -> muscle cells.
993.779 -> Digoxin accomplishes that by inhibiting the
sodium potassium ATPase pump in cardiac muscle
998.089 -> cells, which is responsible for moving sodium
ions out of the cell and bringing potassium
1002.47 -> ions into the cell.
1004.35 -> As a result of this inhibition, when sodium
concentration in the cardiac cell increases,
1009.56 -> another electrolyte mover known as sodium-calcium
exchanger pushes the excess sodium ions out
1015.23 -> while bringing additional calcium ions in.
1018.089 -> This in turn causes an increase in the intracellular
calcium, which is then available to the contractile
1024 -> proteins.
1025.37 -> The end result is increased force of contraction
and thus increased cardiac output.
1031.5 -> And with that I wanted to thank you for watching
I hope you enjoyed this video and as always
1035.87 -> stay tuned for more.
Source: https://www.youtube.com/watch?v=AJV1BsRnImA