Download Cardiac glycosides, antiarrhymic and antianginal drugs

Drugs for treating heart failure
A. Introduction
• Heart failure (HF) is due to the inability of
the ventricles to pump sufficient blood
thru-out the body.
• There are a number of causes of heart
failure:
• diabetes
from:http://www.nhlbi.nih.gov/health/dci/images/heart_coro
nary_artery.gif
• coronary artery disease
• chronic HT
• MI
• mitral stenosis (inability of mitral valve to
open fully)
• The incidence of heart failure increases
with increasing age.
• About 20% of patients diagnosed with
heart failure die within 1 year of diagnosis,
about 50% die within 5 years.
• There is NO cure for heart failure.
Treatment goals involve treating/removing
the underlying causes in order to improve
the quality of life and/or extend life
expectancy.
B. Pathophysiology of heart failure
• Two important factors which affect cardiac
output, and therefore affect how heart
failure is treated, are preload and afterload
1. Preload
• Immediately before the chambers of the
heart contract they are filled to their
maximum capacity with blood.
• The degree to which heart fibers are
stretched prior to contraction is known as
preload.
• The more these fibers are stretched, the
more forcefully they will contract
2. Afterload
• For the left ventricle to pump blood out of
the heart, it must overcome a fairly
substantial pressure in the aorta.
• Afterload is the pressure in the aorta that
must be overcome for blood to be ejected
from the left side of the heart.
• In heart failure, the heart becomes
weakened and cannot eject all the blood it
receives.
•
• This weakening can occur on the right
side, on the left side or on both sides.
3. Left heart failure aka CHF
• If heart failure is on the left side (more
common), excess blood accumulates in
the left ventricle.
• The wall of the left ventricle becomes
thicker in an attempt to compensate for
this extra blood.
•
• It can only compensate so much, then the
blood “backs up” into the lungs.
•
• This results in classic symptoms: cough,
shortness of breath, especially when a
patient is prone
4. Right heart failure
• Here, blood “backs up” into peripheral
veins.
• This results in classic symptoms: swelling
of feet, ankles (peripheral edema) and
engorgement of organs such as liver
5. Cardiac Output
• Cardiac output (the amount of blood
pumped by the heart per minute) is
significantly decreased during heart
failure.
• This results in an inability of the
cardiovascular system to meet the body’s
demands for oxygen.
• Patients with heart failure experience
constant fatigue.
C. Drug class mechanisms of
action in treating heart failure
• There are a number of different
mechanisms of action when considering
how to treat heart failure:
• 1. Certain drugs increase the force of
contraction. This is called a positive
inotropic effect and is characteristic of:
• a. cardiac glycosides
• b. phosphodiesterase inhibitors
• 2. Certain drugs decrease the heart rate.
This is characteristic of the adrenergic
(beta) blockers.
• 3. Certain drugs relax vascular smooth
muscle which dilates blood vessels and
lowers blood pressure. This is
characteristic of the vasodilators.
• 4. Certain drugs reduce blood volume.
This is characteristic of the diuretics.
• 5. Certain drugs affect the reninangiotensin-aldosterone (RAA) system.
This is characteristic of the ACE inhibitors
• 6. Certain drugs reduce both preload and
afterload. This is characteristic of the
natriuretic peptides.
1a. Cardiac glycoside therapy of
heart failure
• The cardiac
glycosides are
derived from the
foxglove plants,
Digitalis purpurea and
Digitalis lanata
• They have been used to treat heart
disorders for over 2000 years, and were
the mainstay of heart failure treatment until
the discovery of the ACE inhibitors
• Cardiac glycosides have 2 primary
actions:
• 1. Increasing the force of contraction
allows the heart to eject more blood per
beat which increases cardiac output and
improves circulation.
• 2. reduction in heart rate
•
• Digoxin stimulates the vagus nerve, which
slows the activity of the sinoatrial (SA) and
atrioventricular (AV) nodes
• This reduced heart rate (known as a
negative chronotropic effect) is seen as a
lengthening of the PR interval on an ECG.
• The specific mechanism of action of the
cardiac glycosides is inhibition of the
Na1+- K1+-ATPase pump.
• This pump normally removes Na1+ from
the cell and brings K1+ in.
• Inhibition of the pump leads to an
accumulation of Na1+ inside heart muscle
cells
• The increased concentration of Na1+
stimulates the Na1+-Ca2+ exchange
mechanism, leading to an increase in
intracellular Ca2+.
• Elevated Ca2+ results in an increase in the
force of heart contraction
• The primary cardiac glycoside available in
the U.S. is digoxin (Digitek, Lanoxicaps,
Lanoxin).
• It’s ½ life is between 1-2 days, longer in
older patients (those mostly likely to be
taking it).
• The antidote for digoxin is called digoxin
immune fab (Digibind). It binds digoxin and
has a rapid onset of action, less than 1
minute after IV infusion.
• It is necessary to have an antidote
available as nearly 1/3 of patients taking
cardiac glycosides develop symptoms of
toxicity.
• There is a very narrow margin between a
therapeutic dose and a toxic dose.
• Symptoms of toxicity: pulse rate below 60
beats/min., confusion, nausea, diarrhea,
yellow-green halos around lights,
hallucinations
• Vincent van Gogh’s “The Starry Night”
(1889) is believed, by some physicians, to
show evidence of digoxin (aka digitalis)
toxicity, in the way he created yellowgreen halos around the stars.
1b. Phosphodiesterase inhibitor
therapy of heart failure
• Phosphodiesterase inhibitors are used for
short-term control of acute/advanced heart
failure that is unresponsive to the “more
conventional” ( i.e. diuretics and ACE
inhibitors) treatments.
• These drugs block phosphodiesterase in
cardiac and smooth muscle which
prevents the hydrolysis of cAMP.
• An increase in cAMP leads to an increase
in Ca2+.
• Phosphodiesterase inhibitors have 2
primary actions:
• 1. Increasing the force of contraction
(similar to the cardiac glycosides)
• 2. vasodilation
• They are generally used for only 2-3 days
because they may produce potentially
serious adverse effects (ventricular
arrhythmias, severe hypotension,
thrombocytopenia)
• Phosphodiesterase inhibitors include:
• inamrinone (Inocor): IV, peak effect in 10
min.
• milrinone (Primacor): IV, peak effect in 2
min.
2. Beta adrenergic blocker therapy
of heart failure
• Selective beta blockers target beta1
receptors in the heart and kidneys. They
are used in combination with other drugs
to slow the progression of heart failure and
to prolong patient survival.
• They decrease both the heart rate and the
force of contraction.
• At first this appears to be the opposite of
the effects needed in treating heart failure.
• However, there is increased activation of
the sympathetic nervous system in
patients with heart failure that causes
tachycardia and increases stress on the
heart.
• Beta blockers slow the heart rate, which
allows the heart to both fill and function
more effectively.
• Beta blockers used in the treatment of
heart failure include:
• acebutolol: (Sectral)
• atenolol (Tenormin)
• bisoprolol (Zebeta)
• esmolol (Brevibloc)
• The “preferred” beta blockers for the
treatment of heart failure are:
• carvedilol (Coreg)
• metoprolol (Lopressor)
3. Vasodilator therapy of heart
failure
• Vasodilators generally play a minor role in
the drug therapy of heart failure.
• They are used in those unresponsive to
the “more conventional treatments”.
• They act directly on vascular smooth
muscle to relax blood vessels and lower
blood pressure.
• They reduce the symptoms of heart failure
by decreasing cardiac oxygen demand.
• Vasodilators indicated for the treatment of
heart failure include:
• hydralazine (Apresoline): acts on smooth
muscle of arterioles, increases heart rate
and cardiac output
• isosorbide dinitrate (Isordil, Sorbitrate):
causes venodilation, particularly in the
larger veins and vena cava
• This reduces both venous return to the
heart and preload, allowing the heart to
pump more forcefully.
• Adverse effects include dizziness,
headache, hypotension and tachycardia.
4. Diuretic therapy of heart failure
• Diuretics are one of the “more
conventional” treatments for heart failure.
• Diuretic therapy, as well as sodium
restriction is recommended for patients
with mild heart failure
• The main effect produced by the diuretics
is elimination of excess water, Na1+
• Diuretics relieve the symptoms of heart
failure by lowering blood volume and
reducing edema.
• They reduce fluid overload and lower
blood pressure which reduces the
workload on the heart and increases
cardiac output.
• Diuretics produce few side effects and are
often used in combination with ACE
inhibitors.
• To control mild heart failure in patients
with normal kidney function:
• chlorothiazide (Diuril) or
hydrochlorothiazide (Hydrodiuril)
• methylclothiazide (Enduron, Aquatensen)
• For patients with more advanced heart
failure, low kidney function, and/or more
severe edema:
• furosemide (Lasix)
• bumetanide (Bumex)
• torsemide (Demadex)
• Some studies have shown that treatment
of heart failure with a potassium sparing
diuretic reduces mortality.
• These diuretics are more effective when
the aldosterone level is elevated as they
are either:
• competitive inhibitors of the aldosterone
receptor, or
• decrease aldosterone activity by blocking
Na1+ channels in the collecting ducts
• Potassium sparing diuretics used in the
treatment of heart failure include:
• spironolactone (Aldactone)
• eplerenone (Indira)
• amiloride (Midamor)
• triamterene (Dyrenium)
5. ACE inhibitor (ACEI) therapy
of HF
• ACE inhibitors have become the preferred
drugs for the treatment of heart failure.
• They inhibit angiotensin II. Angiotensin II
causes vasoconstriction, and release of
aldosterone and ADH.
• ACEI action promotes vasodilation and
excretion of H2O and Na1+
• In addition, they decrease the inactivation
of an endogenous vasodilator, bradykinin.
• ACE inhibitors which have been approved by the
FDA in the treatment of heart failure include:
• captopril (capoten)
• enalapril maleate (Vasotec)
• fosinopril (Monopril)
• lisinopril (Prinivil, Zestril)
• quinapril (Accupril)
• ramipril (Altace)
6. Natriuretic peptide therapy of HF
• Natriuretic peptide was approved in 2001
for the treatment of heart failure.
• It is a small peptide hormone structurally
identical to a hormone secreted by the
heart, beta-type natriuretic peptide (hBNP)
• When heart failure occurs, the ventricles
secrete hBNP in response to the
increased stretching of the ventricular
walls.
• hBNP acts on the kidney, increasing
excretion of Na1+ and water, thus lowering
blood pressure.
• hBNP also causes vasodilation (which
contributes to reduced preload).
• The natriuretic peptide which has been
approved for the treatment of heart failure
is nesiritide (Natrecor).
• It is approved only for severe heart failure
because of the potentially serious side
effects: apnea, hypotension, arrhythmias.