Heart Failure

1. CV Pharmacol (PHL 322)
Lecture-2
Heart Failure Drugs
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Prof. Dr/ Gamal A. Soliman
Pharmacy College

2. █ Heart Failure (HF)
▪ Heart failure is the inability of the heart muscle to
pumps sufficient blood to meet the needs of the
tissues for oxygen and nutrients.
▪ Heart failure, also known as congestive heart failure.
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3. █ Types of heart failure
1- Left-sided heart failure:
▪ It is the inability of the left ventricle of the heart to pump an
adequate amount of blood to the Aorta (as a result of high
systemic BP).
▪ This result in ,
o Accumulation of blood in the left ventricle So causes
hypertrophy and, as the condition continues, leads to
dilatation.
o Accumulation of blood in the pulmonary veins
(pulmonary congestion) So increases the venous pressure
that result in fluid outflow from the pulmonary capillaries
into the pulmonary tissues and alveoli, causing
pulmonary edema.
o Pulmonary edema leads to tachypnea (rapid breathing)
and dyspnea (difficult breathing).
▪ Over time, left-sided heart failure can lead to right-sided
heart failure.
NOTE
▪ Left-sided heart failure is more common than right-sided
heart failure.
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5. 2- Right-sided heart failure:
▪ It is the inability of the right ventricle of the heart to pump
blood to the lungs (as a result of too weak ventricular M or
pulmonary hypertension).
▪ This result in ,
o Accumulation of blood in the right ventricle causing
hypertrophy and, as the condition continues, leads to
dilatation.
o Accumulation of blood in the vena cava So increases the
systemic venous pressure that result in fluid outflow from
the veins causing edema and ascites.
▪ Some organs like liver are enlarged because they are congested
with blood.
▪ Some areas like the limbs develop pitting edema because fluid
pools in these areas.
▪ Also, neck veins become distended and pulsating
NOTE
▪ As the left-sided heart failure causes pulmonary congestion and
the right-sided heart failure causes systemic venous congestion,
so the disease is called congestive heart failure (CHF) when it
affects both sides
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6. █ Symptoms of heart failure
❖ Symptoms include :
▪ Dyspnea
▪ Breathlessness ‫تنفس‬ ‫ضيق‬
▪ Orthopnea
▪ Generalized lethargy ‫خمول‬ and fatigue
▪ Ankle swelling
❖ Signs include:
▪ Pulmonary edema
▪ High jugular pressure
▪ tachycardia _ due to Increased adrenergic activity
▪ Hepatomegaly (secondary to raised right-sided heart pressures)
▪ Ascites
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7. █ Consequences of heart failure
▪ In HF, COP decreases therefore, all tissues of the body suffer from ischemia and
hypoxia
▪ Brain _ the brain respond to hypoxia by reflex sympathetic stimulation which
result in tachycardia
▪ Kidneys _ the kidney respond to hypoxia by stimulation of RAAS
o Angiotensin II: induces VC, so increases the systemic resistance (increase after
load)
o Aldosterone : induces salt and water retention, so increase edema (increase
preload)
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8. █ The goal of therapy
▪ In case of the left-sided heart failure
o The goal of therapy is to reduce
afterload
o This goal can be achieved by using a
vasodilator to open the way to the left
ventricle, so the left ventricle can pump
blood easily
▪ In case of the right-sided heart failure
o The goal of therapy is to reduce preload
o This goal can be achieved by using a
diuretic to remove extra fluids from the
body, so the right ventricle can pump
blood easily
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9. █ Treatment of heart failure
❖ Non-drug measures
1- Diet (reduce salt and fluid intake)
2- Stop smoking
3- Regular exercise
4- Maintain optimal weight
❖ Drug treatment
1- ACE inhibitors : Captopril, ramipril,
enalapril
2- Diuretics
o Loop diuretic (Furosemide)
o Aldosterone antagonists
(Spironolactone)
3- Vasodilators : Hydralazine, Nitrates
4- Positive inotropes : Digoxin
5- β blockers : Bisoprolol, Metoprolol,
Carvedilol
NOTE
▪ It is not preferable to start treatment with a digitalis group (digoxin) that
increases COP in the presence of increased cardiac preload and afterload.
o Cardiac preload and afterload must be reduced firstly.
▪ Therefore, it is preferable to start treatment with ACE inhibitors and diuretics
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10. [1] ACE inhibitors
▪ Ex: Captopril, ramipril, enalapril
▪ ACE inhibitors are widely used in the treatment of heart failure and hypertension.
▪ These drugs block the ACE so inhibits the conversion of angiotensin I to the potent
vasoconstrictor angiotensin II.
o So, these drugs act as vasodilators, reducing load on the heart and making it easier to
pump blood around the body i.e decreasing both cardiac preload and afterload
▪ Also, ACE inhibitors reduce the secretion of aldosterone, resulting in excretion of salts and
water (diuresis) i.e . decreasing cardiac preload
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Renin ACE
Angiotensinogen Inactive Angiotensin I Active Angiotensin-II

11. [2] Diuretics
▪ Drugs that used to remove salts and extra-fluid (edema) from the body through
urine.
▪ Their major mechanism of action in heart failure is to reduce blood volume, venous
pressure and consequently cardiac preload.
▪ Increased excretion of salt and water by diuretics result in :
o Reduction in the volume of blood that the heart must pump and help lower
venous pressure and consequently cardiac preload.
o Reduction in the pulmonary edema so relieve dyspnea and improve
oxygenation
o Reduction in edema in other parts of the body such as Ankle edema and ascites
▪ Diuretics have no direct effect on the cardiac contractility
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12. Ex:
1- Loop diuretic (Furosemide)
▪ Furosemide is the most widely used diuretic in case of heart failure
▪ It help the excretion of NaCl, KCl and water in the urine causing diuresis So …..
o decrease cardiac preload.
o improves the symptoms secondary to fluid overload as edema and ascites.
❖ Common side effects include:
▪ Hyponatraemia
▪ Hypokalaemia
2- Aldosterone antagonists (Spironolactone)
▪ The most serious side effect of spironolactone is that it can elevates the level of potassium in
the blood to become dangerously high (hyperkalemia).
o Therefore, regular blood tests should be done to check the potassium level.
▪ Although spironolactone belongs to a weak class of diuretics, it reduces the mortality rate in
patients with heart failure who are also receiving ACE inhibitors and other standard
therapy.
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13. [3] Vasodilators
▪ Vasodilators can help relax and dilate the blood vessels.
▪ Vasodilators are effective in acute heart failure because they provide a reduction
of cardiac preload (through venodilation), and reduction of cardiac afterload
(through arteriolar dilation).
❖ Ex: Hydralazine, Nitrates
▪ Hydralazine causes vasodilation by acting mainly on arteries and arterioles but
not veins so reduces the cardiac afterload .
▪ Nitrates dilate veins more than arteries so decrease the cardiac preload.
o Therefore, it is preferable to use hydralazine and nitrates together.
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14. █ Cardiac myocytes (Heart cell)
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15. [4] Positive inotropes (Digitalis, Cardiac glycosides)
▪ Positive inotropes or cardiotonic drugs are drugs that increase the force of heart
muscle contractions, increase COP and pump blood more effectively to all tissues
of the body in patients with HF.
Ex: Digitalis or cardiac glycosides
▪ Cardiac glycosides represent a family of compounds derived from the foxglove
plant (Digitalis purpurea).
▪ Cardiac glycosides include digoxin, digitoxin and Ouabain
▪ The 3 compounds are chemically similar
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16. ❖ Chemical structure
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1- Steroid nucleus with 4 fused rings 2- Lactone ring 3- Sugar molecules
❖ Each cardiac glycoside compound consists of two parts :
1- Non sugar part (Aglycon or genin) _ part that contain steroid nucleus and lactone ring ,
o It is found in all members of cardiac glycosides
o It is the part that is responsible for the pharmacological activities of the glycosides
2- Sugar part (Glycon) _ the sugar part
o It is the part that is responsible for pharmacokinetic of the glycoside –Glycon part differs
from one glycoside to another
▪ All glycosides have the same MOA because the MOA depends on Aglycon part which is
fixed and constant in the 3 compounds

17. ▪ Digoxin is the only cardiac glycoside used now for medicinal purposes.
❖ Pharmacokinetics
▪ Digoxin is 65–80% absorbed after oral administration.
▪ Once present in the blood, digoxin is widely distributed to tissues, including the
heart and CNS.
▪ Digoxin is not extensively metabolized; almost two thirds is excreted unchanged
by the kidneys.
▪ The half-life of digoxin in patients with normal renal function is long (40 hours)
▪ Digoxin is eliminated by the kidneys.
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18. ❖ The sodium-potassium pump
▪ The of Na+ /K+ -ATPase (also known as the
sodium-potassium pump) is the enzyme responsible
for pumping sodium ions out of the cell and
potassium ions into the cell.
▪ This transport function is necessary for the normal
function of the cell
❖ The mechanism of action
A. Cardiac Effects
▪ Cardiac glycosides act by inhibiting the activity of
Na+ /K+ -ATPase enzyme so inhibit cell
membranes from pumping sodium out.
▪ This leads to the accumulation of Na+ inside the
heart cells
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19. ▪ The accumulation of sodium ions inside the heart
cells allows more calcium to accumulate in the cells.
▪ This is because:
o The release of ca from ca-binding stores at the
inner aspect of cell membrane
o Opening Ca channels in the cell membrane
o Decreasing the ability of the Na/ Ca transporter
to push calcium out of the cells.
▪ The accumulated calcium creates stronger heart
muscle contractions (positive inotropic effect),
meaning the heart pumps more blood with each
heartbeat, i.e increases the cardiac output.
▪ The increased COP result in improvement of renal
blood flow causing diuresis so edema starts to
disappear
▪ Further, the diuresis decreases blood volume.
o A decrease in blood volume relieve the workload
of the heart.
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20. B. Extracardiac effects—
▪ Digoxin induce vagal stimulation so decrease the heart rate i.e bradycardia (negative
chronotropic effect)
▪ Due to bradycardia :
o The diseased cardiac muscle takes more time of rest
o The ventricle take more chance for good filling with blood
❖ Indications
▪ Digoxin is mostly used to treat serious heart failure when other medicines do not
help improve the symptoms.
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21. ❖ Side effects
▪ Digoxin has a relatively narrow safety margin.
o The therapeutic plasma concentration range for digoxin is 0.5 - 1.5 ng/ml.
o Plasma concentrations above 2.0 ng/ml can lead to digitalis toxicity
▪ If toxicity occurs with digoxin, it may take several days for the plasma
concentrations to fall to safe levels because of the long half-life.
1- Cardiac symptoms
▪ Bradycardia
▪ The most significant side effect of digoxin is cardiac arrhythmias, some of which
may be life-threatening.
2- Extra cardiac symptoms
▪ GI symptoms: anorexia, diarrhea
▪ Neurologic symptoms: confusion, fatigue, yellow vision (xanthopsia)
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22. ❖ Treatment of toxicity
▪ Stope the drug
▪ Potassium supplementation can reverse the toxic effects of digoxin if the toxicity
is related to hypokalemia.
▪ Antiarrhythmic drugs as lidocaine
▪ Atropine _ in case of severe bradycardia
▪ Fab (Fractionated Antibodies) _ it is the most specific treatment that can be used
to rapidly reduce plasma digoxin levels.
o These antibodies combine with excess digoxin forming complex which
excreted through urine
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23. [5] Beta blockers
▪ Beta blockers work by protecting the heart against the effects of sympathetic
overactivity produced by the brain.
o So protect against tachycardia
▪ They decrease the release of renin in the kidneys _ so help ACE inhibitors
▪ These drugs slow the heart rate and reduce blood pressure which allows the heart
to pump more efficiently.
▪ Most patients with chronic heart failure respond favorably to certain β blockers (Bisoprolol,
Metoprolol, Carvedilol).
NOTES
▪ Beta blockers should be used in small doses
▪ They should be used once patients are clinically stable
▪ Beta-blockers are contraindicated in patients with Asthma.
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The lecture end
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