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Drugs Used In Congestive Heart Failure


When a heart fails to pump blood in a quantity sufficient to fulfil the body requirements, a condition of Congestive Heart Failure (CHF) occurs, which is also known as a Heart Failure (HF).
CHF is caused due to:
1) Narrowing of the arteries supplying blood to the heart muscles,
2) Any congenital heart defects,
3) Endocarditis (infection in heart valves) or myocarditis (infection of heart muscles),
4) Cardiomyopathy (disease of the heart muscles),
5) Any long -term heart valve disease (due to past rheumatic fever or other causes) and high blood pressure, and
6) Past history of the patient who has suffered from myocardial infar ction or heart attack and the injured tissue obstructs the normal functioning of heart.
Some common symptoms of CHF are:
1) Fatigue, 2) Swelling or oedema, 3) Shortness of breath, and 4) Increased urination.


The following drugs are employed in the treatment of CHF:
1) Drugs with Positive Inotropic Effects
i) Cardiac Glycosides: Digoxin, Digitoxin, and Ouabain.
ii) Bipyridines/Phosphodiesterase Inhibitors: Amrinone and Milrinone.
iii) β-Adrenergic Agonists: Dobutamine and Dopamine.

2) Drugs without Positive Inotropic Effects
i) Diuretics: Thiazides, Furosemide, and Spironolactone.
ii) Angiotensin Antagonists: ACE inhibitors and Losartan.
iii) β-Adrenergic Antagonists: Bisoprolol, Carvedilol, and Metoprolol.
iv) Vasodilators: Nitrates and Hydralazine.

Cardiac Glycosides

Cardiac glycosides are derived from plant derivatives and are steroidal in nature . A glycoside is a sugar-containing compound in which one of the hydroxyl groups of the sugar molecule is replaced with another compound.
Digoxin, digitoxin, and ouabain are the commonly used cardiac glycosides. Often, the term digitalis refers to the complete group of cardiac glycosides as all the drugs in this group exert the same effects on the heart. They differ only in lipid solubility, rapidity, degree of absorption, protein binding, metabolic pathway, and excretion.

Mechanism of Action

The mechanism of action of digitalis can be explained as follows(figure 1.2):
1) Digitalis exerts a positive inotropic effect due to its ability to potentiate the excitation-contraction coupling. This is possible since digitalis increases the concentration of free intracellular Ca2+ ions.

Screenshot 2021 03 10 18 29 34 709 .docs Drugs Used In Congestive Heart Failure

Cellular Mechanism of Digitalis Action. a) Tendency of Na+ to flow in and K+ to flow out along the concentration gradient; b) Na+ /K+ -ATPase pushing the Na+ out and drawing the K+ in; c) Na+ /Ca2+ exchange mechanism; d) Release of Ca2+ from Sarcoplasmic Reticulum (SR); e) Ca2+ + troponin initiating myocardial contraction.

2) It inhibits the membrane bound Na +
/K + -ATPase transport system (sodium pump), resulting in increase of intracellular Na +ions and loss of intracellular K+ions.
3) As Na+ ions accumulate inside the cell, it activates a Na +/Ca 2+ carrier system (a non -enzymatic protein carrier) within the membrane. The activation of Na+/Ca2+carrier system results in an increase in the influx of Ca 2+ ions. Three Na+ ions are exchanged for each Ca2+ ion, thereby generating an electrogenic potential by this exchanger.
4) Normally, the concentration of Ca2+ ions around the myofilaments is lowered by the Ca2+ ion pump in the Sarcoplasmic Reticulum (SR). The energy for driving this pump is obtained by ATP hydrolysis carried out by Na + K+-ATPase.
However, digitalis inhibits this enzyme and hence less energy is available for driving the Ca2+ ion pump. Thus, the supply of Ca2+ ions from SR around the myofilaments increases, which in turn activates the contractile machinery.
5) The binding of digitalis to sodium pump is inhibited by the K + ions present in the serum. Hence, conditions of hypokalaemia facilitate the action of digitalis. On the other hand, conditions of hyperkalaemia can decrea se cardiac toxicity. Arrhythmia induced by digitalis, is increased by co nditions of hypercalcaemia or hypomagnesaemia.


Route of administration of digitalis is either oral or intravenous. It is not suitable for administration by subcutaneous or intramuscular routes as its absorption from these sites is not re liable and may bring about local irritation, tenderness, swelling, and abscess.

Digitalis does not bind selectively to the myocardium when administered through these sites. Digitalis is a cumulative drug. It has a prolonged half-life and the duration of its action ranges from days to weeks . The prolonged plasma half – life of digitoxin is due to its enterohepatic circulation.

Pharmacological Actions

Cardiac glycosides have the capability of increasing the myocardial contraction frce, which is the most significant property of these drugs. Other than this, they have several extra-cardiac effects on vascular smooth muscles, kidneys, gut and the CNS:
1) Actions on Heart
i) Administration in small doses causes an increase in the vagal tone by sensitisation of baroreceptors and/or activity of the afferent nerves. As a result, sinus activity decreases which le ads to decrease in conductivity, prolongation of refractory period of the AV node, decre ase in atrial refractory period, and bradycardia.
ii) Contractility of the myo cardium increases by a direct positive inotropic action of digitalis on the heart. Thus, the failing heart contracts even more forcefully, which results in increased cardiac output, complete ventricular emptying, and decreased diastolic pressure and ventricular size. Systole lasts for a shorter duration, giving more time for ventricular filling and rest to the heart.
iii) With the increase in contractility of heart, the oxygen consumption in the myocardium increases. On the other hand, decrease in the heart rate and ventricular size decreases oxygen requirements of the heart. Hence, the
general effect of digitalis is an improved ventricular performance of the failing heart without any significant increase in energy requirement.
iv) When administered in comparatively small therapeutic doses, digitalis improves the ability of excitation of the myocardium and the conduction velocity. However, its administration in high doses causes an increased automaticity and decreases the refractory period of the atria and the ventri cles, resulting in extra -systoles, pulsus bigeminus , and ventricular fibrillation.
v) Digitalis slows the conduction velocity in the AV node and His-Purkinje system, regardless of the dose administered. This is achieved by an increase in the refractory period by both vagal as well as the extra -vagal actions of digitalis. Low doses are characterised by a predominance of vagal effects. As the dose is increased, direct depressant action on the AV node is seen.
vi) Digitalis does not act directly to influence the coronary flow. The enhanced coronary circulation is a secondary effect of the increased cardiac output and extended diastole.
vii) Changes evident in an ECG after administration of digitalis includes prolongation of the PR interval (due to delayed conduction) and shortening of QT interval (shorter ventricular systole). Other changes are that the ST segment sags below the isoelectric line , and the T-wave appear smaller, inverted or disappears.

2) Extra-Cardiac Effects of Digitalis

i) On Blood Vessels: Digitalis exerts a minor direct constrictor action on the smooth muscles of arteries and veins.
ii) On Kidneys: Digitalis improves circulation and decreases sympathetic activity, thereby increasing the blood flow to kidneys. This increases the urinary output and relieves oedema in patients with cardiac oedema.
iii) On Gastrointestinal Tract: Digitalis stimulates the Chemoreceptor Trigger Zone (CTZ) in the medulla, thus resulting in nausea and vomiting.
iv) On CNS: Digitalis may produce symptoms of visual disturbances such as blurring of vi sion, photophobia, a dark spot in centre of vision , and disturbances of coloured vision with yellow and green. In some patients, psychic symptoms and confusion may also be seen.

Therapeutic Uses

Cardiac glycosides have the following therapeutic benefits:
1) Patients with congestive heart failure characterised by a dilated, failing heart with low cardiac output (impaired systolic function) are benefited by administration of digitalis.
2) Treatment of low output cardiac failure with digitalis, in patients where t he myocardium is not principally damaged, shows the best results. Examples of such conditions include atrial fibrillation, valvular defects, and hypertension.
3) The management of cardiac arrhythmias (supraventricular tachyarrhythmias), like atrial flutter and atrial fibrillation, occurring either with or without CCF, employs the use of digitalis.

Adverse Effects

Digitalis is highly toxic. It has a low margin of safety with a therapeutic index ranging from 1.5 -3. Patients with stead y-state plasma digoxin le vels report a higher cardiac mortality during maintenance therapy. Nearly 25% of the patients show either of the toxic symptoms, which include:
1) Extra-Cardiac Effects: These adverse effects are seen initially and include anorexia, nausea, vomiting, and abdo minal pain. These effects appear due to gastric irritation, mesenteric vasoconstriction, and CTZ stimulation. The other adverse effects include fatigue, absence of a desire to walk or lift an arm, malaise, headache, mental confusion, restlessness, hyperpno ea, disorientation, psychosis, and visual disturbances . Rare adverse effects include diarrhoea, skin rashes, and gynaecomastia.
2) Cardiac Effects: Digitalis produces almost every type of arrhythmia, including pulsus bigeminus, nodal and ventricular extrasyst oles, ventricular tachycardia, and terminally fibrillation.

Drug Interactions

Cardiac glycosides undergo the following drug interactions:
1) Administration of digitalis with a diuretic results in hypokalaemia, which can precipitate digitalis arrhythmias.

2) Administration of digitalis with calcium synergises the actions of digitalis, thereby precipitating toxicity.
3) Quinidine decreases the binding of digoxin to tissue proteins.
4) Administration of digitalis with adrenergic drugs induces arrhythmias and increases ectopic automaticity.

5) Metoclopramide (gastrointestinal hurrying), sucralfate, neomycin,
sulphasalazine, and antacidsdecreasethe absorption of digoxin by adsorbing it.
6) Atropinic drugs including tricyclic antidepressants increase the absorption of digoxin by delaying its gastric emptying.
7) Erythromycin, omeprazole, and tetracycline increase the bioavailability of digoxin.
8) Propranolol, verapamil, diltiazem, and disopyramide oppose the positive
inotropic action of digitalis and may add to the depression of A-V conduction.
9) Phenobarbitone accelerates the metabolism of digitoxin , thus, reducing its plasma half-life.
10) Administration of succinylcholine by the patients on digitalis therapy causes


Cardiac glycosides are contraindicated in the following conditions:
1) Digitalis is contraindicated in hypokalaemia as its binding to Na+K +-ATPase is increased, thus increasing digitalis toxicity.
2) It is contraindicated in elderly and in patients having severe renal or hepatic
3) It is con traindicated in myocardial infarction as s evere arrhythmias may develop.
4) It is contraindicated in thyrotoxicosis as the patient’s responsiveness decreases, and arrhythmias may also develop.
5) It is contraindicated in ventricular tachycardia as it may precip itate ventricular fibrillation.
6) It is contraindicated in Wolff-Parkinson-White Syndrome as it may result in ventricular failure.
7) Administration of digitalis in patients with a partial A-V block may convert it into a complete A-V block.
8) Digoxin is contrain dicated in myxoedema as its elimination rate decreases, thus, cumulative toxicity of digitalis may be seen.

Treatment of Digitalis Toxicity

The cases of digitalis toxicity can be treated in the following ways:
1) Withdrawal: Administration of digitalis should either be stopped or the dose should be reduced based on the severity of toxicity. Use of potassium depleting diuretics should be discontinued.
2) Potassium Repletion: KCl is administered by oral route (or by slow IV drip) in a dosage of 2gm in every 4 hour s. During this time, ECG of the patient should be continuously monitored. However, in case of a severe AV block, KCl should not be given.

3) Antiarrhythmic Drugs: Ventricular tachyarrhythmias can be suppressed by phenytoin and lignocaine since they have eith er little or no effect on conduction. Phenytoin is administered in a dose of 100mg via IV infusion in every 5 minutes till arrhythmia is treated.
Supraventricular and ventricular tachycardia, without AV block, can be treated by administering propranolol in dosages of 20-80mg/day. Sinus bradycardia and various degrees of AV block can be controlled with
4) Advanced Cases of Life Threatening Digitalis Intoxication: Such conditions can be reversed by inserting a temporary cardiac pacemaker catheter, a long with purified digoxin-specific antibody (digitalis immune fab) fragments.


Bipyridine derivatives ( e.g., amrinone and milrinone) show phosphodieste rase
(PDE) inhibiting activity. These drugs are selective inhibitors of PDE-isoenzyme III, found in the cardiac and smooth muscles.

Mechanism of Action

Bipyridines increase the production of cAMP in the heart and blood vessels , and thus exert a positive inotropic action along with vas odilator activities. Increased levels of intracellular cAMP enable the availability of more intracellular Ca 2+ ions, thus, a more positive inotropism may result.

Therapeutic Uses

Cardiac output is increased. The peripheral vascular resistance and the after-load are decreased with no significant change in heart rate and blood pressure. Bipyridines are used only for the treatment of heart failure or exacerbation of CCF.

Adverse Effects

Given below are the adverse effects of bipyridine derivatives:
1) Amrinone causes nausea, vomiting, liver enzyme changes, and occasionally thrombocytopenia.
2) Milrinone may cause cardiac arrhythmia, bone marrow depression, and liver toxicity.
Due to these adverse effects, these agents are used for short-term therapy only.

β-Adrenergic Agonists

The discovery of beta 1-agonists has sufficed the search for a positive inotropic -agonist with minimal positive chronotropic and arrhythmogenic potential, with dobutamine being the most potential one amongst these agents.

Mechanism of Action

The β-adrenergic agonists increase the cardiac output, and decrease the ventricular filling pressure and pre-load. Some degree of tachycardia is also seen with the use of these drugs. They increase the consumption of oxygen.

Therapeutic Uses

The β-adrenergic agonists have been limited to the management of acute heart failure. They may occasionally be employed in the treatment of refractory CCF.

Adverse Effects

The β-adrenergic agonists may cause tachyphylaxis.


Diuretics are commonly used in the management of CHF. Since the last 50 years, these agents are favoured for CHF treatment.

Mechanism of Action

Diuretics increase the excretion of salt and water. This in turn decreases the ventricular pre -load and the cardiac size, improves pump function , and helps relieve oedema. In CHF patients, aldosterone promotes fibrosis in the heart and blood vessels. This effect of aldosterone is antagonised by spironolactone (an aldosterone antagonist).

Therapeutic Uses

Diuretics are used in the management of all stages of CHF. Furosemide is a very efficient diuretic in treating acute left ventricular failure (cardiac asthma).

Adverse Effects

The adverse effects of various classes of diuretics are:
1) Loop Diuretics: Hypokalaemia is a common adverse effect. Patients on long-term diuretics require potassium supplements and regular monitoring. At high doses, hyponatraemia may occur, whi ch needs careful supervision in heart failure patients. Ototoxicity characterised with tinnitus, vertigo and deafness also occurs at high doses of loop
diuretics. Therefore, intravenous administration of furosemide should not be faster than 4mg/min.
2) Thiazide Diuretics: Due to potassium and sodium loss, the adverse effects of thiazide diuretics are similar to those of loop diuretics. However, the potassium loss is reduced when ACE inhibitors are simultaneously prescribed. Diabetic patients need monitoring as diabetes may occur with thiazide diuretics. Impotence as well as sensitivity may also develop due to the presence of sulphonamide in the drugs.
3) Aldosterone Antagonists: Adverse effects include fibrosis, hypertrophy , arrhythmogenesis, and hyperkalaemia, wh ich require regular monitoring because of its potentially lethal effects in CHF patients due to renal failure. Hyponatraemia and feminisation such as gynaecomastia are other adverse effects. In patients having severe symptomatic systolic heart failure, spironolactone is recommended along with ACE inhibitors.

Angiotensin Antagonists

The ACE inhibitors and angiotensin receptor blockers are included in this group.

Mechanism of Action

Drugs which inhibit the activity of RAS either interfere with the biosynthesis of angiotensin II [Angiotensin Converting Enzyme (ACE) inhibitors], or act as antagonists of angiotensin receptors [Angiotensin Receptor Blockers (ARBs)]. The production of an giotensin II from angiotensin I is inhibited by ACE inhibitors. These agents neutralise the raised peripheral vascular resistance and retention of sodium and water that resulted from angiotensin II and aldosterone.

Pharmacological Actions

The pharmacological actions of angiotensin antagonists are:
1) Reduction in peripheral arterial resistance and after-load.
2) Reduction in aldosterone secretion, thus decreasing the retention of salt and
water. This causes venodilatation and reduces pre-load.
3) Reduction in angiotensin concentration in the tissues, thus reducing angiotensin-induced tissue norepinephrine release.
4) Reduction in the long-term remodelling of heart and blood vessels.

Therapeutic Uses

Angiotensin antagonists are indicated in all symptomatic and asympto matic patients with Left Ventricular (LV) dysfunction . ACE inhibitors ( e.g., enalapril, lisinopril, or ramipril) have a wide diversity of actions and are considered to be better drugs for the treatment of CHF.

Adverse Effects

Angiotensin antagonists give rise to occasional adverse effects that include hypotension, hyperkalemia, angioedema, cough, and syncope. Several studies have suggested that the beneficial effects of ACE inhibitors are reduced when they are given along with aspirin. Actually, ACE inhibitors did not produced any different effects when were administered with or without aspirin.

β-Adrenoceptor Antagonists

The -blockers (most commonly propranolol and other agents having membrane- stabilising activity) were contraindicated in patients with CHF as they were found to precipitate acute decompensation. Yet, it has been found that some of these drugs may be useful in the treatment of diastolic dysfunction or cardiomyopathies in patients requiring bradycardia and in decreasing the contraction velocity. It has been found in the current stud ies that bisoprolol, carvedilol, and metoprolol may decrease mortality in patients with class II and III heart failure.


Vasodilators have an indirect benef icial effect on the heart. Arteriolar dilatation (caused by hydralazine and nitrates) decreases the afterload. Venodilatation (caused by nitrates) decreases pre-load. These agents are useful adjunctive for the primary treatment. Use of hydralazine or isoso rbide on a long -term has been shown to decrease damage to the remodelling heart.

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