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Congestive Heart Failure

Dr Ramesh Chandra

Heart Failure is the inability of the

heart to pump an adequate amount of blood to the bodys need. CONGESTIVE HEART FAILURE refers to the
state in which abnormal circulatory congestion exists a result of heart failure.

Precipitating factors of heart failure

Coronary Artery Disease (70%) Systemic Hypertension Idiopathic

Less Common
Diabetes Mellitus Valvular Disease Rare

Anemia, Connective Tissue Disease, Viral Myocarditis, HIV, Hyper/Hypothyroidism, Hypertrophic Cardiomyopathy, Arrhythmias.

Pathophysiology of cardiac failure

Pathophysiology of cardiac failure

Increase in preload Increase in afterload

Ventricular dilatation leading to hypertrophy

Resistance to outflow of blood ( ventricular pressure and hypertrophy)

Further precipitates heart failure

Further precipitates heart failure

End diastolic volume (EDV) is the amount of blood remaining in the ventricles at the end of the diastole When venous return increases EDV increases Increase in EDV increases preload

Afterload is expressed as tension which must be developed in the wall of ventricles during systole to open the semilunar valves and eject blood to aorta/pulmonary artery It is primarily determined by arterial resistance

Signs and Symptoms

Dyspnoea Persistent coughing/wheezing (with frothy sputum) Oedema Tiredness and fatigue Increased micturition Confusion / impaired thinking Lack of appetite

Pharmacotherapy of Congestive Cardiac Failure

Treatment is aimed at:

Increasing cardiac contractility Decreasing preload Decreasing afterload

Goals of treatment
Alleviate Symptoms Improve quality of life Arrest cardiac modeling Prevent sudden death

Pathophysiologic mechanisms of heart failure and major sites of drug action


Therapeutic Strategy -salt restriction -diuretic therapy -venodilator drugs

1. Preload

2. Afterload

-arteriolar vasodilators -ACEIs & ARBs

3. Contractility

-positive inotropes

Classification of Drugs used in Congestive Heart Failure

Positive Ionotropes : Cardiac Glycosides Phosphodiesterase Inhibitors Sympathomimetics drugs Reduction in Preload : Organic Nitrates Diuretics
: Digoxin, digitoxin : Inamrinone, Milrinone : Dopamine, Dobutamine : Glyceraltrinitrate. : Furosemide, Hydrochlorthiazide

Reduction in afterload : Arteriolar Dilators : Hydralazine. Reduction in Preload and afterload : ACE Inhibitors : Enalapril, Ramipril, Lisinopril. Beta Blockers : Metaprolol, Carvedilol. Aldosterone antagonists : Spirinolactone. Novel Approaches : Natriuretic Peptides : ANP, BNP, CNP NEP Inhibitors : Candoxatril, Sampatrilat

Cardiac Glycosides
Digitalis lanata - Digoxin, Digitoxin Digitalis purpura - Digitoxin

Fox Glove

Strophanthus gratus Ouabain, Strophanthin

Structure of Digoxin

Sugar moiety

Mechanism of action of Digoxin

Inhibition of cardiac Na+ K+ ATPase. intracellular Na+ Na+/Ca2+ exchange intracellular Ca2+ release of calcium from sarcoplasmic reticulum. actin myosin interaction. force of contraction It also increases vagal tone and effective refractory period

MOA of Inotropes

t1/2 : 36 48 Hrs Therapeutic plasma concentration: 0.5- 1.5 ng/ml Toxic plasma concentration: >2 ng/ml Large Vd (main tissue reservoir is Skeletal muscle) Bioavailability : 70% - 80% Metabolized in liver / excreted through kidneys

CHF Paroxysmal supraventricular tachycardia Atrial flutter and atrial fibrillation

Cardiac Manifestations Cardiac arrhythmias Delayed AV conduction Heart block Ventricular fibrillation

adverse effects (contd)

GI Manifestations Nausea Vomiting Anorexia CNS manifestations: Headache Blurring of vision Mental confusion

Hyperkalemia: reduces action of digoxin Hypokalemia: precipitates digoxin toxicity Hypercalcemia: the risk of digoxin induced arrhythmia Quinidine and Verapamil displaces Digoxin from tissue binding sites Enzyme inducers digoxin metabolism Antacids decrease digoxin absorption Hyperthyroidism renal clearance of digoxin

Rx of acute digitalis intoxication

Lignocaine iv for ventricular arrhythmias Antidigitalis antibody Potassium supplementation Atropine - for bradycardia Beta blocker for supraventricular arrhythmias

Myocardial infarction Hypothyroidism Rheumatic carditis Ventricular fibrillation Partial/complete heart block Wolf- Parkinsons White syndrome

Inamrinone Milrinone
positive inotropic effect.
increase rate of myocardial relaxation.

Mechanism of Action
inhibition of type III phosphodiesterase
intracellular cAMP activation of protein kinase A Ca2+ entry through L - type Ca2+ channels

cardiac output peripheral vascular resistance.

Half-life : 2-3 hrs Excretion : In urine Route of administration : Parenteral

Adverse Effects:
Nausea Vomiting Thrombocytopenia Hepatotoxicity Cardiac arrhythmias

Milrinone has more selectivity for PDE III. Additional effectiveness in patients taking Betablockers. Does not stop disease progression or prolong life in CHF patients.

Prescribed to patients when they are non-responsive to other therapies.



Mechanism of Action
Stimulation of cardiac b1-adrenoceptors: positive inotropic and chronotropic effect leading to increase in stroke volume and cardiac output.
Stimulation of b2-adrenoceptors: peripheral vasodilatation leading to reduction in afterload Dopamine is beneficial in patients with renal failure

Route Of Administration:

Pheochromocytoma Tachyarrhythmias

Adverse Effects:
Precipitation or exacerbation of arrhythmias and angina Rapid development of tolerance

Organic Nitrates
Glyceryl trinitrate Moderately volatile Decreases oxygen demand of Myocardium. Reduces Preload.

Mechanism Of Action

t1/2 of 1-3 minutes

Adverse effects
Headache Postural hypotension Facial Flushing Tachycardia

Loop diuretics
MOA Inhibit the activity of the Na+K+2Cl- symporter in the thick ascending limb of the loop of Henle Increase in the urinary excretion of Na+ and ClOther actions: excretion of Ca2+, Mg2+ and K+ Acutely, increase the excretion of uric acid; on chronic administration - reduced excretion of uric acid

Adverse effects
Hyponatremia associated with hypotension, reduced GFR, circulatory collapse, thromboembolic episodes, and in patients with liver disease, hepatic encephalopathy. Hypochloremic alkalosis. Hypokalemia, Hypomagnesemia, Hypocalcemia Ototoxicity Plasma levels of LDL and triglycerides while decreasing plasma levels of HDL cholesterol Skin rashes, photosensitivity, paresthesias, bone marrow depression, and gastrointestinal disturbances

Severe Na+ and volume depletion Hypersensitivity to sulfonamides

Drug interactions
1) Aminoglycosides (synergism of ototoxicity caused by both drugs) 2) Anticoagulants (increased anticoagulant activity) 3) Digitalis glycosides (increases digitalis toxicity) 4) Lithium and Propranolol (increase in levels of the respective drugs) 5) Sulfonylureas (hyperglycemia) 6) Cisplatin (increased risk of diuretic-induced ototoxicity) 7) NSAIDs, probenecid (blunted diuretic response) 8) Amphotericin B (increased potential for nephrotoxicity and intensification of electrolyte imbalance).

Inhibitors of Na+-Cl- symport Sulfonamide derivatives Increase the excretion of K+

Adverse Effects
CNS - vertigo, headache, paresthesias and weakness Gastrointestinal - anorexia, nausea, vomiting, cramping, diarrhea, constipation, cholecystitis, and pancreatitis Hematological - blood dyscrasias Dermatological - photosensitivity and skin rashes Erectile dysfunction

Adverse Effects contd

Abnormalities of fluid and electrolyte balance: extracellular volume depletion, hypotension, hypokalemia, hyponatremia, hypochloremia, metabolic alkalosis, hypomagnesemia, hypercalcemia, and hyperuricemia Decrease glucose tolerance Increase plasma levels of LDL cholesterol, total cholesterol, and total triglycerides. contraindicated in individuals who are hypersensitive to sulfonamides.

Drug interactions
Diminish the effects of anticoagulants, uricosuric agents used to treat gout, sulfonylureas, and insulin Increase the effects of anesthetics, diazoxide, digitalis glycosides, lithium, loop diuretics, and vitamin D. Efficacy reduced by NSAIDs, bile acid sequestrants (reduced absorption of thiazides)

Mineralocorticoids cause retention of salt and water and increase the excretion of K+ and H+ by binding to specific mineralocorticoid receptors. Spironolactone and Eplerenone block the effects of Aldosterone

Mechanism of action
Competitively inhibit the binding of aldosterone to the mineralocorticoid receptor They have the additional benefit of preventing remodelling because of activation of RAAS system in CHF thereby reducing morbidity and mortality

Adverse effects
Hyperkalemia. Induce metabolic acidosis in cirrhotic patients. Gynecomastia, impotence, decreased libido, hirsutism, deepening of the voice, and menstrual irregularities. Diarrhea, gastritis, gastric bleeding, peptic ulcers CNS adverse effects - drowsiness, lethargy, ataxia, confusion, and headache. Skin rashes and blood dyscrasias.

Sodium nitroprusside
Acts by donating NO thereby increasing cGMP levels Reduces both preload and afteroad

Reduces afterload Has additional antioxidant and moderate positive inotropic effect

Angiotenisin Converting Enzyme Inhibitors

Enalapril Ramipril Lisinopril Trandolapril Perindopril Moexipril

Mechanism Of Action
Inhibits angiotensin converting enzyme (ACE) Prevents conversion of AT I to AT II Reduce after load Produce natriuretic action Reduces the effects of elevated RAAS Prevent cardiac remodeling Reduce mortality by 20% Improvement in ventricular function

Adverse Effects
Cough Angioneurotic edema Hypotension Hyperkalemia Teratogenic

Angiotensin II receptor blockers

No benefit in survival compared to ACEI Losartan is used in heart failure only when patients cannot tolerate ACEI.

Beta Blockers
Carvedilol, bisoprolol, labetolol, metoprolol Recommended for advanced heart failure Started with low doses (1/10 th of target dose) and increased slowly over a period of time Block compensatory sympathetic stimulation Reduces left ventricular mass & size

Reduces the incidence of sudden death Reduces remodelling

Reduce oxidative stress in the myocardium

Inhibit renin release

Novel Drugs for CHF

Renin Inhibitors
Aliskiren, Enalkiren, Remikiren Inhibit renin action inhibit conversion of angiotensinogen to angiotensin-I; which is the rate limiting step in angiotensin-II secretion. Trials show decrease in mortality due to CHF when renin inhibitors were given with betablockers/ACEIs/ARBs

Natriuretic Peptides
ANP, BNP & CNP Increase cGMP levels especially in kidneys facilitating Na+ and water excretion. Inhibits renin and aldosterone sectretion Has no effect on cardiac contractility

Nesiritide - recombinant BNP

NEP inhibitors
Candoxatril, Ecadotril, Omapatrilat, Sampatrilat. ANP, BNP & CNP are degraded by neutral endopeptidases in the brush border cells of PCT. NEP inhibitors inhibit this enzymes and thereby raises natriuretic peptide levels; facilitating diuresis.

1. Basic and Clinical Pharmacology. Bertram Katzung, 11th edition. 2. Goodman & Gilmans Pharmacological Basis of Therapeutics. Laurence L Brunton. 12th edition. 3. Principles of Pharmacology. HL Sharma, KK Sharma. 2nd edition.