Heart Failure is the inability of the heart to pump an

adequate amount of blood to the bodys needs. CONGESTIVE HEART FAILURE

refers to the state in which abnormal circulatory congestion exists a result of heart failure.

Definitions:
Congestive heart failure (CHF): pathophysiological state in which the heart is unable to pump blood at a rate commensurate with the requirements of the metabolizing tissues or can do so only from an elevated filling pressure Heart (or cardiac) failure: is an impairment of the heart's ability to fill or empty the left ventricle leading to a complex clinical syndrome characterized by fatigue, shortness of breath, and congestion that are related to the inadequate perfusion of tissue during exertion and often to the retention of fluid.

The Heart has the capacity to adapt to short-term changes in preload or after load.

Progressive failure of myocardial function is due to :

Sudden or sustained changes in the preload (acute mitral regurgitation, excessive Left ventricular hydration) . Sudden or sustained changes in after load (aortic stenosis, severe uncontrolled hypertension). Sudden or sustained change in demand (from severe anemia, or hyperthyroidism).

Pathophysiology of cardiac failure

Decrease in Cardiac output Increase in Pre-load

Ventricular dilatation to increase Cardiac output (compensatory mechanism)

Persistent compensatory mechanism

Leads to
Heart Failure.

Pathophysiology of cardiac failure

Increase In After-load (Hypertension)

Resistance to outflow of blood Ventricular dilatation Persistent dilatation leads to Congestive heart failure

Normal Heart

Pressure Overload Increase systolic pressure

Volume overload

Increase diastolic pressure

Myocardial thickening
Eccentric Hypertrophy

Enlargement of Chambers of Heart

Decrease Myocardial contractility

Pooling Of Venous Blood Decreased Cardiac Output

Forward failure cardiac output

Left heart failure

IHD, Myocarditis, Valvular heart diseases Backward failure Residual blood in left ventricle

Tissue anoxia

Left atrial pressure and volume

Pressure in pulmonary venous circulation renal perfusion Pulmonary arterial hypertension Activation of RAAS

Right heart failure

Right side valvular disease Rt side myocardial disease Pulmonary hypertension

Right ventricular pressure

Na+, H2O retention

PULMONARY CONGESTION and OEDEMA

Congestive Heart Failure

SYSTEMIC VENOUS CONGESTION and PERIPHERAL OEDEMA

Lt. VENTRICULAR FAILURE IHD, Myocardits, Valvular heart

disease

Rt. VENTRICULAR FAILURE Pulmonary HT, Valvular heart

disease

COMPENSATORY MECHANISMS
Activation of NA, ANP Activation of RAAS mechanism Tachycardia Na+ Further stress on myocardium and water retention Cell stretching

Myocardial contractility
cardiac workload

CONGESTIVE HEART FAILURE

COMPENSATORY HYPERTROPHY and DILATATION

Neurohormonal changes Sympathetic activity

Favorable effect HR , contractility, vasoconst. V return, filling

Unfavorable effect Arteriolar constriction After load workload O2 consumption

ReninAngiotensin Aldosterone Vasopressin

interleukins &TNF- Endothelin

Salt & water retention VR Same effect

May have roles in myocyte hypertrophy Vasoconstriction VR

Vasoconstriction after load Same effect

Apoptosis After load

PATHOGENESIS of HEART FAILURE

Preload
Preload is the diastolic muscle sarcomere length leading to increased tension in muscle before its contraction. Pre load depends upon Starlings law. Preload is directly proportional to End diastolic volume (EDV). Starlings law :

Stretching the myocardial fibers during diastole by increasing

end-diastolic volume leads to increase in force of contraction during systole. End diastolic volume(EDV) is the amount of blood remaining in the ventricles at the end of the diastole. When venous return (volume of blood returning to heart increases), EDV increases. Increase in EDV increases preload.

After load
After load 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/pulmunary artery. After load depends on Laplace law.
Laplace law: intraventricular pressure x radius of ventricle wall tension = -------------------------------------------------------2 x ventricular wall thickness

afterload is due to - elevation of arterial resistance - ventricular size - myocardial hypotrophy afterload: due to - arterial resistance - myocardial hypertrophy - ventricular size

Causes of Congestive heart Failure

Predisposing Factors
Myocardial infarction Chronic ischemia Cardiomyopathy Arrhythmias Diastolic dysfunction Valvular diseases
Aortic Stenosis Mitral Stenosis Mitral Regurgitation

Precipitating Causes
Common
Coronary Artery Disease (70%) Systemic Hypertension Idiopathic
Rare
Anemia Connective Tissue Disease Viral Myocarditis Hemochromatosis HIV Hyper/Hypothyroidism Hypertrophic Cardiomyopathy Infiltrative Disease including amyloidosis and sarcoidosis Mediastinal radiation Peripartum cardiomyopathy Restrictive pericardial disease Tachyarrhythmias Toxins Trypanosomiasis (Chagas disease)

Less Common
Diabetes Mellitus Valvular Disease

Signs and Symptoms

The signs and symptoms of heart failure (HF) are due in part to compensatory mechanisms utilized by the body in an attempt to adjust for a primary deficit in cardiac output. Shortness of breath blood pooling in pulmonary veins fluid in lungs occurs during activity, rest, or sleeping Persistent coughing/wheezing produces white/blood mucus Edema (or excess fluid buildup in body tissues) venous pooling swelling in extremities necrosis

 Tiredness/fatigue decreased O2 supply diversion of blood supply from limbs Lack of appetite/nausea decreased blood supply to digestive tract Confusion / impaired thinking Orthopnoea, paroxysmal nocturnal dyspnoea Increased heart rate baroreceptor reflex SNS output

Pharmacotherapy of Congestive Cardiac Failure

Objectives of Treatment:
Increase cardiac contractility Decrease preload ( left ventricular pressure) Decrease afterload (systemic vascular resistance) Normalize heart rate and rhythm.

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

Factor 1. Preload (work or stress the heart faces at the end of diastole)

Mechanism

Therapeutic Strategy

increased blood volume and -salt restriction increased venous tone--->atrial -diuretic therapy filling pressure -venodilator drugs

2. Afterload (resistance against increased sympathetic which the heart must pump) stimulation & activation of renin-angiotensin system ---> vascular resistance ---> increased BP 3. Contractility

- arteriolar vasodilators -decreased angiotensin II (ACE inhibitors)

decreased myocardial -inotropic drugs (cardiac contractility ---> decreased CO glycosides) decreased contractility and decreased stroke volume ---> increased HR (via activation of b adrenoceptors)

4. Heart Rate

Classification of Drugs used in Congestive Heart Failure

Positive Ionotropes : Cardiac Glycosides Phospho di esterase Inhibitors Sympathomimetics drugs Reduction in Preload : Organic Nitrates Diuretics
: Digoxin : 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, Ecadotril,Sampatrilat

Cardiac Glycosides
Fox Glove

derived from plants

Strophanthus - Ouabain Digitalis lanata - Digoxin, Digitoxin increase force of myocardial contraction.

alters electrophysiological properties.

Digitalis purpurea

Digitalis lanata

Strophanthus gratus

Structure of Digoxin

Sugar moiety

Mechanism of action
Mechanism Of Action Of Positive Ionotropicity:
Direct Effect: Inhibition of cardiac Na+ K+ ATPase. Decrease Na+/Ca2+ exchange. Increases increase in intracellular Na+. Increase in Intracellular Ca2+. Increased release of Calcium from Sarcoplasmic reticulum. Increases actin myosin interaction. Increases force of contraction of myocardium.

Mechanism Of Action for Negative Chronotropicity

Inhibits Neuronal Na+ K+ ATPase. Increases Vagal activity. Prolongs the effective refractory Period of Atrio ventricular Node. Decreases conduction Velocity.

Directly acts on Vagus nerve leading to M2 receptor stimulation decreases Acetylcholine and decreases heart rate.

Pharmacokinetics:
T1/2 = 36 48 Hrs Therapeutic plasma concentration: 0.5- 1.5 ng/ml Toxic plasma concentration: >2 ng/ml *digitalis must be present in the body in certain "saturating" amount before any effect on congestive failure is noted this is achieved by giving a large initial dose in a process called "digitalization. Principle tissue reservoir is Skeletal muscle.

Bioavailability : 70% - 80%

Route of Administration : Oral (common) Intravenous (in acute emergency) Metabolized in Liver.
Excretion is through Urine (unchanged).

Properties
Lipid solubility (oil/water coefficient) Oral availability (% absorbed) Half-life in the body (hrs) Plasma protein binding (% bound) Volume of distribution

DIGOXIN
Medium

DIGITOXIN
High

75

> 90

40

168

<20

>80

6.3

0.6

ADVERSE EFFECTS
Cardiac Manifestations : Cardiac dysarrhythmias Delayed AV conduction Heart block ventricular tachycardia Ventricular fibrillation GI Manifestations: Nausea Vomiting Anorexia CNS manifestations: Headache Blurring of vision Mental confusion Yellow Tinted Vision.

Interactions
POTASSIUM Hyperkalemia: reduces enzyme inhibiting actions of digitalis, abnormal cardiac automaticity is inhibited Hypokalemia: facilitates enzyme inhibiting actions CALCIUM Facilitates the toxic actions digitalis by accelerating the overloading of intracellular calcium stores that appears to be responsible for abnormal automaticity Hypercalcemia: increases the risk of digitalis induced arrhythmias MAGNESIUM Opposite to those of calcium.

Contraindications
Hypokalemia: Toxicity

WPW syndrome: VF may occur

Elderly, renal or severe hepatic disease: more sensitive to digitalis Diastolic dysfunction of heart Partial AV block: Complete block

PHOSPHODIESTRASE INHIBITORS
Inamrinone Milrinone
positive inotropic effect.
increase rate of myocardial relaxation. decrease total peripheral resistance and afterload.

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

cardiac output peripheral vascular resistance.

Site of Action Of Phosphodiesterase Inhibitors

Pharmacokinetics
Half-life : 2-3 hrs Excretion : In urine (10-40% ) Route of administration : Parenteral

Adverse Effects:
Nausea Vomiting Thrombocytopenia Liver enzyme changes (Hepatotoxicity) Cardiac arrhythmias Sudden death

Milrinone is ~1o fold more potent. Milrinone has more selectivity for PDE III. T 1/2 = 2.5 h for amrinone and 30-60 min for milrinone.

Effective in patients taking Beta-blockers.

Does not stop disease progression or prolong life in CHF patients. Prescribed to patients when they are non-responsive to other therapies.

Sympathomimetics
Dopamine

Dobutamine

Mechanism of Action:
Stimulation of cardiac b1-adrenoceptors: inotropy leads to chronotropy leading to increase in stroke volume and cardiac output. Stimulation of b2-adrenoceptors: peripheral vasodilatation Increase Myocardial Oxygen demand.

Myocardial Contraction

Pharmacokinetics
Route Of Administration:
Parenteral

Contraindications:
Pheochromocytoma Tachyarrhythmia's

Adverse Effects:
Precipitation or exacerbation of arrhythmias

Angiotenisin Converting Enzyme inhibitors

Captopril Enalapril

Mechanism Of Action
Inhibits angiotensin converting enzyme (ACE) Prevents conversion of ATI to ATII

Decreases preload

Decreases afterload
Decreases cardiac remodeling

ACE Inhibitors Acting Site

ACE Inhibitors Acting Site

Adverse Effects
Cough Angioneurotic edema Hypotension Hyperkalemia

Teratogenic

Organic Nitrates
Glyceryl trinitrate

Moderately volatile Decreases oxygen demand of Myocardium. Reduces Preload.

Mechanism Of Action Of Organic Nitrates

Nitrates Increase nitrites

Myocardial relaxation

Pharmacokinetics
t1/2 of 1-3 minutes

Route of Administration : Sublingual tablet or sublingual spray

Adverse effects
Headache Postural hypotension Facial Flushing Tachycardia

Diuretics
Drugs that increase the rate of urine flow.

Increase the rate of Na & Cl excretion.

Decrease reabsorption of K, Ca & Mg .

Loop Diuretics
Furosemide

Thiazide diuretics
Hydrochlorothiazide

Loop Diuretics :
Furosemide
Bumetanide Torsemide

Mechanism Of Action
Inhibits the coupled Na+/K+/2Cl symporter system in the luminal membrane of the thick ascending limb of the loop of henle reduce NaCl reabsorption. Enchances K+ secretion. Increases Mg & Ca+ excretion. Induces synthesis of renal prostaglandins.

Increases renal blood flow.

Reduces pulmonary congestion & left ventricular filling pressures.

Pharmacokinetics
Bioavailability = 40-70 % Route of administration : Oral / IV Plasma Half Life: 1.5 hrs (Short acting)

Adverse Effects
Ototoxicity : tinnitus, hearing impairment, deafness, vertigo, sense of fullness in ears. Hypokalemic metabolic alkalosis Hyperuricemia Hypovolemia & cardiovascular complications

Thiazide diuretics:
Chlorthiazide Hydrochlorothiazide

Inhibitors of Na+-Cl symport

Predominantly increase NaCl excretion Primary site of action : Distal convoluted tubule

Mechanism Of Action

Bind to Chlorine Binding site of Na-Cl symport. Inhibits the reabsorption of Sodium (Na2+).

Use of multiple drugs in the treatment of heart failure. ACE = angiotensin-converting enzyme.

Treatment options for various stages of heart failure. ACE = Angiotensin-converting enzyme; ARB = angiotensinreceptor blockers. Stage D (refractory symptoms requiring special interventions) is not shown.