Drugs Used in Congestive Heart Failure

Mijala Bajracharya

Congestive Heart Failure (CHF)

CHF is a condition in which the heart is unable to pump sufficient blood to meet the needs of the body. CHF can be caused by an impaired ability of the cardiac muscle to contract or by an increased workload imposed on the heart. Congestion of pulmonary or systemic circulation (backward failure) Reduced output to body tissues (forward failure)

 In initial stages of CHF, the compensatory mechanisms try to maintain the proper cardiac output which are: a) Increased sympathetic activity b) Increased renin-angiotensin-aldosterone activity c) Myocardial hypertrophy and remodelling As time progresses, the compensatory mechanisms fail and gradually clinical symptoms appear .

Compensatory Mechanisms in Heart Failure

Mechanisms designed for acute loss in cardiac output Chronic activation of these mechanisms worsens heart failure

 The basic haemodynamic disturbances seen in congestive heart failure are: A) Increased pulmonary capillary pressure termed as backward failure, which is characterized by dyspnoea and orthopnoea B) Decreased cardiac output termed as forward failure, leading to decreased oxygen supply to the peripheral tissues ( tissue hypoxia)

Causes
coronary artery disease( Arteriosclerotic heart disease)
Myocardial ischemia

Myocardial infarction Arrhythmias

Tachycardia Bradycardia

Valvular heart disease Acute Hypertensive Crisis Chronic Hypertension Idiopathic Causes

Congestive Heart Failure

Left sided Right sided Biventricular

Left-Sided Heart Failure

Left ventricle fails as effective pump Left ventricle cannot eject blood delivered from right heart through pulmonary circulation Blood backs up into pulmonary circulation Increase pressure in pulmonary capillaries forces blood serum out of capillaries into interstitial spaces and alveoli Increase respiratory work and decrease gas exchange occur

Left-Sided Heart Failure

Pulmonary Signs/Symptoms

Left Heart Failure Symptoms

Dyspnea on exertion Paroxysmal nocturnal dyspnea Orthopnea Fatigue, generalized weakness
Pink, frothy sputum

Anxiety, confusion, restlessness Persistent cough

Tachycardia Noisy, labored breathing
Rales, wheezing (cardiac asthma)

Cyanosis (late)

Right-sided Heart Failure

Right ventricle fails as effective pump Right ventricle cannot eject blood returning through venacava Blood backs up into systemic circulation Increased pressure in systemic capillaries forces fluid out of capillaries into interstitial spaces Tissue edema occurs

Right Heart Failure Signs/Symptoms

Tachycardia edema Hepatomegaly Splenomegaly Fluid accumulation in body cavities Ascites Pleural effusion Pericardial effusion

Goals of pharmacologic intervention in HF

alleviate symptoms, slow disease progression, and improve survival Chronic HF is typically managed by a reduction in physical activity; low dietary intake of sodium (<1500 mg/day); treatment of comorbid conditions; and judicious use of diuretics, inhibitors of the reninangiotensin system, and inotropic agents.

Drugs used to treat heart failure

Classification 1) ACE INHIBITORS: Captopril,Enalapril,Fosinopril,Lisinopril, Quinapril ,Ramipril 2) ANGIOTENSIN-RECEPTOR BLOCKERS: Losartan, Valsartan 3) bADRENORECEPTOR BLOCKERS: Atenolol , Carvedilol , Metoprolol

Drugs used to treat heart failure

4) DIURETICS Bumetanide, Furosemide, Hydrochlorothiazide 5) DIRECT VASODILATORS Hydralazine, Isosorbide dinitrate ,Isosorbide mononitrate, Sodium nitroprusside 6) INOTROPIC AGENTS Digoxin, Dobutamine 7) ALDOSTERONE ANTAGONISTS Spironolactone

INOTROPIC DRUGS
Positive inotropic agents enhance cardiac muscle contractility and, thus,increase cardiac output.Eg: Cardiac Glycosides ( Digitalis) Phosphodiesterase inhibitors b-adrenoceptor agonists and dopamine receptor agonists

Cardiac Glycosides - Introduction

Drugs having the cardiac ionotropic property increase in force of contraction
They increase the myocardial contractility and improves cardiac output without proportionate increase in Oxygen consumption Do not increase the heart rate

Digitalis is the genus name for the family of the plants that provide most of the medically useful cardiac glycosides - Digoxin

Sources - Cardiac glycosides

Digitalis purpurea Digitoxin, Gitoxin and Gitalin Digitalis lanata - Digitoxin, Gitoxin and Digoxin Strophanthus gratus Ouabin Thevetia nerifolia Thevetin Convallaria majalis Convallotoxin Bufo vulgris - Bufotoxin

Images of Cardiac Glycosides

Digitalis purpurea

Digitalis lanata

Strophanthus gratus

Chemistry
All Cardiac glycosides
aglycone (genin) part (active pharmacologically) sugar (glucose or digitoxose) attached at Carbon 3 of nucleus

Aglycone Steroid ring (cyclopentanoperhydrophe nanthrene ring) and lactone ring attached at 17th position

Cardiac Glycosides

Mechanism of Action of Cardiac Glycosides

1)Regulation of cytosolic calcium concentration: I. Digitalis binds and inhibits Na+K+-ATPase II. Increased intracellular Na+, and the concentration gradient across the membrane decreases III. Decreased extrusion of Ca via Na+/Ca2+-exchanger into the extracellular space IV. Increased intracellular Ca2+ V. Increased Ca2+ uptake and storage in the sarcoplasmic reticulum VI. Increased amount of Ca2+ released during each action potential from SR VII. Increased availability of Ca2+ for excitation-contraction coupling thus increasing myocardial contractility ( positive inotropic effect) VIII. Increased cardiac output

Mechanism of Action of Cardiac Glycosides(Contd)

2) Increased contractility of the cardiac muscle: Administration of digitalis glycosides increases the force of cardiac contraction, causing the cardiac output to more closely resemble that of the normal heart . Increased myocardial contraction leads to a decrease in enddiastolic volume, thus increasing the efficiency of contraction (increased ejection fraction). The resulting improved circulation leads to reduced sympathetic activity, which then reduces peripheral resistance. Together, these effects cause a reduction in heart rate. Vagal tone is also enhanced, so the heart rate decreases, and myocardial oxygen demand diminishes. Digoxin slows down conduction velocity through the AV node, which accounts for its use in atrial fibrillation.

Pharmacological Actions
1) Cardiac 2) Extracardiac 1) Cardiac actions: Digitalis has direct and indirect actions on the heart. i. Direct action by inhibiting Na+K+-ATPase ii. Indirect action by stimulating vagus (vagomimetic effect)

Cardiac Actions
1) Myocardial contractility: Force of contraction:
Dose dependent increase in force of contraction in failing heart positive ionotropic effect Systole is shortened and prolonged diastole Contracts more forcefully when subjected to increased resistance Increase in cardiac output complete emptying of failed and dilated heart Decrease end diastolic size of failing ventricle Reduction in oxygen consumption The digitalized heart thus can do more work for the same energy. Therfore , digitalis is called a cardiotonic.

2) Heart rate: Digitalis reduces the heart rate( negative chronotropic effect) by direct and indirect actions. In small doses, digitalis decreases heart rate by stimulation of vagus. In toxic doses, it can increase sympathetic activity. 3) Electrophysiological actions: At therapeutic concentrations, digoxin decreases automaticity and increases resting membrane potential by vagal action in atria and A-V node. This may lead to bradycardia and A-V block. Decreases heart rate negative chronotropic effect Decreases rate of AV conduction negative dromotropic effect At higher concentrations, digoxin can increase automaticity in cardiac tissue by direct action as well as by increasing sympathetic activity. This can result in atrial and ventricular arrythmias. The action potential duration is shortened in atria and ventricles.

4) ECG Changes Therapeutic Doses ST depression Lengthening of the PR interval Higher Doses Conduction block

EKG Effects of Digitalis

decrease in R-T interval inversion of T wave Uncoupled P waves (Toxic concentrations) Bigeminy (toxic concentrations)

Extracardiac actions
1) GIT: Anorexia,nausea, vomiting and occasionally diarrhoea. Nausea and vomiting is due to stimulation of chemoreceptor trigger zone( CTZ) and direct action on the gut. 2) Kidney:
Diuresis due to the improvement of circulation

3)Other smooth muscles:

Inhibition of Na+/K+ ATPase increased spontaneous activity anorexia, nausea, vomiting and diarrhoea

4)CNS:
No major visible action in therapeutic doses High doses stimulation of CTZ - nausea and vomiting Toxic doses central sympathetic stimulation, mental confusion, disorientation and visual disturbance

Cardiac glycosides - Pharmacokinetics

Absorption and Distribution:
Cardiac glycosides vary in their absorption, distribution, metabolism and excretion characteristics Presence of food in stomach delays absorption of Digoxin and Digitoxin Digitoxin is the most lipid soluble Vd of Cardiac glycosides are very high All are concentrated in heart, skeletal muscles, liver and kidney

Metabolism:
Digitoxin is partly metabolized in liver and excreted in bile Cardioactive metabolite (digoxin) and other metabolites are reabsorbed in gut wall Digoxin is primarily excreted unchanged in urine and rate of excretion parallels creatinine. So, renal impairment and elderly long half life All CGs are cumulative steady state is attain after 4 half lives

Cardiac Glycosides
Digoxin ROA IV or oral Not bound to Plasma Protein Excreted unchanged in the Urinary tract Digoxin is very potent, with a narrow margin of safety and long half-life of around 36 hours. Digoxin is mainly eliminated intact by the kidney, requiring dose adjustment based on creatinine clearance. Digoxin has a large volume of distribution, because it accumulates in muscle. Digoxin dosage is based on lean body weight. A loading dose regimen is used when acute digitalization is needed.

Cardiac Glycosides
Digitoxin ROA oral or IV More lipid soluble Metabolized by the liver Excreted in Urine and GIT Half-life 5 to 7 days Digitoxin has a much longer half-life and is extensively metabolized by the liver before excretion in feces, and patients with hepatic disease may require decreased doses. This creates difficulty in managing the drug, resulting in its replacement with digoxin

Digitalis Adverse effects

Digoxin has a narrow margin of safety. Monitoring of serum digoxin, electrolyte levels and electrocardiogram(ECG) are important during digitalis therapy. Cardiac and Extracardiac: Cardiac adverse effects: The common cardiac side effect is arrhythmia, characterized by slowing of AV conduction associated with atrial arrhythmias. It can also cause A-V block, atrial tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, and to complete heart block. A decrease in intracellular potassium is the primary predisposing factor in these effects.

 Extracardiac:
GIT: nausea, vomiting and anorexia etc. CNS: CTZ stimulation, headache, blurring of vision, mental confusion etc. Serum Electrolyte: K+ : Digitalis competes for K binding at Na/K ATPase
Hypokalemia: increase toxicity Hyperkalemia: decrease toxicity

Mg2+ : Hypomagnesemia: increases toxicity Ca2+ : Hypercalcemia: increases toxicity

Factors predisposing to digoxin toxicity

a. Electrolytic disturbances: Hypokalemia can precipitate serious arrhythmia. Reduction of serum potassium levels is most frequently observed in patients receiving thiazide or loop diuretics, which can usually be prevented by use of a potassium-sparing diuretic or supplementation with potassium chloride. Hypercalcemia and hypomagnesemia also predispose to digoxin toxicity.

b. Drugs: Quinidine, verapamil, and amiodarone can cause digoxin intoxication, both by displacing digoxin from tissue protein-binding sites and by competing with digoxin for renal excretion. As a consequence, digoxin plasma levels may increaseby 70 to 100 percent, requiring dosage reduction.

 Potassium depleting diuretics and corticosteroids can also increase digoxin toxicity . Hypothyroidism,hypoxia, renal failure, and myocarditis are also predisposing factors to digoxin toxicity.

Digitalis Common Drug interactions

Diuretics: Hypokalaemia (K+ supplementation required) Calcium: synergizes with digitalis Adrenergic drugs: arrhythmia Propranolol and Ca++ channel blockers: depress AV conduction and oppose positive ionotropic effects

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

Treatment of Digitalis Toxicity

reduce dose: 1st degree heart block, ectopic beats AV block: Atropine - 0.6 to 1.2 mg IM Ventricular arrhythmia: Excessive ventricular automaticity: Lidocaine IV (or Phenyton) Tachyarrythmias: Heart rate abnormally increased due to prolong diuretic and digitalis therapy Potassium chloride 20m.mol IV

Antidote Antidote to serious cardiac glycoside intoxication is Digoxin Immune Fab (Digibind).
Digibind is Antibody that is administered parenterally. Binds to the glycoside drug Symptoms of toxicity reduced within 30 to 60 minutes

Digitalis therapeutic Uses

Congestive Heart Failure & Cardiac Arrhythmias Digitalis therapy improves the conditions in CHF, but neither arrest progression nor reverse pathological changes.

Overall Benefit of Digitalis to Myocardial Function

cardiac output cardiac efficiency heart rate cardiac size

Other Beneficial Effects

Restoration of baroreceptor sensitivity Reduction in sympathetic activity increased renal perfusion, with edema formation

Digoxin - Cardiac Arrhythmias

Cardiac dysrhythmia (arrhythmia)
Large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart The hearts too fast or too slow, and may be regular or irregular

Atrial fibrillation is the most common type of arrhythmias although not life threatening
Often irregular and rapid atrial contractions originating in atrial muscles Ultimately interferes with ventricular contractions (heart beat) If treated, it is not life threatening Generally occurs above 50 years of age
Acts by decreasing the number of impulses passing down the AV node direct, vagomimetic and sympathetic action Decreases average atrial ERP increases fibrillation frequency Decreases the ventricular rate and pulse deficit is abolished Can bring down ventricular rate to 70-80/min

Digitalis action:

Digoxin - Cardiac Arrhythmias

Atrial flutter:
Regular and synchronous contractions Atrial rate is less than AF (200-350) Digoxin enhances AV block and reduces ventricular rate Converts atrial flutter to fibrillation reduction in atrial ERP

PSVT:( Paroxysmal supraventricular tachycardia)

Heart rate is 150-200/min IV injection of Digoxin prevents this by increasing vagal tone. The preferred drug for PSVT is adenosine. Propanolol or verapamil can be used. Digoxin has a slower onset of action, hence it is not suitable for acute thearapy. Digoxin is preferred in PSVT, if there is associated heart failure.

Digoxin Digitalization
Digoxin has low therapeutic window and margin of safety is very low Therapeutic level of digoxin is 0.5 1.5 ng/ml It is administered such a way that patient gets maximum benefits with minimal adverse effects Previously rapid digitalization was done but obsolete now Slow digitalization:
Administer digoxin 0.25 mg (or even 0.125mg) daily in the evening full response in 5-7 days If no improvement administer administer 0.375 for 1 week If no, administer 0.5 mg in next week Monitor patient for blood levels, if no monitor in improvement of signs and symptoms If bradycardia, stop the drug

Digitalization contd.
Rapid digitalization (oral):
Administer 0.5 to 1 mg stat 0.25 mg every 6 Hrly Monitor for toxicity Patient is digitalized within 24 Hrs

Rapid IV: Seldom used now

As desperate measure in CHF and atrial fibrillation 0.25 mg slow IV stat followed by 0.1 mg every Hrly