Drugs Used In Heart Failure

Drugs Used In Heart Failure: 

Drugs Used In Heart Failure

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Heart Failure: When Co is inadequate to providethe oxygen needed by the body Pathophysiology of Heart Failure: Systolic failure Diastolic failure It may be Chronic Heart Failure. Acute Heart Failure High output failure.

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Pathophysiology of cardiac performance: Cardiac performance is a function of four primary sectors. Preload. Afterload Contractility Heart rate.

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Compensatory Mechanism:

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Compensatory responses due to decreased CO: Increased sympathetic Activity Activation of Renin-Angiotensin Aldosterone System. Complex down regulatory changes in β 1 adrenoceptors G. Protein effector system , β 3 not down regulated--- ve inotropic effect. Myocardial Hypertrophy-- ↑in muscle, mass– initially better performance , then ischemic changes & ↓ diastolic filling& alterations in diastolic filling, Remodeling: Dilation & slow structural changes in stressed myocardium: --Proliferation of connective tissue & abnormal myocardial cells , like fetal myocytes —die at accelerated rate Release of natriuretic peptide , endothelin & vasopressin

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Approaches for the management of CHF: i . Relief of symptoms and restoration of cardiac function. ii. Arrest/ reversal of disease progression & prolongation of survival. iii. Treatment of underlying cause.

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i. Relief of symptoms and restoration of cardiac function. a) Unloading the stressed heart to ↓ pre-load and after-load with drugs without inotropic effect. More valuable in long term treatment than positive inotropic drugs b) Use of positive inotropic drugs to  the force of contraction of myocardium. Very helpful in acute failure. Also reduce symptom of chronic failure.

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Drugs Used in Cardiac Failure A. Drugs With Positive Inotropic Effects ( Cardiotonic drugs) Cardiac glycosides Digoxin , Digitoxin , Ouabain , Strophanthin , Gitoxin . Phosphodiesterases inhibitors / Bipyridine derivatives Inamrinone ( Amrinone ), Milrinone . β 1 Selective agonists Dobutamine , Dopamine. Investigational agents: Istaroxime Levosimendan

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Drugs Without Positive Inotropic Effects ACE Inhibitors , AT 1 Antagonists: ACE Inhibitors: Captopril , Enalapril , Lisinopril , Quinapril , Benazepril , Fosinopril , Moexipril , Perinodopril , Trandolapril , Ramipril . AT 1 Antagonists: Candesartan , Eprosartan , Irbesartan , Telmisartan , Losartan , Olmesartan & Valsatran . Diuretics Aldosterone Antagonists: Spironolactone , Eplerenone Thiazides : Bendrofluazide , Polythiazide , Metolazone Loop Diuretic: Furosemide , Bumetanide

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Vasodilators: Arteriolar dilators: Hydralazine Venodilators : Isosorbide dinitrate Synthetic Brain Natriuretic Peptide: Nesiritide Competitive inhibitor of endothelin : Bosentan & Tezosentan Beta Adrenoceptor blockers: Carvedilol , Bisoprolol , Metoprolol .

Cardiac Glycosides (Cardinolides): 

Cardiac Glycosides (Cardinolides) Digoxin is the prototype. Sources Digitalis Lanata : Digoxin , Digitoxin , Gitoxin Digitalis purpurea (purple fox glove): Digitoxin , Gitoxin , Gitalin Strophanthus Kombe : Strophanthin Strophanthus gratus : Ouabain Chinese toad skin’s glands: Bufadienolides

Cardiac Glycosides are called as cardiotonic agents as they increase the mechanical efficiency of heart as a pump: 

Cardiac Glycosides are called as cardiotonic agents as they increase the mechanical efficiency of heart as a pump Efficiency Of Heart: Work Done Oxygen consumed Epinephrine increases the work done alongwith oxygen consumption so not labeled as cardiotonic Cardiac Glycosides increase the mechanical efficiency of heart by their positive ionotropic effect. There is no increase in oxygen consumption

Chemistry: 

Chemistry The prototype of cardiac glycosides ( cardenolides ) is Digoxin – the most commonly used. Chemically cardiac glycosides have a steroid nucleus linked to a lactone ring at 17 position& a series of sugars at carbon 3 of te nucleus. Because they lack an ionizable group their solubility is not pH depende nt.

Chemistry of cardiac glycosides:: 

Chemistry of cardiac glycosides :

Pharmacokinetics of Digoxin: 

Pharmacokinetics of Digoxin Oral availability: 65-80% Widely distributed including CNS. Vd 6.3 L/kg, initial large dose (loading dose) is given. PPB---20-40% Only 1/3 metabolized , 2/3 excreted unchanged by the kidneys. Dosage adjustments in renal impairment. Half-life in body36- 40 hours

Pharmacokinetics: 

Pharmacokinetics Digoxin Digitoxin 1 Lipid solubility (oil/water coefficient) Medium High Oral availability: 75% >90% Half-life in body (hours) 40 168 Plasma protein binding (%age bound) 20-40 >90 Percentage metabolized <40 >80 Volumes of distribution (L/kg) 6.3 0.6

Mode of Action of cardiac glycosides: 

Mode of Action of cardiac glycosides Cardiac glycosides inhibit Na+/K+ ATPase (Sodium pump), the membrane bound transporter. A: Inhibition of Na+/K+ ATPase in heart--- positive inotropic effect B. The consequences of inhibition of Na+/K+ ATPase also affect the Electrical function of the heart. C. Cardiac glycosides also modify Autonomic Outflow & this affects electrical properties of heart Inhibition of Na + /K + ATPase in CNS & GIT--- A/E

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A: Inhibition of Na+/K+ ATPase in heart produces positive inotropic effect, by ↑ Calcium ions in vicinity of contractile elements during systole. This occurs in two steps i . Inhibition of Na+/K+ ATPase results in ↑ in intracellular sodium concentration ii. ↑ I/C Sodium alters the driving force for Na+/Ca+ exchanger (NCX). ↓ expulsion of Ca++ from the cell in exchange for Na+. So a small but physiologically important ↑in the free Ca++ is available for next contraction of cardiac muscle. More Ca++ is stored in SR & upon release increases contractile force.

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The ↑ in contractility results in reversal of the compensatory responses to heart failure: ↑ ventricular ejection…. ↓ end diastolic & end systolic cardiac size. ↑ CO & ↑ renal perfusion The above effects lead to a ↓ in sympathetic & renal responses. ↑ renal perfusion -- no renin release--- no formation of Angiotensin ---- no retention of sodium & water through Aldosteron The ↓ in sympathetic tone is beneficial…. ↓ HR, preload & afterload improve the efficiency of heart.

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Pharmacological Effects Cardiac B. Extra cardiac A. Cardaic Effects: a. Mechanical effects ---Positive Inotropic Effect (as discussed in MOA) b. Electrical effects may be: Direct Electrical effects Autonomic effects

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Autonomic effects : At lower doses due to Parasympathomimetic Activity: produce Negative Chronotropic Effect by : i ) Sensitization of baroreceptors . ii) Central vagal stimulation. iii)  muscarinic transmission in Atria & AV node. At higher dose due to  sympathetic activity ---- sensitization of myocardium ----  toxic effects of digitalis.

Direct Electrical Cardiac Effects : 

Direct Electrical Cardiac Effects These effects follow a well defined progression. At therapeutic concentration: Early brief prolongation of action potential (AP). Shortening of AP especially of plateau phase.  in RP of atria & ventricles , ↑ in RP of AV node

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At High concentration--- A/E  in resting membrane potential. Oscillatory delayed after depolarizing(DADs) due to Calcium overload. Premature ventricular depolarization / ectopic beats. Bigeminal rhythm in E.C.G---Ectopic beat after each normal sinus beat . Ventricular tachycardia Ventricular fibrillation

Effects of Digoxin on electrical properties of cardiac tissues: 

Effects of Digoxin on electrical properties of cardiac tissues Tissue or Variable Effects at therapeutic Dosage Effects at Toxic Dosage Sinus node ↓ Rate ↓ Rate Atrial muscle ↓ RP ↓ RP, arrhythmias Atrioventricular Node ↓conduction velocity , ↑RP ↑RP, arrhythmias Purkinje system, ventricular muscle Slight ↓ RP Extrasystoles, tachycardia, fibrillation Electrocardiogram ↑ PR interval , ↓ QT interval Tachycardia, fibrillation, arrest at extremely high dosage RP = Refractory period

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B. Effects on other Organs (with A/E) Smooth Muscles of GIT. CNS & Eye Interaction with Potassium, Magnesium, Calcium. Potassium: K+ & cardiac glycosides interact in 2 ways: They inhibit each other’s binding to Na+/K+ ATPase — so Hyperkalemia ↓ the enzyme inhibiting action of cardiac glycosides. Hypokalemia facilitates enzyme inhibiting action --- ↑ toxicity. ii. Hyperkalemia ↓ the abnormal automaticity --- ↓ toxicity.

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Calcium: It facilitates the toxic actions of cardiac glycosides--- By ↑ overloading of I/C calcium stores--- ↑ abnormal automaticity. So moderately ↑ extracellular Ca++ --- ↑ risk of Digitalis induced arrhythmias--- toxicity. Magnesium: The effects are opposite to Calcium

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Therapeutic Uses of Digoxin i . Chronic Heart Failure: Only used if ACEIs & Diuretics have failed Does not reduce mortality. ( 5 years mortality rate in CHF is 50 % ) It is useful in; Chronic Heart Failure associated with atrial fibrillation: Drug of choice Only 50% patients with normal sinus rhythm are relieved. Chronic Heart Failure with dilated heart & third heart sound.

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ii. Atrial Arrhythmias : Atrial Fibrillation & Flutter: To decrease ventricular rate because it slows AV conduction . Paroxysmal Atrial & AV Nodal Tachycardia Used previously , Now DOC Adenosine & CCBs. C/I in Wolf-Parkinson White Syndrome with Atrial Fibrillation.

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Toxicity: Digoxin has narrow therapeutic window. Therapeutic plasma conc. : 0.5-2 ng /ml Toxic plasma conc : >2 ng /ml GIT: Anorexia, nausea, vomiting & diarrhea– the first signs of toxicity CNS & Eye: Vagal & CTZ stimulation, Fatigue headache , malaise ,confusion disorientation & hallucinations. Eye: blurred vision , halos on dark objects Changes in color perception ; chromotopsia – blindness for green color may occur Rarely Gynaecomastia in males.

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Cardiac A/E: Arrhythmias: AV Junctional Rhythm Ectopic Beats Bigeminal Rhythm Second Degree AV Block Ventricular Tachycardia Ventricular Fibrillation.

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Drug Interactions: Thiazides / Loop diuretics , corticoids --- Hypokalemia ----- ↑ toxicity Calcium: Hypercalcemia -- ↑ Digoxin toxicity Quinidine ↑ toxicity due to ↓renal clearance & displacement from PPB,. Agents releasing catecholamines , sensitize the myocardium to digitalis arrhythmias.

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Broad spectrum Antibiotics; alter GIT flora --- ↑ bioavailability as bacterial metabolism of Digoxin is reduced Cholestyramine decreases absorption of Digoxin Propranolol , Verapamil , Diltiazem & Disopyramide depress AV conduction ,oppose inotropic effect.

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Management of Digitalis Toxicity Withdraw the drug. Run an ECG to judge the extent of toxicity & arrhythmias. Estimate serum K + & digoxin level. Treatment of Hypokalaemia Mild--- oral Potassium supplements, Potassium Chloride ( KCl ) Tablets If severe hypokalemia Potassium Chloride ( KCl ) by I/V injection is given. Stop Thiazide or Loop diuretics & give Spironolactone .

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Treatment of Arrhythmias – Phenytoin , Lignocaine (Drug of choice as they facilitate AV conduction ,depressed by Digoxin ) β - Blockers to counteract the sympathetic stimulation Do not use Quinidine it can increase Digoxin levels---- enhanced toxicity. Cholestyramine : Prevents further absorption of unabsorbed Digoxin .

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In severe toxicity: The serum Potassium is already elevated at time of diagnosis (due to loss of K from skeletal muscles). The automaticity is depressed . The anti-arrhythmic agents may lead to cardiac arrest; so the best treatment is: Insertion of temporary cardiac pace maker catheter Administration of Antibodies to Digoxin ( Digoxin Immune fab ) which may be life saving . Cardioversion only if there is ventricular fibrillation ; otherwise Digoxin induced arrhythmia are made worse by cardioversion

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Other Positive Inotropic Drugs Used In Heart Failure Bipyridine derivatives: Inamrinone ( Amrinone ), Milrinone , Levosimendan (Investigational) MOA & effects: They inhibit enzymes phosphodiesterase -3 found in cardiac & smooth muscles, that inactivates cAMP & cGMP . Effects on Heart: Positive inotropic effects . Inhibition of PDE 3 ----  cAMP ----  Ca ++ influx ---  contraction of cardiac muscle, May also  Ca ++ release from SR. Effects on B.V: Produce vasodilatation . Inhibition of PDE 3 ----  cGMP ---- relaxation of SM.--- reduce preload & afterload

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Therapeutic use: used I/V for Acute decompensated heart failure Exacerbation of chronic heart failure. Toxicity: ↑ risk of mortality on long term use of both drugs Inamrinone : Nausea , vomiting ,arrhythmias ,thrombocytopenia, change in liver enzymes, Milrinone : arrhythmias Less likely to produce thrombocytopenia & liver toxicity

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β 1 Selective agonists: Dobutamine (Synthetic catecholamine), Role in HF: Improve cardiac performance by : Positive inotropic effect-- ↑contractility, ↑ C O Dobutamine is the most commonly Uses: Primarily in acute decompensated HF, due to MI & Surgery-- controlled I/V infusion, DOA a few minutes May be used as intermittent infusion in CHF to reduce symptoms

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Dopamine ---Natural catecholamine. Increases renal blood flow ,higher doses have Positive inotropic effect-- ↑contractility, ↑ C O, Also increase blood pressure. Therapeutic uses: No role in CHF. Useful in acute decompensated HF & oliguric / hypovolumic shock. A/E: both can produce arrhythmia, additive effect with other sympatomimetics

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Drugs Without Positive Inotropic Effects ACE Inhibitors , AT 1 Antagonists: ACE Inhibitors: Captopril, Enalapril, Lisinopril, Quinapril, Benazepril, Fosinopril, Moexipril, Perinodopril, Trandolapril, Ramipril. AT 1 Antagonists: Candesartan, Eprosartan, Irbesartan, Telmisartan , Losartan, Olmesartan & Valsatran.

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M.O.A of ACE Inhibitors in heart failure: ACEIs inhibit the converting enzyme peptidyl dipeptidase (ACE) & prevent formation of Angiotensin II from Angiotensin I. Inactivation of bradykinin by the same enzyme (plasma kininase ) is inhibited, so it accumulates. Bradykinin produces vasodilation directly as well as through ↑ PG synthesis.

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So there is vasodilatation due to ↓ Angiotensin II & ↑ bradykinin  ↓ PVR  Preload & after load. Due to ↓ Angiotensin II, the release of aldosetrone & consequent retention of sodium & water is also ↓ , So ↓ blood volume also contributes to Preload & after load. ↓ remodeling of Heart & BV.

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Use of ACE Inhibitors in HF: First line therapy in heart failure without edema. Useful in asymptomatic to those in severe heart failure . By ↓ Preload & after load ( ↓ PVR , ↓ salt retention ) . ↓ sympathetic activity due to ↓ Ang II , through inhibition of presynaptic effect on NE release. ↓ Mortality & Morbidity ----- ↓ remodeling of Heart & BV. Slow the progress of ventricular dilation & delay the onset of clinical heart failure. AT 1 Antagonists: Only used if patient can not tolerate ACEIs

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Diuretics Aldosterone Antagonists: Spironolactone , Eplerenone Thiazides : Bendrofluazide , Polythiazide , Metolazone Loop Diuretic: Furosemide , Bumetanide They are useful in CHF because they: ↓ venous pressure & preload. ↓ peripheral & pulmonary edema & relieve their symptoms ↓ cardiac size--- better pump function. Do not influence the primary disease process in CHF. .

Spironolactone & Eplerenone:: 

Spironolactone & Eplerenone : MOA: Block cytoplasmic aldosteron receptors in collecting tubules. Role in CHF In advanced HF, ↑ Aldosterone due to ↑ AngiotensinII . As they are direct receptor antagonists to Aldosterone , they prevent salt & water retention , myocardial hypertrophy & Hypokalemia . Monitor serum K +. Reserved for the most advanced cases Spironolactone & Eleprenone also reduce mortality

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Loop Diuretic , I/V Furosemide ,DOC in acute HF specially with pulmonary edema. In CHF resistance may develop to Loop Diuretic so combined with Thiazides Bendrofluazide , Polythiazide , Metolazone or Spironolactone .

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Vasodilators: I/V Effective in acute heart failure. ( Cardiogenic shock, MI). Orally effective for long term therapy of chronic heart failure.  life expectancy in CHF---- reduce mortality: Long term use of Hydralazine & Isosorbide dinitrate also  damaging remodeling of the heart.

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Selective Arteriolar dilator: Hydralazine Primarily  afterload & relieve fatigue due to low CO Selective Venodilator: Isosorbide dinitrate Primarily  preload. Useful in patients with high filling pressure & dyspneoa Non-selective Vasodilators: ACE inhibitors Synthetic Brain Natriuretic Peptide (BNP) : Nesiritide Competitive inhibitor of endothelin: Bosentan

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Synthetic Brain Natriuretic Peptide (BNP) : Nesiritide Prepared by, Recombinant DNA technique. Given I/V. MOA: Activates BNP receptors,  cGMP in SM cells --- vasodilation ----  preload & afterload . Also causes diuresis . A/E: Renal damage & deaths, hypotension. Competitive inhibitor of endothelin : Bosentan & tezosentan Given orally. Therapeutic use: Disappointing results in humans with CHF. Used in Pulmonary hypertension A/E: Teratogenic , hepatotoxic

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Beta Adrenoceptor blockers: Carvedilol , Bisoprolol , Metoprolol . They ↓ motility in selected patients with stable CHF. Suggested mechanisms are: Attenuation of the adverse effects of high concentration of catecholamines including apoptosis. Up regulation of beta receptors ↓ Heart Rate Prevent arrhythmias. Inhibit vascular SM mitogenesis ---↓ Remodeling.

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Management of Acute Heart Failure Acute heart failure occurs frequently in patients of CHF due to:  exertion ,emotion, salt in diet. Non-compliance with medical therapy Metabolic demand– high fever. Anemia Acute myocardial infarction is a common cause of acute heart failure_ with or without CHF. I/V therapy is the rule in acute heart failure.

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Drug Therapy in Myocardial Infarction Drug therapy includes: Relief of Pain, Anxiety and Apprehension: Opioid analgesics (morphine/ Pethidine ) , diazepam. Oxygenation Maintenance of blood volume Correction of acidosis Prevention & treatment of arrhythmias-- Betablockers Treatment of Pump failure Furosemide Vasodilators Inotropic agents– Dopamine & Dobutamine

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Best treatment is emergency revasculization using: Coronary angioplasty & a stent Thrombolytic agents like streptokinase . 8. Prevention of thrombus extension, embolism, venous thrombosis --- Anti-coagulants like heparin. 9. Prevention of remodeling & subsequent CHF—ACE inhibitors 10. Prevention of future attacks Anti-platelet drugs β -Blockers Control of hyperlipidaemia

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Subsets in acute MI Therapy Hypovolemia Volume replacement Pulmonary congestion Diuretic– I/V furosemide , Nitrates Peripheral vasodilation None, or vasoactive drugs Power failure Vasodilators, inotropic drugs Severe shock Vasoactive drugs, inotropic drugs, vasodilators, circulatory assist devices Right ventricular infract Provide volume replacement for LVFP, inotropic drugs. Avoid diuretics. Mitral regurgitation, ventricular septal defect Vasodilators, inotropic drugs, circulatory assistance , surgery