Drug Therapy for Congestive Heart Failure & Cardiac Arrythmias Tay Ju Lee MD INTI

Objectives Congestive Heart Failure Pathophysiology Drug treatment for Congestive Heart Failure Cardiac Arrythmias Pathophysiology Drug treatment for Cardiac Arrhythmias Treatment for Specific Arrhythmias

Congestive Heart Failure Pathophysiology CHF is inability of the heard to pump sufficient CO to maintain healthy tissue and meet body’s physiological needs. It is the consequence of Cardiomyopathy – Structural change MI - Structural change HTN – Excessive afterload Valvular Disease - Excessive afterload Congenital Heart Disease Coronary Artery Disease

Progression of CHF In early stages, heart compensates for decreased CO with tachycardia & myocardial hypertrophy Compensations increase cardiac workload, compromises pumping Sympathetic system activated to improve contractility, but causes vasoconstriction Kidneys begin to release renin, aldosterone causes water retention increasing preload – cardiac dilatation Angiotensin II causes arterial vasoconstriction increasing afterload Cycle continues until ventricles can no longer pump.

NYHA Classification Complement with Heart Failure staging pyramid see Pg 119 Gladson

Drug Therapy in CHF Goals Increase contractility with positive ionotropic drugs Cardiac glycosides PDE inhibitors Decreasing congestion Diuretics Decrease preload & afterload ACE inhibitors Angiotensin-Converting Enzyme Receptor Blockers Vasodilator Beta –Blockers Nitrates

Cardiac Glycosides - Digitalis Digitalis Enhance cardiac contractility by increasing available free intracellular calcium. Inhibit Na + /K + ATPase pump on cardiac cell membrane Pump normally maintains low IC sodium, pumps 3 Sodium ions out in exchange for 2 potassium into cell. When pump inhibited, high intracellular Sodium enhances transport of Ca 2+ into cell via Na + /Ca 2+ exchange mechanism. Increased IC calcium. Greater cardiac contractility and CO, decreasing sympathetic output.

Digitalis Digitalis also enhances delivery of Na + to distal kidney tubules. Activates parasympathetic system - increased vagal tone – antiarrhythmic effect Clinical Use Atrial fibrillation with CHF Use not warranted without AF due to side effects Adverse effects Significant side effects – low therapeutic index Arrhythmias Gastric irritation – nausea & vomiting CNS – headache, dizziness, visual disturbance, hallucinations Digitalis toxicity - bradycardia

Phosphodiesterase Inhibitors Milrinone & Amrinone Inhibitors of PDE III found in cardiac & smooth muscle. When PDE blocked, intracellular AMP increases, increasing release of calcium stores Elevated cAMP causes marked vasodilation Drugs given IV for short periods Adverse effects Nausea & vomiting Tachycardia Serious arrhythmias

Diuretics Diuretics are essential in treatment of CHF, pulmonary congestion and peripheral edema Diuretics decrease fluid retention but does not reduce mortality or slow progression. Thiazide and loop diuretics are used together dose adjusted to pt’s weight Be aware of electrolyte disturbances with diuretics. Spirinolactone – blocks aldosterone receptor Potassium sparing diuretic recommended in NYHA IV if renal function preserved Reduces vascular remodelling.

β-Blockers Carvedilol, metoprolol, bisoprolol In past had been contraindicated as they slow HR and decrease contractility. But selective β-Blockers are useful in CHF stabilized with diuretics & ACE inhibitors Decreases mortality and hospital admissions Benefits due to depression of neurohormonal response to diminished CO, antiarrhythmic effect and reduced workload. Adverse effects – hypotension, fluid retention, worsening heart failure, bradyarrhythmias.

ACE Drugs ACE inhibitors Captopril, Lisinopril, Enalapril, Ramipril Beneficial effects very convincing, drugs used in all stages of CHF, and prevention in pt’s with high-risk of developing CHF Reduce PVR (afterload) and Aldosterone mediated fluid retention. Shown to slow progression and prolong survival Protect against atherosclerosis through antiproliferative effect ARBs Losartan Similar beneficial effect and better tolerated without cough. May be used together with ACEi

Nitrates Isosorbide di nitrate or mononitrate Nitrates reduce myocardial oxygen requirements by dilating smooth muscle and increasing the volume of venous vascular bed  reducing preload and ventricular filling pressure Isosorbide is given orally and useful in pts who cannot tolerate ACEi due to hypotension or renal failure that follows.

Management of decompensated CHF Dobutamine IV - Beta agonist Human B-type natriuretic peptide – nesiritide Produces cardiac vasodilation and natriuresis Reduces preload and afterload and increases CO without increasing HR. Improves glomerular function and decreases sympathetic output Decreases ventricular arrhythmias Loop diuretics – IV furosemide Morphine – vasodilator effect

Cardiac Arrhythmias Pathophysiology Arrhythmias are result of abnormal electrical events that occur in the heart due to Ischemia Hypoxia Excessive myocardial fiber stretch Excessive discharge or sensitivity to catecholoamines Scarred tissue Drug toxicity Electrolyte disturbance

Phases of the action potential: 0, rapid depolarisation; 1, partial repolarisation; 2, plateau; 3, repolarisation; 4, pacemaker depolarisation.

Generation of a re-entrant rhythm by a damaged area of myocardium. The damaged area (brown) conducts in one direction only. This disturbs the normal pattern of conduction and permits continuous circulation of the impulse to occur.

Classification of Antiarrhythmic Drugs Vaughan-Williams classification useful way to discuss antiarrhythmic drugs, classifies drugs according to their electrophysiological effects Class I - Drugs that block sodium channels Class II – Beta-blockers Class III – Drugs that prolong the cardiac action potential Class IV – Calcium channel blockers

Class I Works by blocking Na + channels aka membrane stabilizing agents. They bind more rapidly to open channels to block rapid firing cells. Class Ia - Quinidine, Procainamide Moderate slowing of action potentials by blocking K + currents. Effective in suppressing premature ventricular beats, recurrent ventricular tachycardia and reentry arrhythmias ADR – N/V/D larger doses cause cinchonism – headache vertigo, tinnitus, blurred vision. All antiarrhythmics exacerbate arrhythmias.

Class Ib – Lidocaine, mexilitine, tocainide Block Na+ channels minimally slowing depolarization but also decreasing AP duration by shortening refractory period and suppressing contraction. Used in ventricular tachycardia Class Ic – Flecainide, propafenone Markedly slow phase 0 depolarization Prolonged depressant effect on conduction speed ADR – dizziness, blurred vision and headache Flecainide can induce life-threatening ventricular tachycardia.

Class II Propanolol, acebutolol and esmolol (short acting IV) Beta-adrenergic antagonists Depress sinus node automacity and prolong AV nodal conduction Useful in atrial flutter and atrial fibrillation & can stop reentry Good drugs to treat arrhythmias caused by increased sympathetic activity

Class III Amiadarone & Sotalol (Beta-blocker that delays K + outward current) Class III drugs prolong repolarization and effective refractory period by blocking K + channels Considered to be the most effective antiarrhythmic drugs Amiadarone used for prevention and treatment of both life-threatening atrial and ventricular arrhythmias Also has Na + and Ca 2+ channel blocking abilities and binds β – receptors noncompetitively ADRS – Interstitial pulmonary fibrosis, GI problems, blurred vision, ataxia, dizziness, liver toxicity, neuropathy, bluish skin discolouration Long half-life – months to clear. Hospitalization for monitoring to begin therapy

Class IV Verapamil Calcium Channel Blockers Decreases contractility in pacemaker cells, suppress automatic activity. Verapamil and diltiazem most commonly used in supraventricular tachycardia and atrial fibrillation Both decrease SA node rate and AV node conduction.

Specific arrhythmias and Rx Atrial Fibrillation Most common, defined as erratic quivering and twitching of atrial muscle caused by multiple ectopic foci or rapidly circulating circus movement No P waves AV node controls ventricular response – can be fast or slow Coagulation of blood leading to embolus Treatment IV verapamil or diltiazem Beta-blockers to control ventricular rate Cardioversion or pacemaker/ defibrillator. Amiadarone for drug conversion over days Concurrent anticoagulation treatment with warfarin

Specific arrhythmias and Rx Atrial flutter Rate per minute Flutter waves - sawtooth pattern Radiofrequency ablation If not a candidate then Class Ic or III Atrioventricular block 1 st degree heart block rarely requires treatment Higher degree of block – IV atropine and paced Isoproterenol Permanent pacemaker indicated

Specific arrhythmias and Rx Ventricular Tachycardia Series of premature ventricular contractions in a row Results from rapid firing from single ventricular focus Absent P waves, Wide QRS Ventricular rate between bpm Associated with ischemic heart disease and drugs causing prolonged QT interval Immediate injection with Class I drugs procainamide or lidocaine Recurrent tachycardia – sotalol & amiadarone Torsades de pointes – ventricular tachycardia in twisting fashion due to prolonged QT interval.

Specific arrhythmias and Rx Junctional Tachycardia Arise from reentry circuits within AV node Cessation with vagal maneuvers – carotid sinus massage or adenosine. Drug therapy also effective Ventricular fibrillation Most prevalent arrhythmias in acute cardiac arrest Irregular quivering of ventricular muscle Severely diminished CO Treatment is immediate defibrillation and CPR For recurrent fibrillation, suppression with sotalol or amiadarone plus a beta-blocker Implanted cardioverter defibrillator recommended.

References Gladson Rang & Dale