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Drugs used in Cardiac Arrhythmias Dr.V.V.Gouripur What is an arrhythmia? The rhythm of the heart is normally generated and regulated by pacemaker cells within the sinoatrial (SA) node, which is located within the wall of the right atrium. SA nodal pacemaker activity normally governs the rhythm of the atria and ventricles. Normal rhythm is very regular, with minimal cyclical fluctuation. Furthermore, atrial contraction is always followed by ventricular contraction in the normal heart. When this rhythm becomes irregular, too fast (tachycardia) or too slow (bradycardia), or the frequency of the atrial and ventricular beats are different, this is called an arrhythmia. The term "dysrhythmia" is sometimes used and has a similar meaning. arrhythmia Def'n: 1. an abnormality of rate, regularity, or site of origin of the cardiac impulse, or 2. a disturbance in conduction that causes an alteration of the normal sequence of activation of the atria and ventricles NB: these may arise from abnormal impulse generation, altered conduction, or both Normal Cardiac excitation requires a pacemaker (normally the SA node) and follower cells • Conducting fibers & • Myocardium. Between the atria and ventricle is the AV node which acts as a filter to prevent too frequent activation of the ventricles by supraventricular tachyarrhythmias. 1. 2. 3. Action potentials and conduction in the conducting tissue, atria and ventricles occur due to entry of extracellular sodium through fast Na channels. SA and AV nodes do not use fast Na channels. Instead they rely solely on Ca channels for action potentials and conduction. SA node is the dominant pacemaker because it beats at a rate faster than the AV node 4. Each SA nodal beat is accompanied by one wave of activation affecting the atria, AV node, Bundle branches, Purkinje fibers and myocardium. 5. The heart then rests during diastole before the next sinus beat occurs. The normal cardiac action potential in non conducting tissues (e.g. ventricles) Phase 0-Due to opening of fast Na+ channels (when the threshold potential (~ -70mV) is reached) There is a massive influx of Na+ into the muscle cell, causing a rapid depolarisation Phase 1- Partial repolarisation-Due to closure of the Na+ channels Phase 2-Plateau phase-Due to opening of slow Ca2+ channels Phase 3- Repolarisation-Due to closure of the Ca2+ channels and opening of the K+ channels, causing a massive loss ofK+ out of the cell Phase 4-Pacemaker potential · This phase is unimportant in non conducting heart tissues. In conducting tissues (SA and AV nodes) the pacemaker potential gradually depolarises during diastole to reach the threshold potential, resulting in a spike Conducting tissues always fire action potentials, at varying frequencies (they have intrinsic firing capacity). The SA node fires the fastest and so assumes the role of the pacemaker. Non conducting tissues need a “jump start” impulse from the conducting tissues in order to depolarise (i.e. they are not capable of intrinsically firing, unless under pathological conditions) Mechanism of Arrhythmia Enhanced automaticity Triggered automaticity (normal action potential is interrupted or followed by an abnormal depolarization) Reentry (abnormal impulse conduction) Sometimes the normal wave of activation gets fractionated, giving rise to multiple beats before the next sinus beat comes. This is called ‘reentry’ Re-entry Purkinje fibre Damage e.g. thrombotic clot causes muscle to become ischaemic Ventricular muscle Re-entry Caused by unidirectional block, usually in diseased tissues Probably the cause of many arrhythmias Can occur in atria, ventricles and nodal tissue AP’s conducted only one-way, but conduction is slower Causes a constant loop of AP’s re-exciting repeatedly (Circus Rhythm) The tissue begins to beat independently of input Re-entry 1. 2. 3. Reentry can occur in any part of the heart. It can be stopped by making the unidirectionally blocked tissue become bidirectionally blocked. It can also be blocked by converting unidirectional conduction into bidirectional conduction. i) This can be done with drugs that block Na channels directly or indirectly. Two special cases of reentry in the AV node are: • Paroxysmal supraventricular tachycardia - cause not clear & is often short lasting The other special cause of reentry in the AV node is: • Wolf Parkinson White Syndrome where the normal slowly conducting AV node is straddled by a fast conducting Accessory fibre which resembles atrial tissue. ECTOPIC PACEMAKER SPONTANEOUS (Purkinje Fiber) TRIGGERED PACEMAKER AUTOMATICITY –Delayed afterdepolarisation –Early afterdepolarisation ECTOPIC PACEMAKER DELAYED AFTERDEPOLARISATION –Abnormal Oscillatory Ca Release from SR –Caused by Ca Overload –Elevated Cytosolic Ca Causes Increased Membrane Conductance to Cations –This leads to Oscillatory Depolarization of Cell Membrane ECTOPIC PACEMAKER EARLY AFTERDEPOLARIZATION –Sometimes caused by prolonged action potential duration –Due to oscillatory fluctuation of delayed K+ channels –May also be due to oscillatory inactivation of calcium channels What causes arrhythmias? coronary artery disease-When cardiac cells lack oxygen, they become depolarized, which lead to altered impulse formation and/or altered impulse conduction. Changes in cardiac structure that accompany heart failure (e.g., dilated or hypertrophied cardiac chambers), can also precipitate arrhythmias. Finally, many different types of drugs (including antiarrhythmic drugs) as well as electrolyte disturbances (primarily K+ and Ca++) can precipitate arrhythmias. Types of Arrhythmias (caused by the described mechanisms) Atrial flutter – atria beat rapidly at 250-350 beats per min Supraventricular paroxysmal tachycardia – no more than 200 beats per min. Trivial compared to the other types Atrial fibrillation –350-600 beats per min. Irregular, uncoordinated contractions, fragmentary, ventricles beat at one fifth the rate of the atria, but not regularly. If chronic, then the condition is serious Ventricular fibrillation – immediate cause of death in many fatal causes of MI and electrocution. Ventricles pump too fast. Use electric paddles in order to disrupt contraction pattern and re-instate normal rhythm Ventricular tachycardia – leads to a series of rapid contractions called ventricular extrasystole Clinical symptoms palpitation or fluttering sensation in the chest. a skipped beat -forceful contraction and a thumping sensation in the chest. .) Patients may experience dyspnea (shortness of breath), syncope (fainting), fatigue,, chest pain or cardiac arrest. Treatment Reassurance is important. Most cardiac arrhythmias cause no symptoms, have no hemodynamic importance, and have no prognostic significance but may cause anxiety in a patient who becomes aware of them. In rare cases, a precipitating factor may be identified and modified (eg, excessive intake of caffeine or alcohol). Drug treatment: Antiarrhythmic drug therapy is the mainstay of management for most important arrhythmias. Classification of Antiarrhythmic Drugs based on Drug Action( Table1) CLASS ACTION I. Sodium Channel Blockers Moderate phase 0 depression and slowed conduction (2+); prolong repolarization 1A. DRUGS Quinidine, Procainamide, Disopyramide 1B. Minimal phase 0 depression and slow conduction (0-1+); shorten repolarization Lidocaine 1C. Marked phase 0 depression and slow conduction (4+); little effect on repolarization Flecainide II. Beta-Adrenergic Blockers Propranolol, esmolol III. K+ Channel Blockers (prolong repolarization) Amiodarone, Sotalol, Ibutilide IV. Calcium Channel Blockade Verapamil, Diltiazem Mechanism of Action of Antiarrhythmic Drugs Stop Automaticity –Increase Membrane Threshold for Activation –Cause Membrane Hyperpolarization Mechanism of Action of Antiarrhythmic Drugs Stop Reentry Convert Unidirectional Block to Bidirectional Block Abolish Unidirectional Block Mechanism of Action of Antiarrhythmic Drugs Improve Ventricular Function Slow ventricular rate Increase ventricular filling Increase cardiac output Class I – Blockers + Na Channel Binds to Na+ channels and prevent conduction of ions Bind preferentially to the open channel state (i.e. use-dependent) The more the Na channel is used, the more drug is + CHANNEL BLOCKERS bound REST OPEN REFRACTORY Useful in conditions where channels open frequently Sub-classified into 3 groups: Ia, Ib and Ic Quinidine (class Ia) This broad-spectrum drug is effective for the suppression of VEBs and VT and for the control of narrow QRS tachycardias, including atrial flutter and fibrillation. It is one of the few drugs that may convert AF to sinus rhythm. Elimination half-life (t1/2) is 6 to 7 h. If an initial test dose of quinidine sulfate is tolerated, the maintenance dosage is usually 200 to 400 mg po q 4 to 6 h. Dosing should be adjusted so that QRS Procainamide (class Ia) The main metabolite, N-acetyl procainamide, also has antiarrhythmic effects and contributes to procainamide's efficacy and toxicity. It can be given cautiously IV as 100 mg over 1 to 2 min repeated q 5 min to a usual maximum total dose of 600 mg (rarely up to 1 g) while monitoring BP and ECG. Oral procainamide has a short elimination t1/2 (< 4 h), requiring frequent dosing or use of sustained-release preparations. The usual oral dosage is 250 to 625 mg q 3 or 4 h.. Adverse reactions QRS widening by 25% and QT prolongation to 550 msec suggest toxicity. Almost all patients receiving long-term therapy (> 12 mo) develop serologic abnormalities (notably a positive antinuclear factor test), and up to 40% have symptoms and signs of hypersensitivity (arthralgia, fever, pleural effusions Disopyramide It has an elimination t1/2 of 5 to 7 h. Oral dosing is usually 100 or 150 mg q 6 h. Parenteral dosing, not available. Disopyramide has powerful anticholinergic effects that play only a minor role in arrhythmia management but are responsible for urinary retention and glaucoma; less serious ADR (eg, dry mouth, problems of accommodation, bowel upset, may contribute to noncompliance. Bradycardia may occur Qunidine adverse reactions About 30% of patients develop. GI problems (diarrhea, colic, flatulence) are most common, but fever, thrombocytopenia, and liver function abnormalities also occur. Quinidine syncope is a potentially dangerous idiosyncratic and unpredictable effect caused by torsade de pointes TYPE 1A AGENTS Procainamide Depresses hemodynamics Effective against atrial & ventricular arrhythmia Paradoxical tachycardia PROCAINAMIDE Prolongation of QRS complex Paradoxical tachycardia - prevented by prophylactic digoxin Syncope - due to Torsade de pointes SLE-like Syndrome –reversible & not associated with nephropathy –Procainamide not good for therapy > 6 months –greater toxicity in fast acetylators Bone marrow depression TYPE 1B AGENTS Lidocaine Mexiletine Tocainide Suppress automaticity Shorten action potential duration Prolong refractory period Decrease conduction (especially in ischemic & therefore more depressed tissue) Lesser hemodynamic depression than with Procainamide Lidocaine . It produces minimal myocardial depression and has little effect on the sinus node, atria, or atrioventricular node but acts powerfully on His-Purkinje's and ventricular myocardial tissue. It can suppress the ventricular arrhythmias that complicate MI (VEBs, VT) and reduce the incidence of primary ventricular fibrillation (VF) when given prophylactically in early acute MI. It is used only parenterally. The usual regimen is 100 mg IV over 2 min followed by 50 mg IV 5 min later if the arrhythmia has not reverted. An infusion of 4 mg/min (2 mg/min in patients > 65 yr) should then be started. If it is continued for > 12 h, toxic levels may be reached. Adverse effects; neurologic (tremor, convulsions) rather than cardiac. Drowsiness, delirium, and paresthesias may occur with too-rapid administration. Mexiletine, similar to lidocaine, has few cardiovascular adverse effects, but GI (nausea, vomiting) and CNS (tremor, convulsions) effects may limit its acceptability. Class Ic drugs are among the most powerful antiarrhythmics but have been associated with a significant risk of proarrhythmia and depression of cardiac contractility LIDOCAINE Lidocaine is effective mainly in ventricular tachyarrhythmias Lidocaine is useless orally –extensive first pass metabolism in the liver –metabolite is proconvulsant & not antiarrhythmic –Hence Lidocaine given IV LIDOCAINE Useless in any supraventricular arrhythmia Half life of lidocaine: –distribution phase is 9 min & –elimination phase is 100 min Therefore it is given as a bolus combined with infusion initially as well as with each increase in dose LIDOCAINE Lidocaine is ideal in life-threatening situations: –Effective –Rapid action –Short duration Toxicity –Cardiac depression –CNS stimulation, tinnitus, convulsion, postictal depression TYPE 1C AGENT Propafenone Flecainide Encainide Block sodium entry and beta receptors Minimal change in action potential duration Suppress automaticity Very useful in WPW syndrome Decrease cardiac contractility (don’t give is cardiac mechanical function is poor) Metallic taste on prolonged use TYPE 2 AGENTS (b blockers) Propranolol Metoprolol Suppress Esmolol automaticity (decreased sympathetics) Shorten action potential duration Decrease conduction in SA & AV nodes Class III - Drugs that prolong repolarisation Prolonging the cardiac AP by increasing the refractory period Also have interactions with the ANS Have a diverse pharmacology which is poorly understood Examples are bretyllium and amiodarone Numerous side effects e.g. hepatic injury, hypotension Bretyllium only used for life-threatening ventricular arrhythmias, amiodarone for recurrent ventricular fibrillation Class IV – Ca2+ channel blockers Verapamil, diltiazem, nifedipine Block Ca2+ channels in the plasma membrane especially L-type channels) Reduce slow inward current and force of contraction Also slow conduction of AV node due to calcium channel blockade Verapamil used in acute paroxysmal tachycardia Classification of arrhythmias and drugs of choice Atrial fibrillation and flutter・ ・Digoxin is the drug of choice to slow ventricular response・ ・Alternative drugs that are widely used include verapamil and propanolol・ ・Digoxin, verapamil, and possibly beta-blockers may be hazardous in patients with Wolf-Parkinson-White syndrome (catheter ablation of extra-nodal pathways in WPW is successful)・ ・Subclass IA drugs (quinidine, procainamide, disopyramide) have been used for long-term suppression, but preliminary studies indicate higher mortality than placebo・ ・Class III (amiodarone) and Subclass IC (flecainide, encainide, and propafenone) are also effective for suppression, but may be associated with higher mortality Supraventricular tachycardia ・Vagotonic maneuvers (carotid massage, Valsalva maneuver, gagging) may be effective・ ・Adenosine (short-lived) or verapamil (i.v.) are the drugs of choice for termination・ ・Verapamil is contraindicated in patients with congestive heart failure, those receiving i.v. beta-blockers, and should be used with caution in patients taking oral quinidine・ ・Esmolol (a beta-blocker) or digoxin are alternatives for termination・ ・Cardioversion or atrial pacing may be necessary for some patients・ ・Long-term suppression (possible increase in mortality): Subclass IA, IC, Class II, Class IV, and digoxin・・ Ventricular PVCs or non-sustained ventricular tachycardia No drug therapy for asymptomatic patients・・A beta-blocker for patients with symptoms (syncope, dizziness)・ data indicates higher mortality with encainide and flecainide than placebo・ Sustained ventricular tachycardia Cardioversion (safest and most effective therapy) is preferred by most cardiologists in ventricular tachycardia causing hemodynamic compromise・ ・Lidocaine is drug of choice for acute treatment・・ Alternative drugs are procainamide and bretylium・ ・Long-term suppression: Class II, Class III, Subclass IA, and mexiletine (Class IB)・ Ventricular fibrillation Defibrillation (with CPR) is the treatment of choice; Drugs are used for prevention of recurrence・ Lidocaine is the drug of choice・・ Procainamide, amioradone, bretylium are alternatives・ Cardiac glycoside-induced ventricular tachyarrhythmias ・Lidocaine is drug of choice・ ・Phenytoin, procainamide, or a beta-blocker are alternatives・ ・Digibind should be used in life-threatening cases・ ・Avoid cardioversion and bretylium except for ventricular fibrillation or sustained ventricular tachycardia・ ・Beta-blockers and procainamide can make heart block worse・ THE END