Antiarrhythmic Drugs DR ATIF ALQUBBANY A S S I S T A N T P R O F E S S O R O F M E D I C I N E / C A R D I O L O G Y C O N S U L T A N T C A R D I O L O G Y & I N T E R V E N T I O N A L E P A C H D / E P & C O M P L E X A B L A T I O N K S A U - HS K I N G F A I S A L C A R D I A C C E N T E R K I N G A B D U L A Z I Z M E D I C A L C I T Y
How not to harm a patient with Antiarrhythmic Medications
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Outline Antiarrhythmic Medications Basics of myocyte cell physiology - Ion channels Types and mechanisms of action of AADs Clinical Scenarios To illustrate some major considerations when prescribing antiarrhythmic medications
Antiarrhythmic Medication Purpose: To alter the electrophysiological characteristics of the myocytes To reduce automaticity in spontaneous arrhythmias To decrease the tachycardia zone in re-entrant arrhythmias Mechanism: Interaction with the cardiac ion channels Alteration in conduction velocity and refractory period.
Antiarrhythmic Medication
2 fundamentally different ways of action Class I drugs slow down conduction Class III drugs prolong refractoriness
Class Ia Antiarrhythmic Medication Slow Phase 0 upstroke Class Ib Minimal Phase 0 effect Class Ic Marked slowing Phase 0
Class I Na channel blockers Inhibit depolarization & slow conduction velocity Convert areas of slow conduction or unidirectional block into bidirectional block inhibit reentrant arrhythmias
Antiarrhythmic Medication Class III Prolong AP duration Increase refractoriness Prolong QT Minimal effect on conduction velocity
2 fundamentally different ways of action Class I drugs slows down conduction: fewer active Na+ channels Class III drugs prolong refractoriness: blocking K+ channel outward activity. Increase action potential duration.
Refractory period Propagating wavefront
Proarrhythmia risk of TdP Early studies CAST and SWORD. More studies in the field that demonstrates safety with proper patient selection. Correlates with QT prolongation (mainly class III) and early afterdepolarization. Dose independent like class 1A Dose dependent like Sotalol
Proarrhythmia due to QT prolongation and TdP Risk factors include: Bradycardia baseline QT prolongation female gender Hypokalemia Hypomagnesemia
Antiarrhythmic Medication Problems with the Vaughan Williams Classification Classification scheme over simplified. Most AADs have multiple actions (e.g amiodarone or its metabolites blocks sodium, potassium, calcium, and betaadrenergic receptors). Actions differ in different cardiac tissues. Sicilian Gambit Refined classification system 1991 Based on effects of AADs on channels and receptors
Drug Na Ca K r K s Fast Med Slow Channels Receptors Pumps Alph a Beta M 2 Na-K ATPase Clinical Effects LV Functio n Quinidine H M L Procainamide H M Disopyramide H M L Lidocaine L Mexiletine L Flecainide H H L Propafenone H Propranolol L H Amiodarone L M H M M M Sotalol H H Ibutilide* L Dofetilide H Verapamil L H Diltiazem M Digoxin H Sinus Rate
Class IA drugs quinidine, procainamide, and disopyramide Depress phase 0 (Na-dependent) depolarization, thereby slowing conduction. They also have moderate potassium channel blocking activity (which tends to slow the rate of repolarization and prolong APD). Anticholinergic activity. They tend to depress myocardial contractility.
Procainamide Used in atrial and ventricular arrhythmias. Hemodynamics: hypotension during IV administration due to decrease sympathetic efferent activity. Watch BP and QRS duration during administration.
Class IB drugs lidocaine and mexiletine Used in ventricular arrhythmias. Side Effects: GI and CNS effects most prominent which are dose and concentration related. Tremor usually the first sign of CNS toxicity. Proarrhythmia: Incidence of serious proarrhythmia due to mexiletine is very low.
Class IC drugs flecainide and propafenone Block both the open and inactivated Na channels and slow conduction. They also have K channel blocking activity and can increase the APD in ventricular myocytes.
Flecainide Mainly in Atrial arrhythmias Side effects: CNS including blurred vision, headache, ataxia. Use dependency (greater efficacy at faster heart rate) Proarrhythmia: CAST Trial. In treating Atrial arrhythmias, flecainide may 1:1 AV conduction when AV nodal block is not accomplished. Ventricular proarrhythmia with structurally normal hearts is exceedingly rare.
Propafenone Mainly in Atrial arrhythmias Side effects: Nausea, dizziness, and metallic taste especially with dairy products are the most common. Approximately 10-25% of patients discontinue propafenone treatment because of side effects. Use dependency (greater efficacy at faster heart rate) Proarrhythmia: 1:1 AV conduction when AV nodal block is not accomplished. Ventricular proarrhythmia with structurally normal hearts is exceedingly rare.
Class III amiodarone, ibutilide, and sotalol Block the K channels, thereby prolonging repolarization, the APD, and the refractory period. 28 These changes are manifested on the surface ECG by prolongation of the QT interval, providing the substrate for torsade de pointes. Amiodarone is an exception, with very little proarrhythmic activity.
These drugs also have other antiarrhythmic effects. 29 Sotalol has beta blocking activity Amiodarone can block Na channels in depolarized tissues and may block Ca channels, K channels, and adrenergic receptors Ibutilide, enhances the slow, delayed inward Na current as well as blocking K channels during repolarization.
Some of the class III agents, such as sotalol and ibutilide, exhibit reverse use-dependent effects on repolarization. 30 Thus, the QT interval is longer at slower heart rates and decreases as the heart rate increases. Proarrhythmia typically dose dependent (especially in the case of Sotalol).
Adenosine Used for AV nodal blockade for therapeutic or diagnostic uses. Short duration of action (5 seconds) Side effects: Chest pain and dyspnea during administration are very common but short lived. Proarrhythmia: AF up to 12% (which can be sustained) due to decrease in atrial refractoriness. This may be a problem in patients with bypass tract mediated narrow complex SVT converted to pre-excited AF.
In most cases, AAD should be started at the lowest possible dose and titrated upwards. Therapeutic efficacy monitored with reference to PR interval (flecainide, propafenone, sotalol and amiodarone) QRS (flecainide, propafenone) QT intervals (sotalol and amiodarone) at rest (sotalol) or with exercise (Class IC agents)
Use dependence and reverse use dependence Class I drugs, display use dependence: at faster HR, the Na-channel block increases. Result of binding kinetics, which reflects that at faster HR, there is less time for the drug to unbind from the Na channel before the next action potential begins; thus, at faster HR, the drugs have a more profound effect on conduction velocity than they have at slower HR.
reverse use dependence For Class III drugs, however, the strength of blockade decreases as the HR increases It means that at slower heart rates, the prolongation of the action potential is most pronounced; at faster HR, the effect diminishes. Drug s binding characteristics. Drugs that preferentially bind to closed K channels, for instance, display significant reverse use dependence because phase 4 of the action potential is longer when the HR is slow.
Reverse use dependence has two potential undesirable effects: It causes some Class III drugs to lose potency with rapid heart rates, just when their potency is needed most. Potentiates the tendency of these drugs to cause the pause-dependent Eads that produce torsades de pointes.
Amiodarone is a unique Class III agent as it binds preferentially to open K channels and therefore displays much less reverse use dependence. Consequently, amiodarone does not lose its effect when heart rate increases. The low magnitude of reverse use dependence seen with amiodarone may explain not only its remarkable efficacy against tachyarrhythmias but also its low incidence of producing torsades de pointes.
Clinical Scenario 1 30 year old male Presents for outpatient evaluation following syncopal episode No documented arrhythmias Normal LV function on echo FHx sudden cardiac death Father died suddenly age 50 ECG:
Brugada Syndrome - Type I ECG pattern
Brugada Syndrome Antiarrhythmic medications considerations Beta blockers and Amiodarone do not prevent recurrences of ventricular arrhythmias Class I AADs increase risk of ventricular arrhythmias Most Class I AADs and IV Amiodarone worsen electrical storms Isoproterenol has a beneficial effect in settling electrical storms
Clinical Scenario 2 60 year old female Presents to emergency department with symptomatic tachycardia No history of coronary disease ECG:
Heart rate = 150bpm Atrial Flutter with 2:1 AV conduction
Arrhythmia misdiagnosed as atrial fibrillation with rapid ventricular response. Patient received IV Flecainide
Heart rate = 250bpm Atrial Flutter with 1:1 AV conduction
Atrial Flutter with 2:1 AV conduction Flutter re-entrant circuit s conduction velocity is shorter than AV node refractory period. Atrial Flutter with 1:1 AV conduction AVN refractory period shorter than flutter circuit This tachycardia poorly tolerated hemodynamically Occurs when: AVN conduction increases in presence of high adrenergic tone Or when the Atrial Flutter circuit is slow
Atrial Flutter Flecainide Class Ic Sodium channel blocker Slows conduction velocity through the atrial tissue Slows Atrial Flutter circuit
Atrial Flutter Therapeutic implications RATE CONTROL with Beta blocker or Calcium Channel blocker should be achieved prior to giving a Class 1 medication.
Clinical Scenario 3 31 year old female Presents to emergency with 2 hour history of palpitations Hx recurrent palpitations for 15 years No history of coronary disease or LV dysfunction ECG:
Heart rate = 250bpm Supraventricular tachycardia (DDx AVNRT / AVRT / AT)
31 year old female Adenosine 6mg IV bolus and 10ml saline flush no effect Adenosine 12mg IV bolus ECG:
Pre-excited atrial fibrillation
31 year old female Patient remained hemodynamically stable and cardioverted with IV Procainamide
Wolff Parkinson White Syndrome
Therapeutic Considerations Adenosine causes SVT to convert to Atrial Fibrillation in ~12% patients Pre-excited AF could potentially degenerate into VF Small risk of cardiac arrest Risk increased if Accessory Pathway Effective Refractory Period is <240ms
Summary Appropriate use of antiarrhythmic medication and avoidance of harm involves an understanding of: The interaction of the drugs with cardiac ion channels The electrophysiological mechanism of the arrhythmia Always consider EPS + ablation
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Use dependence and reverse use dependence Drugs that interact with their receptors more at faster heart rates are said to display use dependence. Sodium channel blockers display such characteristics depressing the rate of rise of Vmax more during rapid hear rates. It is postulated that these drugs interact more with their receptors when they are in the open or inactive state rather than in the resting state. Potassium channel blockers, on the other hand, interact more with the receptor in the resting state. This is termed reverse use dependence. An example of the latter is the greater risk of torsade de pointe following a pause or at slow heart rates, the management of torsade de pointe includes pacing or the administration of isoproterenol to accelerate the heart rate and reduce the potential for torsade to recur. Antiarrhythmic agents that exhibit reverse use-dependence are more efficacious at preventing a tachyarrhythmia than converting someone into normal sinus rhythm
During faster heart rates, less time exists for the drug to dissociate from the receptor, resulting in an increased number of blocked channels and enhanced blockade. These pharmacologic effects may cause a progressive decrease in impulse conduction velocity and a widening of the QRS complex. This property is known as "use-dependence" and is seen most frequently with the class IC agents, less frequently with the class IA drugs, and rarely with the class IB agents