Antiarrhythmic Medications



Antiarrhythmic Medications


Julia Cadrin-Tourigny

Katia Dyrda

Paul Khairy

Laurent Macle

StanleY Nattel

Mario Talajic

Peter G. Guerra

Bernard Thibault

Marc Dubuc

Lena Rivard

Blandine Mondesert

Denis Roy



The ultimate purpose of antiarrhythmic drugs is to restore a normal rhythm and/or prevent the onset of recurrent, rapid, or more serious arrhythmias. All antiarrhythmic drugs alter cellular membrane conductance, either directly or indirectly. Their effectiveness is limited and side-effects, both cardiac (e.g., proarrhythmia, hypotension, conduction tissue impairment, worsened heart failure) and noncardiac (e.g., neurologic, gastrointestinal), are common. Antiarrhythmic drugs should, therefore, be carefully selected, titrated, and monitored. As patients respond variably to individual antiarrhythmic drugs, management strategies are typically fraught with trial and error. Underlying structural heart disease involving the conduction tissue or myocardium must be considered when selecting a drug regimen, as well as the hemodynamic stability of the patient, type of arrhythmia, intended duration of therapy, and associated comorbid conditions.

While the intent of drug therapy is to terminate or prevent arrhythmias, some agents can paradoxically increase the frequency of a preexisting arrhythmia, sustain a previously nonsustained arrhythmia, or cause new arrhythmias, a phenomenon called “proarrhythmia.”


ANTIARRHYTHMIC DRUG CLASSIFICATION

Most of the clinically used antiarrhythmic drugs can be classified according to the predominant blocking action they exert on specific ion channels (e.g., sodium,
potassium, or calcium) or on β-receptors and the resulting effects on the action potential of the myocyte. The most commonly used drug classification, proposed by Singh and Vaughan Williams in 1970, is based on these electrophysiologic properties. Although providing a simple and useful conceptual framework, the Vaughn Williams classification suffers many limitations. As it is based on in vitro studies, it does not account for the complex variability of action of antiarrhythmic drugs depending on various factors such as tissue type, heart rate, membrane potential, acute or chronic myocardial damage, and patient age. It also does not adequately reflect the complex action of antiarrhythmic drugs, which extend beyond the predominant class to which they are assigned, as well as the existence of active metabolites. In addition, some drugs may not be categorized within this classification system, such as adenosine and digoxin.

Table 15-1 summarizes the Vaughan Williams classification and gives a description of specific drugs within each class


CLASS I DRUGS

Class I drugs impede sodium (Na+) entry through the cardiomyocyte-membrane sodium channels during the upstroke phase of cellular activation, resulting in a decrease in the rate of rise of phase 0 of the action potential. They are further classified into three subclasses, namely A, B, and C, based on their rate of binding and dissociation from the sodium channel receptor. They show different degree of modification of the upstroke velocity of the action potential, conduction velocity and effects on repolarization. The action potential duration (APD) is increased by class IA drugs, decreased by class IB drugs, and mostly unaffected by class IC drugs.

The subdivision of Class I also reflects the type of cells primarily targeted. Class IA and IC affect both atria and ventricles, with intraventricular conduction being particularly slowed by IC drugs, while class IB drugs mostly exert their action at the ventricular level.

Antiarrhythmic agents in this class typically exert greater inhibitory effects on the upstroke of the action potential at more rapid rates, a characteristic called use-dependence. During faster heart rates, less time is available for the drug to dissociate from the receptor, which results in an increased number of blocked channels and enhanced blockade. Such an effect may lead to a progressive decrease in impulse conduction velocity and widening of the QRS. This is rare with class IB agents since their effect is selective for depolarized tissue, but is more common with class IA and frequent with class IC agents.


CLASS IA DRUGS—QUINIDINE, PROCAINAMIDE, AND DISOPYRAMIDE

Class IA agents moderately depress the phase 0 upstroke in nonnodal tissue, which is sometimes called “fast-channel” or “fast-response” tissue because of the rapidity of phase-0 upstroke and conduction caused by the large phase-0 sodium current. Reduced phase-0 sodium current causes a slowing of depolarization and conduction, and a corresponding prolongation of conduction time in fast-response cells of atrial muscle, ventricular muscle, His-Purkinje cells, and accessory pathways. Their kinetics of onset and offset is of intermediate rapidity (1 to 5 s). These effects are reflected by the surface electrocardiogram (ECG) as an increase in QRS duration.

Class IA agents also have moderate potassium (K+) channel blocking activity, mostly on the rapid component of the late rectifying current (IKr), which tends to slow the rate of repolarization and prolong APD. This effect is reflected by a prolongation of









the QT interval. Unlike to sodium channel blocking activity, the effect on potassium channel is enhanced at slow heart rates (reverse use-dependence) producing maximal APD and QT prolongation in the presence of bradycardia. In predisposed patients, excessive bradycardia-related repolarization-delaying actions of class IA drugs can lead to excess APD and QT prolongation, along with torsade de pointes arrhythmias.








TABLE 15-1 The Vaughan Williams Classification and Description of Specific Drugs




























































































































































































Category

Effect on Action Potential/Drug

Indication, Doses

Special Precautions and Toxicities Cardiac/Non Cardiac

Elimination


I

Sodium channel blockers


A

image


  • ↓ phase 0→ ↓conduction velocity→ ↑ QRS duration (high dose)



  • ↑ APD→ ↑QT (effect on K+ channels, not dose related)



  • Intermediate binding and dissociation

Quinidine

Indications:




  • Maintenance of SR in AF (less effective than IC drugs)



  • Brugada syndrome



  • Idiopathic VT


Dose:


IV: 6-10 mg/kg at 0.3-0.5 mg/kg/min


PO:200-600 mg PO q8h


  • ↓atrial conduction→ risk of 1:1 flutter: use with AV node blocker



  • Proarrhythmia:



  • TdP: Stop if QT >500 or ↑>25% from baseline



  • Risk of reentry



  • GI side effects

Liver

Procainamide

Indications:




  • Chemical cardioversion of AF



  • Acute termination of pre-excited AF



  • Treatment of stable VT


Dose:


IV: 15-18 mg/kg IV (max 1 g) bolus then 2-6 mg/min


PO: 250-1,000 mg q4-6h


  • Hypotension



  • Negatively inotropic



  • Proarrhythmia: same as quinidine



  • Lupus like syndrome

Kidney

Disopyramide

Indications:




  • Mainly used in HOCM



  • Atrial and ventricular arrhythmias


Dose:


IV: 1-2 mg/kg over >15 min, then 1 mg/kg/min then 1 mg/kg/h


PO: 100-300 mg q6-8h


  • Worsening of heart failure (negatively inotropic)



  • Proarrhythmia: same as quinidine



  • Vagolytic effects (sinus tachycardia, acceleration of AF/AF1, urinary retention, glaucoma)



  • Hypoglycemia

Kidney


B

image


  • ↓ APD



  • Rapid binding and dissociation



  • More effective in ischemic/diseased tissue



  • Ineffective in atrial arrhythmias

Lidocaine

Indications:




  • Ventricular arrhythmia, especially in ischemic tissue



  • Arrhythmia associated with digoxin toxicity



  • Rarely terminates monomorphic VT


Dose:


IV: Bolus: 1-2 mg/kg, infusion: 1-4 mg/min


IV use only due to hepatic first pass


  • Dose related CNS side effects (dizziness, confusion, convulsions, paresthesia)



  • Sinus/his-purkinje block

Liver

Mexiletine

Indications:




  • Ventricular arrhythmia



  • Long-QT type 3



  • Pharmacologic effect similar to lidocaine



  • Orally active


Dose:


IV: Bolus; 250 mg in 5-10 min then 250 mg over 1 h, then 0.5-1.0 mg/min


PO: loading: 400-600 mg, then 150-300 mg q8-12h


  • Hypotension and bradycardia



  • CNS and GI side effects

Liver

Phenytoin

Indications:




  • Rarely used as antiarrhythmic



  • Can be used in arrhythmia associated with digoxin toxicity


Dose:


IV: 100 mg q5 min (maximum 1,000 mg)


PO: 1,000 mg then 100-400 mg q12-24h


  • Hypotension,



  • CNS side effects (vertigo, dysarthria, lethargy), lupus, macrocytic anemia

Liver

Tocainide

(discontinued)



C

image


  • ↓ phase 0→ ↓conduction velocity QRS (stop/decrease if ↑>25%)



  • Slow binding and dissociation



  • Use-dependence (maximal effect at rapid heart rates)

Flecainide

Indications:




  • Cardioversion and maintenance of SR inAF, AF1,



  • Arrhythmias associated with WPW



  • Other PSVT



  • Sustained VT,



  • Catecholaminergic polymorphic VT


Dose:


IV: 1-2 mg/kg over >10 min then 0.15-0.25 mg/kg/h


PO: 100-400 mg q12h


  • Proarrhythmia: significant risk; contraindicated in the presence of structural heart disease or CAD



  • Bradycardia/block; caution in patients with sinus node, AV node or bundle branch abnormalities



  • Risk of 1:1 flutter: use with AV node blocker



  • Negatively inotropic



  • Raises pacing threshold

Liver

Propafenone

Indications:




  • Similar indications and effect as Flecainide (+Mild β-blocking properties)


Dose:


IV: 1-2 mg/kg bolus (not available in US/UK)


PO: 450-900 mg for acute conversion (or pill in the pocket)


Maintenance: 150-300 mg po q8-12h


  • Same as flecainide

Liver

Moricizine

(Discontinued)



II

β-blockers


See specific table




III

Potassium Channels Blockers

image


  • K+ channel blockade



  • ↑ APD→ ↑QT duration

Amiodarone


(Wide spectrum of actions.


Chiefly class III, but combines actions from all classes)

Indications:




  • In the US, license only for recurrent VF or hemodynamically unstable VT.



  • Commonly used for AF and AF1.


Dose:


IV: 150 mg over 10 min (may be repeated over 10-30 min) then 1 mg/min for 8 h then 0.5 mg/min for 16 h


PO: 800-1200 mg/day until a total of 10 g, 100-400 mg q24h


  • Sinus bradycardia



  • QT prolongation but very low risk of TdP (<1%)



  • Multiple extra-cardiac side effects: pulmonary toxicity, hepatotoxicity, skin discoloration, photosensitivity, hypothyroidism, hyperthyroidism

Liver

Sotalol


(Class III action combined with β-blocking (class II) action.


Reverse use-dependence)

Indications:




  • Wide range of atrial and ventricular arrhythmias


Dose:


IV: 10 mg over 2 min


PO: 40-160 mg q8-12h


  • High risk of TdP (especially with risk factors, see text for details)



  • Bronchospasm

Kidney

Dofetilide

Indications:




  • Cardioversion of AF/Flutter and maintenance of sinus rhythm



  • Ventricular arrhythmias (not licensed)


Dose:


IV: 2-5 µg/kg


PO: 0.125-0.5 mg q12h


  • TdP 3% (80% in first 3 days after initiation) hospitalization with continuous monitoring for 3 days required

Kidney

Dronedarone


(Properties similar to amiodarone)

Indications:




  • AF and AFl


Dose:


PO: 400 mg q12h


  • Increases mortality in patients with severe LV dysfunction or heart failure, and patients with permanent AF



  • Increases digoxin concentration

Kidney

Azimilide

(Not available commercially)




Ibutilide

Indications:




  • Acute termination of AF/AFl



  • Preexcited AF


Dose:


IV: 1 mg over 10 min (if less, then 60 kg, 0.1 mg/kg)


(IV use only due to hepatic first pass)


  • QT prolongation; TdP in 4%

Liver

Vernakalant

Indications:




  • Acute conversion of AF


Dose:


IV: 3 mg/kg en 10 min, an additional 2 mg/kg may be administered if ineffective after 15 min.


(Not FDA approved, under regulatory review. Approved in Europe)


  • Low risk of ventricular arrhythmia



  • Dysgeusia, sneezing, paresthesia, nausea

Liver

Bretylium

Indications:




  • Effective for VT/VF termination. Synergistic effect with lidocaine


Dose:


IV: 5-10 mg/kg at 1-2 mg/kg/min then 0.5-2 mg/min


PO: 4 mg/kg/day


(Rarely used. Not available in the US)


  • Orthostatic hypotension (60%)



  • Hypertension,



  • Tachycardia,



  • Nausea, vomiting

Liver


IV

Calcium channels blockers

image


  • L-type Ca+ channels blockade



  • ↓ phase 4 automaticity, ↑ refractoriness and conduction time in SA and AV nodes

Verapamil

Indications:




  • Termination AVNRT



  • Rate control of AF and AFl



  • Fascicular VT


Dose:


IV: 5-10 mg over 30-60 s then 0.005 mg/kg/min


PO: 120-360 mg q24h


  • Negatively inotropic: avoid if LV dysfunction



  • Hypotension



  • Bradycardia/AV block, especially when combined with β-blockers

Liver

Diltiazem

Indications:




  • Same as verapamil


Dose:


IV: Bolus 0.25 mg/kg max 20 mg, infusion: 10-15 mg/h


PO: 180-480 mg/24 h


  • Same as verapamil

Liver


Others (not included in Vaughn Williams Classification)

Adenosine


  • AV node blocker


Indications:




  • Termination of PSVT



  • Termination of RVOT VT


Dose:


IV: 6 mg over 2 s followed by saline flush; repeat doses of 12 and 18 mg at 1 min intervals if unsuccessful


  • AF (1-15%)



  • Transient sensation of flushing, dyspnea, chest tightness



  • Bronchospasm in asthmatic patients



  • Efficacy reduced if use of methylxanthines (theophylline/caffeine)

Degraded by endothelial cells and erythrocytes

Digoxin


  • Na+/K+ ATPase pump inhibition



  • Parasympathetic agonist



  • Sympathetic inhibitor


Indications:




  • Rate control of AF/AFl


Dose:


IV: 0.5 mg followed by 0.25 mg q6h ×2


PO: 0.0625-0.25 mg q24h


  • Bradycardia, sinus arrest, AV block, atrial or junctional ectopic tachycardia



  • Visual symptoms, nausea, vomiting, confusion, hyperkalemia

Kidney


AF, atrial fibrillation; AFl, atrial flutter; APD, action potential duration; AV, atrio-ventricular; AVNRT, atrioventricular nodal re-entrant tachycardia; CAD, coronary artery disease; CNS, central nervous system; GI gastrointestinal, HOCM, Hypertrophic obstructive hypertrophic cardiomyopathy; LV, left ventricle; PSVT, paroxysmal supra-ventricular tachycardia; RVOT-VT, Right ventricular outflow track tachycardia; SA, sinoatrial; SR, sinus rhythm; TdP, torsade de pointes; VF, ventricular fibrillation; VT ventricular tachycardia; WPW, Wolf-Parkinson-White.


While IA agents have little effect on the slow-response cells of the normal SA and AV nodes, interactions with the autonomous nervous system may exert indirect changes. In addition, the rate of SA node discharge may increase and AV-nodal conduction may be enhanced by the anticholinergic effect of IA drugs.

The IA agents find their use in the treatment of reentry tachycardias, both at the level of the atria (atrial fibrillation [AF] and flutter) and of the ventricle (ventricular tachycardia), as well as with accessory pathways (Wolff-Parkinson-White [WPW] syndrome).

Intravenous procainamide continues to be used in centers in North America for conversion of AF with an efficacy that is probably less than that with Class IC agents. Along with ibutilide, it is one of the two drugs of choice in the acute treatment of preexcited AF. It can also be administered for acute termination of reentrant ventricular tachyarrhythmias in the setting of preserved left ventricular function with success rates reaching 80%.

Its long-term oral use is limited by its restricted absorption, short half-life, and side effects including gastrointestinal symptoms, agranulocytosis, and lupus-like syndromes. Of note is that N-acetyl-procainamide, a metabolite of procainamide, acts as a class III agent, with little effect on inhibiting sodium current but preserved potassium current blocking properties.

The use of quinidine has been largely abandoned because of a high incidence of gastrointestinal side effects and the proarrhythmic risk of torsade de pointes ventricular arrhythmia. Nevertheless, quinidine can be useful in patients with Brugada syndrome to control arrhythmic storms, to prevent recurrent ventricular arrhythmias, or for the treatment of supraventricular tachyarrhythmia.

Emerging evidence may support a role in minimizing implanted cardioverter-defibrillator (ICD) shocks in patients with the short-QT syndrome and idiopathic ventricular fibrillation associated with the early repolarization syndrome.

Disopyramide is an alternate agent that can be administered both parenterally and orally to treat supraventricular or ventricular tachyarrhythmias. In practice, it is used mainly in younger patients for the management of AF (in combination with an AVnode blocking agent in order to avoid the risk of 1:1 conduction of atrial flutter), for recurrent supraventricular arrhythmias, or in selected patients with PVCs. Due to its negative inotropic properties, it is also a second-line agent in patients with hypertrophic obstructive cardiomyopathy. Dose adjustments are required if renal function is impaired, as the drug is partially excreted by the kidney. It is contraindicated in patients with QT prolongation as it can also cause torsade de pointes. Its use should be limited to patients with preserved left ventricular function because of its negative inotropic effects and the risk of precipitating heart failure. The intravenous loading dose should not exceed 0.5 mg/kg/min as severe hypotension may ensue. Its peripheral anticholinergic actions are responsible for the common side effects such as blurry vision, closed-angle glaucoma, dry mouth, constipation, and urinary retention and, more importantly, for the increased ventricular response to AF or flutter.


CLASS IB DRUGS—LIDOCAINE, MEXILETINE, AND PHENYTOIN

When administered in therapeutic doses, class IB agents cause a negligible decrease in the slope of phase 0 of normal fast-response action potentials. The surface ECG
remains unaffected except possibly for a slight shortening of the QT interval. However, in the presence of cell damage, hyperkalemia, and acidosis, the effect is amplified. The refractory period and, to a lesser extent, the duration of the action potential, can shorten. Purkinje fibers and ventricular myocytes are particularly sensitive to these effects, which are far less notable in atrial tissue. Class IB agents do not influence slow-response cells of normal SA and AV nodes and have a trivial impact on autonomic tone. Fewer proarrhythmic events have been associated with IB agents. The kinetics of onset and offset of these agents is rapid (generally <500 ms).

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Oct 27, 2018 | Posted by in CARDIOLOGY | Comments Off on Antiarrhythmic Medications

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