Cairo University

• Exacerbate the cardiac rhythm disturbance being treated, or

• Generate entirely new clinical arrhythmia syndromes,

Roden and Anderson 2006

The concept that antiarrhythmic drugs can:

Abnormal cardiac rhythms due to digitalis or quinidine have been recognized for decades.

is not new

The past 20 years have seen the

recognition that proarrhythmia is more common

than previously appreciated in certain

populations.

It can in fact lead to substantially increased

mortality during long-term antiarrhythmic therapy.

• A 51-year old man with a history of paroxysmal AF

had been treated with Quinidine and Digoxin for

over five years.

• During a routine nuclear stress test performed before

commencing an exercise programme, a perfusion

defect was noted.

• This raised concern about possible occult coronary

disease and Metoprolol 50mg bid was added to his

regimen pending further investigation.

• Over the next few days, the man experienced Recurrent Dizzy Spells which became increasingly severe.

• He saw his local doctor who noted nothing untoward on examination or ECG.

• Two days later, while driving home from the shopping mall with his three children in the car he had a severe presyncopal spell during which he almost lost control of the car.

• During the remainder of the journey, he had two

more spells of severe lightheadedness.

• His wife then drove him to the local hospital

emergency room and ECG rhythm strips were

recorded there and during his subsequent

admission.

ECG monitor recording showing conversion of atrial fibrillation (first two QRS complexes) to sinus rhythm to sinus rhythm with

a prolonged sinus pause.

Another example, this time with more prolonged sinus slowing

The lessons here are that:

• One must use Combination Therapy cautiously,

• One must consider the possible Additive Effect of Drugs started for other indications and that

• Follow up monitoring to exclude excessive slowing is important.

• One must always have concern about the use of class I antiarrhythmic agents in patients with suspected coronary disease.

A middle-aged farmer with recurrent Atrial

Flutter had been tried on a number of different

antiarrhythmic agents over a period of some years.

None had prevented the recurrences for

which he had required repeated hospital admission

and cardioversion.

Having tried several agents, he was started on Flecainide but his problems became much worse.

His palpitations (which had been previously troublesome but bearable) became very severe, and any exertion led to severe dyspnoea and presyncope with a need to stop and rest for prolonged periods.

The rhythm strips from a routine Holter monitor gave the answer to his problem

Holter monitor recording showing atrial flutter with

varying AV block and controlled ventricular rate

Later during the monitored period, recording showing acceleration of the ventricular rate and broadening of the QRS complexes (mimicking ventricular tachycardia) produced by

flecainide.

This is a proarrhythmic effect of the

Flecainide which acts to slow the flutter rate within

the atria.

This then leads to reduced AV block which

causes paradoxical acceleration of the ventricular

rate and the flecainide also causes broadening of

the QRS complexes.

Class I antiarrhythmic agents should not be

prescribed for A. flutter (or A. fibrillation with

intermittent flutter) without a concomitant AV nodal

blocking agent.

This patient underwent curative ablation for

his Atrial Flutter which obviated the need for

antiarrhythmic drug therapy.

An elderly woman with mitral valve disease and

troublesome AF was prescribed Sotalol and

subsequently became very unwell with episodic

nausea and lightheadedness culminating in a syncopal

spell.

The ECG and rhythm strips gave the answer to

her problem.

12-lead ECG showing sinus bradycardia with

prolongation of the QT interval due to sotalol.

ECG monitor strip recorded later showing more marked sinus bradycardia with recurrent non-sustained

ventricular tachycardia

She had developed marked sinus bradycardia

and prolongation of the QT interval, the latter

resulting in recurrent nonsustained ventricular

tachycardia

This lady had baseline renal impairment and sotalol is excreted by the kidneys so this undoubtedly contributed to increased plasma drug levels and secondary effects.

Knowledge and understanding of the pharmacokinetics of the different antiarrhythmic drugs is therefore very important for the prescribing physician. The sotalol was discontinued and she was started on verapamil.

1. Adverse effects occur in 40 to 60 percent of pts.

2. Since the half-life of Adenosine is brief (less than 5 to 10 seconds), its intended and unintended effects are short-lived.

3. Caffeine or Theophylline should be at the bedside if an untoward effect is considered likely. These drugs competitively antagonize the actions of adenosine.

The primary mechanism of action of Adenosine is to decrease conduction through the AV node.

It can therefore produce a transient first, second, or even higher degree of AV block.

While Bradyarrhythmias and AV Nodal Prolongation are common, Transient Asystole is rare. diMarco, et al., 1985

AV block is also common when Adenosine infusions are given during cardiac stress testing.

The conduction block is of short duration and does not require discontinuation.

However, use of adenosine for nuclear stress testing in patients with evidence of underlying conduction system disease may result in serious complications such as sustained second-degree AV block requiring permanent pacemaker implantation. Makrvus et al., 2008

A few patients develop AF after Adenosine injection.

Adenosine-induced shortening of the atrial action potential and the atrial refractory period (due to activation of outward potassium current) and the induction of frequent ectopic complexes are predisposing factors for the development of AF.

Kabell et al., 1996

Ventricular arrhythmias can occur with use of Adenosine.

Torsade de pointes, has been observed in patients who are likely to have bradycardia-dependent arrhythmias.

Thus, adenosine should be used with caution in patients with a prolonged QTc interval. Wesley, 1992

The use of Adenosine in patients with a recent MI requires particular caution.

The augmented sympathetic tone from adenosine, in addition to the hypercatecholamine state associated with the infarction, may provoke AF, which can precipitate polymorphic ventricular tachycardia.

Kaplan, 2000

 Use of Adenosine in patients with

Wolff-Parkinson-White syndrome may

precipitate VF when administered during pre-

excited AF particularly in patients with

accessory pathways with short refractory

periods, that is <227 msec.Gupta et al., 2002

• Multiple effects on myocardial depolarization and repolarization.

• Its primary effect is to block the potassium channels, but it can also block:

sodium and calcium channels and

The beta and alpha adrenergic receptors. Greene, 1983

Sinus Bradycardia :

Amiodarone can directly cause both sinus

bradycardia and AV Nodal Block, due primarily to

its calcium channel blocking activity (5% overall

incidence of bradycardic events). Goldschlager et al., 2000

Bradycardia requiring a permanent

pacemaker with Amiodarone therapy appears to

be a particular concern in elderly patients with AF

who have had a myocardial infarction and may also

be of greater concern in women than in men. Essebag, 2003 & 2007

Of greater potential concern is amiodarone-induced prolongation of repolarization and the QT interval due to blockade of the potassium channels.

Ventricular arrhythmias may arise in this setting due to early afterdepolarization-dependent triggered activity.

Ventricular Arrhythmias

However, the incidence of Proarrhythmia is very low with Amiodarone, (torsades de pointes in <1%).

No cases of torsades de pointes in the 738 patients treated with amiodarone for at least one year in meta analysis of low dose therapy.

Hobnloser, 1994

Vornerian et al., 1997

Amiodarone has much less of ventricular

proarrhythmic effect than other class III drugs,

such as Sotalol, Ibutilide, and Dofetilide,

particularly when given in lower doses (.Greene, et al., 1983

Vornerian et al., 1997

Podrid, 1995

However, some risk of torsades de pointes

with other factors that can prolong the QT interval:

Other antiarrhythmic drugs,

Hypokalemia, and

Hypomagnesemia (should be avoided or

corrected in patients receiving amiodarone).

Several factors contribute to the rarity of TdP

with Amiodarone:

1. Less heterogeneity of ventricular repolarization

(less QT dispersion).

2. Concurrent blockade of the L-type calcium

channels; and

3. Lack of reverse use dependence

The electrophysiologic mechanisms

responsible for the Low Proarrhythmic Activity of

Amiodarone:

1) Homogeneous lengthening of the AP duration with

less heterogeneity of V. repolarization (less QT

dispersion) compared to other class III

antiarrhythmic drugs.

Hobnloser, 1995

VanOpstal et al., 2001

Droin, 1998

2) Blockade of L-type calcium channels:

(Torsades de Pointes is dependent upon early

after depolarizations that are induced in part by

a calcium current through these channels (.

Low Proarrhythmic activity:

3) Amiodarone tends not to display the Reverse Use

Dependence seen with other class III drugs .

This phenomenon refers to an inverse correlation

between the heart rate and the QT interval; as a

result, the QT interval decreases as the heart rate

increases and is prolonged as the heart rate slows.

Low Proarrhythmic activity:

Sager et al., 1993

Important interactions with ICDs:

• May slow the ventricular tachycardia rate, possibly

precluding its recognition by the device,

• Its major metabolite Desethylamiodarone increases the defibrillation threshold in a dose-

dependent fashion; this effect (with monophasic

and biphasic waveforms). Goldschlager et al., 2001Zhou et al., 1998Pelosi et al., 2000Nielsen et al., 2001

Significant widening of the QRS interval occurs in a

minority of patients treated with Disopyramide

(most likely at high circulating drug levels).

Therapy should be discontinued until the plasma

disopyramide concentration is determined.

Electrocardiographic and proarrhythmic effects

Like other class IA antiarrhythmic drugs,

Disopyramide can prolong the QT interval, possibly

leading to:

Increased ventricular ectopy,

Torsade de pointes or,

Syncope. Casedevant, 1975

Concurrent use of other class I or class III agents

(such as amiodarone or sotalol) can produce an additive

increase in both the QRS and QT intervals.

A similar effect can be induced by the

administration of Erythromycin or Clarithromycin,

drugs that inhibit the metabolism of disopyramide by

inhibiting CYP3A4

The proarrhythmic potential for disopyramide (6 percent) is less than that for the other class IA drugs, quinidine (15 percent) and procainamide (9 percent).

The likelihood of proarrhythmia is increased by:

• hypokalemia,

• hypomagnesemia, and

• bradyarrhythmias.

Podrid, et al., 1987

Wald, 1981Schweitzer, 1982

Intravenous Magnesium Sulfate (an initial

2 gm bolus, with repeated doses as needed) has

been useful in patients with QT prolongation and

torsade de pointes.

Magnesium may act by suppressing afterdepolarizations.

Tzivoni et al., 1988

Like other class IA antiarrhythmic drugs,

Disopyramide can significantly increase the ventricular

rate in patients with uncontrolled AF or A. flutter through:

Increased ventricular response in AF:

Slowing the fibrillation or flutter rate, and

The direct anticholinergic effect of disopyramide

enhancing AV nodal conduction.

Little is known about proarrhythmia due to lidocaine.

Specificity of action and relatively short half-life

probably provide a great degree of safety.

The potential for lidocaine to exacerbate or provoke

arrhythmias has not been systematically evaluated.

Major side effects of intravenous lidocaine

• The primary cardiovascular side effects include sinus

slowing, asystole, hypotension, and shock.

• These problems are most often associated with

overdosing or with the overly rapid administration of

lidocaine.

• The elderly and those with significant preexisting liver

disease are at greatest risk. Pfeifer, 1976Schumacher, 1988

There are two potential cardiac complications

associated with mexiletine: proarrhythmia; and impaired

hemodynamics.

Exacerbation of arrhythmia after mexiletine occurs in

10 to 15 percent of patients.

A depressant effect on sinus node functionVelebit, et al., 1982Podrid, et al., 1987

Among the changes that can occur are:• Conduction Delay, manifested by progressive PR

prolongation or widening of the QRS interval.

• Prolonged Refractoriness, leading to prolongation

of the QT interval in proportion to the plasma

concentration.

• V. Arrhythmias, such as ventricular premature

contractions and ventricular tachycardia.

1)The proarrhythmic effects can occur at normal plasma drug concentrations.

2)Occur in 3 to 12 percent of patients taking usual doses of procainamide.

3) Incidence is lower than that seen with quinidine or the other agents, perhaps because procainamide produces a less prominent prolongation of the QT interval.

4)The most common arrhythmia is Torsade de PointesReiter, 1986

Procainamide, like quinidine and disopyramide,

can significantly increase the ventricular rate in

patients with uncontrolled AF or A. flutter.

Increased ventricular response in AF

1) Like other antiarrhythmic agents, propafenone has

a proarrhythmic effect that can worsen

spontaneous or electrically-induced sustained VT.

2) The overall incidence of proarrhythmia with

propafenone is approximately 5 percent. Stavens, 1985

Podrid, et al., 1987

3. The two best predictors of this complication

are previous VT and decreased ejection

fraction.

4. The proarrhythmic effects of propafenone may

be somewhat reduced by its ß-blocking

activity. Podrid, et al., 1996

Considerable concern about side effects

preclude long-term quinidine therapy in 25 to 50

percent of cases.

The proarrhythmic effects of quinidine often limit

its use in settings in which it might otherwise be

effective.

Cohen, 1977

Ventricular arrhythmias, including isolated PVCs, couplets, bigeminy, and VT, can be induced by quinidine.

Quinidine Syncope", which is probably due to self-terminating torsade de pointes, has been reported to occur in 1.5 percent of pts per year. Morganroth, 1985

It is unrelated to the plasma quinidine level or the

duration of therapy and it often occurs when plasma

concentrations are normal or below the therapeutic range. Roden, 1986

• Frequently associated with significant QT prolongation.

• Precipitated or aggravated by a number of conditions

including hypokalemia, hypomagnesemia, and

bradycardia, and concurrent therapy with digitals.

• Torsade appears to be induced by triggered activity

resulting from early afterdepolarizations associated

with QT prolongation.

Quinidine Syncope and Torsade de Pointes

Roden, 1985Levine,et al., 1985

Roden, 1986, Koster, 1976 & Marganroth 1987

Quinidine can significantly increase the

ventricular rate in patients with uncontrolled Atrial

Fibrillation or Flutter, through:

• Slowing the atrial rate, and

• Enhancing AV conduction by logistic action.

Increased Ventricular Response During AF

Cohen, 1977

• Requires immediate discontinuation of quinidine and of any other drug that prolongs the QT interval.

Quinidine induced Torsade de Pointes

Minardo, et al., 1988

• One goal of therapy is to increase the heart rate,

thereby shortening the delay in repolarization, by:

Pacing the atrium or ventricle or

By the administration of intravenous isoproterenol.Keren et al., 1981

Torsade can also be suppressed by I.V

magnesium sulfate (2 g over one to two minutes,

followed by a maintenance infusion rate of 3 to 20

mg/min). Tzivoni et al., 1988

Quinidine induced TdP

Comparing the efficacy of different therapeutic modalities, torsade was terminated:

in 19 of 19 patients treated with DC countershock,

9 of 9 who underwent Ventricular Pacing at rates of 100 to 120 beats/min,

5 of 6 treated with Isoproterenol, and only 7 of 14 receiving Lidocaine. Roden, 1986

Quinidine induced TdP 

Alkalinization with Sodium Bicarbonate or

Sodium Lactate may diminish the cardiac toxicity of

Quinidine.

At the level of the sodium channel, which is

blocked by quinidine, alkalosis will enhance recovery

of the sodium channel by at least two mechanisms:

Prevention 

Cohen, 1977 & Wasserman et al., 1959

Mason, 1984

Quinidine induced TdP

• Hyperpolarize the cell by decreasing the extracellular

potassium concentration.

• Will drive the reaction

Qud+   +   OH-    <—>    QudOH

To the right, thereby decreasing the availability of the

active charged form of the drug.

Alkalinisoton will:

Quinidine induced TdP

Recognition of the magnitude of the problem of

Pro Arrhythmia has led to important advances in

understanding basic mechanisms.

While the phenomenon of proarrhythmia

remains unpredictable in an individual patient, it can

no longer be viewed as "idiosyncratic."

Clinicians now select AAD therapy in a particular pt

not simply to maximize efficacy to but to minimize

the likelihood of pro-arrhythmia

Avoiding pro-arrhythmia has become a key element

of contemporary new AAD therapy.