icu

2. Cairo University

3. • 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

4. 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.

5. • 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.

6. • 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.

7. • 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.

8. ECG monitor recording showing conversion of atrial fibrillation
(first two QRS complexes) to sinus rhythm to sinus rhythm with
a prolonged sinus pause.

9. Another example, this time with more prolonged
sinus slowing

10. 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.

11. 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.

12. 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

13. Holter monitor recording showing atrial flutter with
varying AV block and controlled ventricular rate

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

15. 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.

16. 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.

17. 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.

18. 12-lead ECG showing sinus bradycardia with
prolongation of the QT interval due to sotalol.

19. ECG monitor strip recorded later showing more marked
sinus bradycardia with recurrent non-sustained
ventricular tachycardia

20. She had developed marked sinus bradycardia
and prolongation of the QT interval, the latter
resulting in recurrent nonsustained ventricular
tachycardia

21. 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.

23. 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.

24.  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

25.  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

26. 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

27. 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

28.  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

29. 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

31. • 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

32. 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

33. 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

34.  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

35.  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

36. 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

37. 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).

38. 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

39. 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

40. 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:

41. 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

42. 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., 2001
Zhou et al., 1998
Pelosi et al., 2000
Nielsen et al., 2001

44.  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

45. 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

46. 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

47. 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, 1981
Schweitzer, 1982

48. 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

49. 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.

51.  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.

52. 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, 1976
Schumacher, 1988

54. 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 function
Velebit, et al., 1982
Podrid, et al., 1987

56. 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.

57. 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 Pointes
Reiter, 1986

58. Procainamide, like quinidine and disopyramide,
can significantly increase the ventricular rate in
patients with uncontrolled AF or A. flutter.
Increased ventricular response in AF

60. 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

61. 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

63. 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

64. 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

65. • 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, 1985
Levine,et al., 1985
Roden, 1986, Koster, 1976 & Marganroth 1987

66. 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

67. • 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

68. 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

69. 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

70. 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

71. • 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

73. 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."

74.  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.