Antiarrhythmic Drugs

1
Antiarrhythmic Drugs

• Donald Blumenthal, Ph.D.
• Department of Pharmacology Toxicology
• Don.Blumenthal_at_pharm.utah.edu
• 585-3094
• Recommended Reading
• Goodman Gilman Online (11th ed.), Chapt. 34
  (www.accessmedicine.com)
• Harrisons Online, Chapt 230 (www.accessmedicine.c
  om)
• Katzung (9th ed.), Chapt. 14, pp. 216-240
• Additional Resources Used to Prepare Handout
• Hurst's The Heart, Manual of Cardiology On-line
  (11th ed.) Part 4 (www.accessmedicine.com)
• Clinical Pharmacology Online (Goldstandard
  Multimedia, www.gsm.com)

2
Learning Objectives

• Understand the mechanistic basis, clinical
  usefulness, and limitations of the
  Vaughan-Williams classification system for
  antiarrhythmic drugs
• Know the V-W class toxicities and other major
  toxicities of clinically important antiarrhythmic
  drugs
• Know the proarrhythmic potential of specific V-W
  classes and drugs
• Understand the importance of use-dependent
  blockade in antiarrhythmic drug efficacy
• Know the drugs of choice for different types of
  arrhythmias

3
Arrhythmias (Dysrhythmias)

• Cardiac depolarizations that deviate from normal
  sinus rhythm or conduction
• Can be due to abnormality in one or more of the
  following
• Site of origin
• Rate or regularity
• Conduction
• Cardiac arrhythmias can be benign (no symptoms),
  associated with mild to moderate symptoms
  (palpitations, syncope), or life-threatening
  (ventricular fibrillation, sudden death)

4
ECGs of Normal and Arrhythmic Hearts (from
Goodman Gilman)
5
History of Antiarrhythmic Drug Therapy

• Some drugs used to treat cardiac arrhythmias have
  been used for hundreds of years (e.g.- quinidine
  and digitalis), but some have only been available
  for a decade or less
• Research in recent years has provided much
  information regarding the cellular mechanisms of
  arrhythmias and the mechanisms by which some of
  the antiarrhythmic drugs act, but the general
  approach to antiarrhythmic therapy remains
  largely empirical (trial and error)
• The recent results of several clinical trials,
  including the Cardiac Arrhythmia Suppression
  Trial (CAST), have indicated that many
  antiarrhythmic drugs may significantly increase
  mortality compared to placebo
• Recent clinical trials, including MADIT, MADIT
  II, and SCD-HeFT, have indicated that ICDs can
  significantly decrease mortality relative to
  antiarrhythmic drug therapy in many patients

6
Cardiovascular Drug Sectionfrom the 1st edition
of Goodman Gilman (1941)
7
Antiarrhythmic Drug Action

• The pharmacological goal of antiarrhythmic drug
  therapy is to reduce ectopic pacemaker activity
  and modify critically impaired conduction
• The ideal antiarrhythmic drug should be more
  effective on ectopic pacemaker and depolarized
  tissues than on normally depolarizing tissues
• The ideal antiarrhythmic drug should decrease
  mortality
• Unfortunately, many of the drugs presently
  available for treating arrhythmias may increase
  mortality

8
Antiarrhythmic Drug Action

• All of the antiarrhythmic drugs act by altering
  ion fluxes within excitable tissues in the
  myocardium
• The three ions of primary importance are Na,
  Ca, and K
• The Singh-Vaughn Williams system classifies
  antiarrhythmic drugs agents by their ability to
  directly or indirectly block flux of one or more
  of these ions across the membranes of excitable
  cardiac muscle cells
• The Sicilian Gambit classification includes the
  effects of drugs on other channels, receptors,
  and ion pumps

9
Ion Fluxes in Cardiac Myoctes (from Katzung)
10
Luo-Rudy Model of the Cardiac Myocyte

• Cardiac ventricular myocytes are actually
  composed of many different ion channels and pumps
  whose expression varies in different regions of
  the heart

11
Time course of myocyte ion fluxes(from GG,
Figure 34-3)
Sodium channel blockers
Calcium channel blockers
Potassium channel blockers
Cardiac glycosides
12
Electrical Activity in the Normal Heart (from
Katzung)

• The different action potentials in different
  regions of the heart reflect differential
  expression of ion channels, particularly Na
  channels
• This leads to differential sensitivity to
  antiarrhythmic drugs

13
Arrhythmogenic Mechanisms

• Enhanced automaticity
• Can occur in cells with spontaneous pacemaker
  activity (diastolic depolarization) or cells that
  normally lack pacemaker activity (ventricular
  cells)
• Afterdepolarizations and triggered automaticity
• Normal depolarizations can trigger automaticity
• Delayed afterdepolarizations (DADs) are
  associated with calcium overload
• Early afterdepolarizations (EADs) are typically
  associated with potassium channel block and can
  lead to torsades de pointes
• Reentry
• The most common cause of arrhythmias
• Can occur in any region of the heart where there
  is a region of non-conducting tissue and
  heterogeneous conduction around that region

14
Automaticity Mechanisms for Slowing Pacemaker
Rate (from Goodman Gilman, 34-10)
Drugs that Inhibit Automaticity
b-Adrenergic blockers
Na and Ca channel blockers
Adenosine and muscarinic blockers
K channel blockers
15
Afterdepolarizations and Triggered Automaticity
(from Goodman Gilman, 34-6)

• DADs arise from the resting potential and result
  from calcium overload
• EADs arise from phase 3 (repolarization phase)
  and result from prolonging action potential
  duration (typically from K channel block)

16
Reentry

• The most common cause of arrhythmias
• Can occur in any region of the heart where there
  is a region of non-conducting tissue and
  heterogeneous conduction around that region
• Anatomically defined reentry refers to reentry
  that involves impulse propagation by more than
  one anatomical pathway between two points in the
  heart
• Wolff-Parkinson-White syndrome
• Atrial flutter
• Paroxysmal supraventricular tachycardia
• AV reentry and AV nodal reentry
• Functionally defined reentry can occur in the
  absence of anatomically defined pathways
• Atrial and ventricular fibrillation
• Torsades de pointes

17
Reentrant Mechanisms AV Nodal Reentry

• In the Common Mode of AV Nodal reentry, the
  anterograde impulse is slowed as it passes
  through the AV node
• The retrograde pathway of the reentrant circuit
  is fast.

• In the Uncommon Mode of AV Nodal reentry, the
  anterograde impulse is fast as it passes through
  the AV node
• The retrograde pathway of the reentrant circuit
  is slowed.

18
Animations of Reentrant Arrhythmias(can be found
at NetPharmacology)
19
Classification of Antiarrhythmic Drugs

• The Singh-Vaughan Williams (aka Vaughan Williams)
  classification system has been widely used to
  classify antiarrhythmic drugs based on mechanism
  of action and is still the primary system used
  for classification
• The Sicilian Gambit is a newer classification
  system that takes into consideration the multiple
  antiarrhythmic actions that most drugs possess
  and the mechanism of a patients arrhythmia

20
Singh-Vaughan Williams Classification

• Class I drugs, those that act by blocking the
  fast inward sodium channel, are subdivided into 3
  subgroups based on their potency (dissociation
  kinetics) towards blocking the sodium channel and
  effects on repolarization
• Subclass IA High/intermediate potency as sodium
  channel blockers and prolong repolarization
  (prolong QT interval) Quinidine, procainamide,
  disopyramide
• Subclass IB Lowest potency sodium channel
  blockers and may shorten repolarization (decrease
  QT interval) Lidocaine, mexiletine
• Subclass IC The most potent sodium channel
  blocking agents (prolong QRS interval) have
  little effect on repolarization (no effect on QT
  interval) Flecainide, propafenone, moricizine
• Potency is a reflection of kinetics of
  dissociation from the sodium channel very high
  potency drugs dissociate slowly (?recovery gt 10
  sec), whereas low potency drugs dissociate slowly
  (?recovery lt 1 sec)

21
Singh-Vaughan Williams Classification

• Class II drugs act indirectly on
  electrophysiological parameters by blocking
  beta-adrenergic receptors (may slow sinus rhythm,
  prolong PR interval if adrenergic-dependent)
  Propranolol, esmolol, acebutolol
• Class III drugs prolong repolarization (increase
  refractoriness, prolong QT interval, no effect on
  QRS interval, little effect on rate of
  depolarization)
• Block fast outward K current Amiodarone,
  sotalol, dofetilide
• Block slow inward Na current Ibutilide
• Class IV drugs are relatively selective AV nodal
  L-type calcium-channel blockers (slow sinus
  rhythm, prolong PR interval) Verapamil,
  diltiazem
• (Note Dihydropyridines have minimal effects on
  AV node depolarization)

22
Singh-Vaughan Williams Classification

• Miscellaneous
• In addition to the standard classes (IA, IB, IC,
  II, III, and IV) there is also a miscellaneous
  group of drugs that includes digoxin, adenosine,
  magnesium and other compounds whose actions do
  not fit the standard four classes

23
Advantages of the Vaughn Williams Antiarrhythmic
Drug Classification System

• It is a convenient means to classify the many
  antiarrhythmic drugs by their primary mechanism
  of action
• It is a useful conversational shorthand
• Drugs within a specific class or subclass often
  exhibit similar adverse effects
• It is a useful starting point for deciding which
  drug to use for treating a particular patient

24
Class Toxicities of Antiarrhythmic Drugs (adapted
from Woosley, 1991)
25
Relative Efficacies of Antiarrhythmic
Drugs(adapted from Melmon and Morelli, 3rd ed.)
26
Drugs of Choice for Major Arrhythmias (Based on
GG 11th ed., Table 34-2)

• Premature atrial, nodal or ventricular
  depolarization
• No drug therapy indicated
• Atrial fibrillation, flutter, and PSVT
• AV nodal blockers to control ventricular
  response
• Adenosine, Class II, Class IV, digoxin
• Note AV nodal blockers may be harmful in WPW
  syndrome
• Depending on arrhythmia Class III, Class IA,
  Class 1C
• Ventricular tachycardia (w/ remote MI)
• Amiodarone, Class III, Class I
• Ventricular fibrillation
• Lidocaine, amiodarone, Class III, Class I
• Torsades de pointes
• Acute Magnesium, isoproterenol
• Chronic Class II

27
Drawbacks of the Singh-Vaughn Williams
Antiarrhythmic Drug Classification System

• Drugs within a class do not necessarily have
  clinically similar effects
• Almost all of the currently available drugs have
  multiple actions
• The metabolites of many of the drugs may
  contribute significantly to the antiarrhythmic
  actions or side effects
• Thus, an empirical approach is used by many
  clinicians to determine the most effective agent
  to use for a given patient

28
Sicilian Gambit Classification

• An alternative classification system, known as
  the 'Sicilian Gambit', has been proposed that is
  based on arrhythmogenic mechanisms
• This system identifies one or more 'vulnerable
  parameters' associated with a specific
  arrhythmogenic mechanism
• A vulnerable parameter is an electrophysiological
  property or event whose modification by drug
  therapy will result in the termination or
  suppression of the arrhythmia with minimal
  undesirable effects on the heart
• Unlike the Vaughan Williams classification
  system, this system can readily accommodate drugs
  with multiple actions
• This multidimensional classification system is
  significantly more complex than the standard
  Vaughan Williams system, but provides a more
  flexible framework for classifying antiarrhythmic
  drugs based on pathophysiological considerations

29
Actions of Antiarrhythmic Drugs(adapted from
Hursts the Heart, 10th ed.)
30
Lidocaine and mexiletine (Class IB)

• Lidocaine is a widely used antiarrhythmic and
  local anesthetic. It is only used IV for treating
  arrhythmias because of first-pass metabolism.
  Mexiletine is lidocaine's orally active congener.
  
• Both are used to treat acute, life-threatening
  ventricular arrhythmias. Although lidocaine has
  long been the first choice for treating
  ventricular arrhythmias, ECC/AHA 2000 guidelines
  for cardiopulmonary resuscitation recommend IV
  amiodarone before lidocaine for treatment of
  ventricular fibrillation or pulseless ventricular
  tachycardia.
• Mexiletine does not prolong QT interval and can
  be used in patients with a history of torsades or
  DILQTs. Lidocaine is ineffective for prophylaxis
  of arrhythmias in post-MI patients.
• Severe interactions can occur with
  co-administration of other antiarrhythmic agents,
  especially amiodarone.
• The most frequent side effects are CNS including
  tinnitus and seizures, and occasionally
  hallucinations, drowsiness, and coma.

31
Procainamide (Class IA)

• Effective against both supraventricular and
  ventricular arrhythmias (including atrial
  arrhythmias associated with WPW syndrome) can be
  administered IV and orally.
• Its major metabolite, N-acetylprocainamide
  (NAPA), has predominantly Class III
  antiarrhythmic actions. Fast acetylators (50
  of the population) quickly convert procainamide
  to NAPA.
• When procainamide is given orally, both
  procainamide and NAPA can contribute to the
  antiarrhythmic effects and toxicities initial
  dosing should be conservative and monitoring of
  plasma concentrations is recommended.
• Up to 40 of patients discontinue therapy within
  6 months due to side effects.
• Between 15 and 20 of patients develop a
  lupus-like syndrome, which usually begins as mild
  arthralgia, but can be fatal if allowed to
  progress. These symptoms are reversed if therapy
  is stopped, but patients need to be warned of the
  early warning symptoms so therapy can be aborted
  before serious problems develop.

32
Disopyramide (Class IA)

• Useful for supraventricular arrhythmias, and
  ventricular arrhythmias only in patients with
  good ventricular function because of its negative
  inotropic effects.
• The drug has anticholinergic effects which may be
  useful in some patients with vagally mediated
  paroxysmal supraventricular tachycardias, but the
  anticholinergic effects limit therapy in many
  patients.

33
Quinidine (Class IA)

• Useful in treating supraventricular and
  ventricular arrhythmias, but there are
  significant risks of ventricular arrhythmias and
  other side effects.
• Torsades is likely to be the major cause of
  quinidine syncope, which occurs in as many as
  5-10 of patients within the first few days of
  therapy. Patients with a history of long QT,
  torsades, or hypokalemia should not be treated
  with quinidine.
• Patients with heart failure can have
  proarrhythmias and digoxin interactions.
• Common side effects include hypotension, GI
  problems (diarrhea and vomiting), and cinchonism
  (tinnitus, blurred vision, and headaches).
• Quinidine is a potent inhibitor of hepatic CYP2D6
  and is associated with more drug interactions
  than any other antiarrhythmic drug.

34
Propafenone (Class IC)

• Used to treat symptomatic supraventricular
  arrhythmias and suppress life-threatening
  ventricular arrhythmias.
• It is structurally similar to propranolol and has
  beta-blocking activity in addition to its sodium
  channel blocking activity. At therapeutic
  concentrations it can have significant
  beta-blocking activity which must be considered
  in patients with heart failure.

35
Flecainide (Class IC)

• A potent fast inward sodium channel blocker used
  to treat symptomatic supraventricular arrhythmias
  and documented life-threatening ventricular
  arrhythmias.
• Because of the risks of proarrhythmias identified
  in the CAST trials, the drug is not considered a
  first-line agent and should not be used in
  patients with impair ventricular function,
  myocardial ischemia, or recurrent myocardial
  infarctions.
• The agent lowers ventricular function in most
  patients. It also raises the threshold of pacing
  and cardiac defibrillators and should be used
  with caution in patients with pacemakers or ICDs.

36
Verapamil and diltiazem (Class IV)

• Useful in treating a variety of arrhythmias of
  atrial or supraventricular origin. They are also
  more effective than digoxin in controlling
  ventricular rate in patients with atrial
  fibrillation.
• High doses can cause AV block or suppression of
  SA node, particular when used in combination with
  beta-blockers, digoxin or other drugs that
  inhibit the SA and AV nodes. Should be used with
  caution in combination with drugs that inhibit SA
  and AV function, lower LV function, or lower
  blood pressure.
• Contraindicated in patients with heart failure,
  impaired LV function, sick sinus syndrome, heart
  block, severe hypotension or reentrant
  arrhythmias due to WPW or LGL syndrome.
• Administration of these calcium channel blockers
  to patients with atrial tachycardias resulting
  from WPW can worsen the arrhythmia by
  facilitating antegrade conduction through the
  ancillary tract leading to ventricular
  fibrillation.
• The most common side effect of verapamil is
  constipation.
• Grapefruit juice is known to increase the plasma
  concentrations of verapamil because of its
  inhibitory effects on CYP3A4 in the gut wall.

37
Ibutilide (Class III)

• Unlike other Class III agents, ibutilide prolongs
  repolarization by increasing inward sodium flux
  through the slow inward sodium channels.
• It is used IV to rapidly convert atrial
  arrhythmias to normal sinus rhythm it is the
  only agent indicated for this purpose.
• Class IA or Class III drugs should not be used
  concurrently, or within 4 hours of ibutilide
  dosing, to avoid the possibility of DILQTS and
  torsades.
• Ibutilide is contraindicated in patients with
  prolonged QT, torsades or other polymorphic
  ventricular arrhythmias, or who are taking drugs
  that prolong QT or are associated with torsades.

38
Sotalol (Class III and II)

• The racemic d,l mixture of sotalol has both Class
  II and Class III effects. The l-isomer causes
  the beta-blocking effects, while the d-isomer
  causes the effects on prolonging the action
  potential. The l-isomer causes significant
  beta-blocking effects at doses well below those
  required for the antiarrhythmic effects of the
  d-isomer.
• The combination of effects makes the drug
  effective in a variety of atrial and ventricular
  arrhythmias, though because of the proarrhythmic
  effects of Class III agents (torsades), high
  concentrations of the drug should only be used to
  treat life-threatening ventricular arrhythmias.
• The drug is contraindicated in patients with QT
  prolongation, bradycardia, torsades,
  hypomagnesemia, hypokalemia, bronchospasm,
  pulmonary edema, heart failure, or AV block.
• Because of the risk of arrhythmia or MI, abrupt
  cessation of drug therapy should be avoided
  instead gradually reduce dosage over a 1 to 2
  week period or substitute a different
  beta-blocker.
• Drug combinations that enhance the
  pharmacological effects of sotalol
  (beta-blockade, QT prolongation, AV blockade)
  should be used with caution.

39
Amiodarone (Class III/other)

• Though amiodarone is formally classified as a
  Class III antiarrhythmic, it has multiple actions
  and is more appropriately considered a "broad
  spectrum" antiarrhythmic.
• Although it prolongs QT interval, its potential
  to cause proarrhythmias (torsades) is
  significantly lower than other Class III agents
  and it is one of the few antiarrhythmic agents to
  have consistently decreased mortality in many
  (but not all) clinical trials.
• It is approved for use in refractory
  life-threatening ventricular arrhythmias, but its
  therapeutic role has been expanding to include a
  variety of arrhythmias ranging from
  supraventricular to ventricular.
• Used IV, amiodarone is superior to lidocaine and
  other agents for the treatment of ventricular
  fibrillation (2000 ECC/AHA guidelines), and it is
  also used orally to suppress a variety of
  arrhythmias, even in combination with ICDs.

40
Amiodarone (cont.)

• The safety of amiodarone for chronic therapy is
  controversial because of its variable and complex
  pharmacokinetics and many adverse effects, some
  of which can be fatal.
• Without loading doses, it can take several weeks
  to months to achieve steady-state plasma levels.
  Similar, it can take many months to clear the
  drug, with an elimination half-life ranging from
  26 to 107 days (mean of 53 days).
• The most common serious adverse effects are
  pulmonary fibrosis and interstitial pneumonitis
  (2-15 of patients on chronic amiodarone), which
  is fatal in 10 of these patients. The
  pneumonitis is reversible if drug is stopped
  early on, thus clinical assessment and chest
  x-rays are required every 3 months.

41
Amiodarone (cont.)

• Other adverse effects include
• GI disturbances,
• hepatotoxicity (which can be fatal 30 of
  patients have elevated serum liver enzymes),
• hyperthyroidism and hypothyroidism (2-24
  incidence amiodarone is structurally similar to
  thyroid hormone and contains large quantities of
  iodine),
• peripheral neuropathy (20-40 incidence, but
  reversible by lowering dose),
• dermatological reactions (15-20) including
  photosensitivity (10), which can result in
  blue-gray skin color, and various visual
  disturbances (10).
• Virtually all patients on drug for more than 6
  months develop corneal microdeposits which can
  eventually interfere with vision.
• Amiodarone can interfere with the clearance of
  many drugs.

42
Digoxin (Misc.)

• Digoxin is a cardiac glycoside that acts by
  inhibiting the sodium/potassium ATPase. This ion
  pump is ubiquitously expressed so digoxin affects
  a variety of excitable tissues including the
  heart, CNS and ANS.
• Digoxin is used to control ventricular rate in
  patients with atrial tachycardias.
• Digoxin increases vagal tone, thus inhibiting AV
  nodal conduction.
• Dioxin can actually exacerbate atrial arrhythmias
  because it can cause calcium overload, but
  therapeutic efficacy is measured by the drug's
  ability to protect the ventricles by reducing the
  number of impulses passing through the AV node.
• Digoxin has a relatively narrow therapeutic index
  and is known to interact pharmacokinetically with
  quinidine and other antiarrhythmic agents.

43
Adenosine (Misc.)

• Adenosine is an endogenous compound that is an
  agonist for purinergic receptors.
• It is given as a rapid IV bolus to acutely treat
  paroxysmal supraventricular tachycardia.
• It potently blocks AV nodal conduction within
  10-30 seconds of administration.
• It has a half-life of elimination of 1.5-10
  seconds.
• Common side effects, which are short-lived,
  including facial flushing, dyspnea, and chest
  pressure.

44
Proarrhythmias

• Proarrhythmias are drug-induced arrhythmias
• Digitalis-induced proarrhythmias have been
  recognized for many years
• Two recently recognized ventricular
  proarrhythmias seen with antiarrhythmic drugs
• Torsades de pointes (associated with drug-induced
  long QT syndrome (DILQTS))
• Quinidine (2-8 of patients, can occur at
  subtherapeutic doses)
• Sotalol (common, but dose-dependent)
• N-acetylprocainamide (metabolite of procainamide)
• Amiodarone (DILQT is common, but torsades is
  uncommon)
• Ibutilide (4-8)
• Dofetilide (1-3)
• CAST proarrhythmia
• Flecainide (and encainide)

45
Torsades de Pointes ("twisting of the points")

• Torsades is a polymorphic arrhythmia that can
  rapidly develop into ventricular fibrillation
• Associated with drugs that have Class III and
  Class IA actions (potassium channel blockers and
  drugs that prolong repolarization) and cause
  Drug-Induced Long QT Syndrome (DILQTS)
• Also seen with many other drugs (terfenadine,
  erythromycin, chlorpromazine under certain
  circumstances (see www.torsades.org for an
  up-to-date list)
• FDA now requires in vitro HERG toxicity assays
• Usually occurs within the first week of therapy
• Preexisting prolonged QT intervals may be
  indicator of susceptibility
• Potentiated by bradycardia (and can therefore be
  controlled by pacing)
• Often associated with concurrent electrolyte
  disturbances (i.e. hypokalemia, hypomagnesemia)

46
ECG of Patient with Prolonged QT Interval and
Torsades de Pointes (From Katzung)
47
CAST Proarrhythmia

• Monomorphic, sustained ventricular tachycardia
  first recognized in CAST trials with encainide
  and flecainide
• Patients with underlying sustained ventricular
  tachycardia, coronary artery disease, and poor
  left ventricular function (left ventricular
  ejection fraction lt40) are at greater risk to
  develop this form of proarrhythmia (these were
  the patients enrolled in the CAST trials)

48
Use(Rate)-Dependent Channel Blockade

• Many of the sodium (Class I) and calcium (Class
  IV) channel blockers preferentially block sodium
  and calcium in depolarized tissues
• Enhanced sodium or calcium channel blockade in
  rapidly depolarizing tissue has been termed
  "use-dependent blockade"
• Responsible for increased efficacy in slowing and
  converting tachycardias with minimal effects on
  tissues depolarizing at normal (sinus) rates
• Many of the drugs that prolong repolarization
  (Class III drugs, potassium channel blockers)
  exhibit negative or reverse rate-dependence
• These drugs have little effect on prolonging
  repolarization in rapidly depolarizing tissue
• These drugs can cause prolongation of
  repolarization in slowly depolarizing tissue or
  following a long compensatory pause, leading to
  repolarization disturbances and torsades de
  pointes

49
Affinity of Channel Blocker Drugs for Different
Channel States (from Katzung)

• Channel blocker drugs with higher affinity for
  the Active and Inactive states of the ion channel
  will demonstrate positive use-dependence
• Drugs with fast dissociation kinetics (low
  potency) will only show efficacy in rapidly
  depolarizing tissue

50
Possible Mechanisms for Differential Affinity of
Channel Blocking Drugs for Different Channel
States (from Katzung)

• Drug binding sites of use-dependent drugs might
  only be accessible to drug when the ion channel
  is in specific states
• This might be due to the drugs limited access
  to the drug-binding site from within the channel
  or because conformational gates sterically
  block the drugs access to the binding site

51
Examples of Channel Blockers ShowingUse-Dependent
Blockade

• Quinidine, procainamide, and disopyramide
  preferentially bind to the Active state of the
  sodium channel
• Amiodarone binds almost exclusively to the
  Inactive state of the sodium channel
• Lidocaine binds Active and Inactive states of the
  sodium channel
• Verapamil and diltiazem bind Active and Inactive
  states of the calcium channel
• Quinidine, bretylium, and sotalol show reverse
  use-dependence with regard to potassium channel
  blockade

52
Therapeutic Considerations and Challenges

• Most of the currently available antiarrhythmic
  drugs are hazardous, unpredictable, and often
  ineffective
• The therapeutic index of most antiarrhythmic
  drugs is narrow
• The choice of a drug should be based on an
  assessment of the benefits vs risks of treatment
• The benefits of therapy may be difficult to
  establish, particularly in relatively
  asymptomatic patients
• Patients most likely to benefit are those most at
  risk for adverse drug effects
• Results of the CAST study indicate that the
  identification of an arrhythmia does not
  necessarily indicate that therapy should be
  instigated
• Any predisposing factors should be eliminated
  before therapy is started
• Electrolyte abnormalities, particularly potassium
• Proarrhythmic drugs
• Myocardial ischemia and other predisposing
  conditions

53
Optimizing Antiarrhythmic Drug Therapy

• Three trial-and-error approaches are widely used
  to determine the appropriate antiarrhythmic drug
• Empiric. Based upon the clinician's past
  experience
• Serial drug testing guided by electrophysiological
  study (EPS). Requires cardiac catheterization
  and induction of arrhythmias by programmed
  electrical stimulation of the heart, followed by
  a delivery of test drugs
• Drug testing guided by electrocardiographic
  monitoring (Holter monitoring). Continuous
  24-hour recording of a ECG before and during
  each drug test to predict optimal efficacy
• The Electrophysiologic versus Electrocardiographic
  Monitoring (ESVEM) study concluded that there
  may not be any significant difference between the
  predictive value of these latter two techniques

54
Optimizing Antiarrhythmic Drug Therapy Genetic
considerations

• In the case of hereditary long QT syndrome,
  identification of the genetic basis of the
  arrhythmia may be critical in coosing the
  appropriate therapy that can effectively prevent,
  rather than precipitate, sudden cardiac death
• Stress and increased sympathetic tone can
  precipitate VF in most patients with hereditary
  LQT (best treated with ?-blockers)
• However, in approximately 10-20 of LQT patients,
  VF is precipitated by slow heart rate (which
  would be facilitated by ?-blockers)
• The presence of a variety of genetic variants of
  LQT involving a number of different ion channel
  protein (but having a similar clinical phenotype)
  suggests that optimal drug therapy for this and
  other arrhythmias should be determined
  pharmacogentically
• This will require the availability of genetic
  tests and antiarrhythmic drug trials based on
  genetic profiles

55
Non-Drug Antiarrhythmic Therapies

• Drug therapy is rarely indicated in benign
  arrhythmias except to relieve debilitating
  symptoms (syncope, dizziness)
• Several surgical procedures have become
  first-line therapies for arrhythmias
• Radiofrequency (RF) catheter ablation
• Wolff-Parkinson-White syndrome
• AV nodal reentry
• Atrial ectopic tachycardia atrial fibrillation
• Some types of monomorphic ventricular
  tachycardias
• Implantable cardioverter/defibrillator devices
  (ICDs)
• Can pace, cardiovert, and defibrillate
• Considered by some to be superior to Class I and
  Class III drugs in treating ventricular
  tachycardias
• A significant number of patients with an ICD will
  still require drug therapy to prolong battery
  life and reduce inappropriate shocks

56
Antiarrhythmic Therapy (Singh Breithardt,
1997, Am J Cardiol)

• "Therapeutic approaches to cardiac arrhythmias
  continue to change rapidly, as indicated by the
  recent acceptance of a number of revolutionary
  concepts. These include
• (1) the recognition that time-honored
  antiarrhythmic drugs that act essentially by
  slowing cardiac conduction (class I agents) may
  increase mortality despite suppressing cardiac
  arrhythmias. The result has been a shift to
  agents that act largely by prolonging cardiac
  repolarization (class III agents)
• (2) the realization that radiofrequency catheter
  ablation may produce permanent cures in many
  forms of arrhythmia, especially those of
  supraventricular origin and
• (3) the introduction and refinement of the
  implantable cardioverter-defibrillator (ICD),
  which has the potential for prolonging survival
  by terminating ventricular tachycardia and
  fibrillation (VT/VF)."