Article Text

Antiarrhythmic drugs: from mechanisms to clinical practice
  1. Dan M Roden
  1. Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  1. Dan M Roden MD, Director, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 532C Medical Research Building-I, Nashville, TN 37232-6602, USA email: Dan.Roden{at}

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All drugs currently marketed for the treatment of arrhythmias were developed in the absence of knowledge of the specific molecules the drugs target to achieve their therapeutic and adverse effects. Nevertheless, combining the characterisation of drug effects in vitro and in whole animal models with medicinal chemistry approaches to modify existing molecules has led to new compounds with related pharmacologic actions derived from older drugs (for example, procainamide begat flecainide). It has thus been natural to group drugs with common mechanisms of action. This approach can be useful for the clinician to the extent it allows prediction of a patient's response to a given drug. One widely used scheme is that popularised by Vaughan Williams in which drugs are subdivided into four broad “classes”.1 The Vaughan Williams classification has been criticised because many drugs fall into multiple classes (table1): quinidine both blocks sodium channels and prolongs action potentials (class I + III), while amiodarone blocks sodium channels, exerts antiadrenergic actions, prolongs action potentials and QT intervals by blocking potassium channels, and blocks calcium channels (classes I + II + III + IV, respectively).2 ,3 Moreover, both compounds exert other important pharmacologic actions, such as inhibition of specific pathways of drug elimination (both), α blockade with vasodilation (quinidine), and interaction with nuclear thyroid hormone receptors (amiodarone). These actions probably contribute to some of the effects observed during treatment with these compounds.

Table 1

Antiarrhythmic drugs exert a multiplicity of electrophysiologic actions

A virtue of the Vaughan Williams' approach to classification is that drugs of a common “class” frequently exhibit similar toxicities, notably proarrhythmia. This likely reflects the fact, discussed below and elsewhere in this series, that while the mechanisms whereby drugs suppress arrhythmias are incompletely defined and likely highly variable from patient to patient, the mechanisms underlying proarrhythmia are better understood and less variable among patients. Thus, for example, sodium channel blocking drugs with slow onset and offset kinetics of block (the “class Ic” (and to a lesser extent “Ia”) effect, seen with flecainide) are likely to produce conduction slowing at normal rates and the stereotypical set of toxicities, described below (proarrhythmia: sodium channel block). As our understanding of the molecular basis of these and other proarrhythmia syndromes (and indeed arrhythmias in general) evolves, it seems likely that drugs exerting antiarrhythmic effects yet lacking the potential to cause serious toxicity may be developed.

The “Sicilian Gambit” proposed an alternate approach to classifying antiarrhythmic drug actions.2 In this scheme, the arrhythmia mechanism assumes primacy, and antiarrhythmic drugs (or other treatments) are then classified by the way in which they interact with arrhythmogenic triggers or substrates to suppress arrhythmias. A near trivial example is macroreentry based on the presence of a bypass tract. Understanding this mechanism then allows the clinician to select drugs that target the portion of the circuit at which pharmacologic interruption is most likely (the AV node) or target the circuit by ablation of the accessory pathway. The identification of such a “vulnerable parameter” in an arrhythmia mechanism should, in theory, allow development of entirely new approaches to treatment. For example, it is increasingly recognised that altered intracellular calcium homeostasis may play an important role in arrhythmias in settings such as heart failure. Drugs targeting the molecular events that make altered intracellular calcium homeostasis arrhythmogenic might therefore attack the “vulnerable parameter” in this situation.

Differential drug effects in atrial flutter versus atrial fibrillation was an interesting (and it turns out incorrect) prediction of the initial publication of the Sicilian Gambit. It was postulated that atrial fibrillation should respond particularly well to drugs that prolong atrial refractoriness, while atrial flutter would respond especially well to drugs that slow conduction. In fact, clinical studies have demonstrated that the exact opposite occurs. Drugs with predominant QT prolonging effects (dofetilide, ibutilide) are more effective in atrial flutter than in atrial fibrillation, whereas drugs with predominant sodium channel blocking effects (flecainide) are more effective in fibrillation than flutter. It seems likely that QT prolonging agents are especially effective because they prolong refractoriness in an especially vulnerable portion of the circuit to terminate flutter (or that they affect the boundaries of the circuit). Thus, this interesting exception to the initial prediction of the Sicilian Gambit merely serves to reinforce the underlying concept, that a full understanding of arrhythmia mechanisms is desirable to use available treatments rationally and to develop new ones.


A contemporary view is that all drugs exert their desirable and undesirable effects by interacting with specific molecular targets.2 ,3 A common set of targets for antiarrhythmic drugs are ion channels, the pore forming protein structures that underlie ionic currents flowing during the action potential. Specificity of drug action is achieved by drugs that target only a single population of ion channels. The virtue of this approach is that side effects (caused by interaction with other targets) are rare. Unfortunately, as discussed below, targeting individual cardiac ion channels may result in significant proarrhythmia. Amiodarone is an example of a drug with multiple ion channel and other target molecules, and it seems likely that the low incidence of proarrhythmia during amiodarone treatment reflects the fact that “antidotes” to specific proarrhythmia syndromes are built into the drug's mechanism of action. On the other hand, extracardiac side effects are particularly common during amiodarone treatment, again reflecting this multiplicity of pharmacologic targets. A detailed discussion of all the pharmacologic actions of all available antiarrhythmics is beyond the scope of this review. Nevertheless, it is useful to consider widely used drugs with respect to pharmacologic actions that assume special relevance in clinical management. These include proarrhythmia syndromes discussed below and other important adverse effects presented in table 2 as well as pharmacokinetic properties presented in table 3.

Table 2

Important side effects of antiarrhythmic drugs

Table 3

Clinically important pharmacokinetic characteristics of antiarrhythmic drugs

Proarrhythmia: torsades de pointes

Torsades de pointes is estimated to occur in 1–8% of patients exposed to QT prolonging antiarrhythmics: sotalol, quinidine, dofetilide, and ibutilide fall into this category. While this reaction is generally viewed as “unpredictable”, certain risk factors can be identified: female sex, underlying heart disease (particularly congestive heart failure or cardiac hypertrophy), hypokalaemia, and hypomagnesaemia. In patients receiving these drugs for atrial fibrillation (the majority in contemporary practice), the reaction is quite uncommon when the underlying rhythm is actually atrial fibrillation but tends to occur shortly after conversion to sinus rhythm; ibutilide may be an exception.4 The clinical parallels between torsades de pointes in drug associated cases and in the congenital long QT syndromes has suggested the possibility that some patients displaying apparently “idiopathic” responses to drugs may in fact harbour subclinical congenital long QT syndrome mutations. With the identification of the disease genes in the congenital form of the syndrome has come the possibility of testing this idea, an area of very active research.5

Most drugs that cause torsades de pointes have as a major pharmacologic action block of a specific repolarising potassium current, IKr. Thus, patients are thought to develop drug induced torsades de pointes either because the channels underlying IKr are unusually sensitive to drug block (which is now recognised with hypokalaemia and with some mutations) or because they harbour subclinical mutations in other repolarising channels. In the latter case, baseline QT intervals can be normal because of a robust IKr, but block of the current produces exaggerated QT prolongation.

The management of torsades de pointes includes recognition, withdrawal of any offending agents, empiric administration of magnesium regardless of serum magnesium, correction of serum potassium to 4.5–5 mEq/l, and manoeuvres to increase heart rate (isoprenaline (isoproterenol) or pacing) if necessary. Long term management of patients with QT prolongation on a congenital or even acquired basis usually relies on β blockers, although in some cases pacemakers or implantable cardioverter defibrillators (ICDs) are advocated.

Proarrhythmia: sodium channel block

The first drugs used to suppress cardiac arrhythmias were quinidine, procainamide, and lidocaine, which share the common property of sodium channel block. Modifications in these chemical structures led to compounds with more potent sodium channel blocking capability. Indeed agents with this property (flecainide, propafenone) are very effective in suppressing isolated ectopic beats and are among the drugs of choice for treatment of re-entrant supraventricular tachycardia in patients with no underlying structural heart disease. However, extensive clinical studies with these agents, and drugs that are no longer available but that exerted very similar pharmacologic properties, have identified a number of serious liabilities of sodium channel block.

First, in patients with a history of sustained ventricular tachycardia related to a remote myocardial infarction, exacerbation of ventricular tachycardia is common. Such exacerbation presents as a pronounced increase in frequency of episodes, which are often slower than pre-drug, but less organised and more difficult to cardiovert. Treatment of this arrhythmia by additional sodium channel block is undesirable; β blockers or sodium infusion have been found effective in anecdotes. Deaths have been reported. The mechanism of ventricular tacchyarrhythmia (VT) in these cases is thought to relate to slow conduction in border zone tissue, and the conduction slowing caused by sodium channel blockers tends to further exacerbate the clinical arrhythmia.

Second, the rate of atrial flutter, a macroreentrant arrhythmia occurring in the right atrium, is usually slowed by sodium channel block. When this occurs, the patient who pre-drug had atrial flutter at 300/min and 2:1 atrioventricular (AV) transmission with narrow complexes at 150/min may present with wide complex tachycardia at 200/min, representing a slowing of atrial flutter to 200/minute and 1:1 AV transmission. QRS widening often accompanies this fast rate since sodium channel block is enhanced at fast rates.6 The management of this entity requires recognition, withdrawal of offending agents, and AV nodal blocking drugs. This reaction can occur not only in patients being treated with flecainide, propafenone, or quinidine for atrial flutter (where, as described above, sodium channel blockers may not be especially effective) but also in patients whose presenting arrhythmia is atrial fibrillation and is “converted” by drug to atrial flutter. Many experts would not prescribe these drugs to patients with atrial fibrillation or flutter without co-administering an AV nodal blocking drug.

Third, sodium channel block increases threshold for pacing and defibrillation.

Fourth, the use of the sodium channel blockers flecainide or encainide to suppress ventricular extrasystoles in patients convalescing from myocardial infarction was found in the cardiac arrhythmia suppression trial (CAST) to increase mortality.7 While the mechanism underlying this effect is not known, a synergistic action of sodium channel block and recurrent transient myocardial ischemia to provoke ventricular tachycardia or ventricular fibrillation is strongly suspected from clinical and animal model studies. The clinical implication of CAST for contemporary antiarrhythmic treatment and antiarrhythmic drug development cannot be underestimated. As a result of this landmark trial:

  • non-sustained ventricular arrhythmias are generally not treated (or treated with antiadrenergic agents);

  • we recognise increasingly that the risk of adverse reactions to antiarrhythmic drugs is driven by an interaction between the drug and an abnormal electrophysiologic substrate;

  • drug development moved away from drugs with prominent sodium channel blocking properties to drugs with more prominent effects to prolong action potentials8;

  • and non-pharmacologic therapy has emerged as a major mode of treatment.9

Most importantly, CAST demonstrated the power of the controlled clinical trial to evaluate treatments for any disease and the dangers of relying on surrogate end points (such as extrasystoles) to guide drug therapy.

Effect of drugs on long term arrhythmia mortality

A number of other studies have also supported a detrimental effect of sodium channel blockers in the post-myocardial infarction population. Early trials with disopyramide and mexiletine both showed trends to increased mortality. In CAST-II, moricizine was found to increase mortality notably in the two weeks following the institution of treatment, although the effect long term was less striking than with flecainide and encainide. A meta-analysis10 and a non-randomised post-hoc analysis11 suggested that quinidine or procainamide treatment in patients with atrial fibrillation was associated with a higher mortality than among patients not receiving these agents. The role of antiarrhythmic drugs to maintain sinus rhythm versus AV nodal blocking drugs or other treatment to control rate in atrial fibrillation is being studied in AFFIRM, whose results should be available in the next 2–3 years.

One consequence of CAST was a general consensus, on the part of clinical investigators and regulatory authorities, that licensing new antiarrhythmic drugs might well require demonstration that those drugs did not increase mortality. Two large mortality trials have been conducted with “pure” IKr blocking compounds: SWORD tested the dextro-rotary (non-β blocking) isomer of sotalol, and DIAMOND tested dofetilide. In SWORD, d-sotalol increased mortality,12 whereas in DIAMOND, dofetilide produced no effect on mortality.13 These differences likely arose from differences in trial design, and in particular efforts to minimise the possibility of torsades de pointes during long term treatment in DIAMOND. Amiodarone has been tested in a CAST-like population and been found to exert a modest effect to decrease mortality,14 an effect that may be potentiated by co-administration of β blockers.15 Despite numerous attempts, calcium channel blockers have not been shown to exert a major effect to reduce mortality following myocardial infarction. ALIVE is testing a new potassium channel blocking agent (azimilide). At this point, the mainstay of drug treatment to reduce mortality following myocardial infarction remains therapies directed at maintaining a normal cardiovascular “substrate”, such as β blockers, angiotensin converting enzyme (ACE) inhibitors, HMG-CoA reductase inhibitors (statins), and aspirin.

Drug interactions

Because antiarrhythmic drugs often have narrow margins between the doses or plasma concentrations required to achieve a desired therapeutic effect and those associated with toxicity, drug interactions tend to be especially prominent. This difficulty is exacerbated by the fact that most patients receiving antiarrhythmic drugs receive other treatments as well. Conceptually, drug interactions arise from two distinct mechanisms, pharmacokinetic and pharmacodynamic. Pharmacokinetic drug interactions arise when one drug modifies the absorption, distribution, metabolism, or elimination of a second. Pharmacodynamic interactions arise because of interactions that blunt or exaggerate pharmacologic effects without altering plasma drug concentrations.

The greatest likelihood of important pharmacokinetic drug interactions arises when a drug is eliminated by a single pathway and a second drug is administered that modifies the activity of that pathway. Identification of specific genes whose expression results in the enzymes or transport systems mediating drug disposition has led to the realisation that, in some patients, mutations in these genes can result in abnormal drug disposition even in the absence of interacting drugs. Thus, the field of drug interactions and of genetically determined drug disposition are closely linked. The clinical consequences of modulating a drug disposition pathway depend on the pharmacologic effects produced by altered parent drug concentrations and/or altered concentrations of active metabolites whose generation depends on the pathway targeted. These general principles are best understood by considering specific examples (table 4).

Table 4

A molecular view of drug metabolism


More drugs are metabolised by this enzyme than by any other.CYP3A4 is expressed not only in the liver, but also in the intestine and other sites, such as kidney. Presystemic drug metabolism by CYP3A4 in the intestine and the liver is one common mechanism whereby some drugs have a very limited systemic availability. The activity ofCYP3A4 varies widely among individuals, although there is no genetically determined polymorphism yet described. As shown in table 4, many widely used cardioactive agents are substrates for CYP3A4 and inhibition or induction of CYP3A4 activity can lead to important drug interactions.

Perhaps the most spectacular example of aCYP3A4 mediated drug interaction was that between terfenadine and the CYP3A4inhibitors erythromycin or ketaconazole.16 Terfenadine is a very potent IKr blocker in vitro but is ordinarily almost completely (> 98%) metabolised by CYP3A4before entry into the systemic circulation. With co-administration of CYP3A4 inhibitors, this presystemic metabolism is inhibited, terfenadine plasma concentrations rise > 100 fold, and torsades de pointes can ensue. A similar mechanism also explains torsades de pointes during treatment with astemizole and cisapride, and has led to withdrawal or limitations of the drugs' use. CYP3A4 metabolism is induced by co-administration of drugs such as rifampin, phenytoin, and phenobarbital. In this circumstance, concentrations ofCYP3A4 substrates may fall, with attendant loss of pharmacologic effect. This has been well documented with quinidine and mexiletine.


This enzyme is expressed in the liver and is responsible for biotransformation of many β blockers (timolol, metoprolol, propranolol), propafenone, and codeine. CYP2D6“poor metabolisers” are deficient inCPY2D6 activity, on a genetic basis; 7% of whites and African Americans (but very few Asians) are poor metabolisers. Quinidine and a number of antidepressants (both tricyclics and selective serotonin reuptake inhibitors such as fluoxetine) are potent CYP2D6 inhibitors. When these inhibitors are given to patients receiving β blockers or propafenone (which has weak β blocking activity), or such substrate drugs are administered to patients who are poor metabolisers, exaggerated β blockade occurs. Indeed, clinical data strongly support the idea that absence of CYP2D6 activity increases the likelihood of side effects during propafenone treatment.17 On the other hand, absence ofCYP2D6 activity in a patient receiving codeine results in failure of biotransformation to a more active metabolite (morphine). Thus, in this situation, inhibition of drug metabolism actually leads to a (“paradoxical”) decrease in pharmacologic effect.


Movement of drugs across cell membranes is increasingly recognised as a process dependent on normal expression and function of specific “transport” molecules. The most widely studied of these is P-glycoprotein, expressed on the luminal aspect of enterocytes, on the biliary canalicular aspect of hepatocytes, and the capillaries of the blood–brain barrier. Many widely used drugs are P-glycoprotein substrates, although the functional consequences of P-glycoprotein inhibition are small because most drugs have other pathways for their elimination. Clinically, the most important P-glycoprotein substrate in cardiovascular use is digoxin, which does not undergo extensive metabolism by enzymes such asCYP3A4 or CYP2D6. Rather, its bioavailability is limited by re-excretion by P-glycoprotein into the intestinal lumen, and its elimination is accomplished by excretion by P-glycoprotein and possibly other transporters in liver and kidney. The effect of multiple, structurally unrelated drugs such as quinidine, verapamil, amiodarone, cyclosporine, erythromycin, and itraconazole to increase digoxin concentrations likely has the common mechanism of P-glycoprotein inhibition.18

Pharmacodynamic drug interactions

Pharmacodynamic interactions tend to manifest primarily in patients with underlying heart disease. Thus, when β blockers and calcium channel blockers are co-administered, pronounced bradycardia or heart block occurs primarily in patients with underlying conduction system disturbances. Similarly, exacerbation of heart failure is more of a problem when multiple drugs with cardiodepressant actions (including, prominently, antiarrhythmics) are co-administered to patients with underlying heart disease.

Putting it all together: matching the patient, the drug, and the arrhythmia

Decades of clinical investigation and, more recently, whole animal, cellular, molecular, and genetic studies, have now positioned clinicians to more rationally prescribe and monitor treatment with drugs designed to treat cardiac arrhythmias. A number of very important principles can be enunciated based on these data.

Establish a firm diagnosis

The treatment of ventricular tachycardia as aberrantly conducted supraventricular tachycardia not only exposes patients to risk, but delays appropriate therapy. Other diagnostic issues that may impact on choice of treatments include recognition of specific arrhythmias “syndromes”, such as torsades de pointes, “idiopathic” ventricular tachycardia arising in the right ventricular outflow tract or the conducting system, polymorphic ventricular tachycardia with a short QT interval arising in a patient with acute ischaemia, and pre-excitation, particularly in a patient with atrial fibrillation (table 5). Each of these syndromes has a specific identified mechanism, and specific treatments that are indicated and contraindicated, based on mechanistic principles.

Table 5

Clinical conditions modifying choice of antiarrhythmic agents

Anticipate side effects

Unfortunately, the choice of specific agents to be used in common arrhythmia syndromes is often driven more by the clinician's estimate of a likely adverse effect rather than a clear understanding of mechanism or that one drug demonstrates efficacy that is superior to another. Thus, sodium channel blocking agents such as flecainide or propafenone are highly inappropriate to use in treating patients with atrial fibrillation in patients with ischaemic cardiomyopathy, yet are among the drugs of choice in patients with no structural heart disease.19 Disopyramide is a reasonable option for some patients with atrial fibrillation, but should not be used in patients with glaucoma or prostatism because of the likelihood of precipitating extracardiac adverse effects. Patients with borderline long QT intervals may be at increased risk for torsades de pointes during QT prolonging treatments such as sotalol or dofetilide.

Another variation of this consideration is the presence of chronic non-cardiac disease (table 5). Thus, amiodarone may be relatively contraindicated in a patient with advanced lung disease for two reasons. First, some data suggest such patients may be at increased risk for amiodarone mediated pulmonary toxicity. The second, more important, difficulty with amiodarone from a practical point of view is the likelihood that the patient will present at some point in the future with an exacerbation of dyspnoea, and it will be very difficult, if not impossible, to sort out whether the drug or the underlying disease is responsible. Similarly, drug induced lupus is sufficiently common during long term treatment with procainamide that this drug is especially difficult to use in patients with diseases such as rheumatoid arthritis.

Consider polypharmacy

Many patients for whom antiarrhythmic drug treatment is prescribed are receiving other drugs for cardiac or non-cardiac indications. The prescribing physician should therefore be particularly vigilant when new drugs are added to or removed from a complex regimen in a patient with advanced heart disease, as the likelihood of unanticipated drug actions is high. Drugs that call for special vigilance are those known to be inhibitors of specific metabolic pathways (table 4).

Approach to evaluation of treatment

General principles of rational drug use apply especially to narrow therapeutic index agents such as antiarrhythmics. The baseline arrhythmia should be qualified (for example, do episodes of atrial fibrillation occur daily or monthly?).19 Low drug doses that produce efficacy are more desirable than higher ones. Plasma concentration monitoring, ECG evaluation, and interval history should be evaluated during treatment to detect or anticipate potential toxicity. Therapeutic goals should be defined as therapy starts: Get rid of all atrial fibrillation? All symptoms? Should the patient with cardiac arrest survive to get to the hospital, or be discharged from the hospital?20 Drugs should not be declared ineffective unless those goals are met in a compliant patient receiving doses just below those that produce, or are likely to produce, toxicity.

Finally, patients never “fail” drugs—drugs fail patients.

Trial acronyms

AFFIRM: Atrial Fibrillation Follow-up Investigation of Rhythm Management
ALIVE: Azimilide post-Infarct Survival Evaluation
CAMIAT: Canadian Amiodarone Myocardial Infarction Arrhythmia Trial
CAST: Cardiac Arrhythmia Suppression Trial
DIAMOND: Danish Investigation of Arrhythmia and Mortality on Dofetilide
EMIAT: European Myocardial Infarction Amiodarone Trial
IMPACT: International Mexiletine and Placebo Antiarrhythmic Coronary Trial
SPAF: Stroke Prevention in Atrial Fibrillation
SWORD:  Survival With Oral d-sotalol


Supplementary materials

  • Additional references for "Antiarrhythmic drugs: from mechanisms to clinical practice" by Dan Roden. Heart 2000;84:339-346.

    Mechanisms of antiarrhythmic drug action

    1. Antzelevitch C, Sun ZQ, Zhang ZQ, et al. Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and Torsades de Pointes. J Am Coll Cardiol 1996;28:1836-48.
    2. Balser JR, Nuss HB, Orias DW, et al. Local anesthetics as effectors of allosteric gating. Lidocaine effects on inactivation-deficient rat skeletal muscle Na channels. J Clin Invest 1996;98:2874-86.
    3. Coromilas J, Saltman AE, Waldecker B, et al. Electrophysiological effects of flecainide on anisotropic conduction and reentry in infarcted canine hearts. Circulation 1995;91:2245-63.
    4. El-Sherif N, Chinushi M, Caref EB, et al. Electrophysiological mechanism of the characteristic electrocardiographic morphology of torsade de pointes tachyarrhythmias in the long-QT syndrome: detailed analysis of ventricular tridimensional activation patterns. Circulation 1997;96:4392-9.
    5. Fujiki A, Usui M, Nagasawa H, et al. ST segment elevation in the right precordial leads induced with class Ic antiarrhythmic drugs: insight into the mechanism of Brugada syndrome. J Cardiovasc Electrophysiol 1998;10:214-18.
    6. Harrison DC. Current classification of antiarrhythmic drugs as a guide to their rational clinical use. Drugs 1986;31:93-5.
    7. Hondeghem LM, Katzung BG. Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 1977;472:373-98.
    8. Johnson EA, McKinnon MG: The differential effect of quinidine and pyrilamine on the myocardial action potential at various rates of stimulation. J Pharmacol Exp Ther 1957;120:460-8.
    9. Klein GJ, Bashore TM, Sellers TD, et al. Ventricular fibrillation in the Wolff-Parkinson-White syndrome. N Engl J Med 1979;301:1080-5.
    10. Krishnan SC, Antzelevitch C. Flecainide-induced arrhythmia in canine ventricular epicardium. Phase 2 reentry? Circulation 1993;87:562-72.
    11. Myerburg RJ, Kessler KM, Cox MM, et al. Reversal of proarrhythmic effects of flecainide acetate and encainide hydrochloride by propranolol. Circulation 1989;80:1571-9.
    12. Roden DM, Wilde AA. Drug-induced J point elevation: a marker for genetic risk of sudden death or ECG curiosity? J Cardiovasc Electrophysiol 1999;10:219-23.
    13. Roden DM, Spooner PM. Inherited long QT syndromes: a paradigm for understanding arrhythmogenesis. J Cardiovasc Electrophysiol 1999;10:1664-83.
    14. Roden DM, Hoffman BF. Action potential prolongation and induction of abnormal automaticity by low quinidine concentrations in canine Purkinje fibers. Relationship to potassium and cycle length. Circ Res 1985;56:857-67.
    15. Stewart RB, Bardy GH, Greene HL. Wide complex tachycardia: misdiagnosis and outcome after emergent therapy. Ann Intern Med 1986;104:766-71.
    16. Vorperian VR, Zhou ZF, Mohammad S, et al. Torsades de Pointes with an antihistamine metabolite - potassium channel blockade with desmethylastemizole. J Am Coll Cardiol 1996;28:1556-61.

      Clinical evaluations of antiarrhythmic drug efficacy and adverse effects
    1. Beta-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. JAMA 1982;247:1707-14.
    2. Cairns JA, Connolly SJ, Roberts R, Gent M, The Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Lancet 1997;349:675-82.
    3. Daoud EG, Strickberger SA, Man KC, et al. Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery. N Engl J Med 1997;337:1785-91.
    4. IMPACT Research Group. International mexiletine and placebo antiarrhythmic coronary trial: I. Report on arrhythmia and other findings. J Am Coll Cardiol 1984;4:1148-63.
    5. Julian DG, Jackson FS, Prescott RJ, et al. Controlled trial of sotalol for one year after myocardial infarction. Lancet 1982;i:1142-7.
    6. Julian DG, Camm AJ, Frangin G, et al, The European Myocardial Infarct Amiodarone Trial Investigators. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet 1997;349:667-74.
    7. Juul-Möller S, Edvardsson N, Rehnqvist-Ahlberg N. Sotalol versus quinidine for the maintenance of sinus rhythm after direct current cardioversion of atrial fibrillation. Circulation 1990;82:1932-9.
    8. Kowey PR, Levine JH, Herre JM, et al, Intravenous Amiodarone Multicenter Investigators Group. Randomized, double-blind comparison of intravenous amiodarone and bretylium in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or fibrillation. Circulation 1995;92:3255-63.
    9. Mason JW. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. Electrophysiologic Study versus Electrocardiographic Monitoring Investigators. N Engl J Med 1993;329:452-8.
    10. Mcanulty J, Halperin B, Kron J, et al. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997;337:1576-83.
    11. Minardo JD, Miles WM, Heger JJ, et al. Clinical characteristics of patients with ventricular fibrillation during antiarrhythmic therapy. N Engl J Med 1988;319:257-63.
    12. Morganroth J, Horowitz LN. Flecainide: its proarrhythmic effect and expected changes on the surface electrocardiogram. Am J Cardiol 1984;53:89B-94B.
    13. Oral H, Souza JJ, Michaud GF, et al. Facilitating Transthoracic Cardioversion of Atrial Fibrillation with Ibutilide Pretreatment. N Engl J Med 1999;340:1849-54.
    14. Podrid PJ, Schoeneberger A, Lown B. Congestive heart failure caused by oral disopyramide. N Engl J Med 1980;302:614-18.
    15. Roden DM, Woosley RL, Primm RK. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J 1986;111:1088-93.
    16. Roy D, Talajic M, Thibault B, et al. Pilot study and protocol of the Canadian Trial of Atrial Fibrillation (CTAF). Am J Cardiol 1997;80:464-8.
    17. Stambler BS, Wood MA, Ellenbogen KA. Antiarrhythmic actions of intravenous ibutilide compared with procainamide during human atrial flutter and fibrillation - electrophysiological determinants of enhanced conversion efficacy. Circulation 1997;96:4298-306.
    18. The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801-7.
    19. The Cardiac Arrhythmia Suppression Trial II Investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 1991;327:227-33.
    20. The Multicenter Diltiazem Post-Infarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988;319:385-91.
    21. UK Propafenone PSVT Study Group. A randomized, placebo-controlled trial of propafenone in the prophylaxis of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation. Circulation 1995;92:2550-7.
    22. UK Rythmodan Multicentre Study Group. Oral disopyramide after admission to hospital with suspected acute myocardial infarction. Postgrad Med J 1984;60:98-107.
    23. Weinberg BA, Miles WM, Klein LS, et al. Five-year follow-up of 589 patients treated with amiodarone. Am Heart J 1993;125:109-20.
    24. Winkle RA, Mason JW, Griffin JC, et al. Malignant ventricular tachy-arrhythmias associated with the use of encainide. Am Heart J 1981;102:857-64.
    25. Wolfe CL, Nibley C, Bhandari A, et al. Polymorphous ventricular tachycardia associated with acute myocardial infarction. Circulation 1991;84:1543-51.
    26. Wyse DG, Anderson JL, Antman EM, et al. Atrial fibrillation follow-up investigation of rhythm management: The AFFIRM study design. Am J Cardiol 1997;79:1198-202.

      Pharmacokinetics, pharmacodynamics, and pharmacogenetics
    1. Caraco Y, Sheller J, Wood AJ. Impact of Ethnic Origin and Quinidine Coadministration on Codeine's Disposition and Pharmacodynamic Effects. J Pharmacol Exp Ther 1999;290:413-22.
    2. Data JL, Wilkinson GR, Nies AS. Interaction of quinidine with anticonvulsant drugs. N Engl J Med 1976;294:699-702.
    3. Leahey EB Jr, Reiffel JA, Drusin RE, et al. Interaction between quinidine and digoxin. JAMA 1978;240:533-4.
    4. Priori SG. Exploring the hidden danger of noncardiac drugs. J Cardiovasc Electrophysiol 1998;9:1114-16.
    5. Roden DM, Kim RB. Pharmacokinetics, pharmacodynamics, pharmacogenetics, and drug interactions. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. Philadelphia: WB Saunders, 2000:882-90.
    6. Siddoway LA, Thompson KAMKT, McAllister CB, et al. Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 1987;75:785-91.
    7. Thompson PD, Melmon KL, Richards JA, et al. Lidocaine pharmacokinetics in advanced heart failure, liver disease and renal failure in man. Ann Intern Med 1973;78:499-508.
    8. Woosley RL, Drayer DE, Reidenberg MM, et al. Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome. N Engl J Med 1978;298:1157-9.