Class I antiarrhythmic agents

This chapter is relevant to Section G7(iii)  of the 2023 CICM Primary Syllabus, which asks the exam candidate to "understand the pharmacology of antiarrhythmic drugs".  Specifically, the drugs of interest here are the Class I agents by Vaughan Williams classification, a  group of membrane stabilisers which are united by their common mechanism of effect, which is interference with the fast sodium current in cardiac myocytes. Only one past paper SAQ (Question 9 from the second paper of 2012) focused on these drugs directly, and it was mainly interested in their electrophysiology.

In summary:

  • Common features of all Class I agents:
    • All have local anaesthetic effects 
    • All bind to a site in the pore of the Nav1.5 subunit of the fast voltage-gated sodium channel
    • All prefer to bind to open or inactivated sodium channels (though some remain bound even when the channels return to their resting state)
    • Effects are more pronounced in ischaemic tissue
  • Subclasses of Class I agents:
    • In the Vaughan Williams classification, Class I agents are divided into three subclasses according to their receptor dissociation kinetics:
      • Class Ia: intermediate dissociation kinetics,
      • Class Ib: fast dissociation kinetics, and
      • Class Ic: slow dissociation kinetics
    • Each class has distinct effects on the shape of the cardiac action potential:
      Effects of antiarrhythmic drugs on the cardiac action potential
  • Origin of the antiarrhythmic effect:
    • Suppression of excitability (by depressant effect on Phase 0)
    • Slowed conduction (by depressant effect on Phase 0)
    • Prolonged repolarisation (by increasing the action potential duration)
  • Electrophysiological properties:
    • Class Ia agents
      • Prolongs the duration of the action potential (mainly by their potassium channel blocker effects)
      • Therefore, prolong the QT interval
      • Prolong the QRS complex because of a longer Phase 0
      • Use-dependence: block effect (and QRS prolongation) is more pronounced in tachycardia because of slow dissociation from the binding site in diastole
    • Class Ib agents
      • Have no effect on the duration of Phase 0
      • Therefore, do not prolong the QRS
      • Dissociate rapidly from the binding site, therefore free from use dependence
      • Shorten the duration of the action potential, mainly by preventing late sustained sodium current
      • Therefore, shorten the QT interval
    • Class Ic agents
      • Prolong Phase 0 more than other subclasses
      • Therefore, prolong the QRS duration
      • Dissociate slowly from the binding site, which means they are highly use-dependent (with tachycardia, QRS prolongation is greatest)
      • Have little effect on the duration of the action potential and therefore do not prolong the QT interval

Though it appears that virtually everybody has at some stage published a paper or written a blog post about Class I agents, it was remarkably difficult to track down enough information about the origins and mechanisms of their unique electrophysiological properties. What is offered here was pieced together from several sources, none of which could be recommended independently, as each has substantial shortcomings.  Shenasa et al (2020) and the antiarrhythmic chapter from Goodman & Gillman were probably the least useless. Reading through Carmeliet & Mubagwa (1998) would probably also have been productive, if the author had any patience. 

Pharmacokinetics of Class I agents

The pharmacokinetics of Class I agents is by far the most boring and least examinable part of this entire topic, and it is highly unlikely that anybody will ever be interested in them. All things considered, one could easily just present this by picking one agent for each subclass as a representative. 

Name Procainamide Lignocaine Flecainide
Class Class Ia antiarrhythmic Class Ib antiarrhythmic Class Ic antiarrhythmic
Chemistry Aminobenzamide monocarboxylic acid amide monocarboxylic acid amide
Routes of administration Oral and IV IV, inhaled, subcutaneous Oral
Absorption Oral bioavailability = 75-95% Oral bioavailability = 35% Excellent GI absorption (90%); bioavailability is ~ 95%
Solubility Highly water soluble; pKa 9.32 pKa = 7.9; about 25% is not ionised at pH 7.4 pKa = 9.3; mainly water soluble at physiological pH
Distribution VOD = 1.5-2.5L/kg; only 15-25% protein bound VOD= 0.6-4.5L/kg; 60-80% protein-bound VOD = 8.7 L/kg; 40% protein-bound
Target receptor Nav1.5 subunit of the fast voltage-gated sodium channels Nav1.5 subunit of the fast voltage-gated sodium channels Nav1.5 subunit of the fast voltage-gated sodium channels
Metabolism Hepatic metabolism of some variable fraction, into active metabolites (NAPA) Hepatic metabolism (90-95%) 70% of a dose undergoes hepatic metabolism (and some people are slow metabolisers)
Elimination Half-life 3-4 hours; a significant proportion of the drug is excreted unchanged in the urine Minimally renally excreted; half-life 10-20 minutes following IV bolus 30% is excreted renally as unchanged drug; half-life is about 20 hours
Time course of action Duration of action is similar to half-life of the drug and its metabolites, ~ 4-8 hrs Duration of action is similar to half-life Duration of action is similar to half-life
Single best reference for further information Giardina (1984) Weinberg et al (2015) TGA PI

Now that this silliness is behind us, the real money is in the pharmacodynamic effects. 

Class I antiarrhythmic agents

The selection of agents presented here in chronological order of market appearance is not made available for any educational reason, and represents a pointless historical digression. Another would be to mention that quinidine has been known since 1853 as an antipyretic, and that the use of Cinchona bark goes back centuries and potentially millennia, though the ancient indigenous civilizations of Peru were presumably more interested in its antimalarial properties, as we have not yet found any cave paintings depicting cardiac action potentials.

Class I antiarrhythmic agents
Drug Year of availability Subclass
Quinidine 1912-2019 Ia
Lignocaine 1948 Ib
Procainamide 1950 Ia
Mexiletine 1976 Ib
Disopyramide 1977 Ia
Flecainide 1985 Ic
Propafenone 1989 Ic

Clinically, one usually encounters these drugs in the management of ventricular arrhythmias, for which purpose they seem almost uniquely suited. Specifically, the Australian ICU trainee will find themselves using lignocaine quite often, and occasionally seeing patients chronically on flecainide or mexiletine. Other drugs such as procainamide are widely used around the world and have strong support from various royal societies and professional organisations, but for some stupid reason are not available in Australia (I'm looking at you, TGA). 

Electrophysiological effects of Class I antiarrhythmic agents

This group of drugs receive little attention from the CICM examiners, which is unfortunate, as their use falls into the "low frequency, high consequence" territory of medical education (i.e. when you really need them, you also really need to know them). Question 9 from the second paper of 2012 was so far the only SAQ which focused on these substances, devoting 70% of the total mark to comparing and contrasting "the electrophysiological effects" of Class I agents. Apparently this "lent itself very well to a tabular format", and specifically "there is an excellent table in Stoelting which answers this question nicely." Presumably, they were referring to this:

Table of antiarrhythmic drug effects from Stoelting

This table is actually from the 2015 (3rd) edition of Stoelting (p.419), which antedates the examiner comment, but is in fact identical to the 2nd edition (just more colourful). It also does not contain diagrams of action potentials, which seems to be an essential part of a high-scoring answer, as somehow the ability to reproduce accurate well-labelled diagrams is equated with a high-level understanding of the subject. By the same logic, an inkjet printer could be accused of understanding pharmacology. Still, diagrams are important, and the trainees are invited to reproduce these simplified versions in their exam:

Effects of antiarrhythmic drugs on the cardiac action potential

This monochrome-and-dots version should be easy to reproduce in biro, but has zero explanatory power. Yes, the shape of the action potential is changed, but why is it so? The next section makes some effort to elaborate on this, at the cost of frustrating the impatient reader. In case they want to see what a succinct professional take on this topic might look like, they are redirected to Shenasa et al (1995) or Shenasa et al (2020).

Effects of Class I agents on the shape of the cardiac action potential

Recall the shape of the normal cardiac action potential, which everybody always ends up having to draw for their exams:

cardiac action potential phases

Recall also that Phase 0 is the phase of rapid inward sodium current, which depolarises the membrane rapidly to a potential of around +40 mV. 

Phase 0 of the cardiac cycle

This rapid depolarisation is due to the opening of fast voltage-gated sodium channels, which are the drug target of Class I agents. As you can see, they are called fast for a reason. Phase 0 of the cardiac action potential, during which they remain open, lasts only about 0.5 milliseconds.

These sodium channels have three basic states:

  • The resting state, where they are waiting quietly for an action potential to arrive
  • The open state,  when the channel is activated and conducts a sodium current 
  • The inactivated state, where the channel is not conducting a sodium current, but has not yet returned to its resting state. During this absolute refractory period, the sodium channel cannot be activated again. This period is often quite quick, less than 100 msec.

Sodium channel blockers mostly tend to bind to a specific binding site in the pore of subunit Nav1.5, which is only available when the channel is open or inactivated. Thus, the kinetics of their relationship with the drug target are state-dependent: they have little affinity for the receptors in their resting state, and dissociate from their drug target with every diastole. It is this dissociation which gives different properties to the a, b and c subclasses of Class I antiarrhythmics. Specifically, Vaughan Williams subdivided these drugs in the following fashion:

  • Class Ia: intermediate dissociation kinetics,
  • Class Ib: fast dissociation kinetics, and
  • Class Ic: slow dissociation kinetics

The diagram from Scholz (1994) below, albeit somewhat distorted by time and crude scanning techniques, allows us to compare the channel dissociation kinetics of a selection of Class I agents. It has been colourised to illustrate the fact that some of these drugs do not neatly fall into the aforementioned subclassification category. However, if you ignore the weird Rauwolfia extracts at the bottom, order appears to be maintained. 

Dissociation constants of Class I antiarrhythmics and their subclassification

So: how do these dissociation kinetics change the shape of the cardiac action potential? Well. It was initially thought that the effect on the action potential and the clinical effect was largely the consequence of drug-receptor kinetics. To quote Vaughan Williams (1984), 

"...the actions of lidocaine and other class 1 drugs can be attributed to interference with recovery from inactivation of sodium channels, without involving other effects"

However, as it turns out, essentially none of the actions of Class 1 agents on the action potential are related to their dissociation from the receptor (though it is important, and does play a role in use dependence). 

Effect of Class I agents on the duration of the action potential

In summary:

  • Class Ia agents prolong the duration of the action potential mainly by their potassium channel blocker effects, which is really a Class III thing.
  • Class Ib agents shorten the duration of the action potential, mainly by preventing late sustained sodium current
  • Class Ic agents have little effect on the duration of the action potential

When represented accurately (i.e. looking at actual measurements from real muscle), the action potential prolongation would seem relatively trivial. For example,  Salata & Wasserstrom (1987), reporting on the effects of quinidine, produced the following grainy image:

the effect of quinidine on the cardiac action potential, from Salata & Wasserstrom (1987)

The main reason for this prolonged repolarisation isa potassium channel blocker effect, completely unrelated to the sodium channel block produced by these drugs (Roden et al, 1988). Specifically, Class Ia agents act on the delayed rectifier currents (Ik), which are responsible for Phase 3 of the action potential. 

In contrast, Class Ib agents like lignocaine shorten the duration of the action potential, also by a relatively trivial looking fraction. They are thought to exert their effect during Phase 2 of the cardiac action potential. During this period, there is thought to be some sort of sustained "window" current of sodium. It is hard to say why it is called the "window" current, but one can imagine it as something like a draft in a cold part of the house, as it is conducted via the same fast voltage-gated sodium channels, leaking in because their inactivation process is incomplete. Of the total sodium flux, about 1-2% is thought to occur in this way (Noble & Noble, 2006). This inward sodium current is a depolarising influence, as it brings positive change into the cell, and therefore the inhibition of this current increases the efficiency of repolarisation and shortens the duration of Phase 2. The effect of therapeutic concentrations is probably rather modest, but Bigger & Mandel (1970), by using progressively higher and higher doses of lignocaine, were able to change the shape of the action potential to a significant degree:

effects of increasing lignocaine concentration on AP duration from Bigger & Mandel (1970)

Realistically, your patient's action potentials would never end up looking like that, because the concentration here (0.1 mmol/L of lignocaine) is in fact 23.4mg/L, over four times higher than the maximum acceptable therapeutic concentration (the range being 1.5-5.0 mg/L).

Effect of Class I agents on Phase 0 of the action potential

It is not uncommon to see diagrams like this one, even in reputable publications:

incorrect but representative diagram of Class I agent activity on the cardiac action potential

Interpreting this diagram literally, one might come to the conclusion that Class Ic drugs prolong the duration of Phase 0 to the point where it occupies almost half of the total action potential duration. In fact, nothing could be further from the truth.

Consider: Phase 0 is normally a fleeting blink of an event, lasting 0.5 milliseconds. The rate of change in voltage is remarkably rapid, generally 250-450 V/sec. Thus, a Class I drug could totally cripple the sodium current and still produce a very short Phase 0. For example, Kus & Sasyniuk (1975), reporting on the effects of disopyramide, reported a change in dV/dt from 433 to 287 V/sec, a 30% increase in the duration of Phase 0 - which would still only bring it from 0.5 msec to 0.65 msec. Even notorious Class Ic agents like flecainide can't stretch this phase to the point where a correctly scaled diagram could ever possibly demonstrate this effect visually in a way which impresses the reader. Observe, a genuine recording from Borchard & Boisten (1982):

The effect of flecainide on the duration of Phase 0, from Borchart and Boisten (1982)

As you can see, the decrease in the slope of Phase 0 is barely noticeable. Consequently, textbook editors have resorted to graph distortion, as there would be no other way to represent it for the purposes of education. The CICM exam candidate is advised to reproduce this inaccuracy in their own diagrams, as it has now become convention, and to draw the action potential correctly would risk losing marks.  

However, this effect - though trivial in the setting of each isolated fibre- has substantial implications for the whole myocardium. These little delays are all cumulative, and they add up to a significant slowing of action potential propagation, which is reflected in the QRS duration of the surface ECG.

Effect of Class I agents on the refractory period

The refractory period of cardiac conducting tissues is  mainly due to the inactivation of sodium channels. Most studies that report this matter tend to focus on the "effective" refractory period, which is defined as the period during which the cell cannot produce an action potential which could depolarise surrounding muscle. In case anyone is wondering what a normal effective refractory period looks like, in most of the studies quoted below it was about 250-350 milliseconds. Different subclasses of I have different effects on the refractory period:

  • Class Ia agents increase the effective refractory period, mainly by making the whole action potential longer. The prolongation is actually rather impressive: for instance, for Kastor et al (1977), procainamide increased the ERP by up to 135 msec. This is generally agreed on, and consistent throughout the literature.
  • Class Ic agents have no effect on the effective refractory period, except for the AV node and atrial muscle, where the refractory period is prolonged (O'Hara et al, 1992). This is the basis of the effect of flecainide on atrial fibrillation, for which it is occasionally used. Again, this seems to be an uncontroversial fact, repeated throughout published studies and textbooks.
  • Class Ib agents shorten the effective refractory period mainly by shortening the duration of the overall action potential, or so it is generally stated in textbooks; but if one digs a little deeper, one discovers that this is not exactly an established scientific fact. For example,  Josephson et al (1973) demonstrated that it is true for Purkinje fibres. The shortening was not particularly exciting: the ERPs were only different by 20-30 msec. Conversely,  Li & Northover (1992) found that lignocaine had the opposite effect in anaesthetised rats, and for the subjects of experiments by Harrison et al (1963) and Olssen et al (1975), the ERP increased in some and decreased in others. Even more bizarrely, when another Class Ib agent (mexelitine) was tested by Burke et al in 1986, it shortened the ERP in lower doses, and prolonged it in high doses, whereas lignocaine showed a consistent and dose-dependent ERP-shortening effect. Finally, where lignocaine is discussed in terms of its local anaesthetic effects, it is usually said to increase the refractory period of neurons, adding to the confusion. 

What are we to make of this, dear reader? For the CICM trainee, it would probably be wisest to write an answer where Class Ib agents shorten ERP, because that's what the textbooks tend to say. In this post-truth scenario, the most important thing is to agree with whatever the examiner has been reading, and we can virtually guarantee that none of them are cardiac electrophysiology researchers. For the casual reader, it is only possible to marvel at the confidence of those textbooks, and wonder where it comes from, because no references are provided in support of their statements, and when people do offer references, they are pointless (for example, referring to an obsolete manufacturter's product information pamphlet). 

Effect of Class I agents on the surface ECG

In summary:

  • Class Ia drugs prolong both the QRS and QT
  • Class Ib drugs have no effect on the QRS, and slightly shorten the QT.
  • Class Ic drugs markedly prolong the QRS, and have minimal effect on QT.

The attentive reader will have noticed that QRS prolongation depends on the Phase 0 effects of the drugs, and the QT duration depends on the Phase 2 and Phase 3 effect. In addition, some Class I agents exhibit variable QRS effects depending on the heart rate, which is called "use-dependence".

The phenomenon of use-dependence

The tendency of certain Class I agents to favour inactive sodium channels and to dissociate slowly from the receptors makes them more effective during faster heart rates. Observe: each time the channel opens, block develops, and then gradually un-develops during diastole. Ergo, the shorter your diastole, the less block you lose between beats, and the more potent the block which affects the next beat. This is manifested as an increase in QRS duration which occurs with tachycardia.

On the other hand, if the drug dissociates extremely rapidly from the sodium channels, its activity will again be unaffected by heart rate. Even with a preposterously short diastole, most of the drug will be gone from the active site long before the next systole - which means tachycardia will not do anything to change the effectiveness of the block.

From this, it follows that Class Ia, Ib and Ic agents should all differ in their degree of use dependence. Extremely rapidly-dissociating drugs  (Class Ib agents such as lignocaine) should exhibit minimal use-dependence, and the QRS length (or VT cycle time, for that matter) should be unaffected by heart rate. Moderately slowly dissociating  Class Ia agents (eg. procainamide) should have a clear use dependence effect, but it should be relatively minor.  Extremely slowly dissociating drugs (Class Ic agents such as flecainide) should be the most affected by use dependence, and their effect should be amplified considerably by a fast heart rate. Moreover, for drugs with use-dependence, the QRS prolongation effect should increase with the duration of the tachycardia, as more and more drug molecules end up trapped at the effect site because frequent systoles prevent them from dissociating.

These were the exact findings of a study by Kidwell et al (1993), who looked at the cycle length of reproduceable monomorphic VT among patients receiving different Class I agents. They measured the VT morphology, measured the R-R interval, and then gave an antiarrhythmic to see how a sustained tachycardia affects the cycle length with different agents.  Observe, the graph from their original study below. As you can see, the VT cycle length was instantly and maximally affected by lignocaine, and then stayed more or less the same (though it did not change much - only about 10 msec). In contrast, with flecainide, cycle length increased significantly with time (up to 165 msec), and this use-dependence effect took forty seconds to fully develop.

Demonstration of use dependence for Class I agents from Kidwell et al (1993) 


Capucci, Alessandro, Daniela Aschieri, and Giovanni Quinto Villani. "Clinical pharmacology of antiarrhythmic drugs." Drugs & aging 13.1 (1998): 51-70.

Carmeliet, Edward, and Kanigula Mubagwa. "Antiarrhythmic drugs and cardiac ion channels: mechanisms of action." Progress in biophysics and molecular biology 70.1 (1998): 1-72.

Vaughan Williams, E. M. "Classification of antiarrhythmic drugs." Symposium on Cardiac Arrhythmias. Sweden, Astra 1970. 1970.

Williams, EM Vaughan. "A classification of antiarrhythmic actions reassessed after a decade of new drugs." The Journal of Clinical Pharmacology 24.4 (1984): 129-147.

Lei, Ming, et al. "Modernized classification of cardiac antiarrhythmic drugs." Circulation 138.17 (2018): 1879-1896.

Pott, C., et al. "Class I antiarrhythmic drugs: mechanisms, contraindications, and current indications." Herzschrittmachertherapie & Elektrophysiologie 21.4 (2010): 228-238.

Shenasa, Mohammad, Mohammad-Ali Shenasa, and Mariah Smith. "Class I Antiarrhythmic Drugs: Na+ Channel Blockers." Antiarrhythmic Drugs. Springer, Cham, 2020. 31-105.

Rosen, Michael R., and Peter J. Schwartz. "The'Sicilian Gambit'-A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms." European Heart Journal 12.10 (1991): 1112-1131.

Shenasa, M., et al. "Electrophysiologic Effects, Clinical Efficacy and Antiarrhythmic and Proarrhythmic Effects of Sodium Channel Blockers in Patients with Ventricular Tachyarrhythmias." Antiarrhythmic Drugs. Springer, Berlin, Heidelberg, 1995. 300-320.

Salata, Joseph J., and J. Andrew Wasserstrom. "Effects of quinidine on action potentials and ionic currents in isolated canine ventricular myocytes." Circulation research 62.2 (1988): 324-337.

Scholz, H. "Classification and mechanism of action of antiarrhythmic drugs." Fundamental & clinical pharmacology 8.5 (1994): 385-390.

Kus, Teresa, and Betty I. Sasyniuk. "Electrophysiological actions of disopyramide phosphate on canine ventricular muscle and purkinje fibers." Circulation research 37.6 (1975): 844-854.

Carmeliet, Edward, and Kanigula Mubagwa. "Antiarrhythmic drugs and cardiac ion channels: mechanisms of action." Progress in biophysics and molecular biology 70.1 (1998): 1-72.

Johnson, E. A., and M. G. McKinnon. "The differential effect of quinidine and pyrilamine on the myocardial action potential at various rates of stimulation." Journal of Pharmacology and Experimental Therapeutics 120.4 (1957): 460-468.

Roden, Dan M., et al. "Quinidine delays IK activation in guinea pig ventricular myocytes." Circulation research 62.5 (1988): 1055-1058.

Borchard, U., and M. Boisten. "Effect of flecainide on action potentials and alternating current-induced arrhythmias in mammalian myocardium." Journal of cardiovascular pharmacology 4.2 (1982): 205-212.

Noble, D., and P. J. Noble. "Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium–calcium overload." Heart 92.suppl 4 (2006): iv1-iv5.

Bigger, J. Thomas, and William J. Mandel. "Effect of lidocaine on the electrophysiological properties of ventricular muscle and Purkinje fibers." The Journal of clinical investigation 49.1 (1970): 63-77.

Cheng, Tsung O., et al. "Effect of quinidine on the ventricular complex of the electrocardiogram with special reference to the duration of the QT interval." American heart journal 51.3 (1956): 417-444.

Kidwell, Gregory A., et al. "Use-dependent prolongation of ventricular tachycardia cycle length by type I antiarrhythmic drugs in humans." Circulation 87.1 (1993): 118-125.

Josephson, Mark E., et al. "Effects of lidocaine on refractory periods in man." American Heart Journal 84.6 (1972): 778-786.

Kastor, J. A., et al. "Human ventricular refractoriness. II. Effects of procainamide." Circulation 56.3 (1977): 462-467.

Li, J. Y. M., and B. J. Northover. "Antiarrhythmic and electrophysiological effects of amiodarone, lignocaine, and penticainide in anaesthetised rats." Cardiovascular research 26.11 (1992): 1116-1120.

HARRISON, DONALD C., J. HENRY SPROUSE, and ANDREW G. MORROW. "The antiarrhythmic properties of lidocaine and procaine amide: clinical and physiologic studies of their cardiovascular effects in man." Circulation 28.4 (1963): 486-491.

Burke, G. H., J. E. Loukides, and N. D. Berman. "Comparative electropharmacology of mexiletine, lidocaine and quinidine in a canine Purkinje fiber model." Journal of Pharmacology and Experimental Therapeutics 237.1 (1986): 232-236.

O'Hara, Gilles, et al. "Effects of flecainide on the rate dependence of atrial refractoriness, atrial repolarization and atrioventricular node conduction in anesthetized dogs." Journal of the American College of Cardiology 19.6 (1992): 1335-1342.