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:

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. 

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:

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:

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:

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. 

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. Specifically, from Lei et al (2018), 

• Class Ia bind the channel in its open state
• Class Ib bind the channel in its inactivated state
• Class Ic bind the channel in its  inactivated state

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. 

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 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 (I_k), 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:

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:

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):

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

This phenomenon represents the clinically useful tendency of certain Class I agents to permit action potential conduction at normal rates, but to suppress high-frequency action potentials. Some agents are more effective during faster heart rates because they favour inactive sodium channels and dissociate slowly from the receptors. 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. The best illustration for this comes from Weirich & Antoni (1998), so good that no modification is required:

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 and benzocaine) should be potentiated by only the most extreme tachycardia, and the QRS length (or VT cycle time, for that matter) should be unaffected at normal heart rate.
• Moderately slowly dissociating  Class Ia agents (eg. procainamide) should have a rate-dependent block which should be relatively minor in the normal range of heart rates.  
• Extremely slowly dissociating drugs (Class Ic agents such as flecainide) should exert a block observable even at normal heart rates, and be amplified considerably by a fast heart rate. 

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.

 

A better way to look at this may be this relationship by Weirich & Antoni (1990), a diagram which hopefully relieves more ambiguity than it creates:

The classes are added here but this is only because the drugs available in Australia are limited to flecainide and lignocaine, which makes the class distribution cleaner, whereas the original data is more messy. The 1C class of agents in this image is actually drawn to a hypothetical curve for a high concentration, the sort required to occupy 33% of the channels and suppress extrasystoles. The authors summarise,

"the drugs with very fast kinetics ( 1b) exert maximal effects on closely coupled extrasystoles or very fast tachyarrhythmias but only weak effects on beats during sinus rhythm or during physiologically increased heart rate"

which we can interpret as "have use dependence", if we want to be fair, because "very fast tachyarrhythmias" is exactly what you would use these drugs for. One does not start lignocaine infusion to keep a person stable at a heart rate of 80; but clearly at rates of 3-4 Hz (i.e. 180-240 bpm) lignocaine will have some use dependence. 

So, when an exam candidate is asked, "does lignocaine have use dependence", what should they answer? There are several sources of confusion here that may ensnare the reader and aggravate their already threatened nervous system. Firstly, "rate dependence", "use dependence" and "frequency dependence" have all been seen in the literature that describes what appears to be the same phenomenon. The reader may become confused by the apparently interchangeable use of these terms by some authors, and the dedication of other authors to distinct definitions for each, as for example in a classic paper by Starmer et al (1984), where right in the abstract they say:

"Use-, frequency-, and voltage-dependent responses describe patterns of peak I_Na when pulse width, pulse frequency, and pulse amplitude are varied."

Whereas Jörg Weirich, in Monophasic Action Potentials (1997), holds that

"Rate or frequency dependence is ...  QRS widening is more pronounced at faster rates."

And in 1992, the same author:

"The action of most antiarrhythmic drugs which block cardiac ionic channels depends on heart rate, which is established as use- or frequency-dependence"

It does not help that some of these agents are used as sodium channel blockers in other circumstances, most notably lignocaine. The use dependence of local anaesthetics is a known phenomenon, and will appear in search results when one decides to google "lignocaine + use dependence", but is observed at noncardiac frequencies of 5-100Hz (i.e. the firing rate of nociceptive neurons), and is therefore is relevant only to the local anaesthetic actions of this drug.

It also does not help that some authoritative-seeming sources say something completely different about the use-dependence of Class I agents,  and that lignocaine is placed in different categories depending on where you read - Weirich lists it among the agents that have use-dependence within the normal heart rate range, whereas on page 241 of the 14th edition of Katzung it seems to be described as rate-independent ("the rapid kinetics at normal resting potentials result in recovery from block between action potentials and no effect on conduction"). There even seems to be disagreement as to whether a drug is called "frequency-dependent" if its effect is only observed during tachycardia, or whether it is "frequency-dependent" when its effect is observed even during normal rates, or whether "frequency dependence" is the whole phenomenon of rate-related channel binding, in which case all the Class I agents would fall into this category. UpToDate seem to imply that Class Ib agents "rarely" have use dependence, but their reference for this assertion is an out-of-date 1984 paper by Hondeghem & Katzung which confuses things by imposing conditions on that statement. Lignocaine has no use-dependence, they hold, except at a membrane potential less negative than -105 mV (it is -90 mV in normal resting myocytes),  and at high concentrations (higher than the usual therapeutic concentration), and in a state of acidosis. In short, when asked about the use dependence of lignocaine, the exam candidate should produce some multicoloured markers and begin to draw a series of dose-response curves under different physiological conditions, until they are interrupted by the alarmed yelling of the examiner.