This chapter is relevant to Section G8(iv) of the 2017 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.
- 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:
- 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.
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.
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.
|Drug||Year of availability||Subclass|
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).
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).
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:
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:
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).
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 (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:
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).
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.
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:
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).
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 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.