This chapter isrelevant toSectionG8(iv) of the2017CICM Primary Syllabus, whichasks 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, agroup of membrane stabilisers which are united by their common mechanism of effect, which isinterference with the fast sodium currentin cardiac myocytes.Only one past paperSAQ (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 Iagents:
- All have local anaesthetic effects
- All bind to a site in the pore of the Nav1.5 subunit of the fast voltage-gatedsodium 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)
- Prolongedrepolarisation (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 Ibagents
- 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 Icagents
- 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 theduration 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 uniqueelectrophysiological 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 leastuseless. Reading throughCarmeliet & 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 thisentire 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 1853as an antipyretic, and that theuse ofCinchonabark 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 cavepaintingsdepicting 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 procainamideare widely used around the world and have strong support from various royal societies and professional organisations, but for some stupid reason arenot 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 reallyneedthem, you alsoreallyneed 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 wellto atabular format", and specifically "there is an excellent table in Stoelting which answers this questionnicely."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 somehowthe ability to reproduce accurate well-labelled diagrams isequated 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, butwhyis it so? The next section makes some effort to elaborate on this, at the cost of frustrating the impatient reader. Incase they want to see what a succinct professional take on this topic might look like, they are redirected to Shenasa et al (1995)orShenasa et al (2020).
Effects of Class Iagents 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 toa 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 notconducting 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 specificbinding 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 arestate-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 weirdRauwolfiaextracts 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
- 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 theduration of the action potential
When represented accurately (i.e. looking at actual measurements from real muscle), the action potential prolongation would seemrelatively trivial. For example,Salata & Wasserstrom (1987), reporting on the effects ofquinidine, 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 isconducted 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 theinhibition of this current increases the efficiency of repolarisation and shortens the duration of Phase 2. The effect of therapeutic concentrations is probably rather modest, butBigger & 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/Lof lignocaine) isin fact23.4mg/L, over four times higher than the maximum acceptable therapeutic concentration (the range being1.5-5.0 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 diagramliterally, 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 0.65msec. 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, asthere 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, andto draw the action potential correctly would risklosing 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 significantslowing 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 asthe 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 periodmainly 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 byHarrison 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
- Class Ia drugs prolong both the QRS and QT
- Class Ibdrugs have no effect on the QRS, andslightlyshorten the QT.
- Class Icdrugs 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 durationdepends 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 Iagents 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 extremelyrapidlyfrom 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.
Quinidine, disopyramide, procainamide, lidocaine, mexiletine, flecainide, and propafenone are all class I antiarrhythmic drugs (table 1) used for the treatment of various atrial and ventricular arrhythmias.What is a Class 1 antiarrhythmic mechanism? ›
Class I antiarrhythmic drugs are sodium channel inhibitors that act by slowing myocardial conduction and, thus, interrupting or preventing reentrant arrhythmia.What are the 4 antiarrhythmic drugs? ›
There are four main groups of antiarrhythmic medications: class I, sodium-channel blockers; class II, beta-blockers; class III, potassium-channel blockers; class IV, calcium-channel blockers; and miscellaneous antiarrhythmics, or unclassified antiarrhythmics.What is Class 1 antiarrhythmic use dependence? ›
Background: Type I antiarrhythmic drugs block the cardiac sodium channel in a use-dependent fashion. This use-dependent behavior causes increased drug binding and consequently increased sodium channel blockade at faster stimulation rates.What are Class 2 antiarrhythmics? ›
Class 2 antiarrhythmics include beta-blockers, which exert their therapeutic effects by blocking epinephrine. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels.What is an example of a Class 1 antiarrhythmic? ›
Sodium-channel blockers comprise the Class I antiarrhythmic compounds according to the Vaughan-Williams classification scheme. These drugs bind to and block fast sodium channels that are responsible for rapid depolarization (phase 0) of fast-response cardiac action potentials.What is the difference between Class 1 and Class 2 antiarrhythmics? ›
Class I agents interfere with the sodium (Na+) channel. Class II agents are anti-sympathetic nervous system agents. Most agents in this class are beta blockers. Class III agents affect potassium (K+) efflux.What are Class 2 antiarrhythmic drugs examples? ›
Class II, beta blockers: These drugs slow down the heart rate, often by blocking hormones such as adrenaline. Examples include acebutolol, atenolol, bisoprolol, metoprolol, nadolol and propranolol.What are Class 1 C antiarrhythmics? ›
Class IC antiarrhythmic drugs (AADs) perform their antiarrhythmic action mainly by blocking rapid sodium channels, thereby slowing down the Phase 0 of the monophasic action potential and consequently the impulse conduction, mainly in the common myocardial cells.What are Class 3 antiarrhythmic drugs? ›
Amiodarone, sotalol, dofetilide, and ibutilide are examples of class III drugs that are currently available. Amiodarone and sotalol have other antiarrhythmic properties in addition to pure class III action, which differentiates them from the others. However, all have potential serious adverse events.
Class I: Fast sodium (Na) channel blockers
Ia -Quinidine, procainamide, disopyramide (depress phase 0, prolonging repolarization) Ib -Lidocaine, phenytoin, mexiletine (depress phase 0 selectively in abnormal/ischemic tissue, shorten repolarization)
We'll focus on class I antiarrhythmics which are further broken down into 1a, 1b, and 1c. All three groups work on Na+ channels in the cardiac myocytes, so class I medications are also called Na+ channel blockers.What class is amiodarone? ›
Amiodarone is considered a class III anti-arrhythmic drug. It blocks potassium currents that cause repolarization of the heart muscle during the third phase of the cardiac action potential.What are Class 5 antiarrhythmics? ›
Class 5 antiarrhythmic drugs are a miscellaneous group of medications that do not belong to a traditional class of antiarrhythmics. These drugs have varied mechanisms of action and uses. The medications in this class are digoxin.What are Class 4 antiarrhythmics used for? ›
WHAT ARE CLASS IV ANTIDYSRHYTHMICS AND HOW DO THEY WORK? Antidysrhythmics, also known as antiarrhythmics, are drugs used to prevent abnormal cardiac rhythms such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation.What are Class 1 B antiarrhythmics drugs? ›
|Tocainide||Cytochrome P450 1A2||enzyme|
|Aprindine||Alpha-1-acid glycoprotein 1||carrier|
We'll focus on class I antiarrhythmics which are further broken down into 1a, 1b, and 1c. All three groups work on Na+ channels in the cardiac myocytes, so class I medications are also called Na+ channel blockers.Which phase of the action potential do Class 1 antiarrhythmic drugs affect? ›
The SVW classification categorizes antiarrhythmic drugs into four classes (Table 27.1). Class I denotes sodium (Na+) channel blocking activity, with resultant delay in phase 0 depolarization and/or altered action potential duration.