Sodium channel binding vs use-dependence

[ChessMaster3000]

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Class 1C binds sodium channels more avidly than 1A or 1B (with 1B being the least avid sodium binding). 1C also displays the most use-dependence, again, with 1 B being the least use-dependent. Could somebody explain if these two principles are in fact the same? As in, does the fact that 1C has the highest affinity translate directly into its use-dependence, or are these two different properties?

 

[ChessMaster3000]

thought I would bump this to see if anyone had any words of wisdom. thanks in advance!

 

[notbobtrustme]

yea, if anyone could help with this, I'd be eternally grateful. I still don't understand what is meant by use-dependence and how that relates to channel inhibition.

 

[MissWilder]

yea, if anyone could help with this, I'd be eternally grateful. I still don't understand what is meant by use-dependence and how that relates to channel inhibition.

According to our pharm notes (I went to those because we had EXCELLENT professors):
Use/State -Dependent:
Drugs bind more rapidly to open or inactivated Na+ channels
Drugs have greater effect in tissues more freq. depolarizing
= Use/state dependence (cells discharging at abnormally high frequency are preferentially blocked)

Which makes sense , if you are having arryhythmias, then the Na+ channels are going to be more active --> more frequent depolarizations so you would want your drugs binding to those channels preferentially over the less active ones.
Hopefully that helps @notbobtrustme

They then went on to state that the Class 1 drugs are simply divided by their kinetics. 1C slowest > 1A intermediate > 1B fastest which was already stated above.
I couldn't find anything about 1C have the greatest use dependence @ChessMaster3000, Where did you see that?

All I could find was that 1C can show , more than the other classes, effects on normal heart rates not just arrhythmias which makes them more "dangerous." And the other point that seems to be asked all the time is that Lidocaine is the "drug of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia."

 

[ChessMaster3000]

According to our pharm notes (I went to those because we had EXCELLENT professors):
Use/State -Dependent:
Drugs bind more rapidly to open or inactivated Na+ channels
Drugs have greater effect in tissues more freq. depolarizing
= Use/state dependence (cells discharging at abnormally high frequency are preferentially blocked)

Which makes sense , if you are having arryhythmias, then the Na+ channels are going to be more active --> more frequent depolarizations so you would want your drugs binding to those channels preferentially over the less active ones.
Hopefully that helps @notbobtrustme

They then went on to state that the Class 1 drugs are simply divided by their kinetics. 1C slowest > 1A intermediate > 1B fastest which was already stated above.
I couldn't find anything about 1C have the greatest use dependence @ChessMaster3000, Where did you see that?

All I could find was that 1C can show , more than the other classes, effects on normal heart rates not just arrhythmias which makes them more "dangerous." And the other point that seems to be asked all the time is that Lidocaine is the "drug of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia."

It was in the context of a UW questions @MissWilder . I cant remember the question ID right now, but basically, my question centers around understanding why 1C is dangerous for post-MI. I understand that 1C affects normal heart rate more than just arrhythmias. Is this related to its use dependence? That's what I don't understand

Thanks!

 

[MissWilder]

Well, I may be totally off, but the way that I think about it :
Post MI the conduction in the heart is going to be all out of whack so would you really want something that is going to cause a channel block that is the longest lasting? Probably not. Plus the fact that they can go after "normally" firing cells, would we want to screw with the ones that are functionally normally? Not really. It's also the most potent and has the most tendency to cause arrhythmias so if there are better safer drugs out there we should go for those. And with Lidocaine, it makes sense that after an MI we would use that because it's like a quick little jolt to get things back to normal plus it's going to go after the dead tissue so it's perfect! (OK, probably a major oversimplification but sometimes, I have to go the easy route!)

I think UWorld is getting there info from "Flecainide increased mortality more than two-fold in post MI patients treated for premature contractions’ (CAST, Cardiac arrhythmia suppression trial)"
I know I haven't address the issue of use-dependence @ChessMaster3000 but I still can't find anything. It seems the large risk of causing arrhythmias is the big contraindication of use.
Hope this clears this up, and I haven't made things worse!

 

[Praxia]

why 1C is dangerous for post-MI. I understand that 1C affects normal heart rate more than just arrhythmias. Is this related to its use dependence?

Use dependence=Ability to bind to AND DISSOCIATE from the in-use(open, inactivated) channels.
State dependence=Ability to bind to a particular state of the channel (in this case open, inactivated)

Now, that bit about Ic being dangerous in Post-MI arrhythmias (or, for that matter any) is because with increased HR, there are many more of open inactive channels that can be blocked. But Ic can't dissociate fast enough(negligible use-dependence), so it enhances "the number of channels blocked" with every next heart beat. Therefore, it literally ends up occupying MOST of the Na channels. Highly pro-arrhythmic.

Now, the Ib have highest use-dependence, therefore their blockade lasts briefly and then they dissociate. After that, normality of rhythm sets in.

Hope it helps.

 

[ChessMaster3000]

Use dependence=Ability to bind to AND DISSOCIATE from the in-use(open, inactivated) channels.
State dependence=Ability to bind to a particular state of the channel (in this case open, inactivated)

Now, that bit about Ic being dangerous in Post-MI arrhythmias (or, for that matter any) is because with increased HR, there are many more of open inactive channels that can be blocked. But Ic can't dissociate fast enough(negligible use-dependence), so it enhances "the number of channels blocked" with every next heart beat. Therefore, it literally ends up occupying MOST of the Na channels. Highly pro-arrhythmic.

Now, the Ib have highest use-dependence, therefore their blockade lasts briefly and then they dissociate. After that, normality of rhythm sets in.

Hope it helps.

So would you say Ic is the most state-dependent but least use-dependent, and Ib is least state-dependent and most use-dependent? Or, does the state-dependence not matter for Ib's safety/efficacy in post-mI arrhythmias? As in, the most important factor in Ib use for post-MI is its use dependence?

Tangentially, is the fact that Ic binds most avidly to sodium channels (as I phrased it in my OP), equivalent to its state dependence?

 

[Praxia]

Yes and yes. In fact, we won't be able to explain use-dependence without the concept of state-dependence and avidity.

About the post-MI part. The infarcted tissue remains depolarised for extended periods(localized hyperkalemia) and consequently prolonged inactivated state.
The class I drugs have more tendency to block them. However, if they produce a prolonged block, then there's more of a chance for arrhythmias to arise. The solution to this problem is Ib drugs, which produce a very short lived block. So that, now, the existent arrhythmia is cleared out by transient block, but new arrhythmias are not possible because cells return to their "normal" unblocked self very quickly (high use dependence of Ib).

This is all best to MY knowledge. If I am wrong somewhere, then please, correct me. Hope it helps.

 

[Praxia]

So basically, we could treat post-MI arrhythmias with any of the class I. But to avoid the dangerous "channel-blockade" arrhythmias, we prefer Ib.

 

[alicealicealice]

About the post-MI part. The infarcted tissue remains depolarised for extended periods(localized hyperkalemia) and consequently prolonged inactivated state.
The class I drugs have more tendency to block them. However, if they produce a prolonged block, then there's more of a chance for arrhythmias to arise. The solution to this problem is Ib drugs, which produce a very short lived block. So that, now, the existent arrhythmia is cleared out by transient block, but new arrhythmias are not possible because cells return to their "normal" unblocked self very quickly (high use dependence of Ib).

I followed this up until the end..Praxias explanation made sense until he said "high use dependence of Ib ." UWorld says that IB is the LEAST use dependent which goes along with the above explanation. However I want to make sure Im not missing something here...should it have said "low use dependence of IB"?

The way I get it is that ischemia = delayed return from inactive to resting.
High Use dependence = greater preference for Active AND Inactive over resting.
All Class I have use dependence, but class IB has the least.
Because Class IB has low use dependence, it will bounce quickly off of the normal tissue Na channels (which cycle from inactive to resting in the normal way), but will preferentially stay on the ischemic channels just because they are inactivated longer.
The net result is having less cumulative effect on the normal channels as compared to the other classes, while still blocking the ischemic tissue (the source of the arrhythmia) which makes them the safest in MI.

The converse is that IC will be the worst post MI because they are the most use dependent, hence will cumulatively block normal tissue as well as ischemic tissue, knocking out way too much of the myocardium.

 

[Fatalis]

picmonic says the same thing, IB is the least use dependent

 

[ChessMaster3000]

I followed this up until the end..Praxias explanation made sense until he said "high use dependence of Ib ." UWorld says that IB is the LEAST use dependent which goes along with the above explanation. However I want to make sure Im not missing something here...should it have said "low use dependence of IB"?

The way I get it is that ischemia = delayed return from inactive to resting.
High Use dependence = greater preference for Active AND Inactive over resting.
All Class I have use dependence, but class IB has the least.
Because Class IB has low use dependence, it will bounce quickly off of the normal tissue Na channels (which cycle from inactive to resting in the normal way), but will preferentially stay on the ischemic channels just because they are inactivated longer.
The net result is having less cumulative effect on the normal channels as compared to the other classes, while still blocking the ischemic tissue (the source of the arrhythmia) which makes them the safest in MI.

The converse is that IC will be the worst post MI because they are the most use dependent, hence will cumulatively block normal tissue as well as ischemic tissue, knocking out way too much of the myocardium.

got it, that makes sense

 

[Praxia]

I was quite confused myself:/
I could not find anything suitable on use dependence until I bumped into this excerpt online from -Encyclopedia of Molecular Pharmacology, vol 1 by Stefan Offermanns.
It's just that this one makes quite a lot of sense.

 

[notbobtrustme]

Just had this doozy of a question on uworld and the explanation didn't help either.

Basically, dude comes in, does a heart stress test with no ST elevations/depressions or chest pain. His QRS complex duration is 95msec and his QTc interval is 410 msec. While he recovers, his QRS is 125msec and his QTc is 400msec. What drug is he on?

A.) Atenolol
B.) Digoxin
C.) Dofelitide
D.) Flecainide
E.) Verapamil

 

[alicealicealice]

In terms of test taking strategy, I would throw out atenolol, digoxin and verapamil immediately as they would act mainly on the PR interval which is not mentioned (ABCD act on AV to prolong PR = adenosine, beta blockers, CCBs, Digoxin)
Then I would eliminated Dofelitide as it is a K blocker and would prolong QTc which is normal in this patient, so that leaves Flecainide.
Flecainide is classically associated with QRS prolongation with exercise and immediately afterward.
This makes sense because Class IC is the strongest and most use dependent Na blocker. It increases the slope of phase 0 (which roughly corresponds with QRS) without extending the ERP and because it is use dependent, Flecainide's QRS prolonging effect increases as the HR increases.
https://www.inkling.com/read/zipes-...e-6th/chapter-63/antiarrhythmics-and-exercise
Also, to integrate points, TCA (tricyclic antidepressant) overdose prolongs QRS by blocking cardiac myocyte Na channels. This is why the initial treatment for TCA overdose is NaHCO3. The Na competes with the TCA for cardiac Na channels and the bicarb reduces the affinity of the TCA for the Na channel. Unlike aspirin overdose, giving sodium bicarb has nothing to do with urine alkalinization for excretion. So relating the QRS with phase 0 and Na channels in your mind is a good rule of thumb when you may be forced to guess.

 

[notbobtrustme]

Yea that's what I did but I felt dirty because I couldn't reason it through. Thanks for the explanation!

 

[InvoluntarySoul]

according to uworld, use dependance for IC is QRS duration is normal at rest and prolonged by increase of heart rate (more Na channels activated)

 

[Doc M87]

according to uworld, use dependance for IC is QRS duration is normal at rest and prolonged by increase of heart rate (more Na channels activated)

@InvoluntarySoul can u explain how blocking Na channels prolongs QRS? APD is decreasing in IC drugs then how QRS is prolonging? I know phase 0 is associated with ventricular depolarization but can't conclude as to how QRS is widening.