Skip to content

Antiarrhythmics (Lesson 6 – Digoxin, Adenosine, Atropine, Isoproterenol, and Ivabradine)

  • by

An overview of the so-called unclassifiable antiarrhythmics, including their mechanism of action, indications, and side effects.

This is eric from strong medicine and in this next to last video on antiarrhythmics i’ll be talking about the unclassifiable drugs specifically the jaxon adenosine atropine and super terran all and evaporating i’ll go through each one at a time so let’s start with the oldest one digoxin digitalis purpurea also known as the common foxglove is a flowering plant originally

Native to europe but now it can be found in parts of north america it was first used as a treatment for heart failure in the 18th century in itself that’s pretty remarkable given that it’s beneficial effects in heart failure are very modest and would seem to be below the limit of detection using just non systematic subjective observations in the 20th century various

Compounds of similar structure and effects were isolated from related plants and are now collectively known as cardiac glycosides of the cardiac glycosides digoxin is by a large margin the most well-known and most widely used to understand the mechanism of the jackson i’ll need to review an aspect of normal cardiac physiology we haven’t yet discussed in all cells

There is a sodium potassium atpase also called the sodium potassium pump this transmembrane protein pumps sodium out of the cell in exchange for potassium entering the cell this helps to maintain a normally high extracellular sodium concentration and the high intracellular potassium concentration and also helps to maintain the normal negative resting membrane

Potential because this translocation of ions occurs against electrochemical gradients energy is required in the form of atp there’s another transmembrane protein in myocytes which acts as a sodium calcium exchanger this exchanger can trade sodium for calcium ions across the membrane in either direction depending upon the electrochemical gradient of each at that

Moment the jackson works by inhibiting the sodium potassium pump the most proximal consequence is that the intracellular sodium increases this leads to a lower gradient driving sodium into the cell which means less calcium is being exchanged out of the cell so intracellular calcium increases that is cytosol ‘ok calcium increases if you recall from lesson three

In this series high cytosolic calcium promotes further release of calcium from an intracellular structure called the sarcoplasmic reticulum in turn this strengthens myocardial contraction when this mechanism doesn’t seem directly relevant to its anti rhythmic effects it does explain a significant portion of arrhythmias caused by digoxin as the elevated cytosolic

Calcium can lead to a phenomenon called delayed after depolarizations after the polarizations are discussed in my video on mechanisms of arrhythmias there is a link in the video description through a separate incompletely understood mechanism digoxin also increases vagal tone on the heart which leads to slowing down of the sinus rate and increase in the duration

Of the av nodes refractory period and a decrease in the av nodes conduction velocity that is how quickly impulses travel through the av node there are only two significant indications for digoxin atrial fibrillation and atrial flutter with rapid ventricular response and heart failure with reduced ejection fraction however due to the jackson’s extensive toxicity

It is considered to be a second or third line agent and is usually not used unless both of the above indications are present as already implied digoxin is one of the most toxic of antiarrhythmics has a very narrow therapeutic window and is particularly dangerous in patients with unstable renal function it also has many drug drug interactions digit levels can be

Checked but usually only the upper limit of the therapeutic range is of interest in other words if a patient’s serum didge level is in the toxic range a dose reduction is warranted but the dose is not increased if the level appears to be sub-therapeutic provided the adequate clinical response seems to be present so what does this awful toxicity profile look like

First presentation of digits ox the city varies depending on whether toxicity is acute or chronic however cardiac toxicity is present in both situations the cardiac toxicity of digoxin consists just of its proa rhythmic effects these are related to one of two mechanisms first the effect of increased vehicle tone in cells expressing the slowed action potential

Such as the sinus node in av node second episodes mentioned a minute ago the increased intracellular calcium or more specifically the interest cytosolic calcium that was helpful for increasing contractility leads to delayed after depolarizations the program ik toxicity of the jackson increases with hypokalemia hypomagnesemia and hypercalcemia noncardiac toxicity

Of the jackson includes gi distress as well as a broad range of neuropsychiatric problems such as dizziness fatigue depression confusion and a variety of visual disturbances including altered color vision digoxin toxicity is associated with almost every arrhythmia but there are several which have a particularly strong association in other words if you see any

Of the following rhythms in a patient known to be on digoxin you should immediately suspect digit oxus ‘ti first are two that are associated with a v block from excessive vagal tone atrial fibrillation with an unusually slow ventricular response and a fib with complete heart block and an accelerated escape rhythm and the next two rhythms are from digoxin causing

Delayed after the polarizations atrial tachycardia with two the one av block meaning only one of every two ectopic p-waves are conducted to the ventricles and last a particularly distinctive rhythm called bi-directional ventricular tachycardia this rhythm is a special case vt in which the particular beats alternate between two different morphologies and which

Can easily be mistaken for ventricular bigeminy the second drug to discuss is adenosine adenosine is a purine nucleoside the same one that’s in rna and atp the primary anti rhythmic action of adenosine is to suppress av nodal conduction that is it induces av block and does so very dramatically a less important action is to suppress automaticity and a non anti

Rhythmic action is a dilation of coronary arteries via smooth muscle relaxation so what are the indications for adenosine well in general as an anti rhythmic there are two the first is to terminate reentrant rhythms that depend upon the av node these include avnrt and avrt if you want to know more about those rhythms there will be relevant links in the video

Description so here is an example of an unknown super ventricular tachycardia that was suspected to be in avnrt a rhythm strip was continuously recorded during adenosine administration so what’s going on here well adenosine was given approximately here and as you can see the tachyrhythmia terminates here then there is a pause in which there is no electrical activity

In the heart at all for nearly 2 seconds then what appears to be a sinus p wave that demonstrates the sinus node has recovered from the overdrive suppression caused by the tachycardia but the av node hasn’t recovered yet so the sinus p wave is blocked and not conducted to the ventricles but then after about another second there is another sinus p wave and this one

Is conducted showing that the av node has recovered the arrhythmia has terminated and the patient is back in sinus the second indication for adenosine is to uncover hidden atrial activity in known super ventricular tachycardias to aid and diagnosis this is particularly helpful when trying to distinguish atrial flutter in atrial tachycardia from other rhythms so

Here is part of another rhythm strip it’s difficult to tell what’s going on here with any degree of certainty there are definitely some extra waveforms that are in the beginning of the t wave that are suggestive of atrial activity but you can’t be certain what’s going on when the raid is this fast adenosine is given here and after just a second a v block kicks in

And the underlying atria activity is revealed in this case the extremely rapid rate of atria activity is indicative of flutter then since the ventricles haven’t seen any activity from above a latent pacemaker located within the ventricles starts to spontaneously fire giving you what are called ventricular escape beats on the ekg then the adenosine starts wearing

Off with one conducted qrs complex before the patient falls back into the previous tachycardia which you now know to be atrial flutter with two to one av block since no part of the reentry circuit of atrial flutter is located in the av node itself adenosine does not terminate the rhythm it just very briefly blocks its transmission to the ventricles one of the

Most unique aspects of adenosine to pharmacology is its very short half-life on the order of seconds therefore if delivered too slowly by the time the medication has been fully injected the first portion of it has already been metabolized so one must adopt a slightly unusual means of administration using a three-way stopcock in which the drug shown here as the

Small syringe is quickly pushed then the stopcock is immediately turned to the large saline containing syringe which is then also rapidly pushed critically heart transplant recipients are very sensitive to adenosine and if you choose to use it on such a patient the dose must be reduced when it comes to the side-effects of adenosine the one that is experienced

By literally almost every patient is that it creates a brief but incredibly profound sense of being unwell i’ve had numerous patients tell me that they felt themselves dying which makes sense because the drug literally induces cardiac standstill the good news is that the sensation only lasts for about 10 seconds though this can feel like minutes to the patient

So please warn your patients about this ahead of time a bolus of adenosine has also been rarely reported to induce actual cardiac arrest i’ve never heard of this happening with the patient at any hospital i’ve worked that but because of the risk you should always have a crash cart in the room during administration and of course they’ll be on a cardiac monitor

Because it’s critical to see and record what happens finally it’s considered contraindicated in patients with high degree av block or sinus node dysfunction in whom the effects of adenosine may last longer than anticipated or desired i’m going to talk about atropine and isoproterenol together since they have overlapping physiologic effects and indications as

Atropine antagonizes the parasympathetic nervous system while a sip at eronel is an agonist with a sympathetic nervous system atropine more specifically is an anti muscarinic which means it blocks acetylcholine actions on the muscarinic receptors within the parasympathetic nervous system normally the parasympathetic nervous system provides input to the sinus and

Av nodes via the vagus nerve that essentially tell the heart to slow down a bit both a slower sinus rates and decreased av conduction atropine interferes with that signal so predictably it’s indications include symptomatic sinus bradycardia or symptomatic av block there’s actually a bit of disagreement as to what when atropine should be considered a first-line

Agent for these indications or if it should be epinephrine or transcutaneous pacing as first-line agents this is probably best considered on a case-by-case basis depending upon the patient’s blood pressure science of shock suspected level of av block that is wherein the av node his bundle complex the block may be occurring and on the availability of pacing for

Example in a patient with type 2 second-degree heart block in which the level of block is felt to actually be below the av node atropine is unlikely to help there is no parasympathetic innervation there side effects of atropine are many you may recall mnemonic for the anticholinergic toxin how does a hair red as a beet dry as a bone blind as a bat and mad as

A hatter that largely describes the side effects of atropine but the most clinically relevant acute side effects of atropine are various tachyarrhythmias and urinary retention other frequent effects include dry mouth blurred vision and confusion there is one specific population that requires additional consideration atropine is completely ineffective in heart

Transplant recipients as their transplants left them with no vagal innervation of the heart moving on to isoproterenol also known as isoprene deline in some parts of the world it is a synthetic catecholamine similar in structure to epinephrine and norepinephrine but acts only on the beta 1 and beta 2 receptors with no significant alpha effect it is used as a

Second or third line agent in tour saw a pond in lesson four on the potassium channel blockers i discussed the concept of reverse use dependence in which the effect of class three antiarrhythmics was greatest at slower heart rates so when a patient presents with taurus odd due to medication toxicity increasing the heart rate will help to limit the effect of

That concept of med it’s generally used as a tempering measure while temporary pacing is getting set up which itself is only done if the first-line treatment forretress odd magnesium has already been insufficient in the past isoproterenol was also used frequently for treatment of symptomatic sinus bradycardia however it is now very rarely used for this purpose

Due to its side effects these include hypotension due to the beta-2 agonists of alpha agonism various tachyarrhythmias angina restlessness and anxiety and tremor it just makes people feel revved up and lousy and the final drug to discuss in this video series is evaporating if gabardine is a more recently developed anti rhythmic approved by the fda here in the

U.s. in 2015 that is unique in its mechanism because it inhibits the so-called funny current i have not mentioned the funny current since lesson one so let me remind you in myocytes within the sinus and av nodes where the slow response action potential is expressed the resting membrane potential is not at an equilibrium there’s actually a small depolarization

Current called the funny current that is carried by sodium and potassium ions when the spontaneous depolarization of the cell hits a certain threshold the l-type calcium channels open and the full action potential is triggered this is the mechanism responsible for pacemaker cells normal automaticity if vavra dien by blocking the funny current decreases the rate

With which these cells spontaneously depolarize in other words it decreases normal automaticity the primary consequence of which is slowing of the sinus rate if aberdeen’s indications include heart failure with reduced ejection fraction in patients who remain with an elevated heart rate despite beta-blocker therapy it’s also used in stable angina for patients who

Are intolerant or with contraindications to beta blockers and in a condition called inappropriate sinus tachycardia i don’t know whether it’s because doctors don’t really know about it yet or because they aren’t convinced by the available evidence but evaporating is still a relatively uncommon drug to see used in clinical practice the most common side effect of

Evaporating is pretty predictable sinus bradycardia and sinus arrest other notable side-effects are that it increases the risk of developing atrial fibrillation and it also causes a visual disturbance called phosphenes which are visual disturbances characterized by areas of unusual brightness in the field of view halos or transient splotches of moving color and

Light that’s it for this video on the unclassifiable antiarrhythmics the next and final video will discuss how to choose the appropriate anti rhythmic in specific clinical situations as well as some common pitfalls with anti rhythmic therapy

Transcribed from video
Antiarrhythmics (Lesson 6 – Digoxin, Adenosine, Atropine, Isoproterenol, and Ivabradine) By Strong Medicine