Okay, so Digoxin is one of those topics in medicine that has always been a little nebulous to me. It didn't help that my pharm profs were about as interesting as bingo night at the community center. That and I'm half retarded.
So here is my review of Dig. It is by no means exhaustive. Please post your thoughts or corrections.
This is probably more aggressive med-student, intard (half intern, half retard), or other resident oriented.
Digoxin
1. Digoxin -- What is it?
Digoxin is a cardiac glycoside. Glyco-who? Yeah, my cards attending didnt even know what that meant. 'Glycoside' is a throwback to Organic chemistry. Basically a glycoside is a sugar group attached to a non-carbohydrate group. There's a decent review of glycosides on wikipedia. So a glycoside is basically a O-chem description of it's basic structure and 'cardiac' is there to direct our attention to where its primary effects play out.
So 'cardiac glycoside' really means some O-chem weirdness that interfaces within the cardio-sphere.
You can increase your geek power with the following trivia and history: Cardiac glycosides have actually been in use for thousands of years and come in many shapes and forms throughout nature. Squill, Oubain, Oleander, et cetera are other glycosides that have been used for various purposes throughout history. Digoxin (aka Dig, Lanoxin, Lanoxicaps, Digitek, 12-Hydroxydigitoxin) got its start with William Withering in 1785 and was originally thought to be an effective treatment for 'Dropsy' (the old school term for 'edema').
But we know that Dig is a cardiac glycoside with positive ionotropy = Dig is some type of O-chem thing that increases the strength of cardiac contractions.
2. Mechanism of Action (MOA)/Pathophys
What's important here is that my review of the pathophys is by NO means utterly complete. My review is more on the short yellow bus side of things. There is a pretty intense review of it on emedicine here (http://emedicine.medscape.com/article/154336-overview). Also, the BRS Physiology book has some pretty helpful pics too.
I found it helpful to think about the MOA in three arms.
The abbreviated version is as follows and a bit more detailed explanation follows:
The cardiac cells have these large sodium and potassium exchangers to help maintain electroneutrality, concentration gradients, and all that other physiology crap that we try to cram in the night before the exam right? So in the cardiac cells, the sodium and potassium pump moves sodium out of the cell and potassium into the cell from the extracellular space. Digoxin competes with K+ for binding spots on the pump. When digoxin binds, that said pump is rendered worthless for a time. So if you stop pumping Na+ out and K+ in then you start changing the concentration of Na+ and potassium in the cell right? More Na+ inside the cells and more potassium outside the cell.
Now we move to the Na+/Ca++ exchanger located within that same cell. This exchanger helps to regulate the amount of calcium in cardiac cells by kicking calcium out of the cell and pulling sodium into the cell. It doesn't use ATP to exchange, though. It relies on the low/high concentration of Na+ inside/outside the cell to drive the transport of calcium out of the cell. Thus, if you increase sodium on the inside of the cell then you basically spank that exchanger on it's big protean fanny (i.e. abolish the concentration gradient) and you get more calcium in the cell.
More calcium means stronger contractions. (This is done by several mechanisms which will not be discussed here.)
If you follow the above link, there is also some discussion as to how Digoxin increases automaticity. My cave-man brain didn't find that information as clinically useful to remember so I refer you elsewhere for that explanation.
And if anyone knows how Digoxin enhances parasympethetic activity, I would really like to know. My cards attending, who is wicked smart, and cards fellow were both clueless about that particular MOA. Anyone know? Please post a reference if you know.
What I do know is that Dig enhances parasympethetic activity and thus increases vagal tone (among other things) and that contributes a large part to the AV node inhibition that Dig is known for.
3. Metabolism
A couple of important points to keep in mind here.
1. Digoxin winds up in urinal (i.e. renal excretion)
2. Thyroid status, age, and meds will alter serum levels
Digoxin is renally excreted. This absolutely clutch to keep in mind. Folks that come in with various degrees of renal failure can have a wide array of dig-toxic findings (discussed below.)
Other things that affect Dig metabolism:
This section is probably one of the weaker ones. I am an ED resident so starting Dig and all the nuances/trials related to its uses are not as pertinent to me. But here is a very brief review of how and when Dig is used and not used.
A) Rate Control -- Digoxin can be used as a rate control for Afib and Aflutter and other atrial tachyarrythmias (though my familiarity is with the former two primarily). This is not acute action and requires dig loading followed by maintenance doses. This is accomplished through Dig's AV node blocking MOA.
B) CHF -- the long of the short of it, as I understand it, is that Dig does NOT affect morbidity or mortality CHF patients but does improve symptoms in select patients.
There have been many trials but two of the big ones are the RADIANCE trial which compared stopping dig in CHF patients on diuretics and ACE-inhibitors versus not-stopping it. People that were discontinued from Dig had worsening CHF, etc.
The DIG trial was the good ol' randomized, double-blind daddio that showed no mortality benefit but symptomatic improvement with Digoxin in CHF. Digoxin, from this trial, benefited patients with severe/class IV symptoms, cardiomegaly on CXR, and/or ejection fraction <25%. dig =" bad" style="font-weight: bold;">
5. Digoxin Toxicity
It takes 6-12 hours post-dig ingestion for a serum dig level to reflect actual levels in the body. So when someone presents with acute dig toxicity, a dig level may be helpful if it's elevated but is otherwise worthless.
I.e. patients can be dig toxic with a normal dig level.
The clinical picture trumps lab values. And that's not a bad approach to medicine in general; treat the patient and not the number.
Dig toxicity can do just about anything to a person clinically. I've seen a few people turned into weird animals, others declared me a genius, and some actually thought ol' Presidente GW Bush was a phenonemal public speaker.
There are five things that I think are helpful to remember about symptoms and dig toxicity.
1) Dec CNS symptoms -- drowsy, fatigue, lethargy, etc
2) Inc GI symptoms -- nausea, vomiting, diarrhea (very common)
3) Visual symptoms -- yellow discoloration (Xanthopsia is the fancy medical term for all you purists out there) blue discoloration, flashing halo's, and other visual changes
4) Cardiac badness -- tachycardia, bradycardia, arrest, and everything else in between
ECG findings. If you find yourself getting pimped on a ECG and your attending wants a differential for 'what could cause this type of arrythmia' a great answer is 'Digoxin'. Digoxin can literally cause every type of arrythmia except for the following three: irregularly irregular Atrial fibrillation, Atrial flutter, and a Mobitz 2 (I am not positive about the Wenkebach). You will NEVER see the above three rhythms (plus or minus a Mobitz 1 (anyone know?)) with Dig toxicity.
The three classic rhythms with dig toxicity are a PAT with AV block, biventricular tachycardia, and slow and regular afib; this ECG will have no p waves but will be regular as the day is long (because a junctional escape rhythm keeps the ventricles beating), and it will generally be fairly bradycardic due to the junctional pace. I have seen the slow/reg Afib twice, and both patients were dig-toxic and symptomatically bradycardic.
The most common ECG finding is PVCs which sucks because that is so freaking non-specific.
And every other type of arrythmia is fair game for digoxin except for the three noted above.
Treating a dig-toxic patient has several steps. First and always most important is hemodynamically stability. But that is not necessarily dig-specific.
So the first dig-specific treatment issue is Potassium. Hypokalemic patients will have an exagerrated effect because there is less K+ to compete with Dig. So in effect you have more dig. So check a K+ and replete aggresively. The same goes for Mg++, because Mag is a cofactor for the Na+/K+ ATPase. Replete K+/Mg+ level aggresively.
BUT if a patient is hyperkalemic that could be catastrophic.
Hyperkalemia is bad prognostic sign in dig-toxic patients.
Severe dig-toxicity causes hyperkalemia because the Na+/K+ ATPase is so poisoned that serum potassium is now being elevated which compounds predisposition for arrythmia nasty. So what do hyperK+ cardiac unstable patients need? Calcium right? You wanna push that calcium gluconate or pound them with Ca-Chloride?
Congratulations doctor you just killed your patient, somebody call a lawyer. NO calcium for dig-toxic patients! Their myocardium is already loaded with calcium. More calcium is going to lock those myofibrils down and create the 'stone heart'. Either that or they are going to go into some aweful arrythmia that will not respond to anything.
So what does the hyperK+ dig-toxic patient need? Hemodialysis and if the K+>5, it is a true emergency and is generally fatal unless treated. This brings up another great point. Hemodialysis is really not a great modality to eliminate digoxin in dig-toxicity; digoxin has a high volume of distribution (ie it's all up in the tissues and thus not as amenable to being cleared from the blood by dialsysis). These patients need Digibind.
Digibind is a monocolonal antibody that binds digoxin. This renders digoxin ineffective and then they ride that wonderful golden stream right out of the body and into the white porcelain god bound ever-so-tightly like two star-crossed lovers.
Digibind has specific indications though. The five I know of are as follows: (1) >.1mg/kg or >4mg ingestion in peds or >10mg ingestion in adults (2) Dig serum > 5 (3) K+ >5 (4) Cardiac badness (ie arrythmia) (5) rapid progression of symptoms.
The only other two things I would think about are atropine and activated charcoal.
If your going to use atropine, use it early.
Activated charcoal is not recommend, by the American Academy of Toxicologists, for routine use. But if you have a known ingestion that is very acute. Then you may want to consider it.
------------------------------------------------------------------------------------------------
There's always more but that's what helped me understand the nuts and bolts of Digoxin in a Sesame Street sort of way. I hope it helps you.
I used DynaMed, NEJM, eMedicine, wikipedia, and other sources to educate my brain on the matter. My thanks and acknowledgement goes out to those higher lifeforms for their extensive scholarship on the matter.
Digoxin is a cardiac glycoside. Glyco-who? Yeah, my cards attending didnt even know what that meant. 'Glycoside' is a throwback to Organic chemistry. Basically a glycoside is a sugar group attached to a non-carbohydrate group. There's a decent review of glycosides on wikipedia. So a glycoside is basically a O-chem description of it's basic structure and 'cardiac' is there to direct our attention to where its primary effects play out.
So 'cardiac glycoside' really means some O-chem weirdness that interfaces within the cardio-sphere.
You can increase your geek power with the following trivia and history: Cardiac glycosides have actually been in use for thousands of years and come in many shapes and forms throughout nature. Squill, Oubain, Oleander, et cetera are other glycosides that have been used for various purposes throughout history. Digoxin (aka Dig, Lanoxin, Lanoxicaps, Digitek, 12-Hydroxydigitoxin) got its start with William Withering in 1785 and was originally thought to be an effective treatment for 'Dropsy' (the old school term for 'edema').
But we know that Dig is a cardiac glycoside with positive ionotropy = Dig is some type of O-chem thing that increases the strength of cardiac contractions.
2. Mechanism of Action (MOA)/Pathophys
What's important here is that my review of the pathophys is by NO means utterly complete. My review is more on the short yellow bus side of things. There is a pretty intense review of it on emedicine here (http://emedicine.medscape.com/article/154336-overview). Also, the BRS Physiology book has some pretty helpful pics too.
I found it helpful to think about the MOA in three arms.
- Na+/K+ ATPase poison which eventually leads to positve ionotropy
- Enhances the parasympathetic arm of the nervous system (increases vagal tone and thus inihibits the AV node and thus decreases heart rate)
- Increases automaticity of cardiac cells (the chance/likelihood that cardiac cells will spontaneously depolarize/contract on their own and apart from the SA node)
The abbreviated version is as follows and a bit more detailed explanation follows:
- Dig = Na+/K+ ATPase poison via competitive inhibition with K+
- Increasing Na+ concentration in the cell (via #1) stops the expulsion of calcium from the heart by abolishing the gradient that the Na+/Ca++ exchanger uses
- (#2) causes increased calcium in the cardiac cells which increases strength of contraction
The cardiac cells have these large sodium and potassium exchangers to help maintain electroneutrality, concentration gradients, and all that other physiology crap that we try to cram in the night before the exam right? So in the cardiac cells, the sodium and potassium pump moves sodium out of the cell and potassium into the cell from the extracellular space. Digoxin competes with K+ for binding spots on the pump. When digoxin binds, that said pump is rendered worthless for a time. So if you stop pumping Na+ out and K+ in then you start changing the concentration of Na+ and potassium in the cell right? More Na+ inside the cells and more potassium outside the cell.
Now we move to the Na+/Ca++ exchanger located within that same cell. This exchanger helps to regulate the amount of calcium in cardiac cells by kicking calcium out of the cell and pulling sodium into the cell. It doesn't use ATP to exchange, though. It relies on the low/high concentration of Na+ inside/outside the cell to drive the transport of calcium out of the cell. Thus, if you increase sodium on the inside of the cell then you basically spank that exchanger on it's big protean fanny (i.e. abolish the concentration gradient) and you get more calcium in the cell.
More calcium means stronger contractions. (This is done by several mechanisms which will not be discussed here.)
If you follow the above link, there is also some discussion as to how Digoxin increases automaticity. My cave-man brain didn't find that information as clinically useful to remember so I refer you elsewhere for that explanation.
And if anyone knows how Digoxin enhances parasympethetic activity, I would really like to know. My cards attending, who is wicked smart, and cards fellow were both clueless about that particular MOA. Anyone know? Please post a reference if you know.
What I do know is that Dig enhances parasympethetic activity and thus increases vagal tone (among other things) and that contributes a large part to the AV node inhibition that Dig is known for.
3. Metabolism
A couple of important points to keep in mind here.
1. Digoxin winds up in urinal (i.e. renal excretion)
2. Thyroid status, age, and meds will alter serum levels
Digoxin is renally excreted. This absolutely clutch to keep in mind. Folks that come in with various degrees of renal failure can have a wide array of dig-toxic findings (discussed below.)
Other things that affect Dig metabolism:
- Thyroid. Hyperthyroid patients chew through their dig faster so they will need increased concentrations. Hypothyroid are the exact opposite and will require less.
- Age -- them older peeps are kind of like hypothyroid patients; i.e. less is better. This is probably due to decreased GFR in older folks more than anything else.
- Meds -- there are mega-lists of drugs that affect the serum levels of digoxin. The general trend is for meds to increase serum levels of digoxin. A few drugs that I keep in mind are Amio (increases dig levels), Erythromycin/Clarithro (and some other Abx increases dig), Captopril (increases dig), and cholecystyramine (and other binding resins decrease the amount of dig in your system). That is just to name a few.
This section is probably one of the weaker ones. I am an ED resident so starting Dig and all the nuances/trials related to its uses are not as pertinent to me. But here is a very brief review of how and when Dig is used and not used.
A) Rate Control -- Digoxin can be used as a rate control for Afib and Aflutter and other atrial tachyarrythmias (though my familiarity is with the former two primarily). This is not acute action and requires dig loading followed by maintenance doses. This is accomplished through Dig's AV node blocking MOA.
B) CHF -- the long of the short of it, as I understand it, is that Dig does NOT affect morbidity or mortality CHF patients but does improve symptoms in select patients.
There have been many trials but two of the big ones are the RADIANCE trial which compared stopping dig in CHF patients on diuretics and ACE-inhibitors versus not-stopping it. People that were discontinued from Dig had worsening CHF, etc.
The DIG trial was the good ol' randomized, double-blind daddio that showed no mortality benefit but symptomatic improvement with Digoxin in CHF. Digoxin, from this trial, benefited patients with severe/class IV symptoms, cardiomegaly on CXR, and/or ejection fraction <25%. dig =" bad" style="font-weight: bold;">
5. Digoxin Toxicity
- Toxicity is dose dependent but don't depend on serum levels. Go with the clinical picture.
- Get an ECG. There are 3 classic arrythmias. 3 you never see. And everything else in between.
- There are a wide array of symptoms, the primary being decreased CNS, increased visual, increased GI, and cardiac arrythmia and arrest badness.
- Treatment depends on clinical context. Know your K+ level (NO Calcium!), use atropine early, digibind, activated charcoal on a case-by-case basis
- Digibind has 5 indications for use.
It takes 6-12 hours post-dig ingestion for a serum dig level to reflect actual levels in the body. So when someone presents with acute dig toxicity, a dig level may be helpful if it's elevated but is otherwise worthless.
I.e. patients can be dig toxic with a normal dig level.
The clinical picture trumps lab values. And that's not a bad approach to medicine in general; treat the patient and not the number.
Dig toxicity can do just about anything to a person clinically. I've seen a few people turned into weird animals, others declared me a genius, and some actually thought ol' Presidente GW Bush was a phenonemal public speaker.
There are five things that I think are helpful to remember about symptoms and dig toxicity.
1) Dec CNS symptoms -- drowsy, fatigue, lethargy, etc
2) Inc GI symptoms -- nausea, vomiting, diarrhea (very common)
3) Visual symptoms -- yellow discoloration (Xanthopsia is the fancy medical term for all you purists out there) blue discoloration, flashing halo's, and other visual changes
4) Cardiac badness -- tachycardia, bradycardia, arrest, and everything else in between
ECG findings. If you find yourself getting pimped on a ECG and your attending wants a differential for 'what could cause this type of arrythmia' a great answer is 'Digoxin'. Digoxin can literally cause every type of arrythmia except for the following three: irregularly irregular Atrial fibrillation, Atrial flutter, and a Mobitz 2 (I am not positive about the Wenkebach). You will NEVER see the above three rhythms (plus or minus a Mobitz 1 (anyone know?)) with Dig toxicity.
The three classic rhythms with dig toxicity are a PAT with AV block, biventricular tachycardia, and slow and regular afib; this ECG will have no p waves but will be regular as the day is long (because a junctional escape rhythm keeps the ventricles beating), and it will generally be fairly bradycardic due to the junctional pace. I have seen the slow/reg Afib twice, and both patients were dig-toxic and symptomatically bradycardic.
The most common ECG finding is PVCs which sucks because that is so freaking non-specific.
And every other type of arrythmia is fair game for digoxin except for the three noted above.
Treating a dig-toxic patient has several steps. First and always most important is hemodynamically stability. But that is not necessarily dig-specific.
So the first dig-specific treatment issue is Potassium. Hypokalemic patients will have an exagerrated effect because there is less K+ to compete with Dig. So in effect you have more dig. So check a K+ and replete aggresively. The same goes for Mg++, because Mag is a cofactor for the Na+/K+ ATPase. Replete K+/Mg+ level aggresively.
BUT if a patient is hyperkalemic that could be catastrophic.
Hyperkalemia is bad prognostic sign in dig-toxic patients.
Severe dig-toxicity causes hyperkalemia because the Na+/K+ ATPase is so poisoned that serum potassium is now being elevated which compounds predisposition for arrythmia nasty. So what do hyperK+ cardiac unstable patients need? Calcium right? You wanna push that calcium gluconate or pound them with Ca-Chloride?
Congratulations doctor you just killed your patient, somebody call a lawyer. NO calcium for dig-toxic patients! Their myocardium is already loaded with calcium. More calcium is going to lock those myofibrils down and create the 'stone heart'. Either that or they are going to go into some aweful arrythmia that will not respond to anything.
So what does the hyperK+ dig-toxic patient need? Hemodialysis and if the K+>5, it is a true emergency and is generally fatal unless treated. This brings up another great point. Hemodialysis is really not a great modality to eliminate digoxin in dig-toxicity; digoxin has a high volume of distribution (ie it's all up in the tissues and thus not as amenable to being cleared from the blood by dialsysis). These patients need Digibind.
Digibind is a monocolonal antibody that binds digoxin. This renders digoxin ineffective and then they ride that wonderful golden stream right out of the body and into the white porcelain god bound ever-so-tightly like two star-crossed lovers.
Digibind has specific indications though. The five I know of are as follows: (1) >.1mg/kg or >4mg ingestion in peds or >10mg ingestion in adults (2) Dig serum > 5 (3) K+ >5 (4) Cardiac badness (ie arrythmia) (5) rapid progression of symptoms.
The only other two things I would think about are atropine and activated charcoal.
If your going to use atropine, use it early.
Activated charcoal is not recommend, by the American Academy of Toxicologists, for routine use. But if you have a known ingestion that is very acute. Then you may want to consider it.
------------------------------------------------------------------------------------------------
There's always more but that's what helped me understand the nuts and bolts of Digoxin in a Sesame Street sort of way. I hope it helps you.
I used DynaMed, NEJM, eMedicine, wikipedia, and other sources to educate my brain on the matter. My thanks and acknowledgement goes out to those higher lifeforms for their extensive scholarship on the matter.
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