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John79
Does anyone know how digitalis cause it's vagomimetic effects (decreased FRP of AV node)? And how does digitalis cause hypokalemia?
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go read Katzung. He will answer your question.
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ajl102
I'm not sure that hypokalemia is a digitalis effect. It is a contraindication - K+ and dig compete for the same ATPase. Possibly a general efflux of K+ from cells (due to inhibition of the ATPase usually pumping K+ in) leads to a rise in extracellular K+ and loss in the urine. If the renal Na+/K ATPase were inhibited by dig, this would cause a hyperkalemia - so no easy answer there.
As for the vagomimetic effects, here's Katzung (chap. 13):
"In the lower portion of the dose range, cardioselective parasympathomimetic effects predominate. In fact, these atropine-blockable effects are responsible for a significant portion of the early electrical effects of digitalis. This action involves sensitization of the baroreceptors, central vagal stimulation, and facilitation of muscarinic transmission at the cardiac muscle cell. Because cholinergic innervation is much richer in the atria, these actions affect atrial and atrioventricular nodal function more than Purkinje or ventricular function."
Likewise it excites all kinds of exciteable tissue - central chemoreceptors, smooth mucles. Anything with a Na/K ATPase presumably.
Digitalis is CONFUSING. It does everything, and then it does the opposite. It decreases SA node rate at therapeutic levels, and increases it at toxic levels.
How should I handle this drug for the boards?
As for the vagomimetic effects, here's Katzung (chap. 13):
"In the lower portion of the dose range, cardioselective parasympathomimetic effects predominate. In fact, these atropine-blockable effects are responsible for a significant portion of the early electrical effects of digitalis. This action involves sensitization of the baroreceptors, central vagal stimulation, and facilitation of muscarinic transmission at the cardiac muscle cell. Because cholinergic innervation is much richer in the atria, these actions affect atrial and atrioventricular nodal function more than Purkinje or ventricular function."
Likewise it excites all kinds of exciteable tissue - central chemoreceptors, smooth mucles. Anything with a Na/K ATPase presumably.
Digitalis is CONFUSING. It does everything, and then it does the opposite. It decreases SA node rate at therapeutic levels, and increases it at toxic levels.
How should I handle this drug for the boards?
ajl102 is correct.
Digitalis inhibits K binding to the Na/K ATPase, specifically, by competitively binding to the K-site. The consequence is increased intracellular Na --> increased intracellular Ca (via the consequent slowing of the Na/Ca exchanger. Thus more intracellular Ca and increased cardiac contractility.
Thus digitalis does NOT cause hypokalemia (if anything, digitalis toxicity will lead to HYPERkalemia). But -- HYPOkalemia will amplify the effects of digitalis (less competition for binding --> increased effect), and is thus a contraindication.
As for renal handling, I think ajl102 is incorrect. Increased extracellular K (as a consequence of digitalis toxicity) would NOT lead to hypokalemia via renal losses. The kidney is very efficient at reabsorbing K, and only in the case of severe hyperkalemia (or perhaps a loop or thiazide diuretic) would increased K be lost in the urine. Even so, hyperkalemia would nonetheless be maintained.
If the renal Na+/K ATPase were inhibited by dig, this would cause a hyperkalemia - so no easy answer there
of course it is. Every cell in the body has a Na/K ATPase. thus digitalis toxicity would be hyperkalemia. Just remember that early signs of digitalis toxicity are important clues -- nausea, vomiting, visual distubances, etc.
Digitalis inhibits K binding to the Na/K ATPase, specifically, by competitively binding to the K-site. The consequence is increased intracellular Na --> increased intracellular Ca (via the consequent slowing of the Na/Ca exchanger. Thus more intracellular Ca and increased cardiac contractility.
Thus digitalis does NOT cause hypokalemia (if anything, digitalis toxicity will lead to HYPERkalemia). But -- HYPOkalemia will amplify the effects of digitalis (less competition for binding --> increased effect), and is thus a contraindication.
As for renal handling, I think ajl102 is incorrect. Increased extracellular K (as a consequence of digitalis toxicity) would NOT lead to hypokalemia via renal losses. The kidney is very efficient at reabsorbing K, and only in the case of severe hyperkalemia (or perhaps a loop or thiazide diuretic) would increased K be lost in the urine. Even so, hyperkalemia would nonetheless be maintained.
If the renal Na+/K ATPase were inhibited by dig, this would cause a hyperkalemia - so no easy answer there
of course it is. Every cell in the body has a Na/K ATPase. thus digitalis toxicity would be hyperkalemia. Just remember that early signs of digitalis toxicity are important clues -- nausea, vomiting, visual distubances, etc.
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ajl102
Yeah, sorry about that renal handling thing. That was just rank speculation, should have qualified that. I was trying to think think of any way the drug could cause hypokalemia, as the poster asked.
What about the effects on Refractory Period and Action Potential Duration - any insight into those?
I think the "classic" effects of the drug are to slow conduction velocty through the AV node and increase contractility. I have also read about paradoxical effects, which lead to its toxicity (PSVTs, etc) and also cause confusion in medical students.
What about the effects on Refractory Period and Action Potential Duration - any insight into those?
I think the "classic" effects of the drug are to slow conduction velocty through the AV node and increase contractility. I have also read about paradoxical effects, which lead to its toxicity (PSVTs, etc) and also cause confusion in medical students.
What about the effects on Refractory Period and Action Potential Duration - any insight into those?
do I have to do all the work here?
digitalis has direct vagomimetic effects on the AV node (slowing conduction). This increases ERP/APD. This is why digitalis is so often used in the treatment of atrial fibrillation. don't worry about exactly HOW this works, just know that this is what happens.
do I have to do all the work here?
digitalis has direct vagomimetic effects on the AV node (slowing conduction). This increases ERP/APD. This is why digitalis is so often used in the treatment of atrial fibrillation. don't worry about exactly HOW this works, just know that this is what happens.
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ajl102
Right, got that. Therapeutic actions of dig are straightforward. It's the paradoxical effects that are hard to stomach for me, mostly because they're so...paradoxical. I looked it up in Lilly so I could stop thinking about it.
In dig toxicity, three things happen, all of them arrhythmogenic:
Resting membrane voltage gets less negative and closer to threshold (Na/K ATPase normally creates an outward current, negative cell interior). This can lead to excess spontaneous APs, ie ectopic rhythms. It can also keep the fast voltage-gated Na channels closed, slowing conduction, possibly allowing for reentrance.
Extra intracellular Ca++ can cause delayed afterdepolarizations.
Excess intracellular Ca++ activates a Ca++ dependent K+ channel that can increase efflux of K+. This is why we can see decreased APD and ERP in dig toxicity.
So...in toxic doses conduction can be slowed in one population of cells while another piece of tissue might be made more excitable or less refractory. This is the "fragmentation" of conduction that can cause PSVTs. Add in excess vagal input causing AV block, and you have a dangerous drug.
In dig toxicity, three things happen, all of them arrhythmogenic:
Resting membrane voltage gets less negative and closer to threshold (Na/K ATPase normally creates an outward current, negative cell interior). This can lead to excess spontaneous APs, ie ectopic rhythms. It can also keep the fast voltage-gated Na channels closed, slowing conduction, possibly allowing for reentrance.
Extra intracellular Ca++ can cause delayed afterdepolarizations.
Excess intracellular Ca++ activates a Ca++ dependent K+ channel that can increase efflux of K+. This is why we can see decreased APD and ERP in dig toxicity.
So...in toxic doses conduction can be slowed in one population of cells while another piece of tissue might be made more excitable or less refractory. This is the "fragmentation" of conduction that can cause PSVTs. Add in excess vagal input causing AV block, and you have a dangerous drug.
Thanks for the input guys (I was the original poster). I made a mistake about asking how digitalis causes hypokalemia. I misinterpreted the fact that hypokalemia can exacerbate digitalis toxicity, didn't know that digitalis is a competetive inhibitor of the K binding site.
Digitalis is confusing.
The "fragmentation" of conduction through the atria is also therapeutic for atrial flutter, converting atrial flutter to atrial fibrillation. The depolarization wavefront fractionates because vagal effects are not uniform throughout the atria and the atrial refractory period may be shortened at some points but not in others (on ECG, there are no detectable P waves because there is no synchronous depolarization and action potentials arrive at the AV node at random intervals, leading to an erratic ventricular rhythm with fluctuating R-R intervals). The increased atrial impulses seen in atrial fibrillation interfere with one another during transmission through the AV node and proportionately fewer atrial impulses transmit to the ventricle during atrial fibrillation than in atrial flutter. As a result ventricular rate decreases by the conversion of atrial flutter to atrial fibrillation and the ventricles are protected.
So I geuss converting atrial flutter to atrial fibrillation is to stabilize the patient before attempting defibrillation? This is way more than I want to know for one drug.
Digitalis is confusing.
The "fragmentation" of conduction through the atria is also therapeutic for atrial flutter, converting atrial flutter to atrial fibrillation. The depolarization wavefront fractionates because vagal effects are not uniform throughout the atria and the atrial refractory period may be shortened at some points but not in others (on ECG, there are no detectable P waves because there is no synchronous depolarization and action potentials arrive at the AV node at random intervals, leading to an erratic ventricular rhythm with fluctuating R-R intervals). The increased atrial impulses seen in atrial fibrillation interfere with one another during transmission through the AV node and proportionately fewer atrial impulses transmit to the ventricle during atrial fibrillation than in atrial flutter. As a result ventricular rate decreases by the conversion of atrial flutter to atrial fibrillation and the ventricles are protected.
So I geuss converting atrial flutter to atrial fibrillation is to stabilize the patient before attempting defibrillation? This is way more than I want to know for one drug.
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ajl102
If someone has chronic atrial fib, I've heard it's sometimes better to let it go than convert it. Starting the atrium back up is risking systemic emboli, ie strokes, and atrial fib keeps the CO at an average level that's reasonable. People live with it for years, indefinitely.
Have you ever heard atrial fib through a stethoscope? It is striking. The first time I heard it in a patient I honestly started to panic, the blood rushed out of my face and the hair on my neck stood on end. Sounds like a basketball bouncing down stairs. Random. I'm looking at this man thinking, "How on earth can you be breathing with your heart making that sound?" He had a murmur (or two) as well, making the rhythm even more impossibly complex, sounded like the cartoon jalopy... Guy was 90 years old and only retired for about five years from work as a welder or something.
Have you ever heard atrial fib through a stethoscope? It is striking. The first time I heard it in a patient I honestly started to panic, the blood rushed out of my face and the hair on my neck stood on end. Sounds like a basketball bouncing down stairs. Random. I'm looking at this man thinking, "How on earth can you be breathing with your heart making that sound?" He had a murmur (or two) as well, making the rhythm even more impossibly complex, sounded like the cartoon jalopy... Guy was 90 years old and only retired for about five years from work as a welder or something.
