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The Secret Connection Between Digoxin, Reversible Cell Damage, and Trousseau’s Sign That USMLE Step 1 Bosses Know

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USMLE Step 1 Ion Channels Digoxin

By the end of this USMLE Step 1 lesson, you will be able to answer the following questions:

  1. Use mechanism of digoxin to explain effect on contractility.
  2. Effect of hypokalemia on digoxin effects?  Why?
  3. What histologic changes would you see visually in transient ischemia?  Why?
  4. What is the clinical presentation of someone with hypercalcemia?  Why does this make sense?
  5. What is the clinical presentation of someone with hypocalcemia?  Why does this make sense?
  6. Trousseau’s sign: use the underlying membrane physiology to try and explain why this occurs

Since the USMLE Step 1 is a test of your ability to apply and connect your knowledge, being able to connect such disparate things as reversible cell damage and digoxin effects will be critical to reaching your peak potential.  This is the exact strategy I used to score 270 on the USMLE Step 1.

NOTE: Many of these concepts I discuss here build on a previous lesson, which you may want to reference.

Ready for the recall-type USMLE Step 1 questions?

What sets the normal Na/K gradient across the cell membrane?

Na+/K+ ATPase (pump that uses ATP)

So what does the Na/K ATPase (pump) actually do?

It uses ATP to DRIVE Na+ and K+ AGAINST their concentration gradients

Normally, Na+ would NOT want to move outside the cell, because the outside is POSITIVE relative to the inside, and the Na+ concentration is much higher outside. Thus, we need the energy derived from ATP hydrolysis to drive these ions against their respective gradients.

How many ions of each does it move, and in what direction?

3 Na+ OUT; 2K+ IN

But doesn’t Na+ normally want to move INSIDE the cell?

Yes, when Na+ channels open, Na+ will move INSIDE the cell, because of the concentration gradient (more Na+ outside the cell), and electrical gradient (inside of cell negative relative to outside).

This is what makes the Na/K ATPase special – it moves Na+ and K+ against their respective concentration gradients, which requires the use of ATP.

What would the membrane potential be if I were to block the Na+/K+ ATPase (more or less negative)?

Na+/K+ ATPase ↓ → Na+ accumulation inside cell, and K+ accumulation outside the cell

Recall that the majority of the resting membrane potential is determined by the K+ gradient. In other words, if the K+ gradient ↓ → membrane potential LESS negative

Membrane potential will be more positive (less negative)

What effects would hyperkalemia have on membrane potential?

Similar effects to blocking Na+/K+ ATPase activity. In hyperkalemia, there is more K+ extracellularly. Thus, there will be a weaker concentration gradient for K+ across the membrane (recall that the majority of K+ is intracellular).

In other words, since the resting membrane potential is determined largely by K+ conductance (i.e. at rest, there are more K+ channels open than any other ion channels), K+ concentration gradient ↓ → resting membrane potential less negative

Clinically, what ion can you give to someone with hyperkalemia? How is this thought to help?

Clinically, often you give Ca++ to patients with hyperkalemia. In hyperkalemia, recall that the resting membrane potential is more depolarized, meaning that it is CLOSER to the action potential threshold (You can imagine that it would NOT be beneficial for your heart cells to fire more easily, as this leads to arrhythmia).

Ca++ is thought to (and is shown experimentally*) to raise the threshold for depolarization, albeit transiently. Thus, when hyperkalemia ↑ membrane potential, moving it closer to the action potential threshold, you give Ca++ to ↑ the action potential threshold.

What is the mechanism by which Ca++ is pumped out of the cell? What drives this process?

Na+/Ca++ exchanger.

Here, again, Ca++ is moving AGAINST its chemical gradient (recall: there is more Ca++ outside the cell than inside). Thus, the energy provided by Na+ moving DOWN its concentration gradient allows for the transport of Ca++ out.

This is analogous to how the energy from ATP was used to pump Na+ and K+ against their respective concentration gradients.

USMLE Step 1 Ion Channels Digoxin

Digoxin – blocks what protein? At which site?

Blocks Na+/K+ ATPase

Binds to the site for K+ binding (i.e. K+ and digoxin compete for the same binding site).

Wait!

I strongly recommend that you attempt to answer the final questions by yourself first, before looking at the answers.  Remember, the USMLE Step 1 exam will test your ability to make connections on the spot. The more practice you have, the higher your score!  Then, when you think you might know the answer (or are completely stumped), look at the answers below!

What should you do next?

  1. Turn the narrative, “Pathogenesis to Presentation” questions into Anki cards by copy/pasting the question/answer into the “Front” and “Back” fields in Anki.  Do the same for the fundamental facts that you were unfamiliar with, to maximize your chances of USMLE Step 1 success!  Remember: the USMLE is a test of understanding, so the better you can understand these questions, the better your score!
  2. Add reverse cards when appropriate to your Anki cards
  3. Re-word the questions/explanations as desired, and BOLD the important text to make it easier to review in the future
  4. Learn something new?  Something unclear?  Comment below!
  5. If you liked this post, please consider sharing it on Facebook/Twitter!  I judge the utility of these posts by the number of comments / shares they receive, so if you’d like more, or would like a particular topic addressed, please let us know!

**Out of curiosity, I looked up to see what literature there was on serum Ca++ levels and membrane excitability.  If you’re interested in learning more, there’s a paper on the topic…from 1968(!!!).  Awesome!

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