By the end of this USMLE Step 1 lesson, you will be able to answer the following questions:
- Use mechanism of digoxin to explain effect on contractility.
- Effect of hypokalemia on digoxin effects? Why?
- What histologic changes would you see visually in transient ischemia? Why?
- What is the clinical presentation of someone with hypercalcemia? Why does this make sense?
- What is the clinical presentation of someone with hypocalcemia? Why does this make sense?
- 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.
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.
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.
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)
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
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.
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.
Binds to the site for K+ binding (i.e. K+ and digoxin compete for the same binding site).
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!
Recall that K+ and digoxin compete for the same binding site (this is competitive inhibition). Thus, if there is less K+ → digoxin will bind more strongly → potentiation of digoxin effects
In other words, BEWARE DIGOXIN TOXICITY IN HYPOKALEMIA
We can make sense of this by thinking that Ca++ is increasing the depolarization threshold generally, throughout their body. Thus, they will feel slow (fatigability, lethargy), and be weak (areflexia/weakness) that may even lead to coma.
Take a minute to think about this.
These signs of neuromuscular hyperexcitability include:
Chvostek’s sign: Tapping of facial nerve → contraction of facial muscles (classic sign you should know for USMLE Step 1)
Trousseau’s sign: Occlusion of brachial artery with BP cuff → carpal spasm (another USMLE Step 1 classic)
Hyperactive deep tendon reflexes (more of a Step 2 question, although useful in the grand scheme)
Since in hypocalcemia, cells are already closer to depolarization, depolarizing the membrane w/ transient ischemia presumably → action potential → muscle contraction.
What should you do next?
- 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!
- Add reverse cards when appropriate to your Anki cards
- Re-word the questions/explanations as desired, and BOLD the important text to make it easier to review in the future
- Learn something new? Something unclear? Comment below!
- 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!