Acetazolamide and the potassium-sparing diuretics

Acetazolamide and the potassium-sparing diueretics may be used to induce diuresis, but that effect is incidental to their primary indication. In this video from our Fluid and Electrolytes Masterclass, you'll learn about the mechanism of action of these medications, how acetazolamide prevents altitude sickness, and why aldactone can be used for diuresis (but probably shouldn't be).

This is video #4 in our free teaching series on diuretics.

In case you missed the first three videos of this Fluids and Electrolytes Masterclass series, you can find them here:
1. The philosophy of diuretics
2. Loop diuretics
3. Thiazide diuretics

[00:00:00] Acetazolamide and potassium-sparing diuretics are diuretics but that is incidental to their primary indication. We don't typically use these drugs for their diuretic effect. We use them for some other indication due to another characteristic of the drug. In the case of acetazolamide, we use it to treat metabolic alkalosis, prevent altitude sickness, and treat glaucoma and pseudotumor cerebri. In the case of the sparing diuretics,

[00:00:30] these are great blood pressure medications, are useful in the prevention and treatment of hypokalemia and are great in the treatment of heart failure. We'll start with acetazolamide. Acetazolamide acts at the proximal tubule and like other diuretics is active in the tubular fluid. So it needs to be filtered or secreted into the proximal tubule to be effective. 98% of acetazolamide is protein bound, so it cannot be filtered to glomerulus, meaning it must be secreted

[00:01:00] by the proximal tubule to be active. Secretion is GFR dependent so the lower the GFR, the higher dose you need to have an active effect. You think of the role of the proximal tubule in the kidney, think of big dumb reabsorption. Two-thirds of all the glomerular filtrate is reabsorbed, here. Sodium reabsorption drives the reabsorption of glucose, phosphate, and amino acids and it also drives the secretion

[00:01:30] of hydrogen ions. That secretion of hydrogen ions is dependent on carbonic anhydrase. And that's what we're going to be focusing on with acetazolamide. So, let's take a closer look at how acetazolamide works at the cellular level. Hydrogen secretion is tied to sodium reabsorption. So, water hydrolyzes forms a hydrogen ion and a hydroxyl group. That hydrogen ion is exchanged with sodium

[00:02:00] to be excreted into the tubular fluid. From there, the hydrogen ion binds with filtered bicarbonate. They combine to form carbonic acid and then is hydrolyzed back to water and CO2 using the enzyme carbonic anhydrase. CO2 flows into the tubular cell where it combines with hydroxyl ion from the water. Again, using carbonic anhydrase to reform bicarbonate. So, the

[00:02:30] net result is bicarbonate in the tubular fluid, it’s metabolized and essentially destroyed. And then is reformed in the tubule cell, where it's then reabsorbed. And so, you get filtered bicarbonate being reabsorbed through a complex intermediate pathway. How does acetazolamide play a role here? It blocks the two roles of carbonic anhydrase and that essentially shuts down the entire pathway blocking sodium reabsorption, hence, the diuretic effect.

[00:03:00] In net, acetazolamide increases the renal excretion of sodium, potassium, and bicarbonate. That increased renal excretion of bicarbonate results in a proximal RTA or renal tubular acidosis type 2. This can be used or leveraged to treat metabolic alkalosis and it's using adjuvant therapy to prevent seizures. One other use for acetazolamide is to prevent altitude sickness. So, this is somewhat interesting. Preventing altitude sickness requires

[00:03:30] some degree of hyperventilation. People start with a respiratory rate of 16, and as they ascend the mountain, that respiratory rate may go to 20 but it's still not at the target respiratory rate. The reason the respiratory rate stops going up is the patients reach a degree of respiratory alkalosis that prevents further hyperventilation. This would continue but if you intervene with acetazolamide, you can induce a metabolic

[00:04:00] acidosis and lower the pH down to say 7.5 allowing further hyperventilation back into the target respiratory rate. Moving on to the potassium-sparing diuretics. These are active in the cortical collecting duct. There are four types of potassium-sparing diuretics, amiloride, triamterene, spironolactone, and eplerenone. The first two, amiloride and triamterene are active in the tubular fluid, like all the other

[00:04:30] diuretics and because their protein bound they must be secreted in the proximal tubule. The last two, spironolactone and eplerenone are the only diuretics to get to their active site via the bloodstream and do not need to go through the tubular fluid. Triamterene and amiloride block the sodium channel in the cortical collecting tubule. This channel is called the epithelial sodium channel or eNaC and is essential for the secretion of potassium. If it is blocked, no

[00:05:00] potassium can be secreted by the principal cell. Spironolactone and eplerenone are steroid hormones that regulate gene transcription. They decrease the expression of eNaC, sodium, potassium, ATPase, and the potassium channels required for potassium excretion in the principal cell. These drugs are very effective for the treatment of blood pressure, especially in patients with resistant hypertension. The patients most resistant to the treatment of blood pressure medications.

[00:05:30] This includes amiloride and triamterene as well as it does spironolactone and eplerenone. More importantly, spironolactone and eplerenone have been shown to have a survival advantage in heart failure, making them a critical drug in the treatment of that condition. We discussed that aldactone does not have much of a diuretic effect. That is probably a dose response. Typically today, we use about 25 milligrams daily. But since aldactone is one of our oldest diuretics,

[00:06:00] if you go back to the early 60s and take a look at ads. Here's a case report in an ad, of course, where they describe using aldactone at 100 milligrams QID, sixteen times the typical dose that we use. So they got a big diuretic effect at the cost of a very, very high dose and probably a lot of hyperkalemia.