Diuretics have always been a tough nut for medical students to crack. Probably, because keeping track of all the different ions that are increased or decreased in each separate class is very confusing. And in exam, they have a remarkable propensity of getting jumbled up and hard to remember what diuretic causes what ions to increase or decrease in blood or urine. Probably, this is also the reason why boards are in love with them. To me, what has always worked is the method where you don’t have to remember much, all you have is a good physiological model, from which every detail flows like water (Trust me, the pun was unintended :p ). I have taken no fact for granted, every symptom, every side-effect is tied in a neat pharmacodynamic model. I am pasting these images from my notes. As they say, ‘a picture is worth a thousand words’, I would recommend you to use the text only to familiarize yourselves with these figures, and once you understand these figures, use only these to memories. For those of you guys preparing for USMLEs, or COMLEX this is all the information you need to tackle anything the board cares to throw at you. I have also used some multidisciplinary but related pearls that UWORLD or USMLE loves to throw at you.
Carbonic Anyhdrase(CA) Inhibitors
(Acetazolamide, Prozolamide)
We are in the proximal convoluted tubule. The proximal most part of the renal tubule after bowman’s space. It is here that most ions are re–absorbed, including HCO3– ions. The HCO3– ion that is reabsorbed through the tubule is not the one that was filtered through in the bowman’s space! In fact, the mechanism of re-absorption here is a little indirect. What happens is carbonic anhydrase(CA) converts CO2 and water into HCO3– and H+ ions. H+ ions are then secreted out of the tubule at the luminal side by Na+/H+ exchanger. For every Na+ ion that comes inside the cell, water is dragged with it. Having said this, now let us walk through the figure.
This is a Proximal tubular cell. At the left side is the lumen and right side is the plasma. Ions at the left are going to go in urine. –Zolamides or Carbonic Anhydrase(CA) inhibitors inhibit CA. Following the red arrow this causes ↓ excretion of H+ ions. ↓ in H+ ions, in the PCT cell would cause ↓ exchange of Na+ ions by the Na+/H+ exchanger. This will cause ↑ Na+ in the tubular lumen and as water follows Na+ ions, this will increase urine volume (Hence, the function of diuretics). This ↓ exchange will also cause ↓ H+ ions to be available to bind with filtered HCO3– ions, which will eventually, cause ↑↑ in HCO3– in the luminal side. And so, this way CA inhibitors will cause relative acidosis in the body (Because we are loosing net HCO3–). This side-effect of relative acidosis is desirable in patients with alkalosis. Especially, in altitude sickness. This ↑ HCO3– in the lumin will result in rise of pH here, and what type of stones does alkaline medium facilitates in forming? Yes, you are right if you said Ammonium magnesium phosphate (aka Struvite) stones.
Note that K+ and Cl– ions also are increased in the lumen. This is because bulk of water tends to drag these ions with them. Hence, wherever the water goes, these ions are dragged along. This mechanism is called ‘Solvent Drag’ and is responsible for life threatening hypokalemia with diuretics, in general (except for potassium sparing ones, as we’ll see below). This loss of Na+ from the body will also cause parasthesisas.
In the end, Acetazolamide is a big sulfur containing molecule. So, it can result in sulfonamide hypersensitivity.
Loop Diuretics (or informally; Loops)
(Bumetanide, Ethacrynic acid, Furosemide, Torsemide)
Following PCT, the thin segment of loop is only permeable to water. Followed by the thin segment comes the thick ascending loop. It is here that Loop diuretics work. Na+/K+/Cl– co-transporter is the work horse of this segment. And as evident in the figure below, Loops work by blocking this. By blocking this co-transporter, loop diuretics will result in increased Na+ , K+ and Cl– in the lumen and as water follow these ions, water will also be lost in urine. Low Na+ in the thick ascending cells will cause increased exchange of Na+ for H+ ions. Hence, more H+ will go outside towards the lumen. This concomitant loss of H+ will cause relative increase in HCO3– in the body, causing alkalosis.
In normal (not treated by loop diuretics) thick ascending cells, Ca++ and Mg++ ions get absorbed by seeping through the joints between cells. This because Mg++ and Ca++ align through these joints as rest of the thick ascending portion is lined by Na+ , K+ and Cl– ions ready to be reabsorbed by the co-transporter. And as these have net +ve charge, it results in collection of Mg++ and Ca++ at the joints between cells (where there is no co-transporter) and so they seep into the cells. But with block of co-transporter’s function by loop diuretics, this alignment is lost and hence, Mg++ and Ca++ is lost in urine. Resulting in hypocalcemia and hypomagnesemia.
Stria reticularis in the inner ear also have a Na+ /K+ /Cl– cotransporter , and Loops can inhibit that, causing ottotoxicity. Furosemide is less ottotoxic than Ethacrynic acid as former is an irreversible blocker.
Loop diuretics and Thiazides both are excreted by the same channel that is responsible for excretion of uric acid from the body, hence, they have a potential to compete with uric acid and cause gout. And just like Acetazolamide and Thiazides, Loops also are large sulfur containing molecules, which has a potential of causing sulfonamide hypersensitivity.
Loops, from a different pharmacology, can cause increase in prostaglandins. Prostaglandins can cause vasodilation. Vasodilation will result in hypotension. If you want to counter this effect of loops, what should you do? Remember from cardiology, what do you give to suppress the production of prostaglandins to facilitate closure of ductus arteriosus? you are right if you said Indomethacin (which is an NSAID). So you give NSAIDs.
Thiazides
(Hydrochlorothiazide (HCTZ), Indapamide, Metolazone, Chlorthalidone)
Just deeper to the thick ascending limb of the tubule, is the distal convoluted tubule (DCT). This is the site of action of Thiazide diuretics. Thiazides work by blocking Na+/Cl– co–transporter. This in turn cause decreased Na+ in the body and ↑ Na+ and Cl– in the lumen. And just like the rest, water follows these and K+ follows water by the ‘Solvent Drag’ mechanism. ↓ in Na+ causes, ↑ in the exchange with H+ .Which causes relative alkalosis by exactly the same mechanism with which Loop diuretics cause them, causing hypokalemia. There is so great gradient of Na+ in the DCT that Na+ from the plasma end (to the right side of the figure) flows in with exchange of Ca++ . Ca++ flows in the body and Na+ comes in the DCT cell. Which causes ↓ Ca++ in the DCT cell and increased gradient of it relative to the lumen, so the Ca++ from lumen flows in, causing ↓ in urinary Ca++. This is the reason why Thiazides are indicated as treatment of calcium oxalate stones. But to flow from lumen, the Ca++ channel must be phosphorylated. And this physphorylation is achieved by PTH (Parathyroid Hormone) by binding to the Gs coupled receptor on the plasma side of the cell. This causes ↑ in cAMP which in turn causes ↑ in Protein Kinase A and phosphorylates the Ca++ channel.
Thiazides causes Sulfonamide hypersensitivity and hyperuricemia by the same mechanism that Loops follow.
Thiazides, are also ATP dependent K+ channel opener by a different pharmacology. Do you remember another drug from cardiology that does the same?(Hint: It makes hair grow in unwanted places). This maintains Beta cell polarity in pancreas and hence, insulin is not pumped out. Decrease in Insulin causes? This is easy! HYPERGLYCEMIA(you can make this correction in the figure) and hyperlipidemia. And I guess you have guessed that hirsuitisim causing drug by now; Minoxidil. Just like Minoxidil is used to decrease hypertension by K+ channel opening in smooth muscle cells and maintaining polarity to cause vasodilation, Thiazides also do the same.
Potassium Sparing Diuretics
Potassum sparing diuretics can be divided in roughly 2 categories;
1) Amiloride and Triamterene
2) Spironolactone and Eplerenone
Amiloride and Triamterene are Na+ channel blocker in the principal cells of collecting tubule. And this is all. Na+ doesn’t go in the cell, so water doesn’t go either. But it spares K+ by blocking the excretion of it. This is all to this sub–class. But I would like to add one clinical pearl here. What do you give in bipolar disorder that has a propensity to cause Diabetes Insipidus(DI)? You are right if you said Lithium. Amiloride is the treatment for lithium induced Diabetes Insipidus(DI). To understand it recall, how lithium causes DI. It does it by blocking D2-Aquaporin Channels that are inserted to the lumenal side of the collecting tubules. And how does lithium enters the collecting tubular cell to inhibit these aquaporin channels? it enters via the Na+ channel by competing with Na+ ions and like explained, Amiloride blocks these channels along with K+ channels.
Spironolactone and Eplerenone are aldosterone antagonists. Let us recall what does aldosterone do? Aldosterone kicks out 2 things and kisses welcome 1 thing. Those 2 things that it kicks out are H+ and K+ and what it welcome is Na+ .Blocking this effect will cause Na+ being unwelcomed in and H+ and K+ to stay nice and cozy where they are inside the body. So it will cause increased diuresis and increased K+ and acidosis in the body. Spironolactone (But not Eplerenone) also antagonizes androgen receptors, hence, causing constellation of anti-androgen side-effects.
Osmotic Diuretics
This includes Manitol, which is an osmotic diuretics work by holding water in the plasma. This is all to them.
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