Loop diuretics

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Introduction0:00–0:31

Diuretics are medications that act on the kidneys to increase production of urine - and therefore, eliminates water from the body.
There are 5 main types of diuretics - carbonic anhydrase inhibitors; osmotic diuretics; thiazide and thiazide-like diuretics; potassium sparing diuretics; and last but not least, loop diuretics - which we’ll get intimately acquainted with during this video.
Now, the basic unit of the kidney is called a nephron, and each nephron is made up of a glomerulus, which filters the blood.

Physiology0:31–1:32

Blood enters the glomerulus with the afferent arteriole, and exits the glomerulus from the efferent arteriole. The filtered content then goes through the renal tubule, where excess waste, and molecules (such as ions and water), are removed or filtered through an exchange between the tubule and the peritubular capillaries.
So the renal tubule plays a huge role in secretion and reabsorption of fluid and ions - such as sodium, potassium, and chloride - in order to maintain homeostasis, or the balance of fluid and ions in our body.
The renal tubule has a few segments of its own: the proximal convoluted tubule; the U-shaped loop of Henle, with a thin descending, a thin ascending limb, and a thick ascending limb; and finally, the distal convoluted tubule, which empties into the collecting duct, which collects the urine.
Different kinds of diuretics act on different segments of the renal tubule. Now, loop diuretics - as you might have guessed - act on the loop of Henle.

Mechanism of Action1:32–3:52

To be more specific, they mainly target the thick ascending limb. The thick ascending limb is impermeable to water and it is lined with cuboidal cells that have Na+K+2Cl- cotransporters on the apical surface.
These transporters reabsorb sodium, potassium, and chloride from inside the thick ascending limb back into the blood. As such, they shuttle one sodium into the cell, down its concentration gradient, and that powers the movement of one potassium and two chlorides into the cell as well.
Think of it as a revolving door where sodium is the guy doing all the pushing, and one potassium and two chlorides just follow him in.
This way, approximately 25% of the filtered sodium is reabsorbed in the loop of Henle, mostly in the thick ascending limb.
Now, on the basolateral side of the tubule cell, a Na/K ATPase uses energy in the form of ATP to pump three sodium ions into the interstitial fluid in exchange for letting two potassium ions into the cell.
This helps to maintain the low sodium concentration inside the cell. Finally, both chloride and potassium move from the cell back into the lumen of the thick ascending limb, through special channels on the apical side of the cells that simply “leak” these ions passively.
Funnily enough, the passive movement of potassium generates an electrochemical gradient that increases the reabsorption of calcium and magnesium through a paracellular pathway - meaning, these ions don’t use any channels, but rather they sneak between two epithelial cells and go back in the bloodstream.
Now that’s a lot of activity for such a tiny cell! Ok, now here’s where loop diuretics come into play.
Just to get acquainted with our team here, there’s 4 main diuretics - 3 of them: furosemide, bumetanide and torsemide - are chemically related, in that they are sulfonamide derivatives.
The last non-sulfonamide loop diuretic, ethacrynic acid, is a phenoxyacetic acid derivative. These medications can be administered orally or intravenously, and once they’re in the bloodstream, they get secreted from the peritubular capillaries into the proximal tubule.

Route of Administration3:52–5:41

Then, they make their way to the thick ascending limb and bind to the Na+K+2Cl- cotransporters. Loop diuretics bind to the Cl- site on the transporter and block it, so now sodium, potassium, and chloride can’t be reabsorbed into the bloodstream and they get excreted out with the urine.
Other ions that depend on sodium reabsorption, like calcium and magnesium are excreted as well. Now remember, water follows where sodium goes.
So this means there will be more water molecules in the lumen as well, so more urine is produced. Okay, now regarding calcium, there’s an important distinction from thiazide diuretics, which is another important class of diuretics.
Loop diuretics increase calcium excretion, while thiazide diuretics decrease calcium excretion. There’s a mnemonic to help you remember this fact!
“Loops lose calcium”! Okay, now, along with inhibiting these Na+K+2Cl- cotransporters, loop diuretics also stimulate the release of prostaglandins, which dilate the afferent arteriole.
As a result, they increase the renal plasma flow and they also increase the glomerular filtration rate, or GFR. However, many individuals who take loop diuretics also take non-steroidal anti-inflammatory drugs, or NSAIDs, which inhibit prostaglandin synthesis and thus, they can decrease the loop diuretics’ effect.

Indications5:41–6:41

Ok, so the major indication for diuretics is for the management of edematous states, like heart failure, pulmonary edema, cirrhosis with ascites, or nephrotic syndrome, where fluid builds up in the extracellular space.
However, they can also be used as an alternative agent for hypertension. Since these medications cause water loss through the urine, it leads to decreased plasma volume and cardiac output, resulting in lower blood pressure.
Ok, now aside from edematous states and hypertension, we can use loop diuretics to correct certain electrolyte imbalances like hypercalcemia - or too much calcium in the blood; and hyperkalemia, or too much potassium in the blood.
Last but not least, we can use loop diuretics to treat acute bromide, fluoride, or iodide intoxications because these substances are also reabsorbed in the thick ascending limb.Ok, now finally, there are also some considerations to keep in mind - first, as far as contraindications go, it’s intuitive to not use loop diuretics, or any kind of diuretic for that matter - in a dehydrated patient.

Side Effects6:41–9:00

It’s also important to make sure that you don’t remove too much water from the body - especially when treating edematous conditions; like heart, kidney, and liver failure.
Low levels of circulating fluid can also signal the proximal tubule to reabsorb more uric acid - so in hypovolemic patients, loop diuretics can cause hyperuricemia and gout attacks.
Another interesting side effect is something called hypokalemic metabolic alkalosis - hypokalemic means low serum potassium, and metabolic alkalosis refers to an increase in blood pH which is caused either by too much bicarbonate, or too little hydrogen ions in the blood.
This happens because an increased concentration of sodium ions in the collecting duct make the collecting duct secrete more potassium and hydrogen ions from the blood and into the urine.
The loss of sodium also causes increased excretion of magnesium and calcium, which can lead to hypomagnesemia and hypocalcemia.
However, calcium can be reabsorbed later in the distal convoluted tubule, and thus, hypocalcemia is not very likely to occur.
Now, loop diuretics might occasionally cause ototoxicity and hearing loss, usually with high doses. Also, ototoxicity is more common with ethacrynic acid than with the sulfonamide derivatives.
Luckily, ototoxicity is usually reversible after stopping the medication. Finally, some people develop an allergic reaction to sulfonamide medications - like sulfamethoxazole, an antibiotic, and they might also develop an allergic reaction to the sulfonamide loop diuretics like furosemide, torsemide, and bumetanide.
Even worse, the allergic reaction might cause acute interstitial nephritis and damage the kidneys. For these people, ethacrynic acid is a safer choice.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts! So let’s have a rollercoaster with a big loop, for loop diuretics.

Memory Palace9:00–11:15

The cart is on the upward part, which is thicker to help you remember these drugs act on the thick ascending loop. Inside the cart is a salt shaker, a banana, and 2 swimmers who came out of a chlorinated pool to help you remember Na+K+2Cl- cotransporters are the target.
Now, for the medications, let’s have a hot spring with the sulfuric smell of rotten eggs for the sulfonamide loop diuretics.
So in this pool, we have a kid with his bum sticking out of the water for bumetanide, a kid with only his torso sticking out for torsemide, and their furious father for furosemide.
Ethacrynic acid is a crying extra terrestrial, or ET, who’s not allowed in the hot spring since it’s not a sulfonamide. It would probably melt or something if it touched the water.
For the indications, let’s put them on top of the rollercoaster, since they are all related to high levels of something.
We have a blood pressure cuff wrapped around a water balloon on the top of the rollercoaster for hypertension and edema.
There’s also a banana in a milk bottle up there for hyperkalemia and hypercalcemia. Finally, there’s a broom sweeping up flour, and a broken iodine bottle for bromide, fluoride, or iodide intoxication.
For side effects, we have allergic reactions caused by sulfonamides, so let’s have a kidney with red rashes in the hot spring for allergy and acute interstitial nephritis.
For side effects that involve all 4 drugs, we’ll put them by the ET. First, he’s wearing headphones for ototoxicity.
Now to help you remember ethacrynic acid is the most ototoxic, let’s give him 4 extra ears. By his feet, there’s a banana peel in an empty milk bottle, as well as a broken magnet, for hypokalemia, hypocalcemia, and hypomagnesemia.
Finally, there are shards of uric acid crystals sticking out of the toes of the ET to help you remember gout. Alright, as a quick recap.

Review11:15–12:14

Loop diuretics are a class of medications that are used to remove excess water from the body. There’s four of them: 3 sulfonamide-derivatives - furosemide, torsemide and bumetanide; and one phenoxyacetic acid derivative, ethacrynic acid.
These medications can be administered orally or intravenously, and they act by inhibiting the Na+K+2Cl- cotransporters in the thick ascending limb.
This leads to increased excretion of water, sodium, potassium, and chloride in the urine, as well as calcium and magnesium.
Loop diuretics are commonly used to treat edema caused by heart, kidney, or liver failure, and they are also useful for managing hypertension.
Hypercalcemia and hyperkalemia are two other indications for the use of loop diuretics, as well as bromide, iodide, and fluoride intoxications.
wait, there's more. Here's a mind map with all the mnemonics.

Mind Map12:14–12:26

Go ahead and pause the video. So you can test yourself to see what you remember.
Stay tuned for the answers after the credits.