Carbonic anhydrase inhibitors

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Introduction0:00–0:35

Diuretics are medications that act on the kidneys to increase production of urine, and to eliminate water, certain metabolic wastes, and electrolytes from the body.
There are 5 main types of diuretics; carbonic anhydrase inhibitors, osmotic diuretics, thiazide and thiazide-like diuretics, loop diuretics, and last but not least, potassium sparing diuretics - which is the only class of diuretic that retains potassium, rather than wastes it.
Now, the basic unit of the kidney is called a nephron, and each nephron is made up of a glomerulus, which filters the blood.

Physiology0:35–4:12

The filtered content 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.
The luminal side of the proximal convoluted tubule is lined by tubule cells, which are also known as brush border cells.
The apical surface of these cells, which faces the tubular lumen, is lined with microvilli. Microvilli are tiny projections that increase the cell’s surface area to help it reabsorb more solutes or water.
On the other side is the basolateral surface, which faces the interstitium, or the space between the tubule and the peritubular capillaries.
When a molecule of bicarbonate approaches the apical surface of the brush border cell it binds to hydrogen to form carbonic acid.
At that point, an enzyme called carbonic anhydrase type 4, which lurks in the tubule among the microvilli like a shark, swims along and splits the carbonic acid into water and carbon dioxide.
The overall equation looks like this: H+ + HCO3- <-> H2CO3 <-> H2O + CO2 The water and carbon dioxide happily diffuse across the membrane into the cells where carbonic anhydrase type 2 facilitates the reverse reaction - combining them to form carbonic acid, which dissolves into bicarbonate and hydrogen.
A sodium bicarbonate cotransporter on the basolateral surface snatches up the bicarbonate and a nearby sodium, and shuttles both into the blood.
Meanwhile, that sodium-hydrogen exchanger on the apical surface, pulls sodium into the cell, while pushing hydrogen back into the tubule.
So at the end of the day, there’s a movement of bicarbonate and sodium from the tubule to the blood. Switching gears just a little bit, carbonic anhydrase can also be found in the eyes - specifically, in the middle, vascular tunic of the eye.
Here’s where we can find the ciliary body, which is also lined by epithelial cells that secrete aqueous humor into the posterior chamber of the eye, and carbonic anhydrase helps move bicarbonate from the blood and into that aqueous humor.
Finally, carbonic anhydrase is found in the ventricles of the brain. Here, we can find it in the choroid plexus, which produces cerebrospinal fluid, or CSF for short.
The choroid plexus is also lined with epithelial cells, which have carbonic anhydrase that helps bicarbonate move from the blood into the cerebrospinal fluid.
Ok, so carbonic anhydrase inhibitors bind to the carbonic anhydrase enzymes and inhibit them. These medications usually end in -zolamide, and some can be administered by mouth, such as acetazolamide, while others, such as brinzolamide and dorzolamide, can be administered as eye drops for the treatment of glaucoma.

Mechanism of Action4:12–7:45

But let’s focus on the kidney-related uses first. Administering acetazolamide leads to a decreased bicarbonate reabsorption in the proximal tubules, so more bicarbonate and sodium get excreted in the urine.
So since water flows where the sodium goes, this leads to a mild increase in urine output. This is useful for treating edematous states like pulmonary edema or ascites where fluid builds up in the extracellular space.
As a diuretic, acetazolamide is much weaker than other classes of diuretics like loops and thiazides. So it’s only used to treat edematous states when there’s also alkalosis, or a high blood pH.
It also causes urine alkalinization, or an increase in urine pH. If urine pH is too low, some compounds like cystine, or uric acid in the urine can precipitate and form kidney stones.
So to prevent kidney stone formation, acetazolamide is given to patients who suffer from cystinuria, which is when there’s too much cystine in the urine, or gout where there’s too much uric acid in the blood, and consequently, the urine.
Now, where carbonic anhydrase inhibitors really come in handy is in the treatment of glaucoma - which is when there’s a high pressure inside the eye, typically because of too much aqueous humor being produced.
Although the mechanism isn’t well understood, the secretion of aqueous humor is dependent on bicarbonate production. So, by inhibiting carbonic anhydrase in the epithelial cells of the ciliary body, there’s decrease aqueous humor production, therefore lowering intraocular pressure.
Usually, topical carbonic anhydrase inhibitors like brinzolamide and dorzolamide are used to get the benefits locally, with none of the systemic side effects.
Other uses for carbonic anhydrase inhibitors have to do with their role in cerebrospinal fluid formation and composition.
First, lowering CSF production is useful in conditions such as CSF leakage, usually secondary to trauma or a tumor. With acetazolamide, less CSF is produced, so less is lost.
Acetazolamide can also be used for mountain sickness which can happen to people rapidly climbing to heights greater than 3000 meters above sea level, where air has much less oxygen.
Hypoxia leads to symptoms like weakness, dizziness, headache, nausea, and insomnia. Acetazolamide decreases the amount of bicarbonate in the CSF, lowering its pH.
A low CSF pH leads to an increase in respiratory rate, thereby increasing the amount of oxygen available. For the same reason, acetazolamide can be used in the management of sleep apnea - which is when people stop breathing for short periods of time while sleeping.

Side Effects7:45–9:30

For side effects, carbonic anhydrase inhibitors can cause metabolic acidosis since a lot of bicarbonate is lost in the urine.
When this happens, the body tries to compensate for the bicarbonate loss by releasing chloride from the cells into the blood, leading to hyperchloremia.
Secondly, there’s also a risk for renal stones to form. This is because carbonic anhydrase inhibitors also increases phosphate and calcium excretion, and these are more likely to form calcium phosphate stones in alkaline urine.
This side effect can be prevented by monitoring urine pH, and making sure it doesn’t get too alkaline. Another side effect is renal potassium wasting, because these medications increase natriuresis - meaning more sodium, and along with it, water, reaches the collecting duct.
Inside the collecting duct, more sodium leads to an increased potassium secretion from the blood into the lumen, which is lost in the urine.
With large doses of acetazolamide, patients may develop neurological side effects like drowsiness and paresthesias - which is just a fancy word for that “pins and needles” sensation you’d get if a large cat took a nap on your legs.
Finally, these medications are contraindicated in people with cirrhosis, because when the liver is damaged it has a hard time removing ammonia from the blood.
Carbonic anhydrase inhibitors further decrease urinary excretion of ammonia causing hyperammonemia. This increase in ammonia is toxic to the brain, and can cause hepatic encephalopathy.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts! We’ll use a zombie lamb to represent these medications, since they end in -zolamide.

Memory Palace9:30–11:19

The zombie lamb is trying to decide where to go: he can head for the mountains, which will be our indications, or to the pool, where the side effects are located.
For indications, the mountain in the distance represents mountain sickness, on top is a tasty brain, leaking brain juices for CSF leakage.
The brain also has a pair of bulging eyeballs for glaucoma. At the bottom of the mountain is a water balloon, representing edema, and it’s hitting an alkaline battery, representing alkalosis.
Next, for side effects, the pool represents hyperchloremia, and floating in it, is a large soda can, representing acidosis.
Next, to the pool is a garbage can stuffed with a large banana peel for potassium wasting. A large kidney stone is by the garbage can.
It’s glowing a phosphorus green and there’s milk being poured on it, to help you remember it’s a calcium phosphate stone.
By the pool, is a lady who fell asleep while sunbathing to represent drowsiness. She’s going to end up with a strange set of tan lines because… Her arms and legs are bandaged up to represent peripheral neuropathy.
She’s also got a clothespin on her nose since she’s sleeping next to a pile of smelly fertilizers covering a sickly looking liver, which represents hyperammonemia with cirrhosis.
All right, as a quick recap… carbonic anhydrase inhibitors are a class of medications that act by inhibiting the enzyme carbonic anhydrase.

Review11:19–12:31

Carbonic anhydrase can be found in epithelial cells that line the proximal convoluted tubule of the kidney, as well as those lining the ciliary body in the eyes, and the choroid plexus in the brain ventricles.
Topical carbonic anhydrase inhibitors such as dorzolamide and brinzolamide are used in the treatment of glaucoma. Their systemic counterpart, acetazolamide, can be used to treat edematous states when alkalosis is also present.
It could also alkalize the urine and prevent the formation of uric acid or cystine stones. Furthermore, acetazolamide is useful in the treatment of mountain sickness.
Side effects of acetazolamide include hyperchloremic metabolic acidosis, calcium phosphate renal stones, renal potassium wasting, as well as drowsiness and paresthesia, and they are contraindicated in patients with hepatic cirrhosis.

Mind Map12:31–12:44

But wait, there's more: Here's a mind map with all of the mnemonics from the video. Go ahead and pause the video so you can test yourself to see what you remember.
Stay tuned for the answers at the end.