Carbonic anhydrase inhibitors

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Carbonic anhydrase inhibitors

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Carbonic anhydrase inhibitors

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is a carbonic anhydrase inhibiting diuretic that causes acidosis as it causes decreased HCO3 reabsorption.

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A 65-year-old woman comes to the ophthalmologist's office because of visual changes for 18 months. Medical history includes type 2 diabetes mellitus, chronic liver disease, and hypothyroidism. Examination of her visual fields shows gross deficits in each eye. Fundus examination shows a cup-to-disc ratio of approximately 0.65. Automated perimetry confirms peripheral, asymmetric, bilateral visual field loss. Her intraocular pressure is 28 mm Hg (normal range 8-21 mm Hg). Acetazolamide is prescribed. Which of the following is the most likely adverse effect of this medication?

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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. 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. 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.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Hypertension" Nature Reviews Disease Primers (2018)
  5. "Hypertension" Nature Reviews Disease Primers (2018)
  6. "Non-Classical Inhibition of Carbonic Anhydrase" International Journal of Molecular Sciences (2016)
  7. "Carbonic anhydrase inhibitors in patients with respiratory failure and metabolic alkalosis: a systematic review and meta-analysis of randomized controlled trials" Critical Care (2018)