Thiazide and thiazide-like diuretics

Diuretics are medications that act on the kidneys to increase production of urine, therefore elimination of water from the body.

There are 5 main types of diuretics - carbonic anhydrase inhibitors, osmotic diuretics, loop diuretics, potassium sparing diuretics, and last but not least, thiazide and thiazide-like 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. 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, and a thick ascending limb; and finally, the distal convoluted tubule, which empties into the collecting duct, which collects the urine.

Alright, so thiazide and thiazide-like diuretics are taken perorally, and once in the blood, they travel to the kidneys where they are secreted by the proximal convoluted tubule into the lumen of the renal tubule.

An important point to make here is that they are secreted by the same secretory system that secretes uric acid into the tubule, so they compete with the secretion of uric acid, therefore increasing uric acid levels in the blood.

Next, they travel along with the filtrate until they reach the distal convoluted tubule. This part of the nephron is lined by epithelial cells.

Now, on the luminal side of these cells, there’s a nifty little sodium-chloride transporter. This channel reabsorbs one sodium and one chloride ion together from the tubule, into the cell. Sodium is reabsorbed along with water into the interstitium, and then into the bloodstream.

This tiny cell also has a calcium channel on its luminal side, which allows calcium from the lumen to diffuse into the cell. Once in the cell, calcium is transported out into the interstitium through a sodium-calcium exchanger, that pumps a sodium in, and a calcium out.

Now, since thiazides decrease sodium reabsorption, there’s less sodium in the cell, so the sodium-calcium exchanger works overtime to pump more sodium in, and more calcium out. The decrease in intracellular calcium, in turn, leads to more calcium reabsorption from the urine.

Ok, so let’s meet our diuretic team here, but first, what is a thiazide, and what is a thiazide-like diuretic? Well all these medications have the same effect, the difference stems from their chemical structure.

Thiazides are benzothiadiazine derivatives, like chlorothiazide, and hydrochlorothiazide, and they all end in -thiazide; whereas thiazide-like diuretics, like metolazone, indapamide, and chlorthalidone, are sulfonamide derivatives.

Now, the major indication for diuretics is for the management of hypertension and edematous states. Since these medications cause water loss through the urine, it leads to decreased plasma volume and cardiac output, resulting in lower blood pressure. This also treats edematous states like pulmonary edema or ascites, where fluid builds up in the extracellular space.

These medications are less potent in their diuretic effect when compared to loop diuretics, but they’re much longer lasting.

Thiazides are used mainly as first line antihypertensive agents, since they decrease plasma volume. This also makes them useful as a second line therapy to treat edematous states caused by conditions like heart failure or cirrhosis.

Since they increase calcium reabsorption, they can also be used in individuals with calciuria, to prevent calcium nephrolithiasis, or the formation of calcium oxalate kidney stones. Preventing calcium loss can also slow down the progression of osteoporosis.

Finally, an interesting indication is nephrogenic diabetes insipidus, which is when the kidneys don’t respond to ADH, so they can’t reabsorb water in the distal convoluted tubule and collecting duct, and thus eliminate huge amounts of dilute urine each day. However, individuals usually compensate by also drinking huge amounts of water throughout the day, to replace the losses and maintain blood volume.