Thiazide and thiazide-like diuretics

Definitions & Key takeaways

Thiazide and thiazide-like diuretics are a class of medications used to treat hypertension and edema by promoting the elimination of salt and water from the body. Thiazide diuretics work by inhibiting reabsorption, specifically by blocking the sodium-chloride symporter in the distal convoluted tubule in the kidney. This in turn leads to increased excretion of sodium and water.

The most commonly used thiazides are chlorothiazide and hydrochlorothiazide; and the most commonly used thiazide-like diuretics are metolazone, indapamide, and chlorthalidone. Thiazide and thiazide-like diuretics are generally considered safe and effective drugs for treating high blood pressure and edema. However, they can cause some side effects such as electrolyte imbalances, dehydration, increased blood sugar levels, and increased uric acid levels.

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Introduction0:00–0:30

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.

Physiology0:30–1:20

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.

Mechanism of Action1:20–3:14

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.

Indications3:14–4:52

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.
So… why give these people thiazides if they’re already eliminating so much urine? Well, thiazides induce a mild hypovolemia, and this makes the kidneys respond by reabsorbing more sodium and water in the proximal convoluted tubule.
With less fluid reaching the distal convoluted tubule, fluid balance is maintained. However, thiazides do come with some side effects.

Side Effects4:52–6:14

First off, they tend to tamper with sugar and fat metabolism, causing hyperglycemia and an increase in serum cholesterol and LDL.
They also cause more calcium and uric acid to be retained in the blood, so hypercalcemia and hyperuricemia are a risk. Chronic hyperuricemia could also lead to gout.
Since thiazides increase sodium loss in the urine, short term use causes hyponatremia. To make things worse, increasing urine output can cause hypovolemia, which in turn, triggers the secretion of antidiuretic hormone, or ADH.
ADH binds to specific V2 receptors in the collecting duct, and retains more water relative to sodium, diluting the blood and further lowering the sodium concentration.
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 few 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.
Finally, people with allergic reactions to sulfonamide medications may develop an allergic reaction to thiazides and thiazide-like diuretics.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts! Let’s have a psychic for the thiazides, and she’s holding a seance for her client, who represents the thiazide-like diuretics.

Memory Palace6:14–7:42

The client is Indian, for indapamide, and he’s holding a metallic laser gun, for metolazone, while eating a bowl of colorful salad for chlorthalidone.
On the table, are a few objects representing the indications for these medications. First, instead of a crystal ball, the psychic is using a water balloon sitting on top of a blood pressure cuff, which represents the edematous state and hypertension.
Next, there’s a milk bottle with a kidney stone, representing calciuria, and a bone full of holes, representing osteoporosis.
Finally, there’s a sippy cup for diabetes insipidus. The side effects will be represented by the ghost they summon.
This ghost with red rashes is sitting in a hot spring with the sulfuric smell of rotten eggs, because these medications can cause a reaction in people with a sulfa allergy.
His fingers are swollen with uric acid crystals sticking out, for hyperuricemia and gout. Next to him, are the unhealthy foods that lead to his death.
On one side, there’s a huge stick of butter, for hyperlipidemia, and a giant candy bar, for hyperglycemia. There’s also a box of baking soda with a banana peel on it, for hypokalemic metabolic alkalosis.
On his other side is a short and empty salt shaker, representing hyponatremia. All right, as a quick recap… thiazide and thiazide-like diuretics are medications that block the sodium-chloride symporter in the distal convoluted tubule in order to increase urine output.

Review7:42–8:40

The most commonly used thiazides are chlorothiazide and hydrochlorothiazide; and the most commonly used thiazide-like diuretics are metolazone, indapamide, and chlorthalidone.
They’re mostly used as first-line antihypertensive agents, but can also be administered to reduce edema in heart failure and cirrhosis.
They also increase calcium reabsorption, so they are used to prevent calcium kidney stones and osteoporosis. Finally, they can correct the imbalances in nephrogenic diabetes insipidus.
Common side effects include hyperglycemia, hyperlipidemia, hyperuricemia, hypercalcemia, hyponatremia, hypokalemic metabolic alkalosis, and sulfa allergies.
But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.

Mind Map8:40–8:50

Stay tuned for the answers after the credits.