By Joel Topf, MD - 12th Aug 2019 - Course previews

Thiazide diuretics

Thiazide diuretics are great for preventing kidney stones, but do you know which patients respond best to them? In this video from our Fluids and Electrolytes Masterclass, you'll discover how thiazide diuretics work, the differences between them, and what makes them unique among other diuretics.

In case you missed the first two videos in this series, you can find them here:
1. The philosophy of diuretics
2. Loop diuretics

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If you are a clinician working in internal medicine, you are probably taking care of patients with fluid and electrolyte problems on a daily basis. This course teaches you the nuts and bolts of fluid and electrolyte management. You'll discover what it really means when sodium or potassium levels are abnormal, learn how to diagnose and treat imbalances, and get expert tips for prescribing diuretics.

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Video Transcript

[00:00:00] Thiazide diuretics act at the distal convoluted tubule. This is the third stop in the kidneys, as we wrap through the nephron, looking at sodium handling. Thiazide diuretics act after the loop diuretics. So, thiazide diuretics are active in the tubular fluid. In order to get there, they would need to be filtered. However, they are protein 

[00:00:30] bound and cannot be filtered at the glomerulus and so they enter the tubular fluid by secretion in the proximal tubule. Secretion is GFR dependent. So, the lower the GFR, the less diuretic that reaches the tubule. Let's take a closer look at the mechanism of thiazide diuretics at the cellular level. So, taking a look at the distal convoluted tubule, you have the sodium chloride cotransporter on the basolateral membrane, you have the sodium-potassium 

[00:01:00] ATPase, you have a potassium channel and a chloride channel. Remember, the basolateral membrane is the side that's touching the blood, that's going to be returned to the body and the apical membrane is the tubular side, where the fluid is going to end up in the urine. So sodium is reabsorbed through the sodium chloride cotransporter and then exits the cell via the sodium-potassium ATPase that exchange with potassium and potassium is recycled 

[00:01:30] through a potassium channel. Chloride is reabsorbed and then exits the cell via a basolateral  chloride transporter. Thiazide acts by blocking the sodium chloride cotransporter and that shuts down all the movement of these molecules. Thiazide diuretics increase the renal excretion of sodium, like all diuretics, increased renal excretion of potassium, and increase excretion of hydrogen ions, causing metabolic alkalosis. 

[00:02:00] Unique to the thiazide diuretics is they decrease renal excretion of calcium, lower renal loss of calcium, which makes them useful to prevent kidney stones. We primarily use them to prevent calcium-containing stones and they work best in patients that have primary hypercalciuria, that is patients with excess calcium in the urine, for women that's over 250 milligrams in a 

[00:02:30] 24-hour collection, for men that's over 300 milligrams in a 24-hour collection. There are a number of different thiazides but I want to talk about three in particular. So, the one that most people are most familiar with is hydrochlorothiazide. This is the most popular thiazide found in drug combinations. Metolazone, trade name is Zaroxolyn, is a drug with a much longer half-life and is typically used in patients with low GFRs. 

[00:03:00] Chlorthalidone has the longest half-life of all. Half-life measured in days rather than hours and it was the drug in the largest hypertension trial ever conducted, AllHat. AllHat randomized 42,000 people, enough people to fill a major league baseball stadium. They were assigned to one of four groups: chlorthalidone, amlodipine, lisinopril or doxazosin. 

[00:03:30] The doxazosin group was stopped early because of increased rates of heart failure. The other three went to completion. What they found was there was lowest blood pressure with chlorthalidone compared to the other two controlled drugs. But the idea of the study was to keep the blood pressures the same across the groups and then measure if there was a difference in outcomes at the same blood pressure. So, to this degree, 

[00:04:00] the study wasn't perfectly conducted because there was a difference in blood pressure and they didn't want that. Nonetheless, there was no difference in outcomes across all three drugs. In subgroup analysis, chlorthalidone was superior to amlodipine for the intermediate outcome of heart failure. I'm not sure if anybody was surprised that the diuretic was better than the calcium channel blocker for heart failure. Chlorthalidone versus lisinopril also showed 

[00:04:30] an advantage for heart failure and in addition showed an advantage for stroke. On the basis of this subgroup analysis, looking at heart failure stroke, chlorthalidone was declared the winner of AllHat. Final summary on thiazides. Thiazides act at the distal convoluted tubule. They are a first line antihypertensive drug, though there are regional differences and is the only diuretic that decreases urinary calcium.