How do each of the three most commonly prescribed medications for NDI treatment (chlorothiazide/hydrochlorothiazide, amiloride, and indomethacin) work in the body?

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Topic: Medications
Author: Bichet, Daniel G.
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Hydrochlorothiazide and amiloride are both diuretics. That is, they both normally act as agents that promote the excretion of urine. It seems somewhat paradoxical then, that these two agents are used to reduce the urine flow of NDI patients. In fact, researchers are still unable to explain exactly how these diuretics act as antidiuretics in NDI patients.

A normally functioning kidney reabsorbs the majority of the body water passing through it. The kidney reabsorbs the water through the nephrons and the collecting ducts they flow into. The nephron is the main working unit of the kidney. It consists of a filter, called a glomerulus, and a tiny tube called a tubule. The part of the tubule closest to the glomerulus is called the proximal tubule. The part furthest from it is called the distal tubule. The reabsorption process involves a host of molecular structures working properly and the creation of the proper osmotic conditions between the nephrons and the kidney tissue (interstitium) that surround them. A majority of the body water is reabsorbed through the proximal tubule, but a significant amount is also reabsorbed through the distal tubule and the collecting ducts. People with NDI cannot reabsorb the water flowing through the distal tubule and the collecting ducts.

Some researchers think that thiazide diuretics may reduce the rate at which body fluid filters through the glomerulus. The idea is that if there is a reduced amount of fluid going through the glomerulus, there will be a reduced amount of fluid reaching the distal tubule and the kidney collecting duct. But several studies have shown that thiazides have an antidiuretic effect without reducing the glomerular filtration rate.

Other researchers think that the urine reduction takes place because the thiazides reduce distal tubular sodium reabsorption, increase urinary sodium excretion, and lower extracellular liquid volume. These effects combine to cause an increase of body water reabsorption in the proximal tubules, so there is less fluid reaching the distal tubules and collecting ducts. But one study - the first that directly tested whether thiazides do reduce the amount of fluid that reaches the collecting ducts and distal tubules - showed that the reduction of fluid delivered to the distal tubule was too small to account for the degree of urine reduction. Most recently, a series of experiments designed by Gronbeck, et al., in 1998 found no evidence to support this reduction in fluid to the distal tubule theory. Nonetheless, in combination with a reduction in salt intake, thiazides can reduce urine volume by 20% to 50%.

Whereas thiazides rob the body of potassium, amiloride does not. Thus, it is referred to as a potassium-sparing diuretic. It blocks the transport of sodium from the outer and middle sections of the collecting ducts to the surrounding kidney tissue. Amiloride is less effective in reducing urine output than thiazides. But when it is used with thiazides it helps reduce the urine output more than when thiazides are used alone. Perhaps this additive effect is due to the fact that both diuretics affect different parts of the collecting ducts and distal tubules.

Indomethacin inhibits prostaglandin synthesis in the kidney and also decreases the glomerular filtration rate. Prostaglandins inhibit the ability of AVP to induce water reabsorption in the collecting duct. By reducing the concentration of prostaglandins in the collecting duct, thus blunting the AVP inhibiting action of prostaglandins in this area, indomethacin can enhance the ability of AVP to concentrate urine. Indomethacin is fast acting and useful in emergency situations, but it is not recommended for long-term use because of its side-effects.