How do the medications interact with each other?

Topic: Medications
Author: Bichet, Daniel G.
When hydrochlorothiazide is used in combination with either amiloride or indomethacin, it results in a greater reduction in urine output than achieved by hydrochlorothiazide alone. Though it is still unclear how hydrochlorothiazide actually works to reduce urine output, many researchers think that hydrochlorothiazide causes the person taking it to secrete more sodium in the urine, thus reducing the amount of sodium in the kidney extracellular environment along with reducing the amount of extracellular fluid volume in the kidney. Less sodium and less extracellular fluid creates the osmotic conditions in the kidney that result in more body water than usual being reabsorbed in the part of the kidney nephron called the proximal tubule. This means there is less body water arriving at the distal nephron and collecting duct. (In NDI there is an inability to reabsorb the water flowing through the distal tubules and collecting ducts. This unabsorbed water becomes the excessive urine that is voided by NDI patients).

Amiloride also causes the body to excrete more sodium in the urine. This also results in reduced extracellular sodium and fluid volume. But amiloride has its effect at a different part of the kidney than hydrochlorothiazide. So when the two drugs are used together, they both, working at different locations, cause increased sodium excretion, which changes the osmotic conditions to allow increased absorption of body water at different places in the kidney than the NDI-impaired collecting duct.

Indomethacin, on the other hand, works to reduce urine output by inhibiting prostaglandin synthesis in the kidney. Prostaglandins inhibit the hydroosmotic effect of AVP in the collecting duct. By blocking the action of prostaglandin in the collecting duct, indomethacin enhances the ability of AVP to concentrate urine.

Since the combination of amiloride and hydrochlorothiazide is as effective as the combination of indomethacin and hydrochlorothiazide, and since amiloride has fewer and milder side-effects than indomethacin and hydrochlorothiazide, most clinicians prefer amiloride, reserving indomethacin for emergency uses since its action begins more quickly than the diuretics.