12.01.2 Diuretics for Hypertension
Diuretics are drugs that increase the loss of water from the body. In hypertension, a common diuretic treatment is the combination of a thiazide diuretic and a K+-sparing diuretic (amiloride). The diuretics act at different parts of the kidney tubule. The thiazide diuretics act on the distal convoluted tubule, and the K+-sparing diuretics act on the collecting duct. Another class of diuretics, the loop diuretics (which are used mainly in the treatment of heart failure) act on the loop of Henle.
In the distal tubule (just before the collecting duct) of the kidney, thiazide diuretics inhibit the Na+Cl- co-transporter (Figure 12.1.1), which inhibits Na+ reabsorption to increase the levels of Na+ and Cl- in urine.
Figure 12.1.1 Mechanism of action of thiazide diuretics (Copyright QUT, Sheila Doggrell)
As water reabsorption passively follows electrolyte reabsorption along the kidney tubule, when the levels of Na+ and Cl- in urine are increased, so are the levels of water in the urine. This decreased water reabsorption leads to increased water loss from the body, which in turn leads to decreased blood volume, decreased venous return and decreased blood pressure.
The thiazide diuretics are active after oral administration, which makes them easy to use. They are secreted into the proximal tubule of the kidney, and pass along the kidney tubule to the distal tubule, where they inhibit the Na+Cl- cotransporter in the distal tubule. With most thiazide diuretics, there is a diuretic effect within an hour, and a modest maximal effect is observed i.e. increase in water loss is modest. The main difference between the thiazide diuretics is there duration of action with hydrochlorothiazide, a commonly used thiazide diuretic, having a duration of action of ten hours, which allows it to be used once or twice daily. After having their effect, the thiazide diuretics are excreted in urine. They are a common initial treatment for hypertension, often in combination with a K+-sparing diuretic, an ACE inhibitor or an AT1-receptor antagonist.
The thiazide diuretics are well tolerated, and have only a few adverse effects. They can cause hypokalemia (low levels of potassium), as increasing the amount of water/Na+ delivered to the collecting duct increases K+ loss. This problem with the thiazide diuretics can be overcome by using them with a K+ sparing diuretic (e.g. amiloride). The second adverse effect observed with the thiazide diuretics is hyperuricemia, due to increased uric acid reabsorption. Thus, thiazides should not be given to subjects prone to gout, which is due to the accumulation of uric acid in joints.
To prevent excess K+ loss, thiazide diuretics are often administered with a K+-sparing diuretic. Amiloride is a K+ sparing diuretic. Amiloride inhibits a sodium channel in the late distal tubule/collecting duct (Figure 12.1.2), and this decreases Na+/K+ pumping, and the amount of K+ available for loss/secretion through the K+ channel. Overall, there is an inhibition of the exchange of sodium for potassium in the late distal tubule/collecting by amiloride.
Figure 12.1.2 Mechanism of action of amiloride (Copyright QUT, Sheila Doggrell)
Thus, amiloride indirectly inhibits K+ secretion (loss) into the kidney. Although, it is called a diuretic, amiloride only has a small diuretic effect, with its main use being to prevent the excess K+ loss with the thiazide diuretics. Amiloride is used in combination with a thiazide, often as a single tablet (e.g. amiloride/hydrochlorothiazide), to prevent K+ loss. The most common adverse effect with amiloride is hyperkalemia (high levels of potassium), which is an obvious result from preventing K+ loss.
Thiazide diuretics only have a modest effect on blood pressure, typically lowering it by < 10 mm Hg. Thus, when blood pressure remains high or, as the hypertension progresses, becomes high, other anti-hypertensive drugs are added to the diuretics, and these include vasodilators and β-adrenoceptor antagonists.