Loop diuretics inhibit the sodium-potassium-chloride cotransporter in the thick ascending limb (see above figure). This transporter normally reabsorbs about 25% of the sodium load; therefore, inhibition of this pump can lead to a significant increase in the distal tubular concentration of sodium, reduced hypertonicity of the surrounding interstitium, and less water reabsorption in the collecting duct. This altered handling of sodium and water leads to both diuresis (increased water loss) and natriuresis (increased sodium loss). By acting on the thick ascending limb, which handles a significant fraction of sodium reabsorption, loop diuretics are powerful diuretics. These drugs also induce renal synthesis of prostaglandins, which contributes to their renal action including the increase in renal blood flow and redistribution of renal cortical blood flow. Loop diuretics are the most effective diuretic class because their site of action has a high capacity for sodium reabsorption. Note that efficacy is inversely related to renal function, which can be impaired in heart failure.Therapeutic Uses
Hypertension
Most patients with hypertension, of which 90-95% have hypertension of unknown origin (primary or essential hypertension), are effectively treated with diuretics. Antihypertensive therapy with diuretics is particularly effective when coupled with reduced dietary sodium intake. The efficacy of these drugs is derived from their ability to reduce blood volume, cardiac output, and with long-term therapy, systemic vascular resistance. Thiazide diuretics, particularly chlorthalidone, are considered "first-line therapy" for stage 1 hypertension. Potassium-sparing, aldosterone-blocking diuretics (e.g., spironolactone or eplerenone) are used in secondary hypertension caused by primary hyperaldosteronism, and sometimes as an adjunct to thiazide treatment in primary hypertension to prevent hypokalemia.
Heart failure
Heart failure leads to activation of the renin-angiotensin-aldosterone system, which causes increased sodium and water retention by the kidneys. This in turn increases blood volume and contributes to the elevated venous pressures associated with heart failure, which can lead to pulmonary and systemic edema. The primary use for diuretics in heart failure is to reduce pulmonary and/or systemic congestion and edema, and associated clinical symptoms (e.g., shortness of breath - dyspnea). Long-term treatment with diuretics may also reduce the afterload on the heart by promoting systemic vasodilation, which can lead to improved ventricular ejection.
effects of a diuretic on ventricular stroke volume in heart failure patients
When treating heart failure with diuretics, care must be taken to not unload too much volume because this can depress cardiac output. For example, if pulmonary capillary wedge pressure is 25 mmHg (point A in figure) and pulmonary congestion is present, a diuretic can safely reduce that elevated pressure to a level (e.g., 14 mmHg; point B in figure) that will reduce pulmonary pressures without compromising ventricular stroke volume. The reason for this is that heart failure caused by systolic dysfunction is associated with a depressed, flattened Frank-Starling curve. However, if the volume is reduced too much, stroke volume will fall because the heart will now be operating on the ascending limb of the Frank-Starling relationship. If the heart failure is caused by diastolic dysfunction, diuretics must be used very carefully so as to not impair ventricular filling. In diastolic dysfunction, ventricular filling requires elevated filling pressures because of the reduced ventricular compliance.
Most patients in heart failure are prescribed a loop diuretic because they are more effective in unloading sodium and water than thiazide diuretics. In mild heart failure, a thiazide diuretic may be used. Potassium-sparing, aldosterone-blocking diuretics (e.g., spironolactone) are being used increasingly in heart failure.
Pulmonary and systemic edema
Capillary hydrostatic pressure and therefore capillary fluid filtration is strongly influenced by venous pressure (click here for more details). Therefore, diuretics, by reducing blood volume and venous pressure, lower capillary hydrostatic pressure, which reduces net capillary fluid filtration and tissue edema. Because left ventricular failure can cause life-threatening pulmonary edema, most heart failure patients are treated with a loop diuretic to prevent or reduce pulmonary edema. Diuretics may also be used to treat leg edema caused by right-sided heart failure or venous insufficiency in the limb.
Specific Drugs