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Clinical Disorders: Therapeutic Classes: Mechanism Classes:
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Diuretics
General Pharmacology
Renal handling of sodium and water. To understand the action
of diuretics, it is first necessary to review how the kidney filters fluid and
forms urine. As blood flows through the kidney, it passes into glomerular
capillaries located within the cortex (outer zone of the kidney). These
glomerular capillaries are
highly permeable to water and electrolytes. Glomerular capillary hydrostatic
pressure drives (filters) water and electrolytes into Bowman's
space and into the proximal convoluting tubule (PCT). About 20% of the plasma
that enters the glomerular capillaries is filtered (termed filtration fraction).
The PCT, which lies within the cortex , is the site of sodium, water and
bicarbonate transport from the filtrate (urine), across the tubule wall, and into the
interstitium of the cortex. About 65-70% of the filtered sodium is removed from
the urine found within the PCT (this is termed sodium reabsorption). This sodium is
reabsorbed isosmotically, meaning that every molecule of sodium that is
reabsorbed is accompanied by a molecule of water. As the tubule dives into the
medulla, or middle zone of the kidney, the tubule becomes narrower and forms a
loop (Loop of Henle) that reenters the cortex as the thick ascending limb (TAL)
that travels back to near the glomerulus. Because the interstitium of the
medulla is very hyperosmotic and the Loop of Henle is permeable to water, water
is reabsorbed from the Loop of Henle and into the medullary interstitium. This
loss of water concentrates the urine within the Loop of Henle. The TAL, which is
impermeable to water, has a cotransport system that
reabsorbs sodium, potassium and chloride at a ratio of 1:1:2. Approximately 25%
of the sodium load of the original filtrate is reabsorbed at the TAL. From the
TAL, the urine flows into the distal convoluting tubule (DCT), which is another
site of sodium transport (~5% via a sodium-chloride cotransporter) into the
cortical interstitium (the DCT is also impermeable to water). Finally,
the tubule dives back into the medulla as the collecting duct and then into the
renal pelvis where it joins with other collecting ducts to exit the kidney as
the ureter. The distal segment of the DCT and the upper collecting duct has a
transporter that reabsorbs sodium (about 1-2% of filtered load) in exchange for
potassium and hydrogen ion, which are excreted into the urine. It is important
to note two things about this transporter. First, its activity is dependent on
the tubular concentration of sodium, so that when sodium is high, more sodium is
reabsorbed and more potassium and hydrogen ion are excreted. Second, this
transporter is regulated by aldosterone, which is a mineralocorticoid hormone
secreted by the adrenal cortex. Increased aldosterone stimulates the
reabsorption of sodium, which also increases the loss of potassium and hydrogen
ion to the urine. Finally, water is reabsorbed in the collected duct through
special pores that are regulated by antidiuretic hormone, which is released by
the posterior pituitary. ADH increases the permeability of the
collecting duct to water, which leads to increased water reabsorption, a more
concentrated urine and reduced urine outflow (antidiuresis). Nearly all of the
sodium originally filtered is reabsorbed by the kidney, so that less than 1% of
originally filtered sodium remains in the final urine.
Mechanisms of diuretic drugs. Diuretic drugs increase urine output by the kidney (i.e., promote diuresis). This is accomplished by altering how the kidney handles sodium. If the kidney excretes more sodium, then water excretion will also increase. Most diuretics produce diuresis by inhibiting the reabsorption of sodium at different segments of the renal tubular system. Sometimes a combination of two diuretics is given because this can be significantly more effective than either compound alone (synergistic effect). The reason for this is that one nephron segment can compensate for altered sodium reabsorption at another nephron segment; therefore, blocking multiple nephron sites significantly enhances efficacy.
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 very 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.
Thiazide diuretics, which are the most commonly used diuretic, inhibit the sodium-chloride transporter in the distal tubule. Because this transporter normally only reabsorbs about 5% of filtered sodium, these diuretics are less efficacious than loop diuretics in producing diuresis and natriuresis. Nevertheless, they are sufficiently powerful to satisfy most therapeutic needs requiring a diuretic. Their mechanism depends on renal prostaglandin production.
Because loop and thiazide diuretics increase sodium delivery to the distal segment of the distal tubule, this increases potassium loss (potentially causing hypokalemia) because the increase in distal tubular sodium concentration stimulates the aldosterone-sensitive sodium pump to increase sodium reabsorption in exchange for potassium and hydrogen ion, which are lost to the urine. The increased hydrogen ion loss can lead to metabolic alkalosis. Part of the loss of potassium and hydrogen ion by loop and thiazide diuretics results from activation of the renin-angiotensin-aldosterone system that occurs because of reduced blood volume and arterial pressure. Increased aldosterone stimulates sodium reabsorption and increases potassium and hydrogen ion excretion into the urine.
There is a third class of diuretic that is referred to as potassium-sparing diuretics. Unlike loop and thiazide diuretics, some of these drugs do not act directly on sodium transport. Some drugs in this class antagonize the actions of aldosterone (aldosterone receptor antagonists) at the distal segment of the distal tubule. This causes more sodium (and water) to pass into the collecting duct and be excreted in the urine. They are called K+-sparing diuretics because they do not produce hypokalemia like the loop and thiazide diuretics. The reason for this is that by inhibiting aldosterone-sensitive sodium reabsorption, less potassium and hydrogen ion are exchanged for sodium by this transporter and therefore less potassium and hydrogen are lost to the urine. Other potassium-sparing diuretics directly inhibit sodium channels associated with the aldosterone-sensitive sodium pump, and therefore have similar effects on potassium and hydrogen ion as the aldosterone antagonists. Their mechanism depends on renal prostaglandin production. Because this class of diuretic has relatively weak effects on overall sodium balance, they are often used in conjunction with thiazide or loop diuretics to help prevent hypokalemia.
Carbonic anhydrase inhibitors inhibit the transport of bicarbonate out of the proximal convoluted tubule into the interstitium, which leads to less sodium reabsorption at this site and therefore greater sodium, bicarbonate and water loss in the urine. These are the weakest of the diuretics and seldom used in cardiovascular disease. Their main use is in the treatment of glaucoma.
Cardiovascular effects of diuretics. Through their effects on sodium and water balance, diuretics decrease blood volume and venous pressure. This decreases cardiac filling (preload) and, by the Frank-Starling mechanism, decreases ventricular stroke volume and cardiac output, which leads to a fall in arterial pressure. The decrease in venous reduces capillary hydrostatic pressure, which decreases capillary fluid filtration and promotes capillary fluid reabsorption, thereby reducing edema if present. There is some evidence that loop diuretics cause venodilation, which can contribute to the lowering of venous pressure. Long-term use of diuretics result in a fall in systemic vascular resistance (by unknown mechanisms) that helps to sustain the reduction in arterial pressure.
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. The vast majority of hypertensive patients are treated with thiazide diuretics. Potassium-sparing, aldosterone-blocking diuretics (e.g., spironolactone) are used in secondary hypertension caused by 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.
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.
Specific Drugs
Specific drugs comprising the five class of diuretics are listed in the following table. See www.rxlist.com for more details on individual diuretics.
| Class | Specific Drugs | Comments |
| Thiazide | chlorothiazide | |
| chlorthalidone | thiazide-like in action, not structure | |
| hydrochlorothiazide | prototypical drug; | |
| hydroflumethiazide | ||
| indapamide | thiazide-like in action, not structure | |
| methyclothiazide | ||
| metolazone | thiazide-like in action, not structure | |
| polythiazide | ||
| Loop | bumetanide | |
| ethacrynic acid | i.v. only | |
| furosemide | oral and i.v. | |
| torsemide | ||
| K+-sparing | amioloride | distal tubule Na+-channel inhibitor |
| eplerenone | aldosterone receptor antagonist; fewer side effects than spironolactone | |
| spironolactone | aldosterone receptor antagonist; side effect: gynecomastia | |
| triamterene | distal tubule Na+-channel inhibitor | |
| CA inhibitors | acetazolamide | prototypical drug; not used in treating hypertension or heart failure |
| dichlorphenamide | not used in treating hypertension or heart failure | |
| methazolamide | not used in treating hypertension or heart failure |
Adverse Side Effects and Contraindications
The most important and frequent problem with thiazide and loop diuretics is hypokalemia. This sometimes requires treatment with potassium supplements or with a potassium-sparing diuretic. A potentially serious side effect of potassium-sparing diuretics is hyperkalemia. Other side effects and drug interactions are list below:
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Class |
Adverse Side Effects |
Drug Interactions |
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Thiazide
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· hypokalemia · metabolic alkalosis · dehydration (hypovolemia), leading to hypotension · hyponatremia · hyperglycemia in diabetics · hypercholesterolemia; hypertriglyceridemia · increased low-density lipoproteins · hyperuricemia (at low doses) · azotemia (in renal disease patients)
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· hypokalemia potentiates digitalis toxicity · non-steroidal anti-inflammatory drugs: reduced diuretic efficacy · beta-blockers: potentiate hyperglycemia, hyperlipidemias · corticosteroids: enhance hypokalemia |
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Loop |
· hypokalemia · metabolic alkalosis · hypomagnesemia · hyperuricemia · dehydration (hypovolemia), leading to hypotension · dose-related hearing loss (ototoxicity)
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· hypokalemia potentiates digitalis toxicity · non-steroidal anti-inflammatory drugs: reduced diuretic efficacy · corticosteroids: enhance hypokalemia · aminoglycosides: enhance ototoxicity, nephrotoxicity |
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K+-sparing |
· hyperkalemia · metabolic acidosis · gynecomastia (aldosterone antagonists) · gastric problems including peptic ulcer |
· ACE inhibitors: potentiate hyperkalemia · non-steroidal anti-inflammatory drugs: reduced diuretic efficacy |
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Carbonic |
· hypokalemia · metabolic acidosis
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Revised 03/15/07