Chapter 15. Diuretic Agents

Each segment of the nephron—proximal convoluted tubule (PCT), thick ascending limb of the loop of Henle (TAL), distal convoluted tubule (DCT), and cortical collecting tubule (CCT)—has a different mechanism for reabsorbing sodium and other ions. The subgroups of the sodium-excreting diuretics are based on these sites and processes in the nephron. Several other drugs alter water excretion predominantly. The effects of the diuretic agents are predictable from knowledge of the function of the segment of the nephron in which they act.

The kidney filters plasma water and solutes at the glomerulus at a very high rate (180 L/day) and must recover a significant percentage of most of these substances before excretion in the urine. The major transport mechanisms for the recovery of ions and water in the various segments of the nephron are shown in Figure 15–1. Because the mechanisms for reabsorption of salt and water differ in each of the 4 major tubular segments, the diuretics acting in these segments have differing mechanisms of action. Most diuretics act from the luminal side of the membrane. An exception is the aldosterone receptor antagonist group (eg, spironolactone and eplerenone); these drugs enter the collecting tubule cell from the basolateral side and bind to the cytoplasmic aldosterone receptor.

This segment carries out isosmotic reabsorption of amino acids, glucose, and numerous cations. It is also the major site for sodium chloride and sodium bicarbonate reabsorption. The proximal tubule is responsible for 60–70% of the total reabsorption of sodium. No currently available drug directly acts on NaCl reabsorption in the PCT. The mechanism for bicarbonate reabsorption is shown in Figure 15–2. Bicarbonate itself is poorly reabsorbed through the luminal membrane, but conversion of bicarbonate to carbon dioxide via carbonic acid permits rapid reabsorption of the carbon dioxide. Bicarbonate can then be regenerated from carbon dioxide within the tubular cell and transported into the interstitium. Sodium is separately reabsorbed from the lumen in exchange for hydrogen ions (NHE3 transporter) and transported into the interstitial space by the sodium-potassium pump (Na+/K+ ATPase). Carbonic anhydrase, the enzyme required for the bicarbonate reabsorption process on the brush border and in the cytoplasm, is the target of carbonic anhydrase inhibitor drugs. Active secretion and reabsorption of weak acids and bases also occurs in the proximal tubule. Most weak acid transport occurs in the straight S2 segment, distal to the convoluted part. Uric acid transport is especially important and is targeted by some of the drugs used in treating gout (Chapter 36). Weak bases are transported in the S1 and S2 segments.

Prototypes and Mechanism of Action

Acetazolamide is the prototypic agent. These diuretics are sulfonamide derivatives. The mechanism of action is inhibition of carbonic anhydrase in the brush border and cytoplasm (Figure 15–2). Carbonic anhydrase is also found in other tissues and plays an important role in the secretion of cerebrospinal fluid and aqueous humor. Acetazolamide inhibits carbonic anhydrase in all tissues of the body.

Effects

The major renal effect is bicarbonate diuresis (ie, sodium bicarbonate is excreted); body bicarbonate is depleted, and metabolic acidosis results. As increased sodium is presented to the cortical collecting tubule, some of the excess sodium is reabsorbed and potassium is secreted, resulting in significant potassium wasting (Table 15–1). As a result of bicarbonate depletion, sodium bicarbonate excretion slows—even with continued diuretic administration—and the diuresis is self-limiting within 2–3 days. Secretion of bicarbonate into aqueous humor by the ciliary epithelium in the eye and into the cerebrospinal fluid by the choroid plexus is reduced. In the eye, a useful reduction in intraocular pressure can be achieved. In the central nervous system (CNS), acidosis of the cerebrospinal fluid results in hyperventilation, which can protect against high-altitude sickness. The ocular and cerebrospinal fluid effects are not self-limiting.

Clinical Uses and Toxicity

Acetazolamide is used parenterally in the treatment of severe acute glaucoma (see Table 10–2). Acetazolamide can also be administered orally, but topical analogs are available (dorzolamide, brinzolamide) for chronic use in the eye. Acetazolamide is also used to prevent acute mountain (high-altitude) sickness. It is used for the diuretic effect only if edema is accompanied by significant metabolic alkalosis.

Drowsiness and paresthesia toxicities are commonly reported after oral therapy. Cross-allergenicity between these and all other sulfonamide derivatives (other sulfonamide diuretics, hypoglycemic agents, antibacterial sulfonamides) is uncommon but can occur. Alkalinization of the urine by these drugs may cause precipitation of calcium salts and formation of renal stones. Renal potassium wasting may be marked. Patients with hepatic impairment often excrete large amounts of ammonia in the urine in the form of ammonium ion. If they are given acetazolamide, alkalinization of the urine prevents conversion of ammonia to ammonium ion. As a result, they may develop hepatic encephalopathy because of increased ammonia reabsorption and hyperammonemia.

This segment pumps sodium, potassium, and chloride out of the lumen into the interstitium of the kidney. It is also a major site of calcium and magnesium reabsorption, as shown in Figure 15–3. Reabsorption of sodium, potassium, and chloride are all accomplished by a Na+/K+/2Cl− carrier (NKCC2), which is the target of the loop diuretics. This cotransporter provides part of the concentration gradient for the countercurrent concentrating mechanism in the kidney and is responsible for the reabsorption of 20–30% of the sodium filtered at the glomerulus. Because potassium is pumped into the cell from both the luminal and basal sides, an escape route must be provided; this occurs into the lumen via a potassium-selective channel. Because the potassium diffusing through these channels is not accompanied by an anion, a net positive charge is set up in the lumen. This positive potential drives the reabsorption of calcium and magnesium.

Prototypes and Mechanism of Action

Furosemide is the prototypical loop agent. Furosemide, bumetanide, and torsemide are sulfonamide derivatives. Ethacrynic acid is a phenoxyacetic acid derivative; it is not a sulfonamide but acts by the same mechanism. Loop diuretics inhibit the cotransport of sodium, potassium, and chloride (NKCC2, Figure 15–3). The loop diuretics are relatively short-acting (diuresis usually occurs over a 4-h period following a dose).

Effects

A full dose of a loop diuretic produces a massive sodium chloridediuresis if glomerular filtration is normal; blood volume may be significantly reduced. If tissue perfusion is adequate, edema fluid is rapidly excreted. The diluting ability of the nephron is reduced because the loop of Henle is the site of significant dilution of urine. Inhibition of the Na+/K+/2Cl− transporter also results in loss of the lumen-positive potential, which reduces reabsorption of divalent cations as well. As a result, calcium excretion is significantly increased. Ethacrynic acid is a moderately effective uricosuric drug if blood volume is maintained. The presentation of large amounts of sodium to the collecting tubule may result in significant potassium wasting and excretion of protons; hypokalemic alkalosis may result (Table 15–1). Loop diuretics also reduce pulmonary vascular pressures; the mechanism is not known.

Prostaglandins are important in maintaining glomerular filtration. When synthesis of prostaglandins is inhibited, for example, by nonsteroidal anti-inflammatory drugs (Chapter 36), the efficacy of most diuretics decreases.

Clinical Use and Toxicities

The major application of loop diuretics is in the treatment of edematous states (eg, heart failure, ascites, and acute pulmonary edema). They are sometimes used in hypertension if response to thiazides is inadequate, but the short duration of action of loop diuretics is a disadvantage in this condition. A less common but important application is in the treatment of severe hypercalcemia. This life-threatening condition can often be managed with large doses of furosemide together with parenteral volume and electrolyte (sodium and potassium chloride) replacement. It should be noted that diuresis without volume replacement results in hemoconcentration; serum calcium concentration then will not diminish and may even increase further.

Loop diuretics usually induce hypokalemic metabolic alkalosis (Table 15–1). Because large amounts of sodium are presented to the collecting tubules, potassium wasting may be severe. Because they are so efficacious, loop diuretics can cause hypovolemia and cardiovascular complications. Ototoxicity is an important toxic effect of the loop agents. The sulfonamides in this group may rarely cause typical sulfonamide allergy.

This segment actively pumps sodium and chloride out of the lumen of the nephron via the Na+/Cl− carrier (NCC) shown in Figure 15–4. This cotransporter is the target of the thiazide diuretics. The distal convoluted tubule is responsible for approximately 5–8% of sodium reabsorption. Calcium is also reabsorbed in this segment under the control of parathyroid hormone (PTH). Removal of the reabsorbed calcium back into the blood requires the sodium-calcium exchange process discussed in Chapter 13.

Prototypes and Mechanism of Action

Hydrochlorothiazide, the prototypical agent, and all the other members of this group are sulfonamide derivatives. A few derivatives that lack the typical thiazide ring in their structure nevertheless have effects identical with those of thiazides and are therefore considered thiazide-like. The major action of thiazides is to inhibit sodium chloride transport in the early segment of the distal convoluted tubule (NCC, Figure 15–4). Thiazides are active by the oral route and have a duration of action of 6–12 h, considerably longer than most loop diuretics.

Effects

In full doses, thiazides produce moderate but sustained sodium and chloride diuresis. Hypokalemic metabolic alkalosis may occur (Table 15–1). Reduction in the transport of sodium from the lumen into the tubular cell reduces intracellular sodium and promotes sodium-calcium exchange at the basolateral membrane. As a result, reabsorption of calcium from the urine is increased, and urine calcium content is decreased—the opposite of the effect of loop diuretics. Because they act in a diluting segment of the nephron, thiazides may reduce the excretion of water and cause dilutional hyponatremia. Thiazides also reduce blood pressure, and the maximal pressure-lowering effect occurs at doses lower than the maximal diuretic doses (see Chapter 11). Inhibition of renal prostaglandin synthesis reduces the efficacy of the thiazides. When a thiazide is used with a loop diuretic, a synergistic effect occurs with marked diuresis.

Clinical Use and Toxicities

The major application of thiazides is in hypertension, for which their long duration and moderate intensity of action are particularly useful. Chronic therapy of edematous conditions such as mild heart failure is another application, although loop diuretics are usually preferred. Chronic renal calcium stone formation can sometimes be controlled with thiazides because they reduce urine calcium concentration.

Massive sodium diuresis with hyponatremia is an uncommon but dangerous early toxicity of thiazides. Chronic therapy is often associated with potassium wasting, since an increased sodium load is presented to the collecting tubules; the cortical collecting tubules compensate by reabsorbing sodium and excreting potassium. Diabetic patients may have significant hyperglycemia. Serum uric acid and lipid levels are also increased in some persons. Thiazides are sulfonamides and share potential sulfonamide allergenicity.

The final segment of the nephron is the last tubular site of sodium reabsorption and is controlled by aldosterone (Figure 15–5), a steroid hormone secreted by the adrenal cortex. This segment is responsible for reabsorbing 2–5% of the total filtered sodium under normal circumstances; more if aldosterone is increased. The reabsorption of sodium occurs via channels (ENaC, not a transporter) and is accompanied by loss of potassium or hydrogen ions. The collecting tubule is thus the primary site of acidification of the urine and the last site of potassium excretion. The aldosterone receptor and the sodium channels are sites of action of the potassium-sparing diuretics. Reabsorption of water occurs in the medullary collecting tubule under the control of antidiuretic hormone (ADH).

Prototypes and Mechanism of Action

Spironolactone and eplerenone are steroid derivatives and act as pharmacologic antagonists of aldosterone in the collecting tubules. By combining with and blocking the intracellular aldosterone receptor, these drugs reduce the expression of genes that code for the epithelial sodium ion channel (ENaC) and Na+/K+ ATPase. Amiloride and triamterene act by blocking the epithelial sodium channels in the same portion of the nephron (Figure 15–5). (These drugs do not block INa channels in excitable membranes.) Spironolactone and eplerenone have slow onsets and offsets of action (24–72 h). Amiloride and triamterene have durations of action of 12–24 h.

Effects

All drugs in this class cause an increase in sodium clearance and a decrease in potassium and hydrogen ion excretion and therefore qualify as potassium-sparing diuretics. They may cause hyperkalemic metabolic acidosis (Table 15–1).

Clinical Use and Toxicities

Potassium wasting caused by chronic therapy with loop or thiazide diuretics, if not controlled by dietary potassium supplements, usually responds to these drugs. They are commonly combined with a thiazide in a single pill.

Aldosteronism (eg, the elevated serum aldosterone levels that occur in cirrhosis) is an important indication for spironolactone. Aldosteronism is also a feature of heart failure, and spironolactone and eplerenone have been shown to have significant long-term benefits in this condition (Chapter 13). Some of this effect may occur in the heart, an action that is not yet understood.

The most important toxic effect of potassium-sparing diuretics is hyperkalemia. These drugs should never be given with potassium supplements. Other aldosterone antagonists (eg, angiotensin [ACE] inhibitors and angiotensin receptor blockers [ARBs]), if used at all, should be used with caution. Spironolactone can cause endocrine abnormalities, including gynecomastia and antiandrogenic effects. Eplerenone has less affinity for gonadal steroid receptors.

(See Chapter 13)

Describe the possible interactions of cardiac glycosides (digoxin) with the major classes of diuretics. The Skill Keeper Answer appears at the end of the chapter.

Prototypes and Mechanism of Action

Mannitol, the prototypical osmotic diuretic, is given intravenously. Other drugs often classified with mannitol (but rarely used) include glycerin, isosorbide (not isosorbide dinitrate), and urea. Because they are freely filtered at the glomerulus but poorly reabsorbed from the tubule, they remain in the lumen and "hold" water by virtue of their osmotic effect. The major location for this action is the proximal convoluted tubule. Reabsorption of water is also reduced in the descending limb of the loop of Henle and the collecting tubule.

Effects

The volume of urine is increased. Most filtered solutes are excreted in larger amounts unless they are actively reabsorbed. Sodium excretion is usually increased because the rate of urine flow through the tubule is greatly accelerated and sodium transporters cannot handle the volume rapidly enough. Mannitol can also reduce brain volume and intracranial pressure by osmotically extracting water from the tissue into the blood. A similar effect occurs in the eye.

Clinical Use and Toxicities

The osmotic drugs are used to maintain high urine flow (eg, when renal blood flow is reduced and in conditions of solute overload from severe hemolysis, rhabdomyolysis, or tumor lysis syndrome). Mannitol and several other osmotic agents are useful in reducing intraocular pressure in acute glaucoma and intracranial pressure in neurologic conditions.

Removal of water from the intracellular compartment may cause hyponatremia and pulmonary edema. As the water is excreted, hypernatremia may follow. Headache, nausea, and vomiting are common.

Prototypes and Mechanism of Action

Antidiuretic hormone (ADH) and desmopressin are prototypical ADH agonists. They are peptides and must be given parenterally. Conivaptan and tolvaptan are ADH antagonists. Demeclocycline was previously used for this purpose. Lithium also has ADH-antagonist effects but is never used for this purpose.

ADH facilitates water reabsorption from the collecting tubule by activation of V2 receptors, which stimulate adenylyl cyclase via Gs. The increased cyclic adenosine monophosphate (cAMP) causes the insertion of additional aquaporin AQP2 water channels into the luminal membrane in this part of the tubule (Figure 15–6). Conivaptan is an ADH inhibitor at V1a and V2 receptors. Tolvaptan is a more selective V2 blocker with little V1 affinity. Demeclocycline and lithium inhibit the action of ADH at some point distal to the generation of cAMP and presumably interfere with the insertion of water channels into the membrane.

Effects and Clinical Uses

Agonists

ADH and desmopressin reduce urine volume and increase its concentration. ADH and desmopressin are useful in pituitary diabetes insipidus. They are of no value in the nephrogenic form of the disease, but salt restriction, water restriction, thiazides, and loop diuretics may be used. These therapies reduce blood volume, a very strong stimulus to proximal tubular reabsorption. The proximal tubule thus substitutes—in part—for the deficient concentrating function of the collecting tubule in nephrogenic diabetes insipidus.

Antagonists

ADH antagonists oppose the actions of ADH and other naturally occurring peptides that act on the same V2 receptor. Such peptides are produced by certain tumors (eg, small cell carcinoma of the lung) and can cause significant water retention and dangerous hyponatremia. This syndrome of inappropriate ADH secretion (SIADH) can be treated with demeclocycline and conivaptan. Lithium also works but has greater toxicity.

Toxicity

In the presence of ADH or desmopressin, a large water load may cause dangerous hyponatremia. Large doses of either peptide may cause hypertension in some persons.

Conivaptan and tolvaptan may cause demyelination with serious neurologic consequences if hyponatremia is corrected too rapidly. Conivaptan may cause infusion site reactions. In children younger than 8 years, demeclocycline (like other tetracyclines) causes bone and teeth abnormalities. Lithium causes nephrogenic diabetes insipidus as a toxic effect; because of its other toxicities, the drug is never used to treat SIADH.

(See Chapter 13)

Digoxin toxicity is facilitated by hypokalemia. Therefore, potassium-wasting diuretics (eg, loop agents, thiazides), which are often needed in heart failure, can increase the risk of a fatal digitalis arrhythmia. Carbonic anhydrase inhibitors, though also potassium-wasting agents, are rarely used for their systemic and diuretic effects and are therefore less likely to be involved in digitalis toxicity. The potassium-sparing diuretics, in contrast to the other groups, can be useful in preventing such interactions.

When you complete this chapter, you should be able to:

• □ List 5 major types of diuretics and relate them to their sites of action.
• □ Describe 2 drugs that reduce potassium loss during sodium diuresis.
• □ Describe a therapy that reduces calcium excretion in patients who have recurrent urinary stones.
• □ Describe a treatment for severe acute hypercalcemia in a patient with advanced carcinoma.
• □ Describe a method for reducing urine volume in nephrogenic diabetes insipidus.
• □ List the major applications and the toxicities of acetazolamide, thiazides, loop diuretics, and potassium-sparing diuretics.