The primary renal effect of diuretics is to increase the amount of urine formed or diuresis (water, sodium, urea, and other substances). A large part of this effect is a result of enhanced natriuresis, which is defined as an increase in renal sodium excretion. Diuretics were initially described as a useful therapy to reduce edema in the 16th century. The first agent known to increase urine output was mercurous chloride. In 1930, the antimicrobial sulfanilamide was noted to increase renal Na+ excretion and reduce edema formation in patients with congestive heart failure (CHF). It is interesting that most diuretics were discovered serendipitously when they were noted to increase urine output and change urine composition. These changes in urine were considered an adverse effect of drugs intended for other purposes. Targeted disruption of various renal transporters was not part of the development of these drugs as the mechanism of transport was unknown; instead, diuretics were developed empirically. Diuretics are the most commonly prescribed medications in the United States. They are used to treat a variety of clinical disease states, including hypertension, edema, CHF, hypokalemia and hyperkalemia, hypercalcemia, and nephrolithiasis.
To understand the actions of diuretics, one must first appreciate renal handling of sodium and water. This subject is reviewed in detail in Chapter 2, but is briefly reviewed here. The kidneys regulate extracellular fluid (ECF) volume by modulating NaCl and water excretion. Sodium intake is balanced by the renal excretion of sodium. A normal glomerular filtration rate (GFR) is important for the optimal excretion of sodium and water. Following formation and passage of glomerular ultra-filtrate into the Bowman space, delivery of sodium and water to the proximal tubule is the first site of tubular handling. Along the nephron sodium is reabsorbed by several different transport mechanisms and absorption is regulated by a number of different factors. For example, various hormones (renin, angiotensin II, aldosterone, atrial natriuretic peptide [ANP], prostaglandin, and endothelin) and physical properties (mean arterial pressure, peritubular capillary pressure, and renal interstitial pressure) modify renal handling of sodium and water. Direct effects on tubular transport along the nephron underlie the major influence of these factors on renal sodium and water handling. Sodium reabsorption is driven primarily by Na+-K+-adenosine triphosphatase (ATPase) located on the basolateral membrane of all tubular epithelial cells. This pump provides energy required by transporters located on the apical (luminal) membrane that reabsorb sodium from glomerular filtrate. Cell-specific transporters are present on these tubular cells.
Diuretics act to enhance renal sodium and water excretion by inhibiting these transporters at different nephron sites (Figure 4.1). They act to reduce sodium entry into the tubular cell. With the exception of spironolactone and eplerenone, all diuretics exert their effects from the luminal side of the cell. Thus most diuretics must enter tubular fluid to be effective. Secretion across the proximal tubule via either organic acid or base transport pathways is the primary mode of entry (except for mannitol, which undergoes glomerular filtration). Diuretic potency depends significantly on drug delivery to its site of action, as well as the nephron site where it acts. Other factors that influence diuretic action are the level of kidney function (GFR), state of the effective arterial blood volume (CHF, cirrhosis, and nephrosis), and treatment with certain medications such as nonsteroidal antiinflammatory drugs (NSAIDs) and probenecid. Diuretics may also have a variety of adverse effects, some that are common to all diuretics and others that are unique to specific agents (Table 4.1).
FIGURE 4-1. Sites of diuretic action in the nephron. Sodium chloride reabsorption is reduced by various diuretics in proximal tubule, loop of Henle, distal convoluted tubule, and cortical collecting duct.
TABLE 4-1. Adverse Effects of Diuretic Drugs
SITES OF DIURETIC ACTION IN THE KIDNEY
The initial site of diuretic action in the kidney is the proximal tubule. Transport of sodium in the proximal tubular cell is driven by Na+-K+-ATPase activity, which drives sodium reabsorption by the Na+-H+ exchanger on the apical membrane. The Na+-K+-ATPase uses energy derived from adenosine triphosphate (ATP) to extrude 3 Na+ ions in exchange for 2 potassium ions. This results in a reduction of intracellular Na+ concentration. Sodium can then move down its electrochemical gradient from tubular lumen into the cell via the Na+-H+ exchanger in exchange for an H+ that moves out of the cell against its electrochemical gradient. Secretion of H+ by this exchanger is associated with reclamation of filtered bicarbonate. Two diuretics that impair sodium reabsorption in this nephron segment are mannitol and acetazolamide. Each acts differently to reduce sodium reclamation. Mannitol, an osmotic diuretic, is mainly employed for prophylaxis to prevent ischemic or nephrotoxic renal injury and to reduce cerebral edema. It is a nonmetabolizable osmotic agent that is freely filtered by the glomerulus and enters the tubular space where it raises intratubular fluid osmolality. This effect drags water, which is accompanied by sodium from tubular cells into the tubular fluid. Mannitol is poorly absorbed with oral administration and is active only when given intravenously. It acts in the kidney within 10 minutes and has a terminal half-life (t½) of approximately 1.2 hours in patients with normal renal function. Toxicity develops when filtration of mannitol is impaired, as in acute and chronic kidney disease. Retained mannitol causes increased plasma osmolality, which can exacerbate CHF, induce hyponatremia, and cause a hyperoncotic syndrome. As a result of these effects, mannitol is contraindicated in patients with CHF and moderate-to-severe kidney disease. In addition, mannitol may cause acute kidney injury (AKI) from osmotic nephropathy in high-risk individuals.
The carbonic anhydrase (CA) inhibitor acetazolamide is prescribed to alkalinize the urine (certain drug overdoses), prevent and treat altitude sickness, and decrease intraocular pressure in certain forms of glaucoma. The CA inhibitors disrupt bicarbonate reabsorption by impairing the conversion of carbonic acid (H2C03) into CO2 and H2O in tubular fluid. Excess bicarbonate in the tubular lumen associates with Na+, the most abundant cation in tubular fluid, and exits the proximal tubule. Acetazolamide and other CA inhibitors exert their effect within 30 minutes and maintain a t½ of approximately 13 hours. Over time, the effect of these drugs diminishes as a result of the reduction in plasma and filtered bicarbonate. Metabolic consequences of CA inhibitors include metabolic acidosis and hypokalemia. Hypokalemia results from enhanced delivery of sodium and bicarbonate to the principal cell, which promotes potassium secretion through a change in membrane potential. Calcium phosphate stones may also develop as a complication of therapy (urinary alkalinization). These drugs should be avoided in patients with cirrhosis (increases serum ammonia [NH3]) and those with uncorrected hypokalemia. Because downstream nephron segments such as the loop of Henle, distal convoluted tubule (DCT), and cortical collecting duct (CCD) avidly reabsorb sodium, these 2 drugs are relatively weak diuretics.
Thick Ascending Limb of the Loop of Henle
In this nephron segment, the Na+-K+-2Cl– cotransporter on the apical surface of tubular cells, powered by Na+-K+-ATPase on the basolateral membrane reabsorbs significant amounts of NaCl (20% to 30% of the filtered sodium load). In addition to NaCl, potassium, calcium, and magnesium are reclaimed in this tubular segment. It is not surprising that the most potent diuretics, the loop diuretics, retard the action of this transporter. Loop diuretics consist of those that are sulfonamide derivatives (furosemide, bumetanide, and torsemide) and ethacrynic acid, a non–sulfa-containing loop diuretic. These drugs are used primarily to treat states of volume overload refractory to other diuretics including CHF, cirrhosis-associated ascites and edema, and nephrotic syndrome. Other indications are hypercalcemia and hypertension associated with moderate-to-severe kidney disease, which is often a sodium retentive state. Rarely, these drugs are employed to help correct hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone (SIADH).
Loop diuretics can be administered as either oral or intravenous (IV) preparations. They are well absorbed orally, unless significant bowel edema is present as in severe CHF, cirrhosis, and nephrotic syndrome. Loop diuretics act within 20 to 30 minutes and have a t½ of approximately 1 to 1.5 hours. In healthy subjects given IV furosemide or an equivalent oral dose twice the IV dose, there was no difference in cumulative urine volume, natriuresis, or potassium and chloride excretion. The major difference between the two modes of administration was a 30-minute peak natriuretic action with IV furosemide compared with a 75-minute peak for oral therapy. This difference is likely a consequence of the rapid increase in plasma levels with IV dosing. In patients with chronic kidney disease, the dose of loop diuretic to promote effective natriuresis is higher than in patients with normal kidney function. This is a result of several factors—most important is that a reduced GFR is associated with a reduction in filtered sodium load. For example, the filtered sodium for a patient with a GFR of 100 mL/min is 15 mEq/min, whereas it is only 0.15 mEq/min in a patient with kidney disease and a GFR of 10 mL/min. In advanced chronic kidney disease (creatinine clearance = 17 mL/min), the maximal diuretic response to IV furosemide occurs at 160 to 200 mg, much higher than required in subjects with normal renal function. Decreased delivery of loop diuretic to its site of action is another factor in renal failure that limits efficacy at lower administered doses.
In normal subjects, the dose equivalency for the various loop diuretics is as follows:
The maximum dose of each drug varies based on the indication and the underlying disease state. Table 4.2 notes the approximate ceiling doses for the loop diuretics based on the associated clinical condition. Ceiling dose is defined as the dose that provides maximal inhibition of NaCl reabsorption, reaching a plateau in the diuretic dose-response curve. Adverse effects from loop diuretics are related in part to their therapeutic effect on natriuresis and changes in urine composition. These include hypokalemia, hypocalcemia, hypomagnesemia, volume contraction (which can result in hypotension and shock), and metabolic alkalosis. Groups most susceptible to these untoward effects, in particular volume contraction, are the elderly and patients with hypertension who lack clinical edema. Loop diuretics must also be used cautiously in patients with cirrhosis, to avoid precipitation of the hepatorenal syndrome and in patients treated with digoxin who are at high risk for lethal arrhythmias when hypokalemia develops. Ototoxicity is another complication of high plasma drug levels. Ethacrynic acid is associated with severe ototoxicity and rarely employed except in patients with sulfonamide allergy. Furosemide, torsemide, and bumetanide are contraindicated in patients with sulfonamide allergy. Rarely, mild hyperglycemia occurs in patients as a consequence of inhibition of insulin release by loop diuretics.
TABLE 4-2. Ceiling Doses of Intravenous and Oral Loop Diuretics in Various Clinical Conditions
Distal Convoluted Tubule
The DCT contains the thiazide-sensitive Na+-Cl– cotransporter (NCC), which reabsorbs sodium and chloride delivered from the loop of Henle. This segment reabsorbs approximately 5% to 10% of the filtered sodium load. Thiazide and thiazide-like diuretics inhibit NCC. Drugs include hydrochlorothiazide (HCTZ), metolazone, chlorthalidone, indapamide, and the IV preparation chlorothiazide. Through inhibition of NCC, this class of drugs is used primarily to treat hypertension, particularly in patients with salt-sensitive hypertension. Additional uses include treatment of osteoporosis and nephrolithiasis. Although not intuitively obvious as a therapy for these states, thiazide-type diuretics increase calcium reabsorption in the proximal tubule and the DCT. This increases total-body calcium to enhance bone density in patients with osteoporosis and decreases urinary calcium concentration, thereby reducing renal stone formation. Finally, as is discussed later, thiazides are used in combination with loop diuretics to enhance diuresis and natriuresis in patients who develop diuretic resistance.
Thiazide diuretics are less potent than loop diuretics. They are available as both oral (HCTZ, metolazone, chlorthalidone, and indapamide) and IV (chlorothiazide) preparations. They are well absorbed following oral administration with an onset of action within approximately 1 hour. The t½ is variable between drugs and they have durations of action from 6 to 48 hours, depending on the drug. Although the HCTZ dose ranges from 12.5 to 50 mg/day, most of the benefit occurs with 25 mg/day. Adverse effects develop more frequently with higher doses. Metolazone dosing ranges from 2.5 mg/day up to 10 mg twice daily. Patients treated with metolazone should measure their weight daily to avoid excessive diuresis and volume contraction. Chlorthalidone has a longer half-life (40 hours) and is used most commonly at 25 to 50 mg/day, whereas indapamide is administered at 1.25 to 2.5 mg/day (t½ = 14 hours). Bioavailability is reduced in patients with kidney disease, liver disease, and CHF. Patients with kidney disease, especially those with a GFR less than 25 to 40 mL/min, have limited drug delivery to its site of action. Metolazone, however, appears to maintain efficacy at lower levels of GFR.
Adverse effects associated with thiazide-type diuretics include hypokalemia, hypomagnesemia, hyponatremia, and metabolic alkalosis. As with loop diuretics, hypokalemia can be life-threatening in patients with heart disease and those on digoxin. Patients with cirrhosis are at risk for encephalopathy from associated hypokalemia and elevated plasma NH3 levels. Hypercalcemia can develop in patients at risk, such as those with primary hyperparathyroidism and bed-bound patients. Hyponatremia occurs in patients with excessive antidiuretic hormone (ADH) concentrations that are treated with a thiazide diuretic. This results from the thiazide’s effect to diminish the kidney’s diluting capacity without affecting concentrating ability, allowing ADH to enhance water reabsorption. Hypersensitivity reactions are noted including pancreatitis, hemolytic anemia, and thrombocytopenia. Finally, because of increased proximal uric acid reabsorption promoted by thiazide diuretics, patients can develop hyperuricemia and clinical gout.
Cortical Collecting Duct
The CCD reabsorbs approximately 1% to 3% of the filtered sodium load. Reabsorption of NaCl and secretion of potassium is controlled primarily by aldosterone and the prevailing plasma potassium concentration. Intratubular flow rate and sodium concentration also participate in this process. The CCD principal cell is constructed to perform this function based on the presence of an apical epithelial Na+ channel (ENaC) and potassium channel (ROMK) and a basolateral Na+-K+-ATPase. Sodium is reabsorbed through ENaC and potassium secreted through ROMK following stimulation of the Na+-K+-ATPase (and opening of ENaC and ROMK) by aldosterone and an increased plasma potassium concentration. Medications that inhibit either ENaC transport or Na+-K+-ATPase function increase NaCl excretion while minimizing potassium loss. Potassium-sparing diuretics such as spironolactone and eplerenone competitively inhibit the mineralocorticoid receptor and blunt aldosterone-induced NaCl reabsorption and potassium secretion. These drugs are indicated to treat hypertension, especially hypertension caused by either primary or secondary hyperaldosteronism. They are also useful to reduce edema and ascites in patients with cirrhosis and improve cardiac dysfunction in patients with CHF characterized by an ejection fraction less than 40%. In contrast, amiloride and triamterene reduce NaCl reabsorption and potassium secretion by blocking ENaC. They are employed to reduce potassium losses associated with non–potassium-sparing diuretics and thereby prevent hypokalemia. Most often, they are given in combination with thiazide diuretics (HCTZ and amiloride, HCTZ and triamterene). They may also be added to a regimen that includes loop diuretics.
The potassium-sparing diuretics, in particular spironolactone and eplerenone, work best when aldosterone concentrations are elevated. Spironolactone, which is available only in oral form, is well absorbed. The drug undergoes hepatic metabolism. It has a t1/2 of approximately 20 hours and requires up to 2 days to become effective. The dose range is 25 to 200 mg/day. Eplerenone is a relatively new oral potassium-sparing diuretic that has similar renal effects as spironolactone. It differs from spironolactone in that it has a shorter t½ (4 to 6 hours), is metabolized by the liver (CYP3A4), and excreted primarily (67%) by the kidneys. It is most effective when dosed twice per day. The dose range is 25 to 100 mg/day. Amiloride is well absorbed with oral administration. It has a t1/2 of 6 hours and is excreted by the kidney. Triamterene is similar to amiloride except for a shorter t½ (3 hours). All drugs that act in the CCD are weak diuretics, which is not unexpected because of the limited Na+ reabsorption that occurs in this nephron segment.
The most common and concerning adverse effect of these drugs is hyperkalemia. The groups at highest risk are patients with moderate-to-severe kidney disease and those taking either potassium supplements or medications that impair potassium homeostasis such as the angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and NSAIDs. Other patients who are at risk include those with diabetes mellitus (hyporeninemic hypoaldosteronism) and tubulointerstitial kidney disease. Spironolactone therapy is complicated by gynecomastia and amenorrhea. This occurs because it binds to estrogen and androgen receptors, especially when the dose equals or exceeds 100 mg/day. Eplerenone is specific for the mineralocorticoid receptor and is free of these adverse effects. In addition to hyperkalemia, amiloride causes a mild metabolic acidosis. Nausea and vomiting can also develop with either amiloride or triamterene therapy. Rarely, as with other diuretics, hyponatremia may occur in the elderly.