Diuretic agents

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CHAPTER 19

Diuretic agents

Key terms and definitions

Congestive heart failure (CHF)

Failure of the heart to pump the blood adequately, resulting in lung congestion and tissular edema.

Diuretic

Drug that increases urine output.

Edema

Swelling resulting from abnormal accumulation of fluid in intercellular spaces of the body.

Glomerular filtration

Mechanism by which hydrostatic pressure forces fluid out of the glomerular capillaries and into the renal ducts.

Hypovolemia

Abnormally decreased volume of blood circulating in the body.

Nephrocalcinosis

Renal lithiasis in which calcium deposits form in the renal parenchyma, resulting in reduced kidney function and the presence of blood in the urine.

Nephron

Microscopic functional unit of the kidney, responsible for filtering and maintaining fluid balance; each kidney has approximately 2 million nephrons.

Ototoxicity

Damage to the ear, specifically the cochlea or auditory nerve and sometimes the vestibulum, by a toxin.

Reabsorption

Return to the blood of most of the water, sodium, amino acids, and sugar that were removed during filtration; occurs mainly in the proximal tubule of the nephron.

Synergistic effect

Effect of two chemicals on an organism is greater than effect of either chemical individually.

Urine output

Amount of urine produced in 24 hours; normal urine output averages 30 to 60 mL/hr.

The main purpose of diuretics, or agents that increase urine output, is to eliminate excess fluid from the body. Introduced into medicine in 1958, diuretics are drugs that increase the excretion of solutes and water by directly increasing urine output. Generally, the primary goal of diuretic therapy is to reduce extracellular fluid volume to decrease blood pressure or to rid the body of excess interstitial fluid. Chapter 19 summarizes the essentials of the clinical pharmacology of diuretics, briefly reviewing renal function with an emphasis on acid-base balance. The major groups of diuretics, their modes of action, and common interactions and side effects are summarized. These groups include osmotic diuretics, carbonic anhydrase inhibitors, thiazides, loop diuretics, and potassium-sparing agents.

Renal structure and function

The kidneys are paired retroperitoneal organs found on either side of the spinal cord at the level of the umbilicus. In an adult, each kidney weighs approximately 160 to 175 g and is 10 to 12 cm long. The renal artery provides perfusion to the kidneys. Kidneys receive the highest blood flow per gram of organ weight in the body. Approximately 22% of the cardiac output, or about 1.1 L/min in a normal 70-kg adult, flows through the kidneys. Similar to the heart and brain, the kidney is an active organ (not a passive filter) with high oxygen consumption. For this reason, impaired circulation can cause renal failure or damage.

Figure 19-1 illustrates the kidney and a nephron, which is the functional unit of the kidney, similar to the alveolus in the lung. The nephron is composed of the glomerulus, proximal tubule, loop of Henle, distal tubule, and collecting duct. Almost 75% of the almost 1 million nephrons may need to be compromised before renal disease is apparent. The renal artery branches into the afferent arteriole, which enters and forms the capillary tuft of the glomerulus. This blood flow leaves in the efferent arteriole, which forms the capillary network around the tubules and loop of Henle. This capillary network rejoins to form the renal vein.

The glomerulus is supported and surrounded by an epithelial-lined capsule named Bowman capsule. The glomerular capsule is actually the beginning of the proximal tubule, and filtration of fluid from the blood to the tubule occurs in the glomerulus. This fluid is the glomerular filtrate, which empties into the proximal tubule, goes through the descending and ascending loops of Henle, goes into the distal tubule, and later goes into the collecting duct. Each of the nearly 250 collecting ducts collects urine from about 4000 nephrons. The collecting ducts merge to form larger ducts that eventually empty into the renal papillae and finally empty into the ureter to be stored in the bladder.

The principal function of the nephron is to maintain homeostasis or equilibrium between the internal volume and electrolyte status and the influences of the environment, diet and intake. This mission is accomplished by almost 2 million nephrons through the processes of glomerular ultrafiltration, tubular reabsorption, and tubular secretion. The kidney cannot regenerate new nephrons.

Renal injury, disease, and aging are associated with a gradual decrease in nephron number. The body maintains blood pressure at the expense of extracellular fluid volume (ECFV). Control of ECFV is achieved by adjusting sodium chloride (NaCl) and water (H2O) excretion.

Electrolyte filtration and reabsorption

The ions listed in Box 19-1 are filtered and exchanged in the tubules.

Water is also passively reabsorbed or excreted, depending on the concentration of electrolyte, primarily Na+, in the filtrate. By inhibiting sodium reabsorption, diuretics cause less water to be retained, and more is excreted in the filtrate.

Aldosterone, a mineralocorticoid secreted by the adrenal cortex, increases sodium and water reabsorption in the distal tubule. Spironolactone is a diuretic that increases sodium and water loss by inhibiting aldosterone.

Acid-base balance

Because a fundamental function of the kidney is the control of buffering substances, especially HCO3, diuretics may cause acid-base imbalances to occur as they increase water loss. Figure 19-2 illustrates the hydrogen and bicarbonate pathways that regulate pH. The filtration and reabsorption of Na+, Cl, and HCO3, described previously, can be seen in Figure 19-2.

The important exchange for acid-base balance is that of Na+. Na+ is reabsorbed in the tubules by several means, as follows:

Either low chloride (hypochloremia) or low potassium (hypokalemia) forces Na+ to exchange for H+, producing a loss of H+ and metabolic alkalosis:

< ?xml:namespace prefix = "mml" />HypochloremiaHypokalemia]→Metabolic alkalosis

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Finally, preventing HCO3 in the filtrate from forming CO2 and water leads to a loss of bicarbonate buffer in the urine and metabolic acidosis.

Diuretic groups

The primary therapeutic goal of diuretic use is to reduce the ECFV. NaCl output must exceed NaCl intake. Diuretics primarily prevent Na+ entry into the tubule cell. Diuretics need to access the tubule fluid to exert their action. Once in the tubule fluid, the nephron site at which the diuretic acts determines its effect. The site of action also determines which electrolytes, other than Na+, are affected. All diuretics except spironolactone exert their effects from the luminal side of the nephron.1

Five major groups of diuretics are described in this chapter. Figure 19-3 illustrates the site of action, and Table 19-1 summarizes the mechanism of action and the indications for use of each of the five major groups of diuretics.25

TABLE 19-1

Site and Mechanism of Action, Main Indications, and Other Uses of Diuretics

DIURETIC CLASS (MECHANISM OF ACTION) MAIN INDICATIONS OTHER USES
Osmotic Diuretics
Freely filtered, nonreabsorbable osmotic agents such as mannitol, glycerol, and urea: Reduction of reabsorption of H2O and solutes, including NaCl, primarily in proximal tubule and descending loop of Henle To treat or prevent ARF To reduce intracranial or intraocular pressure
Carbonic Anhydrase Inhibitors
Acetazolamide, methazolamide, and dichlorphenamide: Inhibition of carbonic anhydrase in luminal membrane of proximal tubule, reducing proximal sodium and bicarbonate reabsorption To reduce intraocular pressure in glaucoma; to lower [HCO3]p in mountain sickness; to increase urine pH in cystinuria Periodic paralysis; adjunctive therapy in epilepsy
Loop Diuretics
Furosemide, bumetanide, torsemide, and ethacrynic acid: Inhibition of Na+/K+/Cl reabsorption in thick ascending limb of Henle Hypertension, CHF (in the presence of renal insufficiency or for immediate effect); ARF; CRF, ascites, and nephrotic syndrome Acute pulmonary edema; to enhance urinary excretion of chemical toxins; hypercalcemia
Thiazide Diuretics
Chlorothiazide, hydrochlorothiazide: Inhibition of NaCl reabsorption in early DT Hypertension; CHF; idiopathic hypercalciuria (renal calculi) Nephrogenic diabetes insipidus (prevent further urine dilution from taking place in DT); CRF
K+-Sparing Diuretics
Spironolactone: Competitively blocks actions of aldosterone on CCDs Chronic liver disease: To treat secondary hyperaldosteronism caused by hepatic cirrhosis complicated by ascites Primary hyperaldosteronism (Conn syndrome)
Amiloride and triamterene: Inhibition of the Na+/K+ pump by reducing Na entry across luminal membrane of CCDs CHF: To counteract hypokalemic effect of other diuretics  

image

ARF, Acute renal failure; CCDs, cortical collecting ducts; CHF, congestive heart failure; CRF, chronic renal failure; DT, distal tubule; [HCO3]p, plasma bicarbonate concentration.

Because hypertension affects one-third of adults in the United States,6 the diuretics of most immediate relevance to respiratory and critical care clinicians are those used to treat hypertension and congestive heart failure (CHF). There is evidence that diuretic-based therapy is effective in reducing morbidity and mortality among elderly hypertensive patients.710 Diuretics are also used to aid in the treatment of other conditions associated with fluid retention, such as corticosteroid therapy and certain renal and liver diseases.

Osmotic diuretics

Osmotic diuretics (Table 19-2) are freely filtered at the glomerulus but are not reabsorbed. These agents remain in the tubule lumen and impair the ability of the proximal tubule and thick ascending limb of Henle to reabsorb NaCl. The net result is that osmotic substances are potent diuretics that lead to increased excretion of water and NaCl. The resultant increased delivery of sodium and chloride to the distal tubule results in increased exchange of Na+ for K+, producing a net potassium loss in urine.

TABLE 19-2

Characteristics of Diuretics

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DRUG ROUTE ONSET (min)* PEAK (hr) DURATION (hr) HALF-LIFE (hr) ORAL BIOAVAILABILITY (%) TYPICAL DOSE
Osmotic
Glycerin PO 10-30 1-1.5 4-5 0.5-0.75 ND 1-2 g/kg
Isosorbide PO 10-30 1-1.5 5-6 5-9.5 ND 1-3 g/kg
Mannitol IV 30-60 1 6-8 0.25-1.5 NA 50-100 g
Urea IV 30-45 1 5-6 NA NA 1-1.5 g/kg
Loop
Bumetanide PO 30-60 1-2 4-6 1-1.5 72-96 0.5-2.0 mg
  IV 5 0.25-0.5 0.5-1 1-1.5 72-96 0.5-2.0 mg
Ethacrynic acid PO 30 2 6-8 1 100 50-100 mg
  IV 5 0.25-0.5 2 1 100 50-100 mg
Furosemide PO 60 1-2 6-8 2 60-64 20-80 mg
  IV 5 0.5 2 2 60-64 20-80 mg
Torsemide PO 60 1-2 6-8 3.5 80 5-20 mg
  IV 10 <1 6-8 3.5 80 5-20 mg
Thiazide