Diuretics are drugs that act directly on the kidneys to increase urine volume and to produce a net loss of solute (principally sodium and other electrolytes) and water. [204 ] Currently available diuretics have a number of uses in medicine (e.g., treatment of hypertension, glaucoma, increased intracranial pressure) that are not discussed here. The principal indications for intravenous diuretics in the perioperative period are: (1) to increase urine flow in oliguria; (2) to reduce intravascular volume in patients at risk of acute heart failure from excessive fluid administration; and (3) to mobilize edema.
Renal function depends on adequate renal perfusion to maintain the integrity of renal cells and to provide hydrostatic pressure for glomerular filtration. There are no drugs that act directly on the renal glomerulus to affect the glomerular filtration rate (GFR). In an average-size normal adult human, GFR averages 125 mL/min and urine production approximates 1 mL/min. In other words, 99 percent of the glomerular filtrate is reabsorbed. Diuretics act on specific renal tubal segments to alter reabsorption of water and electrolytes, principally sodium.
There are two basic mechanisms behind renal tubular reabsorption of sodium. (1) Sodium is extruded from the tubular cell into peritubular fluid primarily by active transport of the sodium ion by the Na-K-ATPase pump and by the bicarbonate reabsorption mechanism (see the following). This extrusion of sodium creates an electrochemical gradient causing diffusion of sodium from the tubular lumen into the tubular cell. (2) Sodium also moves from the glomerular filtrate into the peritubular fluid by several different mechanisms. The most important quantitatively is the sodium electrochemical gradient created by active extrusion of sodium from the tubular cell into peritubular fluid. Sodium also is coupled with organic solutes and phosphate ions, exchanged for hydrogen ions diffusing from the tubular cell into the tubular lumen, and coupled to the transfer of a chloride ion or a combination of a potassium and two chloride ions (Na-K-Cl cotransport) from tubular fluid into the tubular cell. Diuretics are classified by their principal site of action in the nephron and by the primary mechanism of their naturetic effect (Table 8-9) .
Mannitol is the principal example of this type of diuretic, which is used for two primary indications: (1) prophylaxis and early treatment of acute renal failure characterized by a decrease in GFR leading to a decreased urine volume and an increase in the concentration of toxic substances in the renal tubular fluid; and (2) to enhance other diuretics by retaining water and solutes in the tubular lumen.
Normally, 80 percent of the glomerular filtrate is reabsorbed isosmotically in the proximal tubule. By an osmotic effect, mannitol limits reabsorption of water and dilutes proximal tubular fluid. This reduces the electrochemical gradient for sodium and limits its reabsorption so that more reaches the distal nephron. Mannitol produces a prostaglandin-mediated increase in renal blood flow that partially washes out medullary hypertonicity that is essential for the counter current mechanism promoting reabsorption of water in the late distal tubule and collecting system under the influence of antidiuretic hormone. The principal toxicity of mannitol is acute expansion of extracellular fluid volume in patients with compromised cardiac function. The drug also reduces chloride and accompanying sodium ion diffusion from the tubular fluid through the pericellular pathway (in between tubular cells) into the peritubular fluid.
Furosemide (Lasix), bumetanide (Bumex), and ethacrynic acid (Edecrin) are three chemically dissimilar compounds that have the same primary diuretic mechanism of action. They act on the tubular epithelial cell in the thick ascending limb of Henle's loop to inhibit the Na-K-2Cl cotransport mechanism. Their peak diuretic effect is far greater than other diuretics currently available. Administered intravenously, these drugs have a rapid onset and relatively short duration of action, owing to both pharmacokinetics and compensatory mechanisms. These three diuretics increase renal blood flow without increasing GFR and redistribute blood flow from the medulla to the cortex and within the renal cortex. These changes in renal blood flow also are short-lived and reflect the reduced extracellular fluid volume that results from diuresis. Carbonic anhydrase inhibition by furosemide and bumetanide and actions on the proximal tubule and on sites distal to the ascending limb remain controversial. All three of the loop diuretics increase release of renin and prostaglandin; indomethacin blunts this release as well as the augmentation of renal blood flow and natruresis. The drugs also produce an acute increase in venous capacitance for a brief time after the first intravenous dose that is blocked by indomethacin.
Potassium, magnesium, and calcium excretion are increased in proportion to the increase in sodium excretion. In addition, there is augmentation of titratable acid and ammonia excretion by the distal tubal leading to metabolic alkalosis, which also is produced by contraction of the extracellular volume. Hyperuricemia can occur but is of little physiological significance usually. The nephrotoxicity of cephaloridine, and possibly other cephalorsporins, is increased. A rare but serious side-effect of the loop diuretics is deafness, which may reflect electrolyte changes in the endolymph.
Because of their high degree of efficacy, prompt onset, and relatively short duration of action, high ceiling or loop diuretics are favored for intravenous administration in the perioperative period to treat the three principal problems cited above. Dosage requirements vary considerably among patients. Some require only 3–5 mg furosemide IV to produce a good diuresis; others may need only the less potent benzothiazides.
Hydrochlorothiazide (HCTZ) is the prototype of more than a dozen currently available diuretics in this class. Although the drugs differ in potency, all act by the same mechanism and have the same maximum efficacy. All are actively secreted into the tubular lumen by tubular cells and act in the early distal tubule to decrease the electroneutral Na-Cl co-transport reabsorption of sodium. Their moderate efficacy probably is because more than 90 percent of filtered sodium is reabsorbed before reaching the distal tubule. Efficacy is enhanced by simultaneous administration of an osmotic diuretic such as mannitol. Benziothiazides increase urine volume and excretion of sodium, chloride, and potassium. Reduced reabsorption of potassium reflects diminished reabsorption time from the higher rate of urine flow through the distal tubule.
This class of diuretics produces the least disturbance of extracellular fluid composition. Principal side-effects include hyperuricemia, decreased calcium excretion, and enhanced magnesium loss. Hyperglycemia can occur as a result of multiple variables. With prolonged use and contraction of extracellular fluid volume, urine formation decreases. Also, these agents have a direct effect on renal vasculature to decrease GFR.
Acetazolamide (Diamox) is the only diuretic of this class available for intravenous administration. Its clinical use is primarily directed to alkalinization of urine in the presence of a metabolic alkalosis that develops commonly from prolonged diuretic therapy. Acetazolamine acts in the proximal convoluted tubule to inhibit carbonic anhydrase in the brush border of the tubular epithelium to reduce destruction of bicarbonate ion (i.e., prevents conversion to co 2 ). Tubular cellular carbonic anhydrase is also inhibited so that conversion of co 2 to carbonic acid is reduced markedly and fewer hydrogen ions are available for the Na-H exchange mechanism. Reabsorption of both sodium and bicarbonate in the proximal tubule is diminished, but more than half of the bicarbonate is reabsorbed in more distal segments of the nephron, to reduce the overall efficacy of the drug.
Spironolactone (Aldactone) is a competitive antagonist of aldosterone. Spironolactone binds to the cytoplasmic aldosterone receptor and prevents conformational change to the active state. The drug aborts the synthesis of active transport proteins in the late distal tubal and collecting system where the reabsorption of sodium and secretion of potassium are reduced.
Triamterene (Dyrenium) and amiloride (Midamar) are potassium-sparing diuretics. They have a moderate naturetic effect that leads to an increased excretion of sodium and chloride with little change or a slight increase in potassium excretion when the latter is low. When potassium secretion is high, the drugs produce a sharp reduction in electrogenic entry of sodium ions into distal tubular cells and thereby reduce the electrical potential that drives potassium secretion.
Both types of potassium-sparing diuretics are used primarily in combination with other diuretics to reduce potassium loss. The principal side effect is hyperkalemia. It is appropriate to limit intake of potassium when using this type of diuretic. It is also appropriate to use this type of diuretic cautiously in patients taking ACE (angiotensin conversion enzyme) inhibitors that decrease aldosterone formation and consequently increase serum potassium concentrations.
Infusion of albumin (5–25% solutions) or other plasma volume expanders (e.g., hetastarch) is often employed to draw water and electrolytes (i.e., edema fluid) osmotically from tissues into the circulation for delivery to the kidneys for excretion. With a reduced circulating blood volume, this is a logical way to increase circulating blood volume and renal perfusion. Because the osmotic effect of albumin and plasma expanders is transient because of their diffusion into tissues, the diuretic effect is limited and water tends to remain in the interstitial space. The same limitation applies to osmotic diuretics such as mannitol, which also diffuse through the capillary membrane.
Dopamine (Intropin) is a catecholamine that has the unique ability to interact with vascular D1-dopaminergic receptors in coronary, mesenteric, and renal vascular beds. By activating adenyl cyclase and raising intracellular concentrations of cyclic-AMP, D1-receptor stimulation leads to vasodilation. Infusion of low doses of dopamine (1–3 µg/kg-1/min-1) causes an increase in glomerular filtration rate, renal blood flow, and na + excretion. As a catecholamine and a precursor in the metabolic synthesis of norepinephrine and epinephrine, dopamine has inotropic and chronotropic effects on the heart. The inotropic effect is mediated by beta1-adrenergic receptors and usually requires infusion rates higher than those able to produce enhanced renal perfusion and diuresis. Infusion rates greater than 8–10 µg/kg -1/min-1 lead to vasoconstriction produced by dopamine activation of alpha1-adrenergic receptors in vascular smooth muscle.