Loop and Thiazide Diuretics

Objectives

This chapter will:

1.
Explain the mechanism of action of loop and thiazide diuretics.
2.
Discuss pharmacokinetics and pharmacodynamics of loop and thiazide diuretics.
3.
Discuss resistance to loop and thiazide diuretics.
4.
Discuss the available evidence to guide the use of loop and thiazide diuretics in the acutely ill patient.
5.
Discuss the adverse effects and toxicity of loop and thiazide diuretics.

Acute kidney injury (AKI) is an increasingly encountered complication, affecting up to 60% of patients admitted to an intensive care unit (ICU). Depending on its cause, as many as 17% of patients with AKI may require renal replacement therapy (RRT) for management of fluid balance, acid base status, or electrolyte disturbances. Patients with AKI have decreased capacity to excrete fluid and solute. Moreover, they often develop AKI in association with conditions precipitating increased capillary permeability, necessitating aggressive fluid resuscitation such as sepsis, major trauma, or burn injury. Therefore these patients are at increased risk for fluid accumulation and complications related to fluid overload. Over the last decades, multiple studies have suggested that a positive fluid balance is associated with increased mortality, worsening lung function and oxygenation, and more major surgical complications. Conversely, after initial resuscitation, achieving a neutral or negative fluid balance has been associated with improved gas exchange, greater ventilator-free days, and reduced ICU length of stay. Achieving a negative fluid balance in critically ill patients, in particular in the setting of AKI or reduced kidney function, commonly necessitates use of diuretic therapy. In general, in acute and critical care settings, loop diuretics and thiazide are used most commonly. This chapter reviews the mechanism of actions and clinical use of loop and thiazide diuretics.

Loop Diuretics

Mechanism of Action

Sodium is filtered by the glomerulus and is part of the ultrafiltrate found in the tubular lumen. Approximately 60% of the filtered sodium is reabsorbed by the proximal tubule, 25% to 30% by the loop of Henle, 5% to 10% by the distal tubule, and 3% to 5% by the collecting duct. It is this variation in fraction of Na+ reabsorption that accounts for the differences in the potency among diuretics. The loop diuretics act predominantly on the medullary and cortical aspects of the thick ascending limb (TAL). They also act on the macula densa cells in the early distal tubule. After being secreted in the tubular lumen by Organic Acid Transporter (OAT) in the proximal tubule, they reach the TAL, where they bind the chloride-binding site of the Na ⁺ -K ⁺ -2Cl ⁻ cotransporter (NKCC2) located on the apical side of the epithelial cells ( Fig. 61.1 ). Chloride is the rate-limiting step in NKCC2 activation. Its inhibition precludes conformational change in the transporter that allows sodium, potassium, and chloride to shift into the cell. The inhibition of sodium chloride (NaCl) reabsorption in the TAL also abolishes the hypertonicity of the interstitium and so inhibits water reabsorption in the collecting duct. Therefore NKCC2 blockade leads to sodium and water loss. Loop diuretics are also weak inhibitors of carbonic anhydrase.

FIGURE 61.1, Mechanism of NaCl reabsorption in the loop of Henle. The Na + ,K + -ATPase, localized in the basolateral membrane, reduces the cytosolic Na concentration and provides the driving force for the operation of the apical NKCC2 transporter, the site of action of loop diuretics. Dashed lines denote passive transport. See text for more details.

In a normally functioning TAL, the Na ⁺ -K ⁺ -ATPase pump on the basolateral membrane pumps sodium out of the cell, therefore creating a sodium gradient that allows NKCC2 to move sodium into the cell and with it, potassium and chloride. To avoid potassium depletion on the luminal side, specialized potassium pores allow backleak of this ion out of the cell. This influx of cations creates a positively charged tubular fluid that allows the paracellular absorption of other positively charged ions such as magnesium and calcium through specialized channels ( Fig. 61.1 ). Therefore loop diuretics, by blocking NKCC2, increase not only fractional excretion of sodium, potassium, chloride, and water but also excretion of calcium and magnesium.

The administration of loop diuretics also has an effect on renal and systemic vasculature. Indeed, administration of loop diuretics triggers prostaglandin release by the kidneys, which leads to local afferent arteriole dilatation with an increase in renal blood flow. These prostaglandins also induce systemic venodilation with consequent increase in venous capacitance and decrease in capillary wedge pressure, an effect used in the treatment of patients with pulmonary edema.

Pharmacokinetics

There are four loop diuretics currently available: furosemide, bumetanide, torsemide, and ethacrynic acid. Because of significant ototoxicity, ethacrynic acid is used rarely. Because it is the only drug in this class that does not contain sulfa, it can, however, be of help when clinicians face a patient with anaphylactic reactions to this compound. Furosemide is by far the most used loop diuretic, evidenced by the fact that it is the only loop diuretic that figured among the top 20 most prescribed drugs in the United States in 2008, which was confirmed in a recent survey among intensivists.

Absorption

The absorption of oral furosemide is highly variable. Bioavailability ranges from 10% to 90%, depending mainly on intestinal mucosal edema, presence or absence of food, and interindividual variation in enzymes implicated in intestinal metabolism of the drugs. Therefore, to get the same effect as an intravenous (IV) dose, the oral dose generally should be increased by two or three times. In most ICU patients, the IV route is preferred. The bioavailability of ethacrynic acid, bumetanide, and torsemide is almost complete ( Table 61.1 ).

TABLE 61.1

Pharmacokinetics of Loop Diuretics

	FUROSEMIDE	BUMETANIDE	TORSEMIDE	ETHACRYNIC ACID
Relative potency	40 IV	1 IV/PO	15–20 IV/PO	50 IV/PO
Bioavailability (%)	10–90	80–100	80–100	≈ 100%
Protein binding (%)	>95	>95	>95	> 95
Onset of action (min)	5 IV; 30 O	< 5 IV; 30–60 O	10 IV; 60 O	5 IV; 30 O
Peak of action (min)	30 IV; 60–120 O	15–30 IV; 60–120 O	60 IV; 60–120 O	30 IV; 120 O
Elimination (%):
Renal	90 *	60	20	30–65
Hepatic	10	40	80	35–40
Half-life (hr)
Normal	1.5–2.0	1.0	3.0–4.0	0.5–2.0
Renal dysfunction	2.8	1.6	4.0–5.0	n/a
Liver dysfunction	2.5	2.3	8.0	n/a
HF	2.7	1.3	6.0	n/a
Maximal effective dose (mg)	40 IV; 80 O	1	15–20	50

IV, Intravenous; PO, oral.

* 50% of a dose is excreted as unchanged active drug in the urine, and 50% is metabolized in the kidney through conjugation with glucuronic acid.

Onset and Peak of Action

Once loop diuretics are absorbed, they are bound to albumin (free fraction < 5%). Because of this low free fraction, only a small proportion is filtered by the glomerulus. Rather, they are secreted into the proximal tubular lumen (S2 segment) by OAT, for which the diuretic has a greater affinity than for albumin. Once secreted in the tubular fluid, it reaches its target receptor in the TAL. Except for torsemide, loop diuretics have similar rapid onset and peak of action (see Table 61.1 ).

Metabolism and Excretion

Loop diuretics have various rates of renal and extrarenal clearance. Furosemide is the loop diuretic with the lowest extrarenal clearance. About 50% of a dose of furosemide is excreted as unchanged active drug in the urine, the remaining 50% being glucuronidated in the kidney. The metabolism and excretion data for all other diuretics are shown in Table 61.1 .

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