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INTRODUCTION

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CASE STUDY

A 65-year-old man has a history of diabetes and chronic kidney disease with baseline creatinine of 2.8 mg/dL. Despite five different antihypertensives, his clinic blood pressure is 176/92 mm Hg and he has 2–3+ edema on exam. He has been taking furosemide 80 mg twice a day for one year now. He has mild dyspnea on exertion. At the clinic visit, hydrochlorothiazide 25 mg daily is added for better blood pressure control and symptoms/signs of fluid ­overload. Two weeks later, the patient presents to the emergency department with symptoms of weakness, anorexia, and generalized malaise. His blood pressure is now 91/58 mm Hg and he has lost 15 kg in two weeks. His laboratory tests are significant for a serum creatinine of 10.8. What has led to the acute kidney injury? What is the reason for the weight loss? What precautions could have been taken to avoid this hospitalization?

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Abnormalities in fluid volume and electrolyte composition are common and important clinical disorders. Drugs that block specific transport functions of the renal tubules are valuable clinical tools in the treatment of these disorders. Although various agents that increase urine volume (diuretics) have been described since antiquity, it was not until 1937 that carbonic anhydrase inhibitors were first described and not until 1957 that a much more useful and powerful diuretic agent (chlorothiazide) became available.

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Technically, a “diuretic” is an agent that increases urine volume, whereas a “natriuretic” causes an increase in renal sodium excretion and an “aquaretic” increases excretion of solute-free water. Because natriuretics almost always also increase water excretion, they are usually called diuretics. Osmotic diuretics and antidiuretic hormone antagonists (see Agents that Alter Water Excretion) are aquaretics that are not directly natriuretic.

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This chapter is divided into three sections. The first section ­covers major renal tubule transport mechanisms. The nephron is divided structurally and functionally into several segments (Figure 15–1, Table 15–1). Several autacoids, which exert multiple, complex effects on renal physiology (adenosine, prostaglandins, and urodilatin, a renal autacoid closely related to atrial natriuretic peptide), are also discussed. The second section describes the ­pharmacology of diuretic agents. Many diuretics exert their effects on specific membrane transport proteins in renal tubular epithelial cells. Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (vaptans, or vasopressin antagonists). The physiology of each nephron segment is closely linked to the basic pharmacology of the drugs acting there, which is discussed in the second section. The third section of the chapter describes the clinical applications of diuretics.

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FIGURE 15–1

Tubule transport systems and sites of action of diuretics. ADH, antidiuretic hormone; PTH, parathyroid hormone.

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Table Graphic Jump Location
TABLE 15–1Major segments of the nephron and their functions.

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