A 65-year-old man comes to the emergency department with severe shortness of breath. His wife reports that he has long known that he is hypertensive but never had symptoms, so he refused to take antihypertensive medications. During the last month, he has noted increasing ankle edema, reduced exercise tolerance, and difficulty sleeping lying down, but he reports no episodes of chest pain or discomfort. He now has pitting edema to the knees and is acutely uncomfortable lying down. Vital signs include blood pressure 190/140 mm Hg, pulse 120 bpm, and respiratory rate 20/min. Chest auscultation reveals loud rhonchi, but an electrocardiogram is negative except for evidence of left ventricular hypertrophy. He is given a diuretic intravenously and admitted to intensive care. What diuretic would be most appropriate for this man's case of acute pulmonary edema associated with heart failure? What are the possible toxicities of this therapy?
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.
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.
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 events on renal physiologic processes (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.
Tubule transport systems and sites of action of diuretics. ADH, antidiuretic hormone; PTH, parathyroid hormone.
Table 15–1 Major Segments of the Nephron and Their Functions.