Drugs that act on the kidney have important applications in renal, cardiovascular, and endocrine disorders. These disorders mainly involve sodium and water homeostasis. Each segment of the nephron—proximal convoluted tubule (PCT), thick ascending limb of the loop of Henle (TAL), distal convoluted tubule (DCT), and cortical collecting tubule (CCT)—has a different mechanism for reabsorbing sodium and other ions. The subgroups of the sodium-excreting diuretics are based on these sites and processes in the nephron. Several other drugs alter water excretion predominantly. The effects of the diuretic agents are predictable from knowledge of the function of the segment of the nephron in which they act.
RENAL TRANSPORT MECHANISMS & DIURETIC DRUG GROUPS
The kidney filters plasma water and solutes at the glomerulus at a very high rate (180 L/day) and must recover a significant percentage of most of these substances before excretion in the urine. The major transport mechanisms for the recovery of ions and water in the various segments of the nephron are shown in Figure 15–1. Because the mechanisms for reabsorption of salt and water differ in each of the 4 major tubular segments, the diuretics acting in these segments have differing mechanisms of action. Most diuretics act from the luminal side of the membrane. An exception is the aldosterone receptor antagonist group (spironolactone and eplerenone); these drugs enter the collecting tubule cell from the basolateral side and bind to the cytoplasmic aldosterone receptor. The kidney contains numerous adenosine and prostaglandin receptors. Agonists and antagonists at these receptors can alter renal function directly and alter the response to the diuretic agents. Prostaglandins are important in maintaining glomerular filtration. When synthesis of prostaglandins is inhibited, for example, by nonsteroidal anti-inflammatory drugs (Chapter 36), the efficacy of most diuretics decreases.
Tubule transport systems in the kidney and sites of action of diuretics. Circles with arrows denote known ion cotransporters that are targets of the diuretics indicated by the numerals. Question marks denote preliminary or incompletely documented suggestions for the location of certain drug effects. ADH, antidiuretic hormone; PTH, parathyroid hormone. (Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 15–1.)
High-Yield Terms to Learn
|Bicarbonate diuretic ||A diuretic that selectively increases sodium bicarbonate excretion. Example: a carbonic anhydrase inhibitor |
|Diluting segment ||A segment of the nephron that reabsorbs solute without water; the thick ascending limb and the distal convoluted tubule are active salt-reabsorbing segments that are not permeable by water |
|Hyperchloremic metabolic acidosis ||A shift in body electrolyte and pH balance involving elevated serum chloride, diminished bicarbonate concentration, and a decrease in pH in the blood. Typical result of bicarbonate diuresis |
|Hypokalemic metabolic alkalosis ||A shift in body electrolyte balance and pH ...|