Page 269 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 15 Diuretic Agents 255

NaHCO /
3
Proximal Na-glucose 2+
convoluted co-transporter NaCl NaCl Ca Distal
tubule (+PTH) convoluted
tubule
1
4
Proximal
straight tubule

7 K +
7
K + H +
2
Ca 2+
Glomerulus Collecting
H 2 O Mg 2+ 7 tubule
Na +
Cortex K + 3 5 NaCl
(+aldosterone)
Outer medulla 2Cl –
K +
Diuretics H +
7
1 Acetazolamide/canagliflozin Thick
ascending
2 Osmotic agents (mannitol, urearetics) limb H O 6
2
3 Loop agents (eg, furosemide) Thin (+ADH)
descending
4 Thiazides limb 2 Collecting
duct
5 Aldosterone antagonists 2 H O
2
6 ADH antagonists Thin
ascending
limb
7 Adenosine Loop of
Henle
Inner medulla

FIGURE 15–1 Tubule transport systems and sites of action of diuretics. ADH, antidiuretic hormone; PTH, parathyroid hormone.

+
(proximal convoluted tubule, PCT). Potassium ions (K ) are (carbonic anhydrase inhibitors, which block NaHCO reabsorp-
3
reabsorbed via the paracellular pathway. Water is reabsorbed tion) has acted predominantly in the PCT. Sodium bicarbonate
+
passively, through both a transcellular pathway (mediated by a reabsorption by the PCT is initiated by the action of a Na /
+
specific water channel, aquaporin-1 [AQP1]) and a paracellular H exchanger (NHE3) located in the luminal membrane of
pathway (likely mediated by claudin-2). Importantly, the water the proximal tubule epithelial cell (Figure 15–2). This transport
+
permeability of the PCT is very high, and hence, the osmolal- system allows Na to enter the cell from the tubular lumen in
+
ity of proximal tubular fluid is maintained at a nearly constant exchange for a proton (H ) from inside the cell. As in all portions
+
+
level, and the gradient from the tubule lumen to surrounding of the nephron, Na /K -ATPase in the basolateral membrane
+
interstitium is very small. As tubule fluid is processed along pumps the reabsorbed Na into the interstitium in order to main-
+
+
the length of the proximal tubule, the luminal concentrations tain a low intracellular Na concentration. The H secreted into
−
of most solutes decrease relative to the concentration of inulin, the lumen combines with bicarbonate (HCO ) to form H CO
2
3
3
an experimental marker that is filtered but neither secreted (carbonic acid), which is rapidly dehydrated to CO and H O by
2
2
nor absorbed by renal tubules. Approximately 66% of filtered carbonic anhydrase. Carbon dioxide produced by dehydration of
+
+
sodium ions (Na ), 85% of the NaHCO , 65% of the K , H CO enters the proximal tubule cell by simple diffusion, where
3
3
2
60% of the water, and virtually all of the filtered glucose and it is then rehydrated back to H CO , facilitated by intracellular
2
3
+
amino acids are reabsorbed by the proximal tubule in normal carbonic anhydrase. After dissociation of H CO , the H is avail-
2
3
−
+
+
humans. able for transport by the Na /H exchanger, and the HCO is
3
Of the various solutes reabsorbed in the proximal tubule, the transported out of the cell by a basolateral membrane transporter
most relevant to diuretic action are NaHCO and NaCl. Until (Figure 15–2). Bicarbonate reabsorption by the proximal tubule
3
recently, of the currently available diuretics, only one group is thus dependent on carbonic anhydrase activity. This enzyme