Page 270 - Basic _ Clinical Pharmacology ( PDFDrive )

256 SECTION III Cardiovascular-Renal Drugs

TABLE 15–1 Major segments of the nephron and their functions.

Primary Transporters
Water and Drug Targets at Diuretic with
Segment Functions Permeability Apical Membrane Major Action
Glomerulus Formation of glomerular filtrate Extremely high None None
+
1
+
Proximal convoluted Reabsorption of 65% of filtered Na /K / Very high Na/H (NHE3), carbonic Carbonic anhydrase
2+
2+
tubule (PCT) CA , and Mg ; 85% of NaHCO 3 , and nearly anhydrase; Na/glucose inhibi-tors, Adenosine
100% of glucose and amino acids. Isosmotic cotransporter 2 (SGLT2) antagonists (under
reabsorption of water. investigation)
Proximal tubule, straight Secretion and reabsorption of organic acids Very high Acid (eg, uric acid) and None
segments and bases, including uric acid and most base transporters
diuretics
Thin descending limb Passive reabsorption of water High Aquaporins None
of Henle’s loop
Thick ascending limb of Active reabsorption of 15–25% of filtered Very low Na/K/2Cl (NKCC2) Loop diuretics
+
+
2+
−
Henle’s loop (TAL) Na /K /Cl ; secondary reabsorption of CA
and Mg 2+
+
Distal convoluted tubule Active reabsorption of 4–8% of filtered Na Very low Na/Cl (NCC) Thiazides
−
2+
(DCT) and Cl ; CA reabsorption under parathy-roid
hormone control
+
+
+
Cortical collecting Na reabsorption (2–5%) coupled to K and Variable 2 Na channels (ENaC), K -sparing diuretics
1
+
+
tubule (CCT) H secretion K channels, H trans- Adenosine antagonists
1
porter, aquaporins (under investigation)
Medullary collecting duct Water reabsorption under vasopressin control Variable 2 Aquaporins Vasopressin antagonists
1 Not a target of currently available drugs.
2
Controlled by vasopressin activity.
Proximal can be inhibited by acetazolamide and other carbonic anhydrase
Lumen- convoluted Interstitium- inhibitors.
urine tubule blood
More recently, inhibitors of the sodium-glucose cotransporter,
Na + isoform 2 (SGLT2; Figure 15–2) have been approved to treat
NHE3 diabetes mellitus. The sodium-glucose cotransporter is responsible
ATP
Na + K + for reabsorbing much of the glucose that is filtered by the glom-
+
HCO 3 + H H + HCO 3 – eruli. Although not indicated as diuretic agents, these drugs have
–
+
diuretic properties accompanied by increased sodium and glucose
Na +
H 2 CO 3 excretion (see below). The diuretic properties are thought to result
H 2 CO 3
from mainly osmotic diuresis.
+ CA CA Organic acid secretory systems are located in the middle third
of the straight part of the proximal tubule (S segment). These
2
CO 2 + H 2 O
systems secrete a variety of organic acids (uric acid, nonsteroidal
H 2 O + CO 2
Cl – anti-inflammatory drugs [NSAIDs], diuretics, antibiotics, etc)
Base – into the luminal fluid from the blood. These systems thus help
Glucose deliver diuretics to the luminal side of the tubule, where most of
them act. Organic base secretory systems (creatinine, choline, etc)
Na +
are also present, in the early (S 1 ) and middle (S ) segments of the
2
SGLT2 proximal tubule.
+
+
FIGURE 15–2 Apical membrane Na /H exchange (via NHE3) LOOP OF HENLE
and bicarbonate reabsorption in the proximal convoluted tubule cell. At the boundary between the inner and outer stripes of the outer
+
+
Na /K -ATPase is present in the basolateral membrane to maintain medulla, the proximal tubule empties into the thin descending
intracellular sodium and potassium levels within the normal range.
Because of rapid equilibration, concentrations of the solutes are limb of Henle’s loop. Water is extracted from the descending limb
approximately equal in the interstitial fluid and the blood. Carbonic of this loop by osmotic forces found in the hypertonic medul-
anhydrase (CA) is found in other locations in addition to the brush lary interstitium. As in the proximal tubule, impermeant luminal
+
border of the luminal membrane. SGLT2, Na /glucose transporter. solutes such as mannitol oppose this water extraction and thus