Page 278 - Basic _ Clinical Pharmacology ( PDFDrive )

264 SECTION III Cardiovascular-Renal Drugs

loop diuretic therapy may worsen thiamine deficiency in patients TABLE 15–6 Thiazides and related diuretics.
with heart failure. Intravenous bumetanide administration has
rarely caused injection site superficial tenderness of the skin, an Total Daily Frequency of Daily
effect not seen with other loop diuretics. Drug Oral Dose Administration
Bendroflumethiazide 2.5–10 mg Single dose
Contraindications Chlorothiazide 0.5–2 g Two divided doses
Chlorthalidone 1 25–50 mg Single dose
Furosemide, bumetanide, and torsemide may exhibit allergic cross-
reactivity in patients who are sensitive to other sulfonamides, but this Hydrochlorothiazide 25–100 mg Single dose
appears to be very rare. Overzealous use of any diuretic is dangerous Hydroflumethiazide 12.5–50 mg Two divided doses
in hepatic cirrhosis, borderline renal failure, or heart failure. Indapamide 1 2.5–10 mg Single dose
Methyclothiazide 2.5–10 mg Single dose
THIAZIDES Metolazone 1 2.5–10 mg Single dose
Polythiazide 1–4 mg Single dose
The thiazide diuretics were discovered in 1957, as a result of efforts 1
to synthesize more potent carbonic anhydrase inhibitors. It subse- Quinethazone 25–100 mg Single dose
quently became clear that the thiazides inhibit NaCl, rather than Trichlormethiazide 1–4 mg Single dose
−
NaHCO transport and that their action is predominantly in the 1 Not a thiazide but a sulfonamide qualitatively similar to the thiazides.
3
DCT, rather than the PCT. Some members of this group retain
significant carbonic anhydrase inhibitory activity (eg, chlorthali-
done). The prototypical thiazide is hydrochlorothiazide (HCTZ). All thiazides can be administered orally, but there are differ-
ences in their metabolism. Chlorothiazide, the parent of the
Chemistry & Pharmacokinetics group, is not very lipid-soluble and must be given in relatively
Like carbonic anhydrase inhibitors and three loop diuretics, all of the large doses. It is the only thiazide available for parenteral admin-
thiazides have an unsubstituted sulfonamide group (Figure 15–8). istration. HCTZ is considerably more potent and should be used
in much lower doses (Table 15–6). Chlorthalidone is slowly
absorbed and has a longer duration of action. Although indap-
amide is excreted primarily by the biliary system, enough of the
H active form is cleared by the kidney to exert its diuretic effect in
N
Cl the DCT. All thiazides are secreted by the organic acid secretory
system in the proximal tubule and compete with the secretion of
NH uric acid by that system. As a result, thiazide use may blunt uric
H N O S S acid secretion and elevate serum uric acid level.
2
2
O 2

Hydrochlorothiazide Pharmacodynamics
CH 3 Thiazides inhibit NaCl reabsorption from the luminal side of
+
−
epithelial cells in the DCT by blocking the Na /Cl transporter
(NCC). In contrast to the situation in the TAL, in which loop
Cl CO NH N 2+
diuretics inhibit Ca reabsorption, thiazides actually enhance
2+
Ca reabsorption. This enhancement has been postulated to
H N O S result from effects in both the proximal and distal convoluted
2
2
tubules. In the proximal tubule, thiazide-induced volume deple-
2+
+
tion leads to enhanced Na and passive Ca reabsorption. In
+
Indapamide the DCT, lowering of intracellular Na by thiazide-induced
2+
+
+
blockade of Na entry enhances Na /Ca exchange in the baso-
H lateral membrane (Figure 15–4) and increases overall reabsorp-
N
Cl CH 3 tion of Ca . Although thiazides rarely cause hypercalcemia as
2+
a result of this enhanced reabsorption, they can unmask hyper-
N calcemia due to other causes (eg, primary hyperparathyroid-
H 2 N O 2 S
ism, carcinoma, sarcoidosis). Thiazides are sometimes useful
in the prevention of calcium-containing kidney stones caused
O
by hypercalciuria. They may also modestly reduce the risk of
CH 3
Metolazone osteoporotic fractures.
The action of thiazides depends in part on renal prostaglan-
FIGURE 15–8 Hydrochlorothiazide and related agents. din production. As described for loop diuretics, the actions