Page 286 - Basic _ Clinical Pharmacology ( PDFDrive )

272 SECTION III Cardiovascular-Renal Drugs

be idiopathic. In these situations, thiazides are also effective but plasma volume reduction, with an associated fall in GFR, lead-
should be used as adjunctive therapy with other measures. ing to enhanced proximal reabsorption of NaCl and water and
decreased delivery of fluid to the downstream diluting segments.
+
However, in the case of Li -induced NDI, it is now known
HYPERCALCEMIA that HCTZ causes increased osmolality in the inner medulla
+
(papilla) and a partial correction of the Li -induced reduction in
Hypercalcemia can be a medical emergency (see Chapter 42). Because aquaporin-2 expression. HCTZ also leads to increased expres-
2+
loop diuretics reduce Ca reabsorption significantly, they can be sion of Na transporters in the DCT and CCT segments of
+
2+
quite effective in promoting Ca diuresis. However, loop diuretics the nephron. Thus, the maximum volume of dilute urine that
alone can cause marked volume contraction. If this occurs, loop can be produced is significantly reduced by thiazides in NDI.
diuretics are ineffective (and potentially counterproductive) because Dietary sodium restriction can potentiate the beneficial effects of
2+
Ca reabsorption in the proximal tubule would be enhanced. Thus, thiazides on urine volume in this setting. Serum Li levels must
+
saline must be administered simultaneously with loop diuretics if be carefully monitored in these patients, because diuretics may
2+
an effective Ca diuresis is to be maintained. The usual approach is reduce renal clearance of Li and raise plasma Li levels into the
+
+
to infuse normal saline and furosemide (80–120 mg) intravenously. toxic range (see Chapter 29). Lithium-induced polyuria can also
Once the diuresis begins, the rate of saline infusion can be matched be partially reversed by amiloride, which blocks Li entry into
+
with the urine flow rate to avoid volume depletion. Potassium collecting duct cells, much as it blocks Na entry. As mentioned
+
chloride may be added to the saline infusion as needed. above, thiazides are also beneficial in other forms of nephrogenic
diabetes insipidus. It is not yet clear whether this is via the same
+
DIABETES INSIPIDUS mechanism that has been found in Li -induced NDI. Acetazol-
amide has also shown efficacy in treating polyuria in nephrogenic
diabetes insipidus with fewer adverse events.
Diabetes insipidus is due to either deficient production of
ADH (neurogenic or central diabetes insipidus) or inadequate
responsiveness to ADH (nephrogenic diabetes insipidus [NDI]). RENAL & CARDIAC PROTECTION
Administration of supplementary ADH or one of its analogs
is effective only in central diabetes insipidus. Thiazide diuret- Aldosterone antagonists have been shown to be cardioprotective in
ics can reduce polyuria and polydipsia in nephrogenic diabetes patients with heart disease. In addition, they may exert an addi-
insipidus, which is not responsive to ADH supplementation. tional benefit in lowering albuminuria in patients with diabetes
Lithium, used in the treatment of manic-depressive disorder, is a and microalbuminuria. Their use has been limited in patients
common cause of NDI, and thiazide diuretics have been found with renal dysfunction because of the increased risk of inducing
to be helpful in treating it. This seemingly paradoxical beneficial hyperkalemia. Finerenone may afford similar cardiac and renal
effect of thiazides was previously thought to be mediated through protection with a lower risk for hyperkalemia.

SUMMARY Diuretic Agents

Clinical Pharmacokinetics,
Subclass, Drug Mechanism of Action Effects Applications Toxicities, Interactions
CARBONIC ANHYDRASE INHIBITORS
−
• Acetazolamide, Inhibition of the enzyme Reduce reabsorption of HCO 3 , causing Glaucoma, mountain Oral and topical preparations
others prevents dehydration of self-limited diuresis • hyperchloremic sickness, edema with available • duration of action
H 2 CO 3 and hydration of CO 2 metabolic acidosis • reduce body pH, alkalosis ∼8–12 h • Toxicity: Metabolic
in the proximal convoluted • reduce intraocular pressure acidosis, renal stones,
tubule hyperammonemia in
cirrhotics

• Brinzolamide, dorzolamide: Topical for glaucoma
SGLT2 INHIBITORS
• Canagliflozin Inhibition of sodium/glucose Inhibition of glucose reabsorption lowers Diabetes mellitus; Available orally. Half-life
cotransporter (SGLT2) in the serum glucose concentration, and approved for the 10–12 h • not recommended
+
+
PCT results in decreased Na reduced Na reabsorption causes mild treatment of in severe renal or liver
and glucose reabsorption diuresis hyperglycemia, not as disease
a diuretic
• Dapagliflozin, empagliflozin: similar to canagliflozin
(continued)