Page 279 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 15 Diuretic Agents 265

of thiazides can also be inhibited by NSAIDs under certain G. Other Toxicities
conditions. Weakness, fatigability, and paresthesias similar to those of carbonic
anhydrase inhibitors may occur. Impotence has been reported
Clinical Indications & Dosage but is probably related to volume depletion. Cases of acute angle-
(Table 15–6) closure glaucoma from hyponatremia caused by thiazide diuretics
have been reported.
The major indications for thiazide diuretics are (1) hypertension,
(2) heart failure, (3) nephrolithiasis due to idiopathic hypercalci-
uria, and (4) nephrogenic diabetes insipidus. Use of the thiazides Contraindications
in each of these conditions is described below in Clinical Pharma- Excessive use of any diuretic is dangerous in patients with hepatic
cology of Diuretic Agents. cirrhosis, borderline renal failure, or heart failure (see text that
follows).
Toxicity
A. Hypokalemic Metabolic Alkalosis POTASSIUM-SPARING DIURETICS
These toxicities are similar to those observed with loop diuretics
+
(see previous text and Table 15–2). Potassium-sparing diuretics prevent K secretion by antagonizing the
effects of aldosterone in collecting tubules. Inhibition may occur by
B. Impaired Carbohydrate Tolerance direct pharmacologic antagonism of mineralocorticoid receptors (spi-
+
Hyperglycemia may occur in patients who are overtly diabetic or ronolactone, eplerenone) or by inhibition of Na influx through ion
who have even mildly abnormal glucose tolerance tests. It occurs channels in the luminal membrane (amiloride, triamterene). Finally,
at higher doses of HCTZ (>50 mg/d) and has not been seen with ularitide (recombinant urodilatin), which is currently still under
+
+
+
doses of 12.5 mg/d or less. The effect is due to both impaired investigation, blunts Na uptake and Na /K -ATPase in collecting
pancreatic release of insulin and diminished tissue utilization of tubules and increases GFR through its vascular effects. Nesiritide,
glucose. Thiazides have a weak, dose-dependent, off-target effect which is available for intravenous use only, increases GFR and blunts
+
+
to stimulate ATP-sensitive K channels and cause hyperpolariza- Na reabsorption in both proximal and collecting tubules.
tion of beta cells, thereby inhibiting insulin release. This effect is
exacerbated by hypokalemia, and thus thiazide-induced hypergly- Chemistry & Pharmacokinetics
cemia may be partially reversed with correction of hypokalemia.
The structures of spironolactone and amiloride are shown in
C. Hyperlipidemia Figure 15–9.
Spironolactone is a synthetic steroid that acts as a competi-
Thiazides cause a 5–15% increase in total serum cholesterol and tive antagonist to aldosterone. Onset and duration of its action
low-density lipoproteins (LDLs). These levels may return toward are determined substantially by the active metabolites canrenone
baseline after prolonged use.
and 7-α-spirolactone, which are produced in the liver and have
D. Hyponatremia
Hyponatremia is an important adverse effect of thiazide diuretics. O
It is caused by a combination of hypovolemia-induced elevation of
ADH, reduction in the diluting capacity of the kidney, and increased H C O
thirst. It can be prevented by reducing the dose of the drug or limit- 3
ing water intake. Genetic studies have shown a link between KCNJ1
polymorphism and thiazide-induced hyponatremia. H C
3
E. Impaired Uric Acid Metabolism and Gout O
Thiazides are the diuretics most associated with development of O
gout. One large study found that thiazide diuretics only increase S C CH 3
the risk of gout in men younger than age 60 years and not in Spironolactone
women or older men. The increased risk in this group of patients
was found to be only about 1%.
Cl N CO NH C NH 2
F. Allergic Reactions NH
The thiazides are sulfonamides and share cross-reactivity with other H N NH
members of this chemical group. Photosensitivity or generalized 2 N 2
dermatitis occurs rarely. Serious allergic reactions are extremely rare Amiloride
but do include hemolytic anemia, thrombocytopenia, and acute
necrotizing pancreatitis. FIGURE 15–9 Potassium-sparing diuretics.