Page 281 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 15 Diuretic Agents 267

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K losses, hyperkalemia is more common when K -sparing diuretics water to be retained in these segments and promotes a water diuresis.
are used as the sole diuretic agent, especially in patients with renal Such agents can be used to reduce intracranial pressure and to
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insufficiency. With fixed-dosage combinations of K -sparing and promote prompt removal of renal toxins. The prototypic osmotic
thiazide diuretics, the thiazide-induced hypokalemia and meta- diuretic is mannitol. Glucose is not used clinically as a diuretic
bolic alkalosis are ameliorated. However, because of variations in but frequently causes osmotic diuresis (glycosuria) in patients with
the bioavailability of the components of fixed-dosage forms, the hyperglycemia.
thiazide-associated adverse effects often predominate. Therefore, it
is generally preferable to adjust the doses of the two drugs separately. Pharmacokinetics

B. Hyperchloremic Metabolic Acidosis Mannitol is poorly absorbed by the GI tract, and when admin-
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By inhibiting H secretion in parallel with K secretion, the K - istered orally, it causes osmotic diarrhea rather than diuresis. For
sparing diuretics can cause acidosis similar to that seen with type IV systemic effect, mannitol must be given intravenously. Mannitol
renal tubular acidosis. is not metabolized and is excreted by glomerular filtration within
30–60 minutes, without any important tubular reabsorption or
C. Gynecomastia secretion. It must be used cautiously in patients with even mild
Synthetic steroids may cause endocrine abnormalities by actions renal insufficiency (see below).
on other steroid receptors. Gynecomastia, impotence, and benign
prostatic hyperplasia (very rare) have been reported with spirono- Pharmacodynamics
lactone. Such effects have not been reported with eplerenone, pre- Osmotic diuretics have their major effect in the proximal tubule
sumably because it is much more selective than spironolactone for and the descending limb of Henle’s loop. Through osmotic effects,
the mineralocorticoid receptor and virtually inactive on androgen they also oppose the action of ADH in the collecting tubule. The
or progesterone receptors.
presence of a nonreabsorbable solute such as mannitol prevents
the normal absorption of water by interposing a countervailing
D. Acute Renal Failure osmotic force. As a result, urine volume increases. The increase in
The combination of triamterene with indomethacin has been urine flow decreases the contact time between fluid and the tubular
reported to cause acute renal failure. This has not been reported epithelium, thus reducing Na as well as water reabsorption. The
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with other K -sparing diuretics. resulting natriuresis is of lesser magnitude than the water diuresis,
leading eventually to excessive water loss and hypernatremia.
E. Kidney Stones
Triamterene is only slightly soluble and may precipitate in the Clinical Indications & Dosage
urine, causing kidney stones.
Reduction of Intracranial and Intraocular Pressure
Contraindications Osmotic diuretics alter Starling forces so that water leaves cells and
reduces intracellular volume. This effect is used to reduce intracranial
Potassium-sparing agents can cause severe, even fatal, hyperka- pressure in neurologic conditions and to reduce intraocular pressure
lemia in susceptible patients. Patients with chronic renal insuf- before ophthalmologic procedures. A dose of 1–2 g/kg mannitol is
ficiency are especially vulnerable and should rarely be treated with administered intravenously. Intracranial pressure, which must be
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these diuretics. Oral K administration should be discontinued if monitored, should fall in 60–90 minutes. At times the rapid lower-
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K -sparing diuretics are administered. Concomitant use of other ing of serum osmolality at initiation of dialysis (from removal of
agents that blunt the renin-angiotensin system (β blockers, ACE uremic toxins) results in symptoms. Many nephrologists also use
inhibitors, angiotensin receptor blockers) increases the likelihood mannitol to prevent adverse reactions when first starting patients
of hyperkalemia. Patients with liver disease may have impaired on hemodialysis. The evidence for efficacy in this setting is limited.
metabolism of triamterene and spironolactone, so dosing must be
carefully adjusted. Strong CYP3A4 inhibitors (eg, erythromycin, Toxicity
fluconazole, diltiazem, and grapefruit juice) can markedly increase
blood levels of eplerenone, but not spironolactone. A. Extracellular Volume Expansion
Mannitol is rapidly distributed in the extracellular compartment
and extracts water from cells. Prior to the diuresis, this leads to
AGENTS THAT ALTER WATER expansion of the extracellular volume and hyponatremia. This effect
EXCRETION (AQUARETICS) can complicate heart failure and may produce florid pulmonary
edema. Headache, nausea, and vomiting are commonly observed in
OSMOTIC DIURETICS patients treated with osmotic diuretics.

The proximal tubule and descending limb of Henle’s loop are B. Dehydration, Hyperkalemia, and Hypernatremia
freely permeable to water (Table 15–1). Any osmotically active Excessive use of mannitol without adequate water replacement
agent that is filtered by the glomerulus but not reabsorbed causes can ultimately lead to severe dehydration, free water losses,