Page 282 - Basic _ Clinical Pharmacology ( PDFDrive )

268 SECTION III Cardiovascular-Renal Drugs

and hypernatremia. As water is extracted from cells, intracellular Pharmacokinetics
+
K concentration rises, leading to cellular losses and hyperkalemia.
These complications can be avoided by careful attention to serum The half-lives of conivaptan and demeclocycline are 5–10 hours,
ion composition and fluid balance. while that of tolvaptan is 12–24 hours.

C. Hyponatremia Pharmacodynamics
When used in patients with severe renal impairment, parenterally Antidiuretic hormone antagonists inhibit the effects of ADH in
administered mannitol cannot be excreted and is retained in the the collecting tubule. Conivaptan and tolvaptan are direct ADH
blood. This causes osmotic extraction of water from cells, leading receptor antagonists, while both lithium and demeclocycline
to hyponatremia without a decrease in serum osmolality.
reduce ADH-induced cAMP by unknown mechanisms.
D. Acute Renal Failure
Acute renal failure has been well described with use of mannitol. Clinical Indications & Dosage
The effect is thought to be mediated by the increase in osmolality. A. Syndrome of Inappropriate ADH Secretion
The incidence of acute kidney injury with mannitol use has been
estimated to be 6–7% of patients who receive the drug. Antidiuretic hormone antagonists are used to manage SIADH when
water restriction has failed to correct the abnormality. This gener-
ally occurs in the outpatient setting, where water restriction cannot
ANTIDIURETIC HORMONE be enforced, but can occur in the hospital when large quantities of
(ADH, VASOPRESSIN) AGONISTS intravenous fluid are needed for other purposes. Demeclocycline
(600–1200 mg/d) or tolvaptan (15–60 mg/d) can be used for
SIADH. Appropriate plasma levels of demeclocycline (2 mcg/mL)
Vasopressin and desmopressin are used in the treatment of cen- should be maintained by monitoring, but tolvaptan levels are not
tral diabetes insipidus. They are discussed in Chapter 37. Their routinely monitored. Unlike demeclocycline or tolvaptan, conivap-
renal action appears to be mediated primarily via V ADH recep- tan is administered intravenously and is not suitable for chronic use
2
tors, although V receptors may also be involved. in outpatients.
1a

ANTIDIURETIC HORMONE B. Other Causes of Elevated Antidiuretic Hormone
ANTAGONISTS Antidiuretic hormone is also elevated in response to diminished
effective circulating blood volume, as often occurs in heart failure.
A variety of medical conditions, including congestive heart failure Due to the elevated ADH levels, hyponatremia may result. As in
(CHF) and the syndrome of inappropriate ADH secretion the management of SIADH, water restriction is frequently the treat-
(SIADH), cause water retention as a result of excessive ADH secre- ment of choice. In patients with heart failure, this approach is often
tion. Patients with CHF who are on diuretics frequently develop unsuccessful in view of increased thirst and the large number of oral
hyponatremia secondary to excessive ADH secretion. medications being used. For patients with heart failure, intravenous
Until recently, two nonselective agents, lithium (see Chapter 29) conivaptan may be particularly useful because it has been found
and demeclocycline (a tetracycline antimicrobial drug discussed that the blockade of V receptors by this drug leads to decreased
1a
in Chapter 44), were used for their well-known interference with peripheral vascular resistance and increased cardiac output.
ADH activity. The mechanism for this interference has not been
completely determined for either of these agents. Demeclocycline C. Autosomal Dominant Polycystic Kidney Disease
is used more often than lithium because of the many adverse Cyst development in polycystic kidney disease is thought to be
effects of lithium administration. However, demeclocycline is mediated through cAMP. Vasopressin is a major stimulus for cAMP
now being rapidly replaced by several specific ADH receptor production in the kidney. It is hypothesized that inhibition of V
2
antagonists (vaptans), which have yielded encouraging clinical receptors in the kidney might delay the progression of polycystic
results. kidney disease. In a large multicenter prospective trial, tolvaptan
There are three known vasopressin receptors, V , V , and was able to reduce the increase in kidney size and slow progression
1b
1a
V . V receptors are expressed in the vasculature and CNS, while of kidney failure over a 3-year follow-up period. In this trial, how-
2
1
V receptors are expressed specifically in the kidney. Conivaptan ever, the tolvaptan group experienced a 9% incidence of abnormal
2
(currently available only for intravenous use) exhibits activity against liver function test results compared with 2% in the placebo group.
both V and V receptors (see below). The oral agents tolvaptan, This led to discontinuation of the drug in some patients.
1a
2
lixivaptan, mozavaptan, and satavaptan are selectively active against
the V receptor. Lixivaptan, mozavaptan, and satavaptan are still Toxicity
2
under clinical investigation, but tolvaptan, which is approved by
the US Food and Drug Administration (FDA), is very effective in A. Nephrogenic Diabetes Insipidus
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treatment of hyponatremia and as an adjunct to standard diuretic If serum Na is not monitored closely, any ADH antagonist can
therapy in patients with CHF. cause severe hypernatremia and nephrogenic diabetes insipidus.