DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

714 Mild facial flushing and headache are the most common
adverse effects associated with desmopressin. Allergic reactions
ranging from urticaria to anaphylaxis may occur with desmopressin
or vasopressin. Intranasal administration may cause local adverse
effects in the nasal passages, such as edema, rhinorrhea, congestion,
irritation, pruritus, and ulceration.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Vasopressin Receptor Antagonists
Table 25–9 lists the structures and selectivity of receptor
antagonists.
Therapeutic Uses. When the kidney peceives the arterial
blood volume to be low (as in the disease states of
CHF, cirrhosis, and nephrosis), AVP perpetuates a state
of total body salt and water excess. V 2
receptor (V 2
R)
antagonists or “aquaretics” may have a therapeutic role
in these conditions, especially in patients with concomitant
hyponatremia. They are also effective in hyponatremia
associated with SIADH. Aquaretics increase
renal free water excretion with little or no change in
electrolyte excretion. Since they do not affect Na +
reabsorption they do not stimulate the TGF mechanism
with its associated consequence of reducing GFR.
Conivaptan, a V 1a
R/V 2
R antagonist, and tolvaptan, a
selective V 2
R antagonist, are FDA-approved for use in
patients with euvolemic or hypervolemic hyponatremia
associated with SIADH. The V 2
R antagonist mozavaptan
is approved in Japan for the treatment hyponatremia
secondary to SIADH caused by malignancy. Although a
large number of vasopressin receptor antagonists are in
preclinical and clinical trials, we will discuss only the
V 2
R antagonists mozavaptan and tolvaptan, and the
V 1a
R/V 2
R antagonist conivaptan (Costello-Boerrigter
et al., 2009).
Mozavaptan. Mozavaptan was the first nonpeptide V 2
receptor antagonist
in clinical use. It was approved for treatment of SIADH secondary
to cancer in Japan in 1996. Mozavaptan causes a dose-dependent
increase in free water excretion with only slight increases in urinary
Na + and K + excretion.
Tolvaptan. Tolvaptan (SAMSCA) is a selective oral V 2
R
antagonist developed through structural modifications
of mozavaptan to create a more selective V 2
R antagonist.
In short-term clinical trials in patients with CHF
and reduced ejection fraction, the drug decreased body
weight and improved dyspnea. In long-term trials, there
was no effect on all-cause mortality, cardiovascular
death, or hospitalization for heart failure; losses in body
weight and increases in Na + concentration were sustained
over the course of the studies. Tolvaptan is
approved for clinically significant hypervolemic and
euvolemic hyponatremia. The drug is labeled with a
black box warning against too rapid correction of
hyponatremia (can have serious and fatal consequences)
and the recommendation to initiate therapy in
a hospital setting capable of close monitoring of serum
Na + . Tolvaptan is containdicated in patients receiving
drugs that inhibit CYP3A4.
Conivaptan. Conivaptan (VAPRISOL) is a nonselective
V 1a
R/V 2
R antagonist that is FDA-approved for the
treatment of hospitalized patients with euvolemic
hyponatremia and hypervolemic hyponatremia. The
drug is available only for intravenous infusion. In CHF
patients, conivaptan increases renal free water excretion
without a change in systemic vascular resistance.
The manufacturer recommends starting administration
with a 20 mg loading dose given over 30 minutes followed
by a continuous infusion of an additional 20 mg
over the first 24 hours. The infusion is then continued
at 20 mg/day for a maximum of three additional
days. The dose can be increased to 40 mg/day if there
is no response to the 20 mg dose. Doses higher than
40 mg/day have no additional benefit. Serum Na + concentration
should not be increased >12 mEq/L in a
24-hour period.
Pharmacokinetics
Mozavaptan. Mozavaptan is available in 30-mg tablets. Few data are
available regarding its pharmacokinetics. It binds to the V 2
R with
much higher affinity than V 1a
R, K i
9.42 ± 0.9 nM versus 150 ±
15 nM, respectively. Its peak effects occur 60-90 minutes after an
oral dose.
Tolvaptan. Tolvaptan is available in 15 and 30 mg tablets and inhibits
the V 2
R with a K i
of 0.43 ± 0.06 nM and the V 1a
R with a K i
of 12.3
± 0.8 nM. Tolvaptan is 29 times more selective for the V 2
R than the
V 1a
R. Most of its effects on renal free water excretion occur in the
first 6-8 hours after administration. Tolvaptan has a t 1/2
of 6-8 hours
and <1% is excreted in the urine. The starting dose is 15 mg once
daily, and this dose can be titrated up to a maximum of 60 mg daily.
Tolvaptan is a substrate and inhibitor of P-glycoprotein and is eliminated
entirely by CYP3A metabolism.
Conivaptan. Conivaptan inhibits the V 1a
R with a K i
of 6.3 ± 1.8 nM
and the V 2
R with a K i
of 1.1 ± 0.2 nM. Total body clearance is 9.5-
10.1 L/hr. It is highly protein bound and has a terminal elimination
t 1/2
of 5-12 hours. Conivaptan is metabolized via CYP3A4 and is
partially excreted by the kidney. Caution should be exercised in those
with hepatic and renal disease. At higher doses clearance may be
reduced in the elderly.
Toxicity, Adverse Effects, Contraindications, Drug
Interactions
Mozavaptan. Mozavaptan’s major side effects are dry mouth and
abnormal liver function tests.
Tolvaptan. Tolvaptan is eliminated by CYP3A4. Plasma concentrations
of the drug are increased by ketoconazole. There is no known
affect on amiodarone, digoxin, or warfarin metabolism. Among the