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

Chlorpropamide, an oral sulfonylurea, potentiates the action of small
or residual amounts of circulating vasopressin and will reduce urine
volume in more than half of all patients with central DI. Doses of
125-500 mg daily appear effective in patients with partial central DI.
If polyuria is not controlled satisfactorily with chlorpropamide alone,
addition of a thiazide diuretic to the regimen usually results in an
adequate reduction in urine volume. Carbamazepine (800-1000 mg
daily in divided doses) also reduces urine volume in patients with
central DI. Long-term use may induce serious adverse effects; therefore,
carbamazepine is used rarely to treat central DI. The antidiuretic
mechanisms of chlorpropamide, carbamazepine, and clofibrate (not
available in the U.S.) are not clear. These agents are not effective in
nephrogenic DI, which indicates that functional V 2
receptors are
required for the antidiuretic effect. Since carbamazepine inhibits and
chlorpropamide has little effect on vasopressin secretion, it is likely
that carbamazepine and chlorpropamide act directly on the kidney to
enhance V 2
-receptor-mediated antidiuresis.
Nephrogenic DI. Nephrogenic DI may be congenital or
acquired. Hypercalcemia, hypokalemia, postobstructive
renal failure, Li + , foscarnet, clozapine, demeclocycline,
and other drugs can induce nephrogenic DI. As many as
one in three patients treated with Li + may develop
nephrogenic DI.
X-linked nephrogenic DI is caused by mutations in the gene
encoding the V 2
receptor, which maps to Xq28. A number of missense,
nonsense, and frame-shift mutations in the gene encoding the V 2
receptor
were identified in patients with this disorder. Mutations in the V 2
-
receptor gene may cause impaired routing of the V 2
receptor to the cell
surface, defective coupling of the receptor to G proteins, or decreased
receptor affinity for vasopressin. The effects of these mutations range
from a complete loss of responsiveness to vasopressin to a shift to the
left of the concentration-response curve. Autosomal recessive and dominant
nephrogenic DI result from inactivating mutations in aquaporin
2. These findings indicate that aquaporin 2 is essential for the antidiuretic
effect of vasopressin in humans.
Although the mainstay of treatment of nephrogenic DI is
assurance of an adequate water intake, drugs also can be used to
reduce polyuria. Amiloride blocks Li + uptake by the Na + channel in
the collecting-duct system and may be effective in patients with mild
to moderate concentrating defects. Patients with severe disease often
do not respond. Thiazide diuretics reduce the polyuria of patients
with DI and often are used to treat nephrogenic DI. The use of thiazide
diuretics in infants with nephrogenic DI may be crucially
important because uncontrolled polyuria may exceed the child’s
capacity to imbibe and absorb fluids. The antidiuretic mechanism of
thiazides in DI is incompletely understood. It is possible that the
natriuretic action of thiazides and resulting extracellular fluid volume
depletion play an important role in thiazide-induced antidiuresis. In
this regard, whenever extracellular fluid volume is reduced, compensatory
mechanisms increase NaCl reabsorption in proximal
tubule, reducing the volume delivered to the distal tubule.
Consequently, less free water can be formed, which should diminish
polyuria. However, studies in rats with vasopressin-deficient DI challenge
this hypothesis. Nonetheless, the antidiuretic effects appear to
parallel the thiazide’s ability to cause natriuresis, and the drugs are
given in doses similar to those used to mobilize edema fluid. In
patients with DI, a 50% reduction of urine volume is a good response
to thiazides. Moderate restriction of Na + intake can enhance the
antidiuretic effectiveness of thiazides.
A number of case reports describe the effectiveness of
indomethacin in the treatment of nephrogenic DI; however, other
prostaglandin synthase inhibitors (e.g., ibuprofen) appear to be less
effective. The mechanism of the effect may involve a decrease in
glomerular filtration rate, an increase in medullary solute concentration,
and/or enhanced proximal fluid reabsorption. Also, since
prostaglandins attenuate vasopressin-induced antidiuresis in patients
with at least a partially intact V 2
-receptor system, some of the antidiuretic
response to indomethacin may be due to diminution of the
prostaglandin effect and enhancement of vasopressin effects on the
principal cells of collecting duct.
Syndrome of Inappropriate Secretion of Antidiuretic
Hormone (SIADH). SIADH is a disease of impaired water
excretion with accompanying hyponatremia and hypoosmolality
caused by the inappropriate secretion of vasopressin.
Clinical manifestations of plasma hypotonicity
resulting from SIADH may include lethargy, anorexia,
nausea and vomiting, muscle cramps, coma, convulsions,
and death. A multitude of disorders can induce
SIADH (Robertson, 2001), including malignancies, pulmonary
diseases, CNS injuries/diseases (e.g., head
trauma, infections, and tumors), and general surgery.
The three drug classes most commonly implicated
in drug-induced SIADH include psychotropic medications
(e.g., selective serotonin reuptake inhibitors,
haloperidol, and tricyclic antidepressants), sulfonylureas
(e.g., chloropropamide), and vinca alkaloids (e.g., vincristine
and vinblastine). Other drugs strongly associated
with SIADH include clonidine, cyclophosphamide,
enalapril, felbamate, ifosphamide, and methyldopa, pentamidine,
and vinorelbine. In a normal individual, an elevation
in plasma vasopressin per se does not induce
plasma hypotonicity because the person simply stops
drinking owing to an osmotically induced aversion to fluids.
Therefore, plasma hypotonicity only occurs when
excessive fluid intake (oral or intravenous) accompanies
inappropriate secretion of vasopressin. Treatment of
hypotonicity in the setting of SIADH includes water
restriction, intravenous administration of hypertonic
saline, loop diuretics (which interfere with kidney’s concentrating
ability), and drugs that inhibit the effect of
vasopressin to increase water permeability in collecting
ducts. To inhibit vasopressin’s action in collecting ducts,
demeclocycline, a tetracycline, has been the preferred
drug, but tolvaptan and conivaptan, V 2
receptor antagonists,
are now available (see next section and Table 25–9).
Although Li + can inhibit the renal actions of vasopressin, it is
effective in only a minority of patients, may induce irreversible renal
damage when used chronically, and has a low therapeutic index.
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CHAPTER 25
REGULATION OF RENAL FUNCTION AND VASCULAR VOLUME