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

710 antidiuretic activity without increasing vasopressor activity.
Substitution of D-arginine for L-arginine greatly reduces vasopressor
activity without reducing antidiuretic activity. Thus, the antidiureticto-vasopressor
ratio for 1-deamino-8-D-arginine vasopressin (Table
25–8), also called desmopressin (DDAVP, MINIRIN, STIMATE, others), is
~3000 times greater than that for vasopressin, and desmopressin now
is the preferred drug for the treatment of central diabetes insipidus.
Substitution of valine for glutamine in position 4 further increases
the antidiuretic selectivity, and the antidiuretic to vasopressor ratio
for deamino [Val 4 , D-Arg 8 ]AVP (Table 25–8) is ~11,000 times greater
than that for vasopressin. Nakamura and colleagues (2000) synthesized
a nonpeptide V 2
-receptor agonist (Table 25–8).
Increasing V 1
selectivity has proved more difficult than
increasing V 2
selectivity, but a limited number of agonists with modest
selectivity for V 1
receptors have been developed (Table 25–8).
Vasopressin receptors in the adenohypophysis that mediate vasopressin-induced
ACTH release are neither classical V 1
nor V 2
receptors.
Since vasopressin receptors in the adenohypophysis appear to
share a common signal-transduction mechanism with classical V 1
receptors, and since many vasopressin analogs with vasoconstrictor
activity release ACTH, V 1
receptors have been subclassified into V 1a
(vascular/hepatic) and V 1b
(pituitary) receptors. V 1b
receptors are also
called V 3
receptors. Vasopressin analogs that are agonists selective
for V 1a
or V 1b
receptors have been described (Table 25–8).
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Chemistry of Vasopressin Receptor Antagonists. The impetus for
the development of specific vasopressin receptor antagonists is the
belief that such drugs may be useful in a number of clinical settings.
Based on receptor physiology, selective V 1a
antagonists may be beneficial
when total peripheral resistance is increased (e.g., congestive
heart failure and hypertension), whereas selective V 2
antagonists
could be useful whenever reabsorption of solute-free water is excessive
(e.g., the syndrome of inappropriate secretion of antidiuretic
hormone [SIADH] and hyponatremia associated with a reduced
effective blood volume). Combined V 1a
/V 2
receptor antagonists
might be beneficial in diseases associated with a combination of
increased peripheral resistance and dilutional hyponatremia (e.g.,
congestive heart failure).
Highly selective V 1
and V 2
peptide antagonists that are structural
analogs of vasopressin have been synthesized (see Table 25–9 for
examples), including both cyclic and linear peptides. [1-(β-Mercaptoβ,
β-cyclopentamethyleneproprionic acid), 2-O-methyltyrosine] arginine
vasopressin, also known as d(CH 2
) 5
[Tyr(Me) 2 ] AVP, has a greater
affinity for V 1a
receptors than for either V 1b
or V 2
receptors; this antagonist
has been employed widely in physiological and pharmacological
studies. Although [1-deaminopenicillamine, 2-O-methyltyrosine] arginine
vasopressin, also called dP[Tyr(Me) 2 ] AVP, is a potent V 1b
receptor
antagonist with little affinity for the V 2
receptor, it also blocks V 1a
receptors. No truly selective peptide V 1b
-receptor antagonist is available.
Peptide antagonists have limited oral activity, and the potency of
peptide V 2
antagonists is species dependent.
DISEASES AFFECTING
THE VASOPRESSIN SYSTEM
Diabetes Insipidus (DI). DI is a disease of impaired
renal water conservation owing either to inadequate
vasopressin secretion from the neurohypophysis (central
DI) or to insufficient renal vasopressin response (nephrogenic
DI). Very rarely, DI can be caused by an abnormally
high degradation rate of vasopressin by circulating
vasopressinases. Pregnancy may accentuate or reveal
central and/or nephrogenic DI by increasing plasma levels
of vasopressinase and by reducing renal sensitivity to
vasopressin. Patients with DI excrete large volumes
(>30 mL/kg per day) of dilute (<200 mOsm/kg) urine
and, if their thirst mechanism is functioning normally,
are polydipsic. In contrast to the sweet urine excreted by
patients with diabetes mellitus, urine from patients with
DI is tasteless, hence the name insipidus.
The urinary taste test for DI has been supplanted by the
approach of observing whether the patient is able to reduce urine
volume and increase urine osmolality after a period of carefully
observed fluid deprivation. Central DI can be distinguished from
nephrogenic DI by administration of desmopressin, which will
increase urine osmolality in patients with central DI but have little or
no effect in patients with nephrogenic DI. DI can be differentiated
from primary polydipsia by measuring plasma osmolality, which
will be low to low-normal in patients with primary polydipsia and
high to high-normal in patients with DI. For a more complete discussion
of diagnostic procedures, see Robertson (2001).
Central DI. Head injury, either surgical or traumatic, in
the region of the pituitary and/or hypothalamus may
cause central DI. Postoperative central DI may be transient,
permanent, or triphasic (recovery followed by
permanent relapse). Other causes include hypothalamic
or pituitary tumors, cerebral aneurysms, CNS ischemia,
and brain infiltrations and infections (Robertson, 2001).
Central DI may also be idiopathic or familial. Familial
central DI usually is autosomal dominant (chromosome
20), and vasopressin deficiency occurs several
months or years after birth and worsens gradually.
Autosomal dominant central DI is linked to mutations
in the vasopressin preprohormone gene that cause the
prohormone to misfold and oligomerize improperly.
The long-term result is accumulation of the mutant
vasopressin precursor in the affected neuron because
the precursor cannot move from the endoplasmic reticulum
into the secretory pathway. Accumulation of
mutant vasopressin precursor causes neuronal death,
hence the dominant mode of inheritance (Robertson,
2001). Rarely, familial central DI is autosomal recessive
owing to a mutation in the vasopressin peptide
itself that gives rise to an inactive vasopressin mutant.
Antidiuretic peptides are the primary treatment for central
DI, with desmopressin being the peptide of choice. For patients with
central DI who cannot tolerate antidiuretic peptides because of side
effects or allergic reactions, other treatment options are available.