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

is 10-40 μg daily either as a single dose or divided into two or three
doses. In view of the high cost of the drug and the importance of
avoiding water intoxication, the schedule of administration should be
adjusted to the minimal amount required. An initial dose of 2.5 μg
can be used, with therapy first directed toward control of nocturia.
An equivalent or higher morning dose controls daytime polyuria in
most patients, although a third dose occasionally may be needed in
the afternoon. In some patients, chronic allergic rhinitis or other
nasal pathology may preclude reliable peptide absorption following
nasal administration. Oral administration of desmopressin in doses
10-20 times the intranasal dose provides adequate desmopressin
blood levels to control polyuria. Subcutaneous administration of
1-2 μg daily of desmopressin also is effective in central DI.
Vasopressin has little, if any, place in the long-term therapy
of DI because of its short duration of action and V 1
receptor-mediated
side effects. Vasopressin can be used as an alternative to desmopressin
in the initial diagnostic evaluation of patients with suspected
DI and to control polyuria in patients with DI who recently have
undergone surgery or experienced head trauma. Under these circumstances,
polyuria may be transient, and long-acting agents may
produce water intoxication.
An additional V 2
receptor-mediated therapeutic application
is the use of desmopressin in bleeding disorders (Mannucci, 1997).
In most patients with type I von Willebrand’s disease (vWD) and in
some with type IIn vWD, desmopressin will elevate von Willebrand
factor and shorten bleeding time. However, desmopressin generally
is ineffective in patients with types IIa, IIb, and III vWD.
Desmopressin may cause a marked transient thrombocytopenia in
individuals with type IIb vWD and is contraindicated in such
patients. Desmopressin also increases factor VIII levels in patients
with mild to moderate hemophilia A. Desmopressin is not indicated
in patients with severe hemophilia A, those with hemophilia B, or
those with factor VIII antibodies. Using a test dose of nasal spray, the
response of any given patient with type I vWD or hemophilia A to
desmopressin should be determined at the time of diagnosis or 1-2
weeks before elective surgery to assess the extent of increase in factor
VIII or von Willebrand factor. Desmopressin is employed widely
to treat the hemostatic abnormalities induced by uremia. In patients
with renal insufficiency, desmopressin shortens bleeding time and
increases circulating levels of factor VIII coagulant activity, factor
VIII-related antigen, and ristocetin cofactor. It also induces the
appearance of larger von Willebrand factor multimers. Desmopressin
is effective in some patients with liver cirrhosis-induced or druginduced
(e.g., heparin, hirudin, and antiplatelet agents) bleeding disorders.
Desmopressin, given intravenously at a dose of 0.3 μg/kg,
increases factor VIII and von Willebrand factor for > 6 hours.
Desmopressin can be given at intervals of 12-24 hours depending
on the clinical response and severity of bleeding. Tachyphylaxis to
desmopressin usually occurs after several days (owing to depletion
of factor VIII and von Willebrand factor storage sites) and limits its
usefulness to preoperative preparation, postoperative bleeding,
excessive menstrual bleeding, and emergency situations.
Another V 2
receptor-mediated therapeutic application
is the use of desmopressin for primary nocturnal
enuresis. Bedtime administration of desmopressin
intranasal spray or tablets provides a high response rate
that is sustained with long-term use, that is safe, and that
accelerates the cure rate. Finally, desmopressin has been
found to relieve post-lumbar puncture headache probably
by causing water retention and thereby facilitating
rapid fluid equilibration in the CNS.
Pharmacokinetics. When vasopressin and desmopressin
are given orally, they are inactivated quickly by
trypsin, which cleaves the peptide bond between amino
acids 8 and 9.
Inactivation by peptidases in various tissues (particularly liver
and kidney) results in a plasma t 1/2
of vasopressin of 17-35 minutes.
Following intramuscular or subcutaneous injection, antidiuretic
effects of vasopressin last 2-8 hours. The plasma t 1/2
of desmopressin
has two components, a fast component (~8 min) and a slow component
(30-117 min). Only 3% and 0.15%, respectively, of intranasally
and orally administered desmopressin is absorbed.
Toxicity, Adverse Effects, Contraindications, Drug
Interactions. Most adverse effects are mediated
through V 1
receptor activation on vascular and GI
smooth muscle; consequently, such adverse effects are
much less common and less severe with desmopressin
than with vasopressin.
After injection of large doses of vasopressin, marked facial
pallor owing to cutaneous vasoconstriction is observed commonly.
Increased intestinal activity is likely to cause nausea, belching,
cramps, and an urge to defecate. Most serious, however, is the effect
on the coronary circulation. Vasopressin should be administered only
at low doses and with extreme caution in individuals suffering from
vascular disease, especially coronary artery disease. Other cardiac
complications include arrhythmia and decreased cardiac output.
Peripheral vasoconstriction and gangrene were encountered in
patients receiving large doses of vasopressin.
The major V 2
receptor-mediated adverse effect
is water intoxication, which can occur with desmopressin
or vasopressin. In this regard, many drugs,
including carbamazepine, chlorpropamide, morphine,
tricyclic antidepressants, and NSAIDs, can potentiate
the antidiuretic effects of these peptides. Several drugs
such as Li + , demeclocycline, and ethanol can attenuate
the antidiuretic response to desmopressin.
Desmopressin and vasopressin should be used cautiously
in disease states in which a rapid increase in
extracellular water may impose risks (e.g., in angina,
hypertension, and heart failure) and should not be
used in patients with acute renal failure. Patients
receiving desmopressin to maintain hemostasis should
be advised to reduce fluid intake. Also, it is imperative
that these peptides not be administered to patients
with primary or psychogenic polydipsia because
severe hypotonic hyponatremia will ensue.
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CHAPTER 25
REGULATION OF RENAL FUNCTION AND VASCULAR VOLUME