Drug Investigation 2 (Suppl.

5): 2-8, 1990

0114-2402/90/0500-0002/$3.50/0
Adis International Limited
All rights reserved.
DISUP1808

Basic Pharmacology of Desmopressin

A Review

Hans Vilhardt
Department of Medical Physiology, University of Copenhagen, Copenhagen, Denmark

Summary

Desmopressin is an analogue of the antidiuretic hormone vasopressin. The structural

changes introduced in the molecule have eliminated the pressor activity of vasopressin
and potentiated the antidiuretic action. The metabolic stability of the peptide is also
increased. Thus, the plasma half-life for desmopressin is 55 minutes compared with a
few minutes for vasopressin. The potent antidiuretic activity of desmopressin makes the
peptide ideal for the treatment of cranial diabetes insipidus. However, it may also be
used for nocturnal enuresis and as a diagnostic agent in determining renal concentrating
capacity. Desmopressin has recently been shown to be successful in the treatment of
certain bleeding disorders.

The principal hormones of the posterior pituitary gland are vasopressin and oxytocin, both cyclic
nonapeptides with a high degree of structural homology. There are no known diseases associated
with oxytocin, whereas impaired or absent production and secretion of vasopressin lead to a
chronic state of polyuria known as diabetes insipidus (Frank 1794). The obvious treatment of
patients with diabetes insipidus would, therefore,
be substitution therapy with vasopressin administered in the form of posterior pituitary extracts
(Kamm et al. 1928; von den Velden 1913) or as
synthetic vasopressin (Chirman & Kinsell 1964;
Moses 1964). However, vasopressin is not ideal as
substitution therapy in diabetes insipidus. As shown
in table I, vasopressin possesses a number of biological properties besides the antidiuretic effect.
These extrarenal actions must be regarded as side
effects and cannot be avoided, as vasopressin, which
has a very short plasma half-life, must be administered in high doses in order to ensure a reason-

able duration of the antidiuretic effect. As a

consequence of these untoward effects, patients
treated with vasopressin often complain of intestinal colic (contraction of intestinal smooth muscle)
and episodes of epistaxis (blood pressure increase).
With the discovery of the chemical structure of
vasopressin (du Vigneaud et al. 1954) and its subsequent synthesis in the laboratory, it also became
possible to synthesise structural analogues of the
Table I. Biological effects of vasopressin
Physiological effect
Antidiuretic activity
Pharmacological effects
Contraction of smooth muscle in intestinal wall and blood
vessels
Contraction of the myometrium
Release of pituitary corticotrophin
Release of factor VIII
Release of tissue plasminogen activator

Pharmacology of Desmopressin

2. Pharmacokinetics

23456789
H2N-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2

1
S

Vasopressin

I
S

23456789
deamino-Cys-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-NH2

1
S

1
S

Desmopressin

Fig. 1. Structural formulae of vasopressin and desmopressin

(I-mercaptopropionic acid-8-D-arginine vasopressin).

peptide. In the 1960s the Czechoslovak Academy

of Sciences produced a large number of such
analogues, aiming at peptides with selective biological effects. These efforts led to the synthesis of
I-deamino-8-D-arginine vasopressin (desmopressin) [Zaoral et al. 1967], which proved to be a highly
selective antidiuretic agent with a ratio between
antidiuretic and vasopressor activities in excess of
2000 : 1 (as compared with 1 : 1 for native vasopressin). Additionally, desmopressin was found to
be metabolically more stable than vasopressin, and
this was reflected in a prolonged duration of action. These qualities suggested that desmopressin
would be an ideal drug for treating patients with
diabetes insipidus without causing side effects. Ferring Pharmaceuticals in Sweden undertook the task
of large-scale production, and desmopressin was
actually registered as a drug in most countries before pharmacokinetic and pharmacodynamic studies had been performed, as previously pointed out
by Pliska & Vilhardt (1980).

0/ Desmopressin

After a single intravenous bolus dose in man,

desmopressin is eliminated from plasma following
a biphasic pattern (Edwards et al. 1973). The initial, fast disappearance rate is thought to represent
a combination of distribution and elimination of
the peptide, whereas the second and slower phase
reflects the rate of elimination of desmopressin from
its distribution compartment. On the basis of published data, Pliska & Vilhardt (1980) calculated the
total clearance in man as ranging between 11.7 and
28.9 ml/min/kg bodyweight. In a more recent study,
Vilhardt et al. (1986) infused normal volunteers
with desmopressin to constant plasma concentrations (fig. 2). The metabolic clearance was calculated as 2.6 ml/min/kg and half-life in plasma as
55 minutes. The apparent volume of distribution
of the peptide was 0.206 L/kg bodyweight. In a
similar study in uraemic patients, Aunsholt et al.
(1986) found a total clearance for desmopressin of
1.4 ml/min/kg and a half-life in plasma of 200
minutes. The decreased rate of elimination in uraemia may be caused by diminished renal excretion.
Burrow et al. (1981) assayed milk from a lac-

:.

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800

B
c
0

~c
u
'c"
0

600

400

ttl

E
(J)

1. Chemistry

0/ Desmopressin

Two structural changes distinguish desmopressin from vasopressin: deamination of cysteine at

the N-terminal of the molecule and substitution of
L-arginine at position 8 with the enantiomer
D-arginine (fig. 1). Desmopressin is, therefore, polarised with a basic amino acid at position 8 and
a lipophilic N-terminal (lack of primary amino
group). The proper chemical name for desmopressin is I-mercaptopropionic acid-8-D-arginine
vasopressin.

ttl

a::

200

0
0

I
2

I
3

Time (hours)
Infusion of desmopressin

Fig. 2. Plasma concentrations of desmopressin during (horizontal bar) and after intravenous infusion of the peptide in
normal volunteers. The infusion was started with a bolus
injection of 51'g followed by 1538 pg/min/kg bodyweight
(n = 8, means SEM) [after Vilhardt et al. 1986, with
permission).

Drug Invest. 2 (Suppl. 5) 1990

tating mother with diabetes insipidus treated with

desmopressin and found only very low concentrations of the peptide.
The prolonged half-life of desmopressin in
plasma may be explained by its greater metabolic
stability compared with native vasopressin (half-life
approximately 5 minutes). Thus, deamination at
position 1 protects the molecule against aminopeptidase activity, and introduction of aD-amino
acid close to the C-terminal peptide bond may diminish the action of carboxypeptidases. However,
little is known about the metabolic degradation of
desmopressin.
Recently, it has been shown that desmopressin
is absorbed from the gastrointestinal tract (fig. 3;
Vilhardt & Bie 1984) and that patients with diabetes insipidus can successfully control their polyuria with desmopressin tablets (Hammer & Vilhardt 1985).

3. Pharmacodynamics of Desmopressin
Since desmopressin is an analogue of the antidiuretic hormone vasopressin, one maya priori assume that it exerts its antidiuretic action via the
same renal pathways as does vasopressin. Indeed,
J ard et al. (1976) and Seif et al. (1978) have shown
that desmopressin, like vasopressin, stimulates
adenylate cyclase in renal tubular cells, leading to
the formation of cyclic adenosine monophosphate.
In addition, vasopressin analogues with selective
antagonistic properties against the antidiuretic effect of vasopressin have been shown to inhibit the
action of desmopressin (Vilhardt, unpublished results). This indicates that desmopressin exerts its
effect via vasopressin receptors (i.e. V2-receptors
as opposed to V I-receptors of smooth muscle tissue). However, conflicting results have been reported as regards the quantitative effect of desmopressin on the adenylate cyclase system. Thus,
Seif et al. (1978) found that desmopressin was more
potent than vasopressin in generating cyclic adenosine monophosphate, whereas Jard et al. (1976)
have reported the opposite.
Despite these discrepancies, it is reasonable to
assume that desmopressin triggers a sequence of

renal cellular events similar to those caused by

vasopressin. Thus, the ligand-receptor complex in
the basolateral cell membrane of the distal tubular
system activates adenylate cyclase, causing formation of cyclic adenosine monophosphate which,
in tum, is believed to activate intracellular protein
kinase (Schlondorff & Franki 1980) followed by a
series of protein phosphorylations, the nature of
which is not fully understood. Ultimately, however, small tubular structures in the cytosol fuse
with the luminal plasma membrane and incorporate protein particles in the form of aggregates into
the membrane (Hays et al. 1985; Wade 1981). The
particles are believed to be penetrated by narrow
channels of sufficient diameter to allow the passage
of water molecules (Carvounis et al. 1979). On
withdrawal of vasopressin, the aggregated particles
rapidly disappear from the cell membrane leaving
it less permeable to water. Prostaglandins may be
involved in these processes, since Kachadorian
(1983) has shown that the prostaglandin synthetase
inhibitor naproxen increases the frequency of
particle incorporation in water transporting
membranes.

4. Indications for Use of Desmopressin

Numerous reports have documented desmopressin as the drug of choice in the treatment of
cranial diabetes insipidus in both adults (Edwards
et al. 1973; Robinson 1976) and children (Aronson
et al. 1973; Becker & Foley 1981). The long lasting
effect of desmopressin (fig. 4) makes it possible for
most patients to control their polyuria with 1 or 2
doses per day. The uterotonic activity of desmopressin is 10 times lower than that of vasopressin
and the drug has been used in pregnant patients
without any untoward effects on mother or fetus
(Burrow et al. 1981; Oravec & Lichardus 1972).
The potent antidiuretic action of desmopressin
is also utilised in the urine concentration test (i.e.
the kidney concentrating test or the desmopressin
test) in patients with suspected renal tubular dysfunction (e.g. pyelonephritis). As an alternative to
the cumbersome 24-hour water deprivation test, a
single dose of desmopressin will produce maxi-

Pharmacology of Desmopressin

800

600

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a;

o~

oe-

~ ~ 400
Q)

<II

"2 ~
::>
_

200

o
200

150

o
160

~
c:

120

Q)

f
~

80

40

It..

40

II)

I~

c~

Desmopressin 20,,9

3
Desmopressin 40,,9

Desmopressin 200,,9

Time (hours)

Fig. 3. Urine osmolality (a), urine volume (b) and free water clearance (e) during 15-minute periods in hydrated human
volunteers following peroral administration of 20, 40 and 200lLg of desmopressin (means SEM, n = 5 for each dose)
[after Vilhardt & Bie 1984, with permission).

mally concentrated urine within 3 to 5 hours

(Aronson & Svenningsen 1974; Curtis & Donovan
1979).
An interesting new indication for desmopressin
is nocturnal enuresis in children and adults (Belmaker & Bleich 1986; Fjellestad-Paulsen et al. 1987;
Pedersen et al. 1985). The rationale for this therapy
is that a single dose of the drug before bedtime will
reduce urine formation over the next 8 to 10 hours,

so that the micturition reflex is not triggered by a

filled bladder. Rittig et al. (1989a,b) claim that
administration of desmopressin to enuretic children and adults may be regarded as substitution
therapy, since they have shown that the normal
nocturnal increase in plasma vasopressin is absent
in some patients with enuresis. Desmopressin could
also be useful in other forms of urinary incontinence and this is under investigation (B. Bengtsson,

Drug Invest. 2 (Suppi. 5) 1990

1000

200

c;
.><

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500 0
.

100

OJ

Ql

0
E

E
:::>
0

I/J

>
Ql
c:

Ql

c:

0
I

Time (hours)

Fig. 4. The effect on (a) urine volume and (b) urine osmolality of an intranasal administration of 20~g of desmopressin
(at arrow) in the form of drops (-) or spray (--) to IO hydrated subjects (means SEM) [after Harris et at. 1987, with
permission].

Ferring Phan'naceuticals, personal communication).

Finally, desmopressin is used as a haemostatic
agent. Doses of desmopressin 10 times higher than
those needed for an antidiuretic effect increase
plasma levels of factor VIII by 300 to 400%, both
in normal subjects (Mannucci et al. 1975; Nilsson
et al. 1979) and in patients with mild or moderate
haemophilia A and von Willebrand's disease (Nilsson et aI. 1982). Haemostasis during bleeding episodes or surgery can be achieved by administration
of desmopressin to these patients (Mannucci et al.
1977; Warrior & Lusher 1983). This eliminates or
reduces both the use of factor VIII concentrates
and the risk of transferring viral agents.
Desmopressin has also been shown to shorten
bleeding time in patients with uraemia (Mannucci
et al. 1983) and to reduce blood loss during openheart surgery, such as bypass operations (Saltzman
et al. 1986). The mechanism of action of desmopressin in these indications remains unclear.

5. Administration of Desmopressin
The most common form of administering
desmopressin is intranasally, either by spray or
drops (fig. 4; Harris et al. 1987) or as injections

(intravenously or subcutaneously). Usual antidiuretic doses are 10 to 40 ILgJkg bodyweight intravenously (Aberg et al. 1979). Peroral doses are
approximately 10 times higher than those given
intranasally.

6. Side Effects of Desmopress;n

Since desmopressin is a powerful antidiuretic
agent, there is a hypothetical risk of water retention
during desmopressin treatment. Fluid retention has,
however, never been reported in patients with diabetes insipidus on long term therapy, but there are
a few reports of water retention in infants after
administration of desmopressin and unlimited access to fluids (unpublished data). Consequently,
fluid intake in infants should be reduced to 50%
for 12 hours after desmopressin intake.
Recently, acute myocardial infarction was reported in a group of patients treated with haemostatic doses of desmopressin during cardiac surgery (Editorial 1989). Mannucci & Lusher (1989),
however, examined the data and raised doubts
about a possible association between desmopressin
and acute myocardial infarction. On a pharmacological basis, such an association seems less likely,
since selectively antidiuretic analogues of vaso-

Pharmacology of Desmopressin

pressin have been shown to increase myocardial

blood perfusion in dogs (Liard 1988).

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Drug Invest. 2 (Suppi. 5) 1990

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Correspondence and reprints: Dr H. Vi/hardt, Department of

Medical Physiology C, Panum Institute, Blegdamsvej 3C, 2200
Copenhagen N, Denmark.