Chemical formula: C₄₆H₆₄N₁₄O₁₂S₂ Molecular mass: 1,069.22 g/mol
Desmopressin is a structural analogue of vasopressin in which the antidiuretic activity has been enhanced by the order of 10, while the vasopressor effect has been reduced by the order of 1500. The clinical advantage of this highly changed ratio of antidiuretic to vasopressor effect is that clinically active antidiuretic doses are far below the threshold for a vasopressor effect.
Desmopressin administration causes a transient increase in all components of the Factor VIII complex (Factor VIII coagulant activity, Factor VIII related antigen, and ristocetin cofactor) and in plasminogen activator. Either directly or indirectly, desmopressin causes these factors to be released very rapidly from their endothelial cell storage sites. In addition, desmopressin may have a direct effect on the vessel wall, with increased platelet spreading and adhesion at injury sites.
Desmopressin is a synthetic analogue of the natural human neurohypophyseal hormone L-arginine vasopressin from which it differs chemically in that the amino group of the cysteine in position 1 is removed and L-arginine has been substituted by the stereoisomeric D-arginine. As a consequence of these changes, the vasopressor action of the molecule is largely lost, whereas the antidiuretic action is enhanced and prolonged many times.
Desmopressin causes a dose-dependent increase in plasma Factor VIII (antihemophilic factor), plasminogen activator, and, to a smaller degree, Factor VIII-related antigen and ristocetin cofactor activities. The mechanism by which desmopressin lowers bleeding time remains speculative.
Structural modifications of vasopressin present in desmopressin result in reduced smooth muscle contracting and vasopressor properties compared with vasopressin and lypressin. Initial studies of intranasal desmopressin at a subtherapeutic dose of 20 mcg resulted in no effect on blood pressure or pulse rate, but mean arterial pressure increases as much as 15 mm Hg were observed with doses of 40 mcg or more. In the therapeutic dose range, cardiovascular changes in normal, healthy volunteers were not considered to be clinically meaningful, but 27 of 32 volunteers had notable changes in systolic and/or diastolic blood pressure, and 8 had notable changes in pulse. Some volunteers experienced increases in diastolic blood pressure of greater than or equal to 20%; one volunteer experienced an increase in systolic blood pressure of 35% (40 mm Hg); and others experienced decreases in diastolic blood pressure, in some cases with compensatory tachycardia.
Desmopressin has been shown to interact with renal (V2) vasopressin receptors which mediate its antidiuretic effect on renal tubes. The extrarenal effects of Desmopressin in normal persons, which include stimulation of the release of Factor VIII coagulant and von Willebrand factory (ristocetin cofactor) and a decrease in blood pressure, may be mediated by interaction with receptors in other tissues which are similar to the renal V2 receptors.
In a modelling study in which intravenous desmopressin was infused over two hours in healthy adult male subjects, the EC50 value was calculated as 1.7pg/ml based on urinary osmolality and 2.4pg/ml based on urinary volume.
Desmopressin has not been reported to stimulate uterine contractions.
Following IV infusion of desmopressin, the increase in plasma Factor VIII activity occurs within 15-30 minutes and peaks between 90 minutes and 3 hours after administration; the increase in Factor VIII activity is dose dependent, with a 300-400% maximum increase reportedly occurring after IV infusion of 0.4 mcg/kg dose. Plasma Factor VIII-related antigen activity has also been reported to peak within 3 hours after IV infusion of the drug.
In vitro, in human liver microsome preparations, it has been shown that no significant amount of desmopressin is metabolised in the liver and thus human liver metabolism in vivo is not likely to occur.
It is unlikely that desmopressin will interact with drugs affecting hepatic metabolism, since desmopressin has been shown not to undergo significant liver metabolism in in vitro studies with human microsomes. However, formal in vivo interaction studies have not been performed.
Subcutaneous administration of desmopressin showed the same plasma half-life, from 3.2 to 3.6 hours, as intravenous desmopressin. The plasma profile indicates that the elimination of desmopressin from plasma follow first order kinetics. There is no significant difference in AUC between subcutaneous and intravenous desmopressin. A similar study in 14 hemophiliac patients also showed that the subcutaneous route of administration is bioequivalent to the intravenous route.
After intranasal administration of desmopressin, the maximum plasma concentration is attained after about 50 minutes.
The plasma half-life is 2-3 hours. Desmopressin is excreted via the kidneys.
After intranasal administration, the systemic bioavailability of desmopressin is approximately 10% of the dose administered.
The antidiuretic effect already begins after 15 minutes. Depending on the dose, it is sustained for 6-24 hours.
The apparent distribution volume of desmopressin is relatively small: about 0,2 l/kg bodyweight, which suggests that the peptide is not distributed in the intracellular compartment. It has been shown that desmopressin does not pass the blood-brain-barrier.
The absolute bioavailability of orally administered desmopressin varies between 0.08% and 0.16%. Mean maximum plasma concentration is reached within 2 hours. The distribution volume is 0.2–0.32 l/kg. Desmopressin does not cross the blood-brain barrier. The oral terminal half-life varies between 2.0 and 3.11 hours.
After oral administration of a single dose of 2 × 200 micrograms desmopressin tablets to healthy subjects, 25% of the subjects had plasma concentrations of desmopressin above 1pg/ml up to at least 14 hours post dosing.
In in vitro studies in human liver microsome preparations, it has been shown that no significant amount of desmopressin is metabolised, and thus human liver metabolism in vivo is not likely to occur. Consequently it is also unlikely that desmopressin will interact with drugs affecting hepatic metabolism. However, formal in vivo interaction studies have not been performed.
About 65% of the amount of desmopressin absorbed after oral administration could be recovered in the urine within 24 hours.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and toxicity to reproduction.
Impairment of renal function, with a rise in serum creatinine as well as hyaline degeneration of tubule epithelia, has been demonstrated in rats at a daily dose of 47.4 micrograms/kg body weight, i.e. at exposures considered sufficiently in excess of the maximum human exposure. The alterations were reversible after termination of desmopressin treatment.
Investigations on the carcinogenic properties are not available.
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