Continuing Education Activity

Desmopressin is a drug that acts on the vasopressin receptors of the body. It has many relevant clinical uses, ranging from nocturnal enuresis to hemophilia. While this drug is relatively safe to use, there are certain side effects to be kept in mind for patients receiving the drug, as well as specific contraindications that limit the population that can receive desmopressin. This activity reviews the indications, mechanism of action, contraindications, and adverse effects. It will also explore the proper monitoring of patients on desmopressin and the role of the inter-professional team required to enhance the outcomes for the patients taking the drug.

Objectives:

• Identify the indications to use desmopressin in a patient.
• Describe the mechanism of action of desmopressin.
• Review the potential adverse effects of desmopressin.
• Summarize the role of an integrated inter-professional team involved in the treatment of the patients receiving desmopressin.

Indications

Desmopressin (1-deamino-8-D-arginine vasopressin) is a synthetic analog of vasopressin, aka antidiuretic hormone created in 1977 used in the treatment of a wide variety of medical conditions to include nocturnal polyuria, hemophilia A, diabetes insipidus, Willebrand disease, uremic bleeding, as well as many off label uses such as an adjunct with hypertonic saline to prevent rapid sodium correction, intracranial hemorrhage associated with varying antiplatelet agents, and trauma resuscitation with active hemorrhage.[1][2][3]

Nocturnal polyuria is a commonly encountered condition seen almost exclusively in the pediatric population, which is responsive to both oral and intranasal desmopressin. Desmopressin is also available to adults who awaken more than two times a night to void.[4]

Hemophilia A is an X-linked autosomal recessive disorder characterized by the deficiency or absence of the clotting factor VIII.[5] Factor VIII is an integral component of the intrinsic coagulation pathway, which, when combined with von Willebrand factor, produces the active factor VIIIA, the cofactor responsible for transforming factor X to factor Xa. Factor Xa activates IIa (thrombin) to enable fibrin formation, all of which are integral to the coagulation cascade.[1] As such, a deficiency in factor VIII results in recurrent bleeding, particularly following surgical procedures or extractions.[5] Patients with hemophilia A are also at increased risk of major bleeding secondary to minor injuries, such as hemarthrosis and immediate and/or delayed bleeding following trauma.[5] Desmopressin in the intranasal or intravenous form has FDA approval for the use in mild to moderate cases of Hemophilia A, substituted with Factor VIII. 

Diabetes insipidus (DI) classically presents with polyuria and polydipsia and can be secondary to multiple other conditions.[6] The two primary types of diabetes inspidus include nephrogenic and central. Nephrogenic diabetes insipidus indicates the inability of the kidneys to respond to antidiuretic hormone or can arise secondary to long-term lithium use or overdose, as well as any multitude of disorders that affect the inherent ability of the kidneys to function optimally.[7][8] Central diabetes insipidus occurs secondary to the inability of the hypothalamus to create ADH and can occur as a result of central neurologic system or head trauma, CNS tumors such as craniopharyngioma, or germinoma, or destruction of ADH by placental enzymes vasopressinase.[9][10][11] In both central and nephrogenic diabetes insipidus, the urine cannot be concentrated optimally with water deprivation, and there is a persistent and continuous excretion of hypotonic urine. Desmopressin administration can be utilized to distinguish between central vs. nephrogenic diabetes insipidus, with a positive response noted in central diabetes insipidus, meaning the kidneys respond appropriately to desmopressin with the expected concentration of the urine and increased reabsorption of fluids, resulting in eutonic urine. 

Uremic platelet dysfunction encompasses multiple pathways and impairments involving uremia, ultimately resulting in platelet dysfunction. While still largely undefined, the most commonly accepted pathogenesis involves platelet dysfunction secondary to impaired platelet adhesiveness and decreased platelet aggregation, as well as abnormal platelet endothelial interaction. Factors that actively contribute to platelet dysfunction in uremic patients include uremic toxins, anemia, and nitric oxide production. 

Uremic platelet dysfunction occurs for several reasons, including circulating uremic toxins, platelet aggregation inhibition by increased nitric oxide production, and anemia resulting in turbulent rather than a laminar flow of blood products.[12] Desmopressin given intravenously has been shown to improve platelet function within 1 hour of administration.[13]

Von Willebrand disease results from a deficiency in von Willebrand factor. This factor is essential in forming the initial platelet plug as a response to subendothelial tissue exposure.[1] In increasing order of severity, the different types of the disease are Type 1, Type 2B and 2M, and type 3. Indications for desmopressin include the treatment of types 1, 2B, and 2M. It is also most effective in treating diseases caused by the variants of Arg1597Gln, Met740Ile, and Tyr1584Cys.[14] Desmopressin has also been found, in observed cases, to decrease the risk of bleeding complications in pregnant patients suffering from a mild to moderate form of the disease with a von Willebrand factor concentration of less than or equal to 20 IU/dL.[15]

In a limited number of studies of patients with subarachnoid hemorrhage, some have demonstrated enough evidence to consider utilizing a single intravenous dose of desmopressin in patients with intracranial hemorrhage pending neurosurgical intervention.[16] 

In a select number of patients suffering from severe hyponatremia with a serum sodium less than 120 mEq/L, studies have demonstrated benefit when utilizing intravenous 3 percent saline while simultaneously initiating desmopressin to prevent rapid correction; decreasing the risk of developing osmotic demyelination syndrome.[17]

Desmopressin has also been utilized in trauma resuscitation and post-surgically to receive hemostasis. Several animal studies have demonstrated that desmopressin is useful in treating severe coagulopathy in injured or post-surgical patients.[16] 

Mechanism of Action

Desmopressin is a selective vasopressin V2 receptor agonist present throughout the collecting ducts and distal convoluted tubules of the kidneys.[1][18] The V2 receptor is a Gs-protein coupled receptor, which, when activated, results in a signaling cascade of adenyl-cyclase, prompting an increase in cyclic adenosine monophosphate (cAMP) in the renal tubule cells, ultimately resulting in increased water permeability. This activity leads to a decrease in urine volume and an increase in urine osmolality. 

The signaling cascade resulting in the production of cyclic adenosine monophosphate also induces exocytosis of von Willebrand factor and factor VIII from its storage sites, as well as the Weibel-Palade bodies and the alpha granules of platelets.[1] Von Willebrand factor functions as the first step in thrombogenesis, acting as the bridging factor of the Gp1b factor on platelets to the subendothelial collagen following tissue injury.[1] By utilizing synthetic ADH analogs, such as desmopressin, the clotting cascade is facilitated and can result in hemostasis.[19]

Administration

Desmopressin can be administered intravenously, as a subcutaneous injection, as an intranasal spray, and, most recently, as a dissolvable sublingual strip. The tablet form has been discontinued in many countries in favor of the intranasal and sublingual forms due to the latter's superior bioavailability.[7] The administration of intravenous and subcutaneous dose forms of the drug are predominantly in the hospital setting. Dosing for both is 0.3 micrograms/kg. Peak blood concentration after intravenous administration occurs within 30 to 60 minutes and after subcutaneous administration within 60 to 90 minutes.[1]

The intranasal form of vasopressin is frequently a choice when administration occurs at home.[20] Each spray typically dispenses 150 micrograms.[1] The intranasal dosage is directly proportional to the patient's weight, with patients weighing less than 50 kg prescribed one spray, or 150 micrograms, and patients over 50 kg prescribed 2 sprays, or 300 micrograms, every 12 to 24 hours. This form of the drug reaches peak levels in 60 to 90 minutes.[1]

Sublingual desmopressin, also known as desmopressin lyophilisate, is administered a sublingual melt tablet at a dosage of 120 micrograms.[21] It is generally used in the pediatric population due to the ease of administration and the increased bioavailability.

Adverse Effects

The major adverse effect of desmopressin for which to monitor is hyponatremia. As desmopressin increases the urine concentration, it can also lead to systemic hyponatremia with physiology similar to the syndrome of inappropriate antidiuretic hormone.[22] In certain instances, the hyponatremia caused by this drug can precipitate seizures. The minor adverse effects that may affect individual patients are headaches, tachycardia, and facial flushing. There have been certain instances where patients receiving desmopressin have suffered from strokes or myocardial infarctions. However, these cases were rare and did not establish with certainty that desmopressin exerted a direct influence in these cases.[1]

Contraindications

Hyponatremia is an absolute contraindication to the administration of desmopressin, except for symptomatic hyponatremia warranting aggressive management with the potential for osmotic demyelinating syndrome. Desmopressin acts primarily in the nephron; this drug is contraindicated in patients with renal impairment.[22] Also, renal function decreases with age; therefore, care is necessary when prescribing this drug in the older population. This drug should also be avoided in younger patients, especially those under the age of 2, as it is difficult to restrict water and fluids in such patients.[1] Additionally, this drug is ineffective in patients suffering from type 3 von Willebrand disease; therefore, these patients should not receive the drug.[1] Finally, patients suffering from thrombocytopenic purpura should not receive desmopressin, as it can precipitate a thrombotic event.[1] Lastly, desmopressin is contraindicated in patients with known hypersensitivity to desmopressin acetate.

Monitoring

Desmopressin is generally well-tolerated in most patients. There are a few instances where patients require monitoring for adverse effects of the drug. Patients receiving desmopressin need monitoring for the occurrence of hyponatremia.[23] Symptoms of hyponatremia include nausea, confusion, or altered mental status.[24] As patients age, they should also be continually monitored for declining renal function, as the therapeutic index and clearance of the drug will change according to the renal function. 

Toxicity

There is no known antidote to an overdose of desmopressin. The most worrisome complication to result from an overdose is water intoxication. This condition would result in a delayed loss of consciousness and seizures in some instances. Patients require immediate admission to the intensive care unit to be monitored and have electrolyte correction.[25]

Enhancing Healthcare Team Outcomes

Desmopressin is a relatively safe drug for use, but it still requires the efforts of an interprofessional healthcare team for optimal therapeutic success. This team will include clinicians, specialists, mid-level practitioners, nurses, and pharmacists, coordinating their activities and sharing information to achieve the best patient outcomes. [Level 5] 

Patients receiving desmopressin to treat hemophilia A or von Willebrand disease can remain at risk of bleeding. As such, these patients require an integrated and cohesive team of specialists consisting of the primary care physician, hematologist, and in some instances, a gynecologist and geneticist. The primary care physician must ensure that the patients are regularly following up with a hematologist or a hemophilia treatment center. In cases of pregnancy, a woman can receive genetic counseling either before becoming pregnant or later on during the pregnancy.[5] Parents with children suffering from these disorders must understand the complications of the disease and the proper administration of the medication in the case of an emergency.