Desmopressin (DDAVP)

aka. 1-desamino-8-D-arginine vasopressin or 1-deamino-8-D-arginine vasopressin (DDAVP)

CLASS

• synthetic vasopressin analogue

INDICATIONS

1. Central diabetes insipidus (DI)
2. Mild-moderate Type A haemophilia
3. von Willebrand disease (Type 1)

ADMINISTRATION / DOSING (Adult)

• intravenous (IV) / subcutaneous (SC) / intramuscular (IM) / oral (PO) / intranasal (IN) / sublingual (SL)
• Diabetes Insipidus
  • SC/IM/IV: 1-4 microgs daily in 1-2 doses (dose at Institution 1 is 0.5 microgs IV)
  • IN: 10-40 microgs, or 40 mircogs divided into 2-3 doses
  • SL: 60-120 microgs TDS (range 120-720 microgs daily)
  • PO: Initially 0.05mg BD (maintenance usually 0.1-0.8 mg/day in divided doses)
  • Of note: ADH activity of 4 microgs IV desmopressin is equivalent to 16 IU of vasopressin
• Haemophilia A (mild) / von Willebrand disease Type 1 (mild-moderate) / Uraemia-related bleeding disorder / Acquired or inherited platelet disorder
  • IV infusion: 0.3 microgs/kg diluted in 50mL 0.9% saline administered over 15-30 min
    • Administer 30 min prior to procedure
  • IN: <50kg 150microgs one nostril / >50kg 150 microgs each nostril
    • Initial response seen after 30 min
• Reversal of antiplatelet agent in intracerebral haemorrhage (ICH)
  • IV infusion: 0.4 microgs/kg diluted in 50mL 0.9% saline administered over 15-30 min (bolus administration may precipitate hypotension)

MECHANISM OF ACTION

• Predominantly acts via V2 receptors (G_s-protein-coupled receptors adenylyl cyclase / cAMP):
  • Basolateral membrane of the collecting duct in the kidneys –> insertion of aquaporin (AQP-2) water channels into the apical membrane –> increases water reabsorption
  • Vascular endothelium –> releases von Willebrand factor and factor VIII –> Reduces bleeding time
  • Vascular smooth muscle –> vasodilation (minor, at standard doses)
• Compared with vasopressin which has an ADH:vasopressor action ratio of 1, desmopressin has a ratio of 2000-4000:1
• Lesser actions:
  • V1 receptors: Vascular smooth muscle of systemic, splanchnic, renal and coronary circulations –> potent vasoconstriction. Also on platelets –> enhances intracellular Ca²⁺ facilitating thrombosis
  • V3 receptors: Pituitary –> ACTH release –> increased cortisol secretion
  • OTR (Oxytocin receptor subtypes): Mammary glands, myometrium, endometrium –> uterine contraction and milk ejection

PHARMACEUTICS

• Stored at 2-8^oC IN / IV, room temperature for PO and SL
• White, fluffy powder, soluble in water and glacial acetic acid
• Excipients: sodium chloride, hydrochloric acid and water for injections
• IV form comes in 4 microgs/mL or 15 microgs/mL
• pH: IN form 5.5 / IV form 4

PHARMACOKINETICS

• Absorption
  • Bioavailability: SC 85% / IN 3.3-4.1% / PO 0.16%
  • T_MAX: IN 15-45 min / PO 50-55 min
• Distribution
  • Vd 26.5 litres
  • Distribution half-life: ~8 min
• Metabolism
  • Minimally hepatically metabolised
• Elimination
  • Renal excretion 52% unchanged
  • Similar to ADH, yet slower
  • 7.6 L/h clearance
  • T_1/2: IN 3-4 hours / IV 1.5-3 hours

PHARMACODYNAMICS

• CNS:
  • Increase ACTH release from pituitary –> Cortisol release
  • Headache, seizures
• CVS
  • Low doses causes vasodilation, high doses may cause vasoconstriction
  • Facial flushing
• RESP
  • Rhinitis, nosebleed
• GIT
  • Nausea, abdominal cramps
• GUT
  • Slight oxytocic effect –> uterine contraction
  • Water retention via ADH action in renal tubules–> can lead to intoxication with polydipsia and use in heart failure
• HAEM
  • Induces release of vWF and factor VIII from endothelial cells –> reduced bleeding time
  • Thought to also: increase density of glycoprotein receptors on the platelet, enhances ability to form procoagulant platelets and increases platelet-dependant thrombin generation by enhancing Na⁺ and Ca²⁺
  • May induce platelet aggregation in von Willebrand disease Type IIb
• OTHER
  • Hyponatraemia

CONTRAINDICATIONS

• Type IIb von Willebrand’s disease
  • Platelet activation may be induced
• SIADH
• Hyponatraemia
• Heart failure
• Polydipsia
• Renal failure when CrCl <50mL/min

VASOPRESSIN AND ITS ANALOGUES

• Argipressin (synthetic vasopressin)
  • Use: Septic shock / cardiac arrest / DI
  • ADH-to-pressor ratio of 1
  • Duration of action: ~20 min
• Desmopressin
  • Use: DI / von Willebrand disease / Type A haemophilia
  • Reduceed vasopressor activity, enhanced ADH-pressor potency, and prolonged duration of action
  • ADH-to-pressor ratio of 2000-4000:1, duration of action 2-6 hours (Secondary to resistance against enzymatic cleavage and delayed absorption from the nasal mucosa
• Terlipressin
  • Use: Hepatorenal syndrome / variceal haemorrhage / Septic shock
  • Quite selective for splanchnic circulation vasoconstriction
  • Duration of action 2-10 hours

References and links

LITFL

• CCC – Central diabetes insipidus
• CCC – Vasopressin
• CCC – Terlipressin

References

• Australian Injectable Drugs Handbook, 8th Edition. (2022). Retrieved 27 August 2022, from https://aidh.hcn.com.au/
• Australian Medicines Handbook. (2022). Retrieved 27 August 2022, from https://amhonline.amh.net.au/       
• Colucci G, Stutz M, Rochat S, Conte T, Pavicic M, Reusser M, Giabbani E, Huynh A, Thürlemann C, Keller P, Alberio L. The effect of desmopressin on platelet function: a selective enhancement of procoagulant COAT platelets in patients with primary platelet function defects. Blood. 2014 Mar 20;123(12):1905-16. doi: 10.1182/blood-2013-04-497123. Epub 2014 Jan 17. PMID: 24443440. [Full free text]
• Holmes CL, Landry DW, Granton JT. Science review: Vasopressin and the cardiovascular system part 1–receptor physiology. Crit Care. 2003 Dec;7(6):427-34. doi: 10.1186/cc2337. Epub 2003 Jun 26. PMID: 14624682; PMCID: PMC374366. [Full free text]
• IBM Micromedex. (2022). Retrieved 27 August 2022, from https://www.micromedexsolutions.com
• Rang, H., Dale, M., Ritter, J., & Flower, R. (2007). Rang and Dale’s pharmacology (6th ed., pp. 425-426). Edinburgh: Churchill Livingstone Elsevier.

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