Posterior Pituitary Hormones (Vasopressin and Desmopressin)

Vasopressin or antidiuretic hormone (ADH) is produced in the hypothalamus but released from the posterior pituitary. It acts equally on vasopressin V1 receptors and V2 receptors. V1 receptors in the kidney increase water but not electrolyte absorption within the distal collecting tubules and collecting ducts. V2 receptor stimulation causes arterial vasoconstriction and smooth muscle contraction in the uterus and gut (at high concentrations of ADH only). Synthetic vasopressin is used medically to treat diabetes insipidus or to control variceal bleeding in portal hypertension. Related medications include:

• Desmopressin, an analogue of vasopressin, is more potent and acts selectively on V1 receptors - so has limited vasoconstrictor activity.
• Terlipressin, a vasopressin derivative, used only in specialist settings for the treatment of oesophageal variceal bleeding.
• Demeclocycline is a tetracycline antibiotic with ADH antagonist properties and thought to act by blocking the renal tubular effect of ADH. It is used to treat the syndrome of inappropriate ADH (SIADH) secretion where the syndrome is chronic and causes are not reversible. Other ADH antagonists are in development.

Treatment of pituitary (or "cranial") diabetes insipidus

Dosage of vasopressin or desmopressin is tailored to produce a regular diuresis every 24 hours to avoid water intoxication. Treatment may be required temporarily e.g. following pituitary surgery or long-term.

Diagnosis of cranial versus nephrogenic diabetes insipidus

Following an intranasal, subcutaneous or intramuscular dose of desmopressin, restoration of the ability to concentrate urine after water deprivation confirms a diagnosis of pituitary diabetes insipidus. Failure suggests nephrogenic diabetes insipidus. This test is not suitable for young children. Nephrogenic diabetes insipidus responds to the use of thiazides.

Treatment of primary nocturnal enuresis^1,3

• Desmopressin reduces urine volume and intravesicular pressure and is licensed for the treatment of nocturnal enuresis for those aged between 5 (preferably over 7 - earlier treatment is not usually needed) and 65.
• The risk of hyponatraemia may be greater with nasal preparations than oral; the nasal route has been removed from this indication as a safety precaution.⁴
• Cochrane review evidence shows that desmopressin rapidly reduces the number of wet nights per week experienced by children but there was some evidence that the benefit was not sustained once treatment had finished.⁵ Not all children respond to desmopressin; factors predicting a good response are the child being 8 or over and fewer initial wet nights (<3/4). Relapse rates are high (50-95%).⁶
• When compared to imipramine, it had a similar efficacy but was more expensive and had fewer side-effects.⁵
• Usually, desmopressin is used as a short-term treatment to allow a child to recover confidence (sometimes when family stress and conflict has developed around the enuresis) or as a temporary measure to help the child for nights spent away from home.
• Drug treatments may also be a helpful adjunct to alarm treatment. Alarms are more effective than desmopressin in producing a sustained response.⁷

Nocturia associated with multiple sclerosis

Desmopressin may be used where other treatments have failed in adults under 65 years. It has also been used to treat nocturia associated with autonomic dysfunction and Parkinson's disease.⁸

Treatment of mild to moderate haemophilia

Desmopressin given by injection boosts factor VIII concentration and is used in mild to moderate haemophilia and von Willebrand syndrome prior to surgery or following trauma. It is also used diagnostically to test fibrinolytic response.

Research use in critical care for the treatment of septic shock and in cardiopulmonary resuscitation (CPR)

Vasopressin is of interest in critical care because of its pressor action. Vasopressin is not recommended as a first-line agent in the treatment of septic shock but may have a role as salvage therapy.⁹ Its use in cardiac arrest is controversial - some reports suggest benefit when combined with epinephrine¹⁰ but it is not yet recommended in Advanced Life Support (ALS) guidelines.

Treatment of bleeding oesophageal varices

Terlipressin and vasopressin infusion can be given as adjunctive treatment in this context, usually prior to definitive treatment and with variable results. Cochrane review¹¹ suggests a 34% relative risk reduction in mortality with terlipressin in contrast to other vasoactive agents (octreotide and somatostatin) for which there was much more limited evidence. Endoscopic intervention remains the usual first-line treatment.

• Care is needed with any conditions that may be aggravated by water retention (e.g. heart failure, hypertension, raised intracranial pressure, renal failure) The elderly are particularly vulnerable.
• Avoid in cardiac insufficiency and conditions treated with diuretics.
• Particular caution should be used with these drugs in patients with cystic fibrosis, due to altered salt and water homeostasis.
• Due to vasoconstriction, these drugs should be avoided in patients with coronary artery disease and other vascular disease.
• In renal impairment, these drugs will be less effective and excreted more slowly.
• Avoid in pregnancy due to oxytocic effect in the third trimester.

Usually vasopressin and desmopressin are well-tolerated. Most common side-effects are abdominal cramp, nausea and vomiting. More serious side-effects include:

• Hyponatraemia and risk of associated convulsions - patients must be advised to avoid fluid overload. Hyponatraemia secondary to the use of desmopressin in children is more common in younger children and particularly at the outset of treatment.¹²

  Avoiding hyponatraemic convulsions (CSM advice): Avoid fluid overload, including swallowing lots of water whilst swimming in the 8 hours after taking the drug. Stop taking desmopressin during illness with vomiting and diarrhoea. Keep to the recommended starting doses Avoid concomitant use of drugs which increase vasopressin secretion (e.g. tricyclics, antidepressants, SSRIs, opioids, clofibrate, chlorpropamide, cyclophosphamide, and vincristine)

• Hypersensitivity reactions and anaphylaxis.
• Emotional disturbance, including cases of increased aggression, has also been reported in children.
• Epistaxis, nasal congestion and ulceration with nasal spray delivery.
• Coronary artery vasoconstriction and cardiac ischaemia - risk highest with vasopressin.
• Peripheral ischaemia and gangrene again due to pressor effects.

Chlorpropamide and carbamazepine potentiate the effect of vasopressin and are sometimes used in cases of partial or mild pituitary diabetes insipidus.

• These drugs require specialist initiation and titration of treatment. Primary care may be involved in prescribing for those under specialist supervision or for continuing treatment once stability is achieved.
• Desmopressin is given by mouth or intranasally or by injection in the unconscious patient. Vasopressin is available nasally or by injection. Patients or their parents/carers must learn how to administer the drugs correctly. Children should be supervised in their use of the nasal spray to prevent accidental overdose.
• Where desmopressin is to be used for nocturnal enuresis, establish normal urine concentrating ability prior to treatment.
• Stick to recommended starting doses.
• Food may reduce the absorption of desmopressin. If this is occurring, give the oral dose at least 1.5 hours after a meal or replace with the intranasal preparation.
• Desmopressin should not be used more than once in 24 hours.
• Monitoring the patient's intravascular volume clinically and with serum sodium can be helpful as optimal dosing is established and when the patient is unwell in a way that may alter salt and water balance (e.g. diarrhoea and vomiting, fever).
• Desmopressin use should not be used for longer than 3 months without a review and stopping for at least a week to assess the need for continuing treatment.
• Gradual discontinuation may be tried when stopping desmopressin for nocturnal enuresis.

• Desmopressin is not a "cure" for nocturnal enuresis - potential benefits and risks must be explained clearly to all concerned before deciding to undertake treatment.
• Limit fluid intake from 1 hour before to 8 hours following dose - children should not drink more than a mug of fluid on any night that desmopressin is given. Avoid caffeinated drinks in particular.
• Avoid ingesting water when swimming.
• Stop desmopressin during periods of diarrhoea and vomiting.
• Seek assessment if headache, nausea or vomiting develops - although these prodromal symptoms of hyponatraemia are common (63% in one study).¹²