Fludrocortisone

Autonomic neuropathy is a common complication of diabetes with up to 40% affected. It is often asymptomatic, but one of the most troublesome and under-appreciated features is postural hypotension. This is a consequence of cardiac and peripheral vasomotor nerve damage, leading to an inability to increase the heart rate and vasoconstrict peripheral blood vessels when changing posture. Symptoms of postural hypotension include dizziness, weakness, blurred vision, tiredness, and loss of consciousness. These are usually more marked on waking or in the early morning. The diagnosis can be made when there is a drop in the systolic blood pressure of at least 20mmHg when checked at least 1 minute after standing, and there are usually abnormalities on cardiovascular reflex testing using electrocardiography. Once symptoms arise, the autonomic damage is likely to be irreversible and the prognosis is poor due to concurrent complications such as cardiac or renal disease. There is little in the way of causal treatment. Supportive measures such as compression stockings and giving patients advice on changing position can be used with varying degrees of success. Pharmacological treatment with fludrocortisone is one option for symptom control. Figure 1 outlines the pharmacological action of fludrocortisone. It is a mineralocorticoid belonging to the class of compounds known as 21-hydroxysteroids. It is highly potent with a half-life of 3.5 hours and is metabolised in the liver. Besides anti-inflammatory and anti-allergenic properties, its mechanism of action is on the distal renal tubules promoting sodium reabsorption and subsequent water retention. Fludrocortisone works by binding to the mineralocorticoid receptor of the cell surface and stimulating sodium reabsorption into the targeted cells in two ways. Firstly, in the early phase, it activates pre-existing epithelial sodium pumps and sodium channels within 20–60 minutes. In the later phase, occurring up to 2 hours later, it increases the cells’ overall transport ability by activating further Na+ transport machinery production. Sodium is then pumped out of the basolateral aspect of the cell into the circulation by Na+/K+ ATPase pumps. This later phase is mediated by the intracellular (or classical) mineralocorticoid receptor, which is a complex that forms part of the steroid hormone receptor family of ligand-dependent transcription factors. Once bound to the mineralocorticoid, the complex undergoes conformational change and ultimately results in transcription and translation of a large number of proteins. These proteins induce expression of Na+ channels, K+ channels, sodium/chloride co-transporter and the Na+/K+ ATPase pumps on the epithelial cell surfaces of the distal renal tubules. The result is that the renal collecting duct becomes an important regulatory site for sodium and water homeostasis and blood pressure control. The summary of product characteristics (SPC) for fludrocortisone states that it is a potent mineralocorticoid and patients on treatment should carry a steroid card. The SPC recommends gradually reducing the dose over weeks or months on withdrawal of fludrocortisone after prolonged therapy. Although long-term safety and efficacy data are lacking there are well-known, predictable side effects of steroids. These include weight gain, oedema, headache, hypertension, skin changes and predisposition to infection. The severity of the side effects relates directly to the dosage, frequency and length of treatment and may be more serious in the elderly. Unfortunately, the trials that have used fludrocortisone for postural hypotension have been short trials with small numbers of subjects. Safety has not been adequately assessed and data on long-term efficacy and safety are lacking. There are two randomised controlled trials using fludrocortisone in patients with symptomatic postural hypotension that was associated with Parkinson's disease and with chronic fatigue syndrome. In 17 patients with Parkinson's disease there was an improvement in a composite autonomic symptom score after three weeks of fludrocortisone 100μg, with no significant effect on blood pressure.1 In 100 patients with chronic fatigue randomised to nine weeks of placebo versus fludrocortisone 100μg the latter was no better than placebo on a global wellness score or measures of blood pressure.2 There has been one small, short trial that assessed the use of fludrocortisone in patients with diabetes, autonomic neuropathy and symptomatic postural hypotension.3 This was a double-blind, cross-over randomised control trial in six patients. Patients were given fludrocortisone 100μg or placebo twice daily for three weeks, followed by a three-week washout period, then crossover to three weeks of the alternative treatment. The results showed a statistically significant improvement in both systolic (154[±29]mmHg versus 110[±16]mmHg; p<0.005) and diastolic blood pressure (88[±11]mmHg versus 76[±4]mmHg; p<0.05) on both tilt table testing and with supine blood pressures (180[±26]mmHg versus 149[±21]mmHg; p<0.05) compared to placebo. In four patients there was significant improvement in symptoms. The other two patients had low albumin and developed ankle oedema. All patients had an increase in plasma blood volume but no change in serum or plasma osmolalities. Following this trial, the same group followed up 14 patients with diabetes and postural hypotension who were using fludrocortisone for 12 months with similar effective results.4 It was concluded that fludrocortisone 100–300μg was effective in the treatment of postural hypotension secondary to diabetic autonomic neuropathy. Postural hypotension is an under-appreciated and often frustrating and debilitating symptom of autonomic neuropathy as a complication of diabetes. A NICE evidence summary on the use of fludrocortisone for postural hypotension from October 2013 states that any pharmacological treatment for postural hypotension needs to be given ‘off licence’ as no drug used in the UK currently has marketing authorisation for the treatment of postural hypotension. The studies described above are summarised by NICE to support decision making for an individual patient, but the summary is not NICE guidance. Although the trials were small, short and underpowered and the long-term efficacy is uncertain, the results in two small trials in patients with diabetes demonstrate that fludrocortisone may have a role to play in orthostatic hypotension secondary to diabetic autonomic neuropathy for up to 12 months; fludrocortisone will likely remain the recommended first choice for the immediate treatment for the symptoms of postural hypotension in this patient population. References are available online at www.practicaldiabetes.com.