Florinef - Fludrocortisone Acetate – Heightened and Longer-Lasting Electrolyte Balance

Fludrocortisone Acetate (also known by the brand name Florinef, sometimes called 9a-FlouoCortisol) is a synthetic form of corticosteroid hormone, a natural substance that is made by the body.

Fludrocortisone Acetate is used, along with other medications, as a replacement therapy if your own adrenal glands are not producing sufficient amounts of the corticosteroid hormones Cortisol and Aldosterone.

In order to understand the importance of Fludrocortisone Acetate, it’s useful to first look in more detail at the adrenal glands and the corticosteroids that they produce, and also associated adrenal gland problems.

The adrenal glands and the production of corticosteroids

Your two adrenal glands are star shaped endocrine glands that sit on top of your kidneys. They form part of the endocrine system, which works with the nervous system and the immune system to help the body cope with different events and stresses. Their role is to produce a number of different hormones that are essential to life.

The central part of the adrenal gland (the adrenal medulla) is responsible for the production of adrenaline. The outer part (the adrenal cortex) produces a class of steroid hormones known as corticosteroids. The corticosteroids are involved in a wide range of physiological systems such as the regulation of inflammation and immune and stress responses. They are important for salt and water balance and for keeping blood pressure normal. They are also needed to break down carbohydrates in your diet.

Corticosteroids are divided into two groups, Glucocorticoids and Mineralocorticoids.

Glucocorticoids and Cortisol

Glucocorticoids such as Cortisol work to control carbohydrate, fat and protein metabolism. They also possess a number of other mechanisms such as acting in an anti-inflammatory capacity, which they do by preventing phospholipid release and decreasing the action of eosinophils (a type of white blood cell involved in the immune system).

Cortisol has a number of vital roles in the body and is essential to many bodily functions. In particular, Cortisol:

  • Plays an important part in the regulation of blood sugar levels by working closely with insulin and by converting proteins into glucose when blood sugar levels are low
  • Assists in the maintenance of a constant blood pressure
  • Helps to reduce inflammation (see above) and supports the immune system
  • Works in conjunction with adrenaline to help the body manage physical and emotional stress

It’s important that Cortisol levels are kept in check - just as too little Cortisol is not good for you; too much Cortisol over sustained periods of time is known to be very bad for your health. The body monitors Cortisol levels via the pituitary gland - the master gland of the endocrine system - which in turn is governed by another brain structure called the hypothalamus.

The pituitary gland secretes a stimulating hormone called ACTH (adrenocorticotropin). ACTH encourages Cortisol production. Therefore, when the body requires more Cortisol, greater amounts of ACTH are secreted to encourage more Cortisol production. However, if the body needs to slow down Cortisol production, ACTH secretion is reduced.

Mineralocorticoids and Aldosterone

Mineralocorticoids such as Aldosterone control electrolyte and water levels, mainly by promoting sodium retention in the kidneys.

Aldosterone regulates electrolytes such as potassium and sodium in the blood. Electrolytes are substances that conduct electricity in the body. Regulating their blood levels is vital for the proper maintenance of heart function and blood pressure.

Potassium is crucial to heart function. Having too much potassium in the blood is called hyperkalemia; having too little is known as hypokalemia. Both of these conditions can affect the way in which your heart functions and can result in irregular heart rhythms that can be life threatening if not treated properly.

If your kidneys excrete too much sodium, a lot of body fluid is also lost. This loss of fluid reduces blood volume which in turn leads to a drop in blood pressure. Aldosterone increases the reabsorbtion of sodium and water and the release of potassium in the kidneys. This increases blood volume and, therefore, increases blood pressure.

The amount of Aldosterone in the body is monitored by the kidneys, which secrete hormones to increase or decrease Aldosterone production as required.

Adrenal Insufficiency - Addison’s Disease

If the adrenal cortex is damaged, the adrenal glands will not be able to produce enough Cortisol and, in some cases, not enough Aldosterone. This condition is known as Addison’s disease (sometimes called primary adrenal insufficiency - not to be confused with secondary adrenal insufficiency). As we mentioned above, it is vital that your body produces enough of these corticosteroids as they are essential to life, you cannot live without them.

Fortunately, Addison’s disease is fairly rare, affecting around one to six in every 100,000 people. However, it can strike either males or females at any time and in any age group. Sometimes Addison’s disease develops gradually with symptoms appearing over a period of time - perhaps even years. In other cases the symptoms can develop very quickly - especially in children and teenagers. In its early stages, Addison’s disease can be difficult to diagnose as many of the symptoms mimic other diseases. Indeed, Addison’s disease is not usually diagnosed until approximately 90% of the adrenal gland(s) has been damaged.

Symptoms of primary adrenal insufficiency can include some or all of the following:

  • Loss of appetite and weight
  • Nausea, vomiting or diarrhoea
  • Muscle weakness
  • Chronic, worsening fatigue
  • Low blood pressure
  • Salt cravings due to the loss of salt
  • Dehydration
  • Hypoglycaemia (low blood sugar levels) especially in children
  • Increased pigmentation of the skin, particularly around scars and bony areas
  • Irregular menstrual cycles in women and some instances the absence of periods altogether
  • Mood swings and mental confusion
  • Loss of consciousness

The slow development of the disease may mean that the symptoms are ignored until they suddenly worsen as a result of stressful event like a severe illness, an accident, excessive heat or physical exertion or a sudden shock such as the death of a loved one. This type of an episode is known as an Addisonian crisis, or acute adrenal insufficiency. Although in most cases, the symptoms of Addison’s disease have become severe enough for a patient to seek medical treatment before a crisis occurs, in around 25 percent of patients symptoms the first time symptoms appear is during an Addisonian crisis.

The symptoms of an Addisonian crisis can include:

  • Sudden violent pain in the lower back, abdomen or legs
  • Severe nausea, vomiting or diarrhoea
  • Possible mental confusion and loss of consciousness
  • Low blood pressure, low blood sugars, high potassium and low sodium levels and a rapid heart rate

In such cases, prompt emergency hospital treatment must be sought because without the appropriate treatment an Addisonian crisis can prove fatal. To this end, many Addisonians wear a medical alert bracelet or pendant with information and identification, and carry a hydrocortisone injectable for use in emergencies.

Around 70% of cases of Addison's disease are caused by an autoimmune response, where the body's own immune cells attack and destroy the adrenal glands. In some cases, other glands of the endocrine system are affected by an autoimmune response - this is referred to as polyendocrine deficiency syndrome.

Apart from autoimmune response, other causes of Addison’s disease include infection, cancer and the surgical removal of particular tumours in the adrenal or pituitary glands or the hypothalamus. Tuberculosis (TB), in particular, may lead to Addison’s disease because one of the effects of a TB infection is the destruction of the adrenal glands. When Addison’s disease was first identified by its namesake Dr. Thomas Addison in 1849, TB was the most common cause of the disease. Nowadays, with improved treatments for TB, TB accounts for less than 20% of cases of Addison’s disease in developed countries.1

Secondary Adrenal Insufficiency

Sometimes, Addison's disease is caused by the pituitary gland's inability to produce sufficient amounts of ACTH. Without ACTH the adrenal glands aren't prompted to secrete Cortisol. This is known as secondary adrenal insufficiency. The causes for this failure on the part of the pituitary gland include Cushing’s disease, infections, reduced blood flow and radiotherapy.

In most cases of secondary adrenal insufficiency people maintain their ability to produce Aldosterone.

How do you treat Addison’s disease?

Treatment involves replacing, or substituting, the hormones that the adrenal glands are not making. Because Addison’s disease cannot be cured but only managed, treatment is for life. Medication regimes need to be tailored to suit each person over the course of their life. They may need to be altered (in consultation with the appropriate medical professional) for example during stressful events such as illness or, where necessary, to take account of the different needs of children and young adults.

It’s in the treatment of Addison’s disease that Fludrocortisone Acetate comes into its own. If a patient is deficient only in Cortisol, oral hydrocortisone tablets can be taken once or twice a day. Hydrocortisone is a synthetic glucocorticoid. However, if a patient is also Aldosterone deficient, Fludrocortisone Acetate also needs to be taken, usually once a day. By combining Fludrocortisone Acetate with a synthetic glucocorticoid such as hydrocortisone, normal adrenal activity is substituted with minimal risk of unwanted effects.

In most cases of secondary adrenal insufficiency, Aldosterone production is maintained. These patients would only require glucocorticoid replacement therapy. Mineralocorticoid replacement therapy would only be needed if their ability to produce Aldosterone had also been compromised.

How does Fludrocortisone Acetate work?

Fludrocortisone Acetate is a synthetic corticosteroid. It has very potent mineralocorticoid properties so, even though it possesses high glucocorticoid activity; it is only used for its mineralocorticoid effects.

The physiological action of Fludrocortisone Acetate is similar to that of hydrocortisone. However, the effects of Fludrocortisone Acetate, especially on electrolyte balance and also on carbohydrate metabolism, are considerably heightened and last much longer. When given in small oral doses the effect of Fludrocortisone Acetate is to produce marked sodium retention and increased urinary potassium excretion. These effects result in an increase in blood pressure.

By mimicking the function of Aldosterone, Fludrocortisone Acetate is, in effect, a synthetic replacement for the Aldosterone an Addison’s patient cannot produce for themselves.

Can any other conditions be treated with Fludrocortisone Acetate?

Orthostatic Intolerance

Orthostatic intolerance (OI) (also called postural hypotension) is a form of dysautonomia, a disorder of the autonomic nervous system. It happens when an affected individual stands up. When we stand around 750ml of thoracic blood is suddenly translocated downwards. In order to maintain blood pressure, cerebral blood flow and even consciousness, our bodies quickly put into effect a series of effective circulatory and neurologic compensations. People with OI lack these mechanisms. Not surprisingly OI can be very debilitating. Apart from drinking at least two liters of fluids every day, treatment involves a combination of medications. Fludrocortisone Acetate can form part of this mix as it is used to increase blood volume, although this an off label use.

Salt-Losing Adrenogenital Syndrome (21-hyroxylase deficiency form)

This condition is more properly known as congenital adrenal hyperplasia. Congenital adrenal hyperplasia describes a group of conditions from a similar source - a family of autosomal, recessive disorders of the steroid hormone production in the adrenal glands that result in Cortisol deficiency. The 21-hyroxylase deficiency form of this syndrome accounts for about 95% of all patients.

As the pituitary gland detects the Cortisol deficiency it releases huge amounts of the stimulating hormone ACTH to boost Cortisol production and bring levels back up to normal. However, the up-shot of this is that adrenal glands overproduce certain intermediary hormones which have testosterone like effects on the foetus and child. This results in virilisation - the clitoris in female newborns can be so enlarged that it the baby’s sex is mistaken or questioned at birth.

Around 75% of affected babies have the salt losing form of the disorder. Salt retaining steroid hormones are deficient which means that if left undiagnosed the baby will continue to lose salt and eventually go into shock. This can prove fatal. As with Addison’s disease, treatment requires hormone replacement and again Fludrocortisone Acetate is used.

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Dosage

For Addison’s disease:

Dosage should be tailored to an individual’s needs as dosage depends on the severity of the disease and the response of the patient. Patients should be continually monitored for signs that indicate dosage adjustment is necessary, such as remissions or exacerbations of the disease and any stress they may be experiencing such as trauma or illness.

The usual dose is 0.1mg of Fludrocortisone Acetate daily, although dosage ranging from 0.1mg three times a week to 0.2mg daily may be required. If hypertension (high blood pressure) develops as a consequence of the therapy, the dose should be reduced to 0.05mg daily. Fludrocortisone Acetate should preferably be administered in conjunction with Cortisone (10mg to 37.5mg daily in divided doses) or hydrocortisone (10mg to 30mg daily in divided doses).

For salt losing adrenogenital syndrome:

The recommended dosage is 0.1mg to 0.2mg of Fludrocortisone Acetate daily. Fludrocortisone Acetate must be taken exactly as directed. You must not increase your dose or take it more often than directed. You must not suddenly stop taking Fludrocortisone Acetate without your doctor's permission as this may lead to an increase in side effects.

Side effects

All medicines can have side effects, which are usually fairly minor in nature. It’s also important to remember that just because a medicine may cause a side effect it does not necessarily mean that it will happen to you. Fludrocortisone Acetate is usually well tolerated but possible side effects include:

  • Sodium and water retention
  • Swelling due to fluid retention (oedema)
  • High blood pressure (hypertension)
  • Headache
  • Low blood potassium level (hypokalemia)
  • Muscle weakness
  • Fatigue
  • Increased susceptibility to infection
  • Impaired wound healing
  • Increased sweating
  • Increased hair growth
  • Thinning of the skin and stretch marks
  • Stomach upsets
  • Decreased bone density and increased risk of fractures of the bones
  • Difficulty in sleeping Depression
  • Weight gain
  • Raised blood sugar level
  • Menstrual irregularities in women
  • Eye problems including raised eye pressure within the eye (glaucoma)
  • Increased pressure in the skull

If you feel unwell while taking Fludrocortisone Acetate, advise your doctor.

Warnings

Do not take Fludrocortisone Acetate if:

  • If you have an allergy to Fludrocortisone Acetate or any of the other ingredients within the medication
  • If you have a systemic fungal infection (fungal infection of the blood)

Before you start to take Fludrocortisone Acetate, you must tell your doctor if:

  • You have tuberculosis
  • You have been immunised or vaccinated recently
  • You have high blood pressure
  • You have glaucoma, or other eye problems or an infection in your eye
  • Your thyroid gland is not working (hypothyroid)
  • You have cirrhosis of the liver
  • You have ulcerative colitis

These conditions may be affected by Fludrocortisone Acetate and need to be taken into account when considering treatment with Fludrocortisone Acetate.

Also tell you doctor if you are diabetic. Fludrocortisone Acetate may make it harder for you to control your blood sugar levels. Monitor your blood sugar levels regularly and inform your doctor of the results. Your diabetic medication or diet may need to be adjusted.

Drug Interactions

Before taking Fludrocortisone Acetate you must tell your doctor or pharmacist about all prescription and non-prescription (over the counter)/herbal products that you take, in particular:

  • Aldesleukin,
  • Aspirin/nonsterodial anti-inflammatory drugs (NSAIDs) such as ibuprofen and indomethacin
  • Blood thinners e.g. warfarin
  • Digoxin
  • Drugs to treat diabetes e.g., insulin and glyburide
  • Hormones e.g. androgens, birth control pills and estrogens
  • Immunosuppressants e.g. cyclosporine and natalizumab
  • Mifepristone
  • Vaccines
  • Drugs that may cause potassium loss e.g. amphotericin B, "water pills" such as furosemide or thiazides
  • Drugs affecting liver enzymes that remove fludrocortisone from your body e.g. rifamycins such as rifampin/rifabutin and certain anti-seizure medicines such as barbiturates/phenytoin.

When taking Fludrocortisone Acetate it is important to check all prescription and non-prescription medicine labels carefully because many medications contain pain relievers/fever reducers (NSAIDs such as aspirin, ibuprofen or naproxen). These drugs may increase your risk for side effects if taken together with Fludrocortisone Acetate. Low-dose aspirin should be continued if prescribed by your doctor for specific medical reasons such as heart attack or stroke prevention.

The Risk of other Infections

Fludrocortisone Acetate may mask some signs of infection, and new infections may appear during their use. You may have decreased resistance and you may be at greater risk of developing very serious infections. Therefore, if you think you may have an infection of any kind while you are taking Fludrocortisone Acetate, you must see your doctor immediately to ensure adequate treatment. Also report any injuries as your ability to heal may also be compromised.

Avoid exposure to chickenpox or measles infection while taking this medication unless you have previously had these infections (e.g. in childhood). If you are exposed to either of these infections and you have not previously had them, seek immediate medical attention.

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose.

Pregnancy and Breast Feeding

Fludrocortisone Acetate should only be given to a pregnant woman if clearly needed. Corticosteroids are known to pass into breast milk. Caution should be exercised when Fludrocortisone Acetate is administered to a nursing woman.

Continuing Care

When taking Fludrocortisone Acetate it is vital that you fully understand your corticosteroid-dependent status and the need to increase dosage under stress inducing conditions. You should carry medical identification indicating your dependence on steroid medication and, if necessary, carry an adequate supply of medication for use in emergencies.

Regular follow-up check-ups are also vital. The dosage of your medication may need to be altered from time to time. You must promptly notify your doctor of any dizziness, severe or continuing headaches, swelling of your feet or lower legs, or unusual weight gain.

Before having any surgery, tell your doctor or dentist that you are using Fludrocortisone Acetate or have taken it within the last 12 months.

References

  1. Munver R, Volfson IA. Adrenal insufficiency: diagnosis and management. Current Urology Reports. 2006;7:80–85.

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