Fludrocortisone

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Continuing Education Activity

Fludrocortisone is a synthetic adrenal steroid with high mineralocorticoid activity that is a commonly used drug to treat adrenocortical insufficiency. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent to interprofessional team members to use fludrocortisone appropriately for various indications.

Objectives:

  • Identify the mechanism of action of fludrocortisone.
  • Describe the potential adverse effects of fludrocortisone.
  • Summarize the appropriate monitoring of fludrocortisone use.
  • Review some interprofessional strategies that can improve patient outcomes when using fludrocortisone therapy.

Indications

Given its strong mineralocorticoid effect, fludrocortisone plays an essential role in the treatment of primary and secondary adrenocortical insufficiency. This drug may also be used to treat congenital adrenal hyperplasia (CAH), which is a congenital enzymatic deficiency disorder that manifests with mineralocorticoid deficiency in up to 75% of cases. Even though this corticosteroid is not approved in the pediatric population by the Food and Drug Administration for uses other than congenital adrenal hyperplasia, it is indicated off-label for adrenocortical insufficiency.[1] It has also been used in the management of septic shock in adults, demonstrating a 90-day all-cause mortality reduction among the group receiving hydrocortisone plus fludrocortisone than among those with placebo[2][3][4][5]

The drug received its patent in 1953 and is on the World Health Organization's List of Essential Medicines.

Mechanism of Action

Fludrocortisone acetate is an inactive pro-drug requiring hydrolyzation by esterases or pseudo-esterases in the liver and other body fluids.[6] Fludrocortisone is a synthetic adrenal steroid with high mineralocorticoid activity and is practically devoid of glucocorticoid effect. As an analog, its mechanism of action and the permissive effects on α-adrenoreceptors are similar to the endogenous mineralocorticoid. High lipid solubility allows fludrocortisone to easily penetrate the plasma membrane and bind with its cytoplasmic receptor.

Upon binding, receptor complex translocates to the nucleus and initiates the transcription of responsive genes to exert its effects. The primary sites of fludrocortisone's effect are the distal convoluted tubules and collecting ducts, where it enhances Na+ and water retention as well as increasing K+, H+ excretion. This pharmacologic effect leads to a generalized ECF volume expansion not specifically targeted to the intravascular space. Thus, it is postulated that its efficacy in orthostatic hypotension management is due to potentiating the pressor effects of various endogenous vasoconstrictors such as norepinephrine and angiotensin II.[7]

Administration

Dosage and Form

Fludrocortisone is available in tablet form, and it can be taken orally with or without a meal. It is usually administered in its acetate form.

For primary adrenal cortical insufficiency usual dose is 0.1 mg per day, and it can be increased up to 0.2 mg per day. However, if hypertension develops, the dosage should be reduced to 0.05 mg per day. Dosing should be gradually tapered down to discontinue therapy.

For the salt-losing type of congenital adrenal hyperplasia, the dose is 0.1 mg/day.

When used off-label for orthostatic hypotension, the dose is normally from 0.1 to 0.2 mg orally once daily. Dosing should start at 0.1 mg by mouth each day, then increase the dose by 0.1 mg per day each week until the appearance of trace pedal edema. The maximum dose is 1 mg per day, although doses in excess of 0.5 mg daily are rarely more effective. Dosing should be with food or milk. Discontinuation of therapy requires gradual dose tapering.

Metabolism

The drug is metabolized by the liver. So, if there is any hepatic impairment, the dose should be adjusted accordingly.

Drug Interactions

  • Administration with proton pump inhibitors and anemia have shown to decrease its absorption.[6]
  • Concurrent use of amphotericin B, diuretics, digoxin with fludrocortisone may cause severe hypokalemia.
  • Using NSAIDs can cause peptic ulcer disease.
  • It can decrease or increase the efficacy of warfarin.
  • It can cause hyperglycemia, so dosages of diabetes drugs (metformin, glipizide, glimepiride, pioglitazone, linagliptin, insulin) must be adjusted.
  • Administration of phenobarbital, Phenytoin, Rifampin can lower blood fludrocortisone levels.
  • Taking estrogen or male testosterone analog can increase the risk of swelling.
  • Fludrocortisone can impair the function of vaccines. Therefore, vaccines should not be given while patients are using fludrocortisone.

Pregnancy Category

Fludrocortisone is a Category C pregnancy drug.

Adverse Effects

Most of the side effect of fludrocortisone is related to mineralocorticoid activity. If this drug is used along with glucocorticoid or other related drugs, the adverse effect increases. Some of the more common or significant side effects appear in the list below:

  • Cardiovascular system: Hypertension (dose-dependent iatrogenic has been described as an adverse effect on children using fludrocortisone for CAH, which correlates with plasma renin activity,  Fluid retention, and edema (May cause swelling of lower limbs), congestive heart failure.[8][9]
  • Nervous System: Headache, increased intracranial pressure, vertigo, change in behavior, convulsion
  • Gastrointestinal: May impair gastric protective barrier and cause stomach ulcer, perforation.
  • Endocrine: Menstrual abnormalities, cushingoid features, growth delay in a child, acute adrenal insufficiency in times of stress
  • Musculoskeletal: Can cause muscle weakness, can reduce muscle mass, increase risk of osteoporosis and pathological fracture, vertebral compression, necrosis of femoral head.
  • Dermatologic: Increased sweating, poor wound healing, hirsutism, thinning of the skin, severe allergic reaction
  • Ophthalmic: cataracts, glaucoma
  • Metabolic: Elevated blood and urine glucose, weight gain
  • Electrolytes Disturbance: Severe hypokalemia, metabolic alkalosis[10]

Contraindications

Fludrocortisone is contraindicated in several conditions. The clinicians should conduct a careful history and examination should be made prior to prescribing this drug. If there is any contraindication to this drug, alternative options should be considered. Contraindications include:

  • Known allergy to this drug
  • Hypertension
  • Hyperaalbuminemia
  • Systemic fungal infection

Monitoring

Since this drug can cause a life-threatening hypersensitivity reaction, the patient must be monitored for the development of any allergic sign symptoms such as rash, breathing problem, swelling of the face, or fever. It is recommended to measure blood pressure regularly while using this corticosteroid as it has been associated with iatrogenic hypertension. Serial plasma renin activity should also be checked. If there is weakness, muscle cramps, blood electrolytes should be checked to identify and treat hypokalemia. Whether diabetic or not, serum blood glucose should be monitored, if diabetic glucose should be controlled with appropriate medications. If the drug is being prescribed for a child for a longer duration, the growth and development of the child should be tracked to see if there is any delay in growth.

Toxicity

The toxicity of any drug depends on its pharmacological activity. Since fludrocortisone works at mineralocorticoid receptors, toxicity will present as excess mineralocorticoid activities such as severe hypertension, not pitting edema, congestive heart failure, severe hypokalemia, metabolic alkalosis, rapid weight gain. Unfortunately, there is no antidote for fludrocortisone toxicity. So, conservative management is the mainstay. Reduction of dose, strict blood pressure control, potassium supplementation may be given.

Enhancing Healthcare Team Outcomes

Fludrocortisone is used all around the world and prescribed by clinicians, including NDs, osteopathic clinicians, physician assistants, and nurse practitioners. Since the drug can interact with many other medications and may cause serious adverse effects or toxicity, interprofessional healthcare team members must be aware of these consequences. All team members, whether involved in prescribing, dispensing, administering, or monitoring fludrocortisone, must be well educated about the pharmacology of this drug. A proper history and physical examination must be considered before initiating fludrocortisone. The patient must be educated about the adverse effects, potential toxicity, and appropriate dosing of this drug so they can use the medication properly. They can report to the clinician within a short timeframe if any adverse events occur or are beginning to manifest.

Interprofessional team discussion that includes all clinicians (including specialists such as endocrinologists), nursing staff, and pharmacists is crucial for every patient. The interprofessional team must monitor the patient at a regular interval and be ready for a prompt response if there are any signs or symptoms of adverse events. Besides the health team and patient, other family members should also be educated about proper dosing, adverse effects, and warning signs. This team approach will drive improved patient outcomes and mitigate potential adverse events. [Level 5]


Article Details

Article Author

Masum Rahman

Article Editor:

Fatima Anjum

Updated:

10/17/2022 6:20:25 PM

PubMed Link:

Fludrocortisone

References

[1]

Bonfig W,Schwarz HP, Blood pressure, fludrocortisone dose and plasma renin activity in children with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency followed from birth to 4 years of age. Clinical endocrinology. 2014 Dec;     [PubMed PMID: 24818525]

[2]

Benner BJM,Alsma J,Feelders RA, Hyponatraemia and hyperpigmentation in primary adrenal insufficiency. BMJ case reports. 2019 Mar 7;     [PubMed PMID: 30850564]

[3]

Annane D,Renault A,Brun-Buisson C,Megarbane B,Quenot JP,Siami S,Cariou A,Forceville X,Schwebel C,Martin C,Timsit JF,Misset B,Ali Benali M,Colin G,Souweine B,Asehnoune K,Mercier E,Chimot L,Charpentier C,François B,Boulain T,Petitpas F,Constantin JM,Dhonneur G,Baudin F,Combes A,Bohé J,Loriferne JF,Amathieu R,Cook F,Slama M,Leroy O,Capellier G,Dargent A,Hissem T,Maxime V,Bellissant E, Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. The New England journal of medicine. 2018 Mar 1;     [PubMed PMID: 29490185]

[4]

Gomes LG,Madureira G,Mendonca BB,Bachega TA, Mineralocorticoid replacement during infancy for salt wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clinics (Sao Paulo, Brazil). 2013;     [PubMed PMID: 23525308]

[5]

Hughes IA,Wilton A,Lole CA,Gray OP, Continuing need for mineralocorticoid therapy in salt-losing congenital adrenal hyperplasia. Archives of disease in childhood. 1979 May;     [PubMed PMID: 475410]

[6]

Polito A,Hamitouche N,Ribot M,Polito A,Laviolle B,Bellissant E,Annane D,Alvarez JC, Pharmacokinetics of oral fludrocortisone in septic shock. British journal of clinical pharmacology. 2016 Dec;     [PubMed PMID: 27416887]

[7]

Bamberg K,William-Olsson L,Johansson U,Jansson-Löfmark R,Hartleib-Geschwindner J, The selective mineralocorticoid receptor modulator AZD9977 reveals differences in mineralocorticoid effects of aldosterone and fludrocortisone. Journal of the renin-angiotensin-aldosterone system : JRAAS. 2019 Jan-Mar;     [PubMed PMID: 30813831]

[8]

Bhattacharyya A,Tymms DJ, Heart failure with fludrocortisone in Addison's disease. Journal of the Royal Society of Medicine. 1998 Aug;     [PubMed PMID: 9816363]

[9]

Willis FR,Byrne GC,Jones TW, Fludrocortisone induced heart failure in Addison's disease. Journal of paediatrics and child health. 1994 Jun;     [PubMed PMID: 8074919]

[10]

Burns A,Brown TM,Semple P, Extreme metabolic alkalosis with fludrocortisone therapy. Postgraduate medical journal. 1983 Aug;     [PubMed PMID: 6622340]