Mineralocorticoids

Mineralocorticoids are a drug class within the corticosteroid family and fludrocortisone is the primary medication within this class. Fludrocortisone is a fluorinated analog of cortisone. The fluorine moiety protects the drug from isoenzyme inactivation in the kidney, allowing it to exert its mineralocorticoid effect. The mechanism of action of mineralocorticoids mimics that of aldosterone. By acting on the mineralocorticoid receptors, fludrocortisone induces the expression of proteins responsible for Na+ reabsorption and K+ excretion by renal tubule cells, which results in Na+ and water retention. Mineralocorticoids are used in the management of diseases characterized by insufficient (or absent) aldosterone activity, such as adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease and congenital adrenal hyperplasia Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme needed in cortisol, aldosterone, and androgen synthesis. The most common subform of CAH is 21-hydroxylase deficiency, followed by 11β-hydroxylase deficiency. Congenital Adrenal Hyperplasia. Adverse effects are related to both mineralocorticoid and glucocorticoid effects and include hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, decompensated heart failure, hyperpigmentation, hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia, Cushing syndrome, hyperglycemia, and hypothalamic-pituitary-adrenal axis suppression.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Chemistry and Pharmacodynamics

Chemical structure

Fludrocortisone is the primary drug in this class.

  • Synthetic mineralocorticoid
  • Fluorinated analog of cortisol

Mechanism of action

  • Mimics the effect of aldosterone → acts on the mineralocorticoid receptors (in cytoplasm) in the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys:
    • Distal convoluted tubule
    • Collecting duct
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription and translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation of proteins for channels on renal tubule cells:
    • ↑ Na+ channels (apical side) → ↑ Na+ reabsorption → water reabsorption
    • ↑ Na+/K+ ATPase (basolateral side) → ↑ K+ excretion through renal outer medullary potassium (ROMK) channels (apical side)
Effects of aldosterone

Effects of aldosterone on the principal cells within the distal renal tubules. Mineralocorticoids work similarly.
ENaC: epithelial Na+ channel
ROMK: renal outer medullary potassium

Image by Lecturio.

Physiologic effects

  • ↑ Plasma Na+ and water retention → ↑ blood pressure
  • ↓ Plasma K+
  • Additionally, has glucocorticoid activity and effects

Pharmacokinetics

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

  • Administered orally
  • Rapid and complete

Distribution

  • 70%‒80% is protein bound:
    • Albumin
    • Corticosteroid-binding globulin
  • The fluorinated structure protects from oxidation (11-beta-hydroxysteroid dehydrogenase isoenzyme) and inactivation in the kidney → allows for mineralocorticoid potency

Metabolism and excretion

  • Hepatic metabolism
  • Excretion:
    • Primarily in urine
    • Minority in feces

Indications

Although fludrocortisone has glucocorticoid activity, it is primarily used for its mineralocorticoid activity (particularly in conditions with inadequate aldosterone production).

  • In conjunction with a glucocorticoid:
    • Adrenal insufficiency
    • Congenital adrenal hyperplasia
    • Septic shock Septic shock Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Septic shock is diagnosed during treatment when vasopressors are necessary to control hypotension. Sepsis and Septic Shock that has not responded to IV fluid resuscitation (off-label use)
  • In conjunction with ↑ salt and/or fluid intake (off-label use):
    • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Postural orthostatic tachycardia syndrome (POTS)
    • Cerebral salt wasting

Adverse Effects and Contraindications

Adverse effects

There are many side effects of fludrocortisone therapy, notably:

  • Cardiovascular:
    • Hypertension
    • Fluid retention and edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • Decompensated congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure
  • Endocrine and electrolyte disturbances:
    • Hyperglycemia and diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
    • Weight gain
    • Cushing syndrome
    • Growth suppression
    • Hypokalemia
    • Metabolic alkalosis Metabolic alkalosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic alkalosis also occurs when there is an increased loss of acid, either renally or through the upper GI tract (e.g., vomiting), increased intake of HCO3-, or a reduced ability to secrete HCO3- when needed. Metabolic Alkalosis
  • CNS:
    • Delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium
    • Psychosis
    • ↑ Intracranial pressure
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Dermatologic:
    • Acne
    • Hyperpigmentation
    • Striae
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin atrophy
    • Delayed wound healing Wound healing Wound healing is a physiological process involving tissue repair in response to injury. It involves a complex interaction of various cell types, cytokines, and inflammatory mediators. Wound healing stages include hemostasis, inflammation, granulation, and remodeling. Wound Healing
  • Musculoskeletal:
    • Myopathy
    • Osteonecrosis
    • Osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
  • GI: ulcers
  • Ophthalmic:
    • Glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
    • Cataracts
  • Withdrawal:
    • Chronic therapy results in hypothalamic-pituitary-adrenal (HPA)-axis suppression.
    • Abrupt discontinuation may cause adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease.

Contraindications and precautions

  • Contraindications:
    • Systemic fungal infection
    • Previous allergy to corticosteroids (potential cross-reactivity)
  • Use with caution:
    • Severe hepatic or renal impairment
    • Congestive heart failure
    • Hypertension
    • Recent acute MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction → risk of myocardial rupture
    • Uncontrolled hyperglycemia

Drug interactions

  • ↑ Risk of hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia:
    • Diuretics
    • Digoxin
    • Amphotericin B
  • ↑ Risk of ulcers and GI bleeding: NSAIDs
  • ↑ Fluid retention:
    • Androgens
  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of fludrocortisone:
    • Proton pump inhibitors
    • Antacids
    • Bile acid sequestrants
  • Dosing adjustment may be necessary for antidiabetic agents.

References

  1. Abed, H., Ball, P.A., Wang, L. (2012). Diagnosis and management of postural orthostatic tachycardia syndrome: A brief review. Journal of Geriatric Cardiology. 9, 61-67. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390096/
  2. Fludrocortisone: Drug information. UpToDate Lexicomp. Retrieved November 7, 2021, from https://www.uptodate.com/contents/fludrocortisone-drug-information
  3. Nieman, L.K. (2021). Pharmacologic use of glucocorticoids. In Martin, K.A. (Ed.), UpToDate. Retrieved November 7, 2021, from https://www.uptodate.com/contents/pharmacologic-use-of-glucocorticoids
  4. Rahman, M., Anjum, F. (2021). Fludrocortisone. [online] StatPearls. Retrieved November 7, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK564331/
  5. Drugbank Online (2021). Fludrocortisone. Retrieved November 7, 2021, retrieved from https://go.drugbank.com/drugs/DB00687
  6. Chrousos, G.P. (2012). Adrenocorticosteroids & adrenocortical antagonists. In Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic & Clinical Pharmacology (12th edition, pp. 697-713). Retrieved from https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf

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