Mineralocorticoids

Definition and Overview

Mineralocorticoids are a class of corticosteroid hormones primarily involved in regulating electrolyte and fluid balance in the body. Endogenously, aldosterone is the principal mineralocorticoid synthesized in the zona glomerulosa of the adrenal cortex. Pharmacologically, mineralocorticoids are used to treat adrenal insufficiency and certain types of hypotension and salt-wasting disorders.

They exert their effects by promoting sodium reabsorption and potassium/hydrogen ion excretion in the distal renal tubules and collecting ducts. These actions lead to increased water retention, expanded extracellular fluid volume, and elevated blood pressure.

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Representative Agents

1. Fludrocortisone acetate – Synthetic mineralocorticoid with potent sodium-retaining properties

2. Aldosterone (endogenous) – Not used therapeutically due to rapid hepatic metabolism

3. Deoxycorticosterone (DOC) and deoxycorticosterone acetate (DOCA) – Rarely used therapeutically; primarily investigational or veterinary

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Mechanism of Action

Mineralocorticoids bind to mineralocorticoid receptors (MRs) located in epithelial tissues (kidney, colon, salivary glands) and non-epithelial tissues (heart, brain, immune cells). Upon binding:

• They promote upregulation of epithelial sodium channels (ENaCs) in renal tubules

• Stimulate Na⁺/K⁺-ATPase pump activity on the basolateral membrane

• Enhance sodium and water reabsorption

• Increase urinary excretion of potassium and hydrogen ions

These effects result in:

• Elevated plasma sodium concentration

• Expanded intravascular volume

• Maintenance of blood pressure

• Correction of hyperkalemia and acidosis

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Pharmacological Effects

System	Effect
Renal	↑ Sodium reabsorption, ↓ potassium and hydrogen ion retention
Cardiovascular	↑ Blood volume and blood pressure
Endocrine	Negative feedback on the renin-angiotensin-aldosterone system (RAAS)
Electrolyte	Hypernatremia, hypokalemia, metabolic alkalosis (with overdosage)

Clinical Indications

1. Primary Adrenal Insufficiency (Addison’s Disease)

   • Combined use of hydrocortisone (glucocorticoid) and fludrocortisone to restore mineralocorticoid activity

2. Congenital Adrenal Hyperplasia (CAH)

   • Fludrocortisone used to manage salt-wasting forms of CAH due to 21-hydroxylase deficiency

3. Orthostatic Hypotension

   • Off-label use of fludrocortisone to expand plasma volume in patients with autonomic failure or neurogenic hypotension

4. Salt-Wasting Syndromes

   • Post-adrenalectomy, enzyme deficiencies, or severe diarrhea-related dehydration requiring sodium retention support

5. Hyporeninemic Hypoaldosteronism

   • Rare use of fludrocortisone in patients with diabetic nephropathy and persistent hyperkalemia

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Fludrocortisone Acetate: Primary Mineralocorticoid Agent

Formulation: Oral tablets (typically 0.1 mg)
Potency: High mineralocorticoid activity; minimal glucocorticoid activity
Dose Range:

• Addison’s disease: 0.05–0.2 mg daily

• CAH: Dose individualized; usual range 0.05–0.2 mg/day

• Orthostatic hypotension: Starting dose 0.1 mg/day with upward titration based on BP and edema

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Pharmacokinetics

• Absorption: Rapid and complete from the GI tract

• Onset of action: Within hours; peak effect within 1–2 days

• Half-life: ~3.5 hours (biologic effect lasts 18–36 hours)

• Metabolism: Hepatic metabolism

• Excretion: Renal

• Protein Binding: Moderate (transcortin and albumin)

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Adverse Effects

• Cardiovascular:

  • Hypertension

  • Edema (especially lower limbs)

  • Congestive heart failure (in patients with cardiac compromise)

• Electrolyte Disturbances:

  • Hypokalemia

  • Metabolic alkalosis

  • Hypernatremia

• Gastrointestinal:

  • Nausea, bloating

  • Rare: peptic ulcer aggravation

• Neurological:

  • Headache

  • Mood changes

  • Insomnia

• Endocrine/Metabolic:

  • Suppression of hypothalamic-pituitary-adrenal (HPA) axis with long-term use

  • Weight gain due to fluid retention

• Musculoskeletal:

  • Muscle weakness (due to potassium loss)

  • Rare: osteoporosis with prolonged use

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Contraindications

• Systemic fungal infections

• Hypersensitivity to fludrocortisone or any excipients

• Uncontrolled hypertension

• Severe congestive heart failure

• Hypokalemia

• Recent thromboembolic events (use with caution)

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Precautions and Warnings

• Monitor serum electrolytes (Na⁺, K⁺) and blood pressure regularly

• Risk of edema and cardiac decompensation in elderly and CHF patients

• Taper slowly to avoid adrenal crisis if used long-term

• Use with caution in diabetic patients due to fluid shifts and potential BP elevation

• HPA axis suppression possible with high-dose or long-term use

• Pregnancy Category C – Use only if clearly indicated; fetal adrenal suppression risk

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Drug Interactions

• Diuretics (loop and thiazide):

  • ↑ Hypokalemia risk

• ACE Inhibitors / ARBs / Potassium-sparing diuretics:

  • May counteract mineralocorticoid-induced sodium retention

• Digitalis glycosides:

  • ↑ Risk of digitalis toxicity due to hypokalemia

• NSAIDs:

  • Enhanced sodium and fluid retention, ↑ BP

• Insulin or hypoglycemic agents:

  • Mineralocorticoids may induce glucose intolerance

• Vaccines:

  • Immunosuppressive doses (rare with fludrocortisone) may reduce vaccine efficacy

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Monitoring Parameters

• Serum electrolytes: Especially sodium and potassium (baseline, then every 1–3 months)

• Blood pressure: Standing and supine readings

• Weight: Rapid weight gain suggests fluid overload

• Renal function: Creatinine and eGFR monitoring

• Edema assessment: Lower extremity swelling

• Signs of heart failure: Dyspnea, orthopnea, jugular venous distension

• HPA Axis function: Especially when used with glucocorticoids

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Patient Counseling Points

• Take fludrocortisone in the morning to mimic natural hormone rhythm

• Report symptoms such as swelling, fatigue, palpitations, weakness, or headache

• Adhere to prescribed salt intake if advised by healthcare provider

• Do not suddenly stop the medication—risk of adrenal crisis

• Inform all healthcare providers about use before surgery or serious illness

• Monitor blood pressure at home if possible

• Recognize signs of low potassium: muscle cramps, irregular heartbeat

• Avoid potassium supplements unless prescribed

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Comparative Notes: Mineralocorticoids vs. Glucocorticoids

Feature	Mineralocorticoids (e.g., fludrocortisone)	Glucocorticoids (e.g., hydrocortisone)
Main Action	Sodium retention, potassium excretion	Anti-inflammatory, immunosuppression
Primary Sites of Action	Kidney tubules	Multiple organs (liver, immune cells)
HPA Axis Suppression	Minimal (at low doses)	Significant with long-term use
Common Use	Addison’s disease, CAH	Asthma, autoimmune disease, allergies
Electrolyte Impact	Alters Na⁺ and K⁺	Less pronounced

Current Clinical Guidelines

• The Endocrine Society Clinical Practice Guidelines for adrenal insufficiency recommend fludrocortisone for all primary adrenal insufficiency patients to maintain sodium and fluid balance

• In CAH, dose is titrated based on growth, electrolytes, and plasma renin activity

• In orthostatic hypotension, low-dose fludrocortisone may be considered as part of a non-pharmacological and pharmacological approach (compression stockings, fluid intake, midodrine)

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Research and Developments

• Investigational agents targeting selective MR modulation are being developed to minimize cardiovascular side effects while preserving renal benefits

• Non-steroidal MR antagonists (e.g., finerenone) are gaining popularity in heart failure and CKD, not as mineralocorticoids but as counter-regulators

• Long-acting formulations and transdermal mineralocorticoids are under evaluation for patients with poor adherence or GI malabsorption

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Veterinary and Special Use

• Deoxycorticosterone pivalate (DOCP) is commonly used in dogs for managing Addison’s disease

• Mineralocorticoid supplementation is considered in hypoadrenocorticism in neonatal animals or wildlife veterinary care

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Availability and Brand Names

• Fludrocortisone acetate:

  • Florinef (discontinued in many countries)

  • Generic versions widely available

• Deoxycorticosterone acetate (DOCA):

  • Primarily veterinary use

• Deoxycorticosterone pivalate (DOCP):

  • Percorten-V (veterinary)

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Summary Table of Mineralocorticoid Activity

Drug	Mineralocorticoid Potency	Glucocorticoid Potency	Therapeutic Use
Aldosterone	100	0	Endogenous hormone
Fludrocortisone	125	10	Addison’s, CAH, hypotension
Hydrocortisone	1	1	Glucocorticoid with mild mineralocorticoid
DOCA / DOCP (vet use)	20	0	Veterinary Addison’s disease