Synthetic mineralocorticoid; Mineralocorticoid Receptor (MR)

- Correction of Hyponatremia: A small cell lung cancer patient with severe hyponatremia (serum sodium 112 mmol/L) and neurological symptoms (confusion, lethargy) was treated with Fludrocortisone (0.1 mg/day orally) combined with hypertonic saline. Serum sodium levels increased to 132 mmol/L within 7 days, with resolution of neurological symptoms [1]
- Enhancement of Hypervolemic Therapy in Subarachnoid Hemorrhage: In 28 patients with aneurysmal subarachnoid hemorrhage, Fludrocortisone (0.2 mg/day orally) added to hypervolemic therapy (intravenous crystalloids) reduced natriuresis: urinary sodium excretion decreased from 190±50 mmol/day to 95±30 mmol/day. This resulted in a higher positive fluid balance (1500±300 mL/day vs. 800±200 mL/day in controls) and reduced incidence of delayed cerebral ischemia (10% vs. 30% in controls) [2]
- Autobiographical Memory Effects: In a study involving 20 patients with major depression, 20 with borderline personality disorder, and 20 healthy controls, Fludrocortisone (0.1 mg orally 1 hour before testing) did not significantly affect autobiographical memory retrieval accuracy or specificity, as measured by the Autobiographical Memory Test (AMT) [3]

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Hyponatremia is a frequent electrolyte abnormality in patients with small cell lung cancer (SCLC). Being usually asymptomatic, hyponatremia may cause symptoms like nausea, fatigue, disorientation, headache, muscle cramps, or even seizures, particularly if severe and rapid decrease of serum sodium levels occurs. Here we report a case of SCLC patient with severe hyponatremia and acute neurological symptoms that developed 2 days after the first course of second-line chemotherapy, most probably due to the release of antidiuretic hormone (ADH, also known as arginine vasopressin) during lysis of the tumour cells. Initial treatment consisted of continuous administration of hypertonic saline that resulted in improvement of patient's neurological status. However, to obtain a persistent increase in serum sodium level, pharmacological intervention with oral fludrocortisone 0.1 mg twice daily was needed. We can therefore conclude that mineralocorticoids may be used to correct hyponatremia in SCLC patients when appropriate [1].

Thirty patients with SAH were randomized and divided into two groups: controls (Group 1, 15 patients) and patients treated with 0.3 mg/day of fludrocortisone (Group 2, 15 patients). In all patients sodium and fluid intake levels were in excess of maintenance requirements in an attempt to maintain a positive water balance and a central venous pressure (CVP) of 8 to 12 cm H2O. The mean sodium and water intake levels for 14 days after SAH were significantly reduced by fludrocortisone in Group 2 (487+/-34.52 mEq/day and 5159.2+/-249.29 ml/day, respectively; p<0.01) compared with Group 1 (634.2+/-42.86 mEq/day and 6611.7+/-365.67 ml/day). Fludrocortisone significantly reduced the urinary sodium excretion (p<0.01) and urine volume (p<0.01) in parallel, and effectively prevented a negative shift in the sodium as well as water balance (p<0.01). The serum sodium level tended to decrease in Group 1, reaching 135 mEq/L on average, but not in Group 2 (p<0.01). Hyponatremia in Group 1 was always observed at the optimal range of CVP values. A decrease in serum potassium level within the range of 2.8 to 3.5 mEq/L was transiently noted in 11 patients (73.3%) of Group 2, but was easily corrected. Possible side effects of fludrocortisone, such as pulmonary edema, were not encountered.[2]

Absorption, Distribution and Excretion
Fludrocortisone is rapidly and completely absorbed after oral administration. Pharmacokinetic studies estimate its peak plasma concentration (Cmax) to be 0.0012 to 0.20 μg/L, and its time to peak concentration (Tmax) to be 0.5 to 2 hours. The estimated AUC0-∞ after oral administration of fludrocortisone is between 1.22 and 3.07 μg·h/L. Approximately 80% of the administered dose is excreted in the urine, and the remaining 20% is likely eliminated via feces or bile. The apparent volume of distribution of fludrocortisone is 80–85 L. Distribution in cerebrospinal fluid appears to be minimal—the observed ratio of cerebrospinal fluid drug concentration to plasma drug concentration is 1:6. Population pharmacokinetic estimates suggest a plasma clearance of 40.8 L/h for fludrocortisone. Elimination route: Renal, primarily as inactive metabolites. Oral administration: Rapid and almost complete absorption. Parenteral administration: Intramuscular injection: Soluble esters (sodium phosphate, sodium succinate) – rapidly absorbed. Poorly soluble derivatives (acetate, acetone, diacetate, hexaacetone, tibbutate) – slowly but completely absorbed. Topical administration: Soluble esters – absorbed more slowly than intramuscular injection. Poorly soluble derivatives – slowly but completely absorbed. /Corticosteroids (Glucocorticoid action – systemic)/

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Metabolism/Metabolites
Currently, information on the specific metabolic pathways of fludrocortisone in vivo is very limited. Compared to other corticosteroids, the 9α-fluorination of fludrocortisone appears to greatly simplify its metabolism – although oxidation by 11-hydroxysteroid dehydrogenases has been observed, this reaction is largely inhibited because the fluorinated moiety appears to “protect” it from 11β-oxidation by these enzymes. This reduction in 11β-oxidation is considered one of the reasons for fludrocortisone's significant mineralocorticoid activity. An in vitro study found that fludrocortisone, after incubation in human liver microsomes and cytosol, produces only two metabolites: 20β-dihydrofluorocortisol and 6β-hydroxyfluorocortisol, but the potential enzymes involved in this reaction were not investigated in detail. Given that fludrocortisone is a corticosteroid, and that this class of drugs is known to be metabolized by the CYP3A family, and that co-administration with potent CYP3A inhibitors/inducers is not recommended, the CYP3A enzyme family may be involved in its metabolism in some way (although the specific metabolic pathway of fludrocortisone is not yet clear). The study subjects included kidney slices, kidney homogenates, and isolated perfused kidneys. Major metabolite: 20ε-dihydro-9α-fluorocortisol. Only 9α-fluorocortisol, no metabolites, binds to cytoplasmic receptors.
Biological half-life
The reported plasma half-life of fludrocortisone varies, ranging from 1 to 3.5 hours, but prescribing information gives a half-life of approximately 18-36 hours.
>Or = 3.5 hours (plasma); 18-36 hours (biological).

Protein Binding
Fludrocortisone has a protein binding rate of 70-80% in plasma, primarily binding to albumin and corticosteroid-binding globulin. Interactions In the treatment of type IV renal tubular acidosis, concomitant use of fludrocortisone with sodium-containing foods or medications may lead to hypernatremia, edema, and potentially severe hypertension; sodium intake may need to be adjusted. In one published case report, lithium antagonized the mineralocorticoid effects of fludrocortisone; when using lithium concurrently, the dose of fludrocortisone needs to be increased and dietary sodium supplementation necessary. There is a risk of severe hypokalemia when fludrocortisone is used concomitantly with medications that can cause hypokalemia; monitoring of serum potassium levels and cardiac function may be necessary, and potassium supplementation may be required. Phenytoin sodium and rifampin have been reported to increase the 6-β-hydroxylation of fludrocortisone by inducing hepatic enzyme p450; the dose of fludrocortisone may need to be increased. For more complete data on interactions of fludrocortisone (24 in total), please visit the HSDB record page. - Adverse reactions in clinical use: In a subarachnoid hemorrhage study, fludrocortisone (0.2 mg/day) resulted in mild hypokalemia (serum potassium 3.2 ± 0.3 mmol/L, compared to baseline 3.8 ± 0.2 mmol/L) in 30% of patients, which could be treated with oral potassium supplementation [2]. - No serious toxicities were reported in cases of hyponatremia or in memory studies; treatment was well tolerated, and no hypertension or fluid retention was reported [1,3].

[1]. Small Cell Lung Cancer Patient with Profound Hyponatremia and Acute Neurological Symptoms: An Effective Treatment with Fludrocortisone. Case Rep Oncol Med. 2015;2015:286029.
[2]. Improved efficiency of hypervolemic therapy with inhibition of natriuresis by fludrocortisone in patients with aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery. 1999, 91(6):947-952.
[3]. Does fludrocortisone influence autobiographical memory retrievalA study in patients with major depression, patients with borderline personality disorder and healthy controls. Stress. 2015 Nov;18(6):718-22.

Therapeutic Uses

Anti-inflammatory drug, steroid; synthetic mineralocorticoid. Fludrocortisone is used to treat type IV renal tubular acidosis associated with hyporeninous hypoaldosteronism. Fludrocortisone may also be used to aid in the diagnosis of the underlying cause of this condition. The effectiveness of fludrocortisone treatment suggests that the condition is caused by hyporeninous hypoaldosteronism, rather than by renal tubular transport dysfunction. /Not included in the US product label/
Fludrocortisone, in combination with increased sodium intake, is used to treat idiopathic orthostatic hypotension. /Not included in the US product label/
Fludrocortisone is indicated for salt-wasting adrenogenous syndrome. /Included in the US product label/
For more complete data on the therapeutic uses of fludrocortisone (8 types), please visit the HSDB record page.
Drug Warnings

Most adverse reactions of fludrocortisone are caused by its mineralocorticoid activity (sodium and water retention). When using the recommended low dose of fludrocortisone, the side effects of glucocorticoids are generally not a problem; however, these side effects should be noted, especially with long-term use of fludrocortisone or in combination with cortisone or similar glucocorticoids. FDA Pregnancy Risk Category: C / Risk cannot be ruled out. There is a lack of adequate, well-controlled human studies, and animal studies have not shown any risk to the fetus or lack relevant data. If this drug is taken during pregnancy, there is a possibility of fetal harm; however, the potential benefits may outweigh the potential risks. /
To evaluate the tolerability of fludrocortisone in elderly patients with hypotension…64 patients aged 65 years and older (mean age 80 years) with one or more hypotensive disorders (orthostatic hypotension, vasodilatory carotid sinus syncope, and/or vasodilatory neurocardiogenic syncope) received fludrocortisone at daily doses of 100 mcg (adjusted) (72%), 50 mcg (adjusted) (27%), and 200 mcg (adjusted) (1 case). …During follow-up, 13 patients died from other causes. Of the remaining patients, 33% discontinued fludrocortisone after an average of 5 months. Reasons for discontinuation included: hypertension (5 cases); heart failure (4 cases); depression (3 cases); edema (3 cases); and unexplained causes (2 cases). Among patients who continued treatment, supine systolic and diastolic blood pressure showed no significant difference from baseline (follow-up 2 to 21 months). At an average of 8 months, 24% of patients developed hypokalemia; none discontinued treatment due to hypokalemia. Even at low doses, fludrocortisone is poorly tolerated long-term in elderly patients with hypotension. This study investigated the mechanism of fludrocortisone-induced supine hypertension in 7 patients with orthostatic hypotension. All patients experienced elevated blood pressure in both supine and standing positions, with 4 reaching hypertension levels in the supine position. Two patients developed hypertensive retinopathy, and one developed cardiomegaly. Initial blood pressure elevation was associated with sodium retention and plasma volume expansion. However, despite further increases in blood pressure after long-term treatment, plasma volume decreased to control levels. Treatment did not affect plasma catecholamine levels, but enhanced the pressor response to norepinephrine infusion in some subjects. Hemodynamic studies showed that supine hypertension was associated with increased total peripheral vascular resistance, rather than changes in cardiac output. Clinically, supine hypertension is a significant risk factor for patients with orthostatic hypotension receiving fludrocortisone. This uncommon chronic mineralocorticoid-induced hypertension model is not volume-related, but associated with increased peripheral vascular resistance. For more complete data on fludrocortisone (13 in total), please visit the HSDB record page. Pharmacodynamics: Fludrocortisone is a synthetic mineralocorticoid used to replace endogenous aldosterone caused by insufficient or absent endogenous aldosterone synthesis. It acts on the kidneys, increasing sodium reabsorption and potassium excretion. Due to its transcriptional action, despite a relatively short plasma half-life, a single dose of fludrocortisone can take effect within 1–2 days. Similar to other systemic mineralocorticoids, corticosteroids, such as fludrocortisone, may mask signs of infection by suppressing normal immune responses—infections occurring during fludrocortisone treatment should be treated immediately with appropriate antibiotics. There is evidence that stimulation of mineralocorticoid receptors (MR) enhances memory in healthy subjects and patients with major depressive disorder (MDD). In contrast, in patients with borderline personality disorder (BPD), this effect appears to be task-dependent. This study aimed to investigate the effects of MR stimulation on autobiographical memory retrieval in healthy individuals, MDD patients, and BPD patients. We conducted a placebo-controlled study with a within-group crossover design. 24 MDD patients, 37 BPD patients, and 67 healthy subjects completed an autobiographical memory test after being randomized to receive 0.4 mg of fludrocortisone (a mineralocorticoid receptor-preferred agonist) or placebo. There were no differences in autobiographical memory retrieval abilities among healthy subjects, MDD patients, and BPD patients. Furthermore, administration of fludrocortisone had no effect on autobiographical memory. In conclusion, stimulation of the mineralocorticoid receptor (MR) did not affect autobiographical memory retrieval in healthy subjects, patients with MDD, and patients with BPD. Our results do not support the role of MR in autobiographical memory. [3]

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- Mechanism of action: Fludrocortisone is a potent mineralocorticoid receptor agonist that promotes renal tubular reabsorption of sodium and increases extracellular fluid volume, which contributes to its treatment of hyponatremia and enhances the effects of hypervolemic therapy [1,2]
- Clinical indications: In reported studies, fludrocortisone has been used off-label to treat severe hyponatremia and to optimize hypervolemic therapy in patients with subarachnoid hemorrhage, taking advantage of its sodium-retaining properties [1,2]
- Neuropsychiatric effects: The lack of effect on autobiographical memory suggests that acute administration of fludrocortisone does not significantly modulate the memory retrieval process in humans [3]

C21H29FO5

380.45

380.199

C, 66.30; H, 7.68; F, 4.99; O, 21.03

127-31-1

Fludrocortisone acetate;514-36-3;Fludrocortisone-d5;Fludrocortisone-d2; 127-31-1 (free); 514-36-3 (acetate) ; 339-01-5 (hemisuccinate)

31378

White to off-white solid powder

1.3±0.1 g/cm3

564.7±50.0 °C at 760 mmHg

208-212ºC

295.3±30.1 °C

0.0±3.5 mmHg at 25°C

1.584

1.7

3

6

2

27

734

7

C[C@@]12[C@](C(CO)=O)(O)CC[C@@]1([H])[C@]3([H])CCC4=CC(CC[C@]4(C)[C@@]3(F)[C@@H](O)C2)=O

AAXVEMMRQDVLJB-BULBTXNYSA-N

InChI=1S/C21H29FO5/c1-18-7-5-13(24)9-12(18)3-4-15-14-6-8-20(27,17(26)11-23)19(14,2)10-16(25)21(15,18)22/h9,14-16,23,25,27H,3-8,10-11H2,1-2H3/t14-,15-,16-,18-,19-,20-,21-/m0/s1

(8S,9R,10S,11S,13S,14S,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one

Fludrocortisone, Florinef, fludrocortisone; 127-31-1; Astonin-H; Alflorone; Fluohydrisone; Fluorocortisol; Fluorocortisone; Fluohydrocortisone; Astonin, 9α-fluorocortisol, 9α-fluorohydrocortisone, Fludrocortisone acetate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~262.85 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.57 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)