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Fludrocortison

Fludrocortisone

HCID 31378
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Grundinformationen

CAS
127-31-1
Standard-SMILES
C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CC[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
InChIKey
AAXVEMMRQDVLJB-BULBTXNYSA-N
Summenformel
C21H29FO5
Durchschnittliche Molmasse
380,4 g/mol
Monoisotopische Masse
380,19990218

Überblick

Fludrocortisone is a mineralocorticoid, a 17alpha-hydroxy steroid, a 21-hydroxy steroid, an 11beta-hydroxy steroid, a 20-oxo steroid, a 3-oxo-Delta(4) steroid, a fluorinated steroid and a C21-steroid. It has a role as an anti-inflammatory drug and an adrenergic agent. It derives from a hydride of a pregnane.

Namen und Bezeichner

Bevorzugter Name
Fludrocortisone
IUPAC
(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
Lokaler Name
Fludrocortison
Englischer Name
Fludrocortisone
Summenformel
C21H29FO5
Molmasse
380.45

Namen und Synonyme

fludrocortisone127-31-1Astonin-HAlfloroneFluohydrisoneFluorocortisolFluorocortisone9alpha-FluorocortisolFludrocortoneFluohydrocortisoneFludroneFludronef
Weitere Namen anzeigen
florinefu5963NSC 11318
F-Cortef9-FluorocortisolF-COL9-FluorohydrocortisoneFludrocortisonaFludrocortisonum9alpha-FludrocortisoneDTXSID7023061

Datenbank-Bezeichner

CAS
127-31-1
PubChem CID
31378
DTXSID
DTXSID7023061
ChEMBL
CHEMBL1201388
ChEBI
CHEBI:50885
UNII
U0476M545B
EC Number
204-833-2
Nikkaji
J10.052H

Eigenschaften

Berechnete Struktureigenschaften

XLogP
1,7
Polarare Oberfläche (TPSA)
94,8 Ų
H-Brücken-Donoren
3
H-Brücken-Akzeptoren
6
Frei drehbare Bindungen
2
Schwere Atome
27
Formalladung
0
Komplexität
734

Experimentelle und physikochemische Eigenschaften

Drugs · 2 Einträge

Pharmaceuticals -> Steroids

Pharmaceuticals -> Listed in ZINC15

LipidsLipids -> Sterol Lipids [ST] -> Steroids [ST02] -> C21 steroids (gluco/mineralocorticoids, progestogins) and derivatives [ST0203]
LogP · 2 Einträge

log Kow = 1.67

0.3

Color/FormCrystals
Solubility · 2 Einträge

In water, 140 mg/L at 25 °C

2.24e-01 g/L

Human Drugs · 2 Einträge

Pharmaceuticals

Adrenal hormones and synthetic substitutes

Endocrine DisruptorsPotential endocrine disrupting compound
Optical RotationSpecific optical rotation: 139 deg at 23 °C/D (c= 0.55 in 95% ethanol)
Physical DescriptionSolid

Sicherheit und Regulatorisches

Sicherheitsangaben dienen nur zur Orientierung und ersetzen weder das Sicherheitsdatenblatt (SDB) des Lieferanten noch geltende Vorschriften oder eine fachliche Bewertung.

GHS-Klassifizierung

GHS Classification · 4 Einträge

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P317, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Gefahrenhinweise

Other Safety InformationIMAP assessments - Pregn-4-ene-3,20-dione, 9-fluoro-11,17,21-trihydroxy-, (11.beta.)-: Environment tier I assessment
FDA Requirements · 1 Eintrag

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fludrocortisone acetate approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Fludrocortisone acetate/

Hazard Classes and CategoriesAcute Tox. 4 (100%)

Sicherheit und Schutzausrüstung

Disposal Methods · 1 Eintrag

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Toxikologische Informationen

Chemie und Industrie

Pharmakologische Informationen

ATC Code · 4 Einträge

H02AA02

H - Systemic hormonal preparations, excl. sex hormones and insulins

QH - Systemic hormonal preparations, excl. sex hormones and insulin

H02AA02

Protein BindingFludrocortisone is 70-80% protein bound in plasma, mostly to albumin and corticosteroid-binding globulin.
Pharmacodynamics · 1 Eintrag

Fludrocortisone is a synthetic mineralocorticoid used to replace endogenous [aldosterone] in conditions resulting in missing or inadequate endogenous synthesis. It acts on the kidneys to increase both sodium reabsorption and potassium excretion. As its effects are exerted at the transcriptional level, a single dose of fludrocortisone may work over the course of 1-2 days despite a relatively short plasma half-life. Like other systemic corticosteroids, fludrocortisone may mask signs of infection by depressing the normal immune response - infections occurring during fludrocortisone therapy should be promptly treated with appropriate antimicrobial therapy.

Mechanism of Action · 3 Einträge

The main endogenous mineralocorticoid, aldosterone, is produced in the zona glomerulosa of the adrenal cortex - it acts on mineralocorticoid receptors in the kidneys to increase sodium reabsorption and potassium excretion, which in turn helps to regulate plasma electrolyte composition and blood pressure. In conditions of adrenal insufficiency, such as Addison’s disease, aldosterone is not produced (or is produced in insufficient quantities) and must be replaced by exogenous mineralocorticoids such as fludrocortisone. Fludrocortisone binding to mineralocorticoid receptors causes alterations to DNA transcription and translation of proteins that result in an increased density of sodium channels on the apical side of renal tubule cells and an increased density of Na<sup>+</sup>-K<sup>+</sup>-ATPase on the basolateral side. These increases in receptor density result in increased plasma sodium concentrations, and thus increased blood pressure, as well as a decreased plasma potassium concentration. Fludrocortisone may also exert a direct effect on plasma sodium levels via action at the Na<sup>+</sup>-H<sup>+</sup> exchanger found in the apical membrane of renal tubule cells. Fludrocortisone also acts on glucocorticoid receptors, albeit with a much lower affinity - the glucocorticoid potency of fludrocortisone is approximately 5-10 times that of endogenous cortisol, whereas its mineralocorticoid potency is 200-400 times greater.

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Stability/Shelf Life
Fludrocortisone acetate tablets should be stored in well-closed containers at room temperature; excessive heat should be avoided. /Fludrocortisone acetate/
Other Experimental Properties · 3 Einträge

DECOMPOSES @ 260-262 °C

ODORLESS OR PRACTICALLY ODORLESS; MP 225 °C; FINE, WHITE TO PALE-YELLOW POWDER /ACETATE/

Crystals, polymorphic, mp 233-234 °C (ocasionally mp 205-208 °C, resolidifying on further heating, then mp 226-228 °C). Specific optical rotation at 23 °C: 123 deg (c = 0.64 chloroform). UV max (ethanol): 238 nm (E 16800). Solubility (mg/mL): water 0.04; acetone 56; alc 20; chloroform 20; ether 4. /21-acetate/

Physikochemische Eigenschaften

Schmelzpunkt
208 · 208-212°C
Siedepunkt
564.7 · 564.7±50.0 °C(Predicted)
Dichte
1.1176 · 1.1176 (estimate)
storage temp.
Refrigerator
Löslichkeit
DMSO (Slightly), Ethanol (Slightly, Heated), Methanol (Slightly, Sonicated)
Aggregatzustand
Solid
pka
12.11 · 12.11±0.70(Predicted)
Farbe
White to Off-White
Wasserlöslichkeit
111 mg/L · 111mg/L(25 ºC)
InChIKey
AAXVEMMRQDVLJB-MPVZUUJONA-N
SMILES
[C@@]12([H])CCC3=CC(=O)CC[C@]3(C)[C@@]1(F)[C@@H](O)C[C@]1(C)[C@@](CC[C@@]21[H])(O)C(=O)CO |&1:0,10,12,14,17,19,22,r|
CAS Datenbank
127 · 127-31-1(CAS DataBase Reference)
EPA chemische Informationen
-9 · Hydrocortisone-9.alpha.-fluoro (127-31-1)
Interactions · 5 Einträge

Concurrent use /of sodium-containing foods or medications/ with fludrocortisone in the treatment of Type IV renal tubular acidosis may result in hypernatremia, edema, and potentially severe increases in blood pressure;adjustment of sodium intake may be required.

In one published case report, lithium antagonized the mineralocorticoid effects of fludrocortisone; increased fludrocortisone dose and dietary sodium supplementation were required during concurrent use.

Risk of severe hypokalemia /when fludrocortisone is used concurrently with hypokalemia-causing medications/; monitoring of serum potassium concentration and cardiac function and potassium supplementation may be required.

Phenytoin and rifampin have been reported to increase 6-beta-hydroxylation of fludrocortisone, via induction of p450 liver enzymes; fludrocortisone dosage increase may be required.

For more Interactions (Complete) data for FLUDROCORTISONE (24 total), please visit the HSDB record page.

Adverse Effects · 1 Eintrag

Most of the adverse effects of fludrocortisone are 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 adverse effects appear in the list below:

Milk ConcentrationsCorticosteroids may be distributed into milk ... . /Corticosteroids/
Toxicity SummarySigns and Symptoms of Overdose
Human Toxicity Excerpts · 3 Einträge

/SIGNS AND SYMPTOMS/ Glucocorticoids may cause fetal damage when administered to pregnant women. One retrospective study of 260 women who received pharmacologic dosages of glucocorticoids during pregnancy revealed 2 instances of cleft palate, 8 stillbirths, 1 spontaneous abortion, and 15 premature births. Another study reported 2 cases of cleft palate in 86 births. Occurrence of cleft palate in these studies is higher than in the general population but could have resulted from the underlying diseases as well as from the steroids. Other fetal abnormalities that have been reported following glucocorticoid administration in pregnant women include hydrocephalus and gastroschisis. Women should be instructed to inform their physicians if they become or wish to become pregnant while receiving glucocorticoids. If glucocorticoids must be used during pregnancy or if the patient becomes pregnant while taking one of these drugs, the potential risks should be carefully considered. /Corticosteroids/

/CASE REPORTS/ The ... case of congestive cardiac failure in a child with Addison's disease secondary to fludrocortisone therapy is presented. A renal adaptation to compensate for chronic salt and water deprivation is suggested as a possible mechanism for the development of congestive cardiac failure in this patient.

/CASE REPORTS/ A severe metabolic alkalosis with compensatory respiratory acidosis and hypokalemia were reported in a 71-yr-old female patient following one yr of treatment with fludrocortisone, 0.2 mg/day, for postural hypotension. Following therapy which included diuretic administration, potassium supplementation and administration of spironolactone, the patient's clinical condition improved.

Drug Induced Liver Injury · 5 Einträge

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

fludrocortisone

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

Populations at Special Risk · 5 Einträge

Glucocorticoids should be used with caution in patients with hypothyroidism or cirrhosis, because such patients often show exaggerated response to the drugs. Glucocorticoids should be used with caution in psychotic patients or patients with hypertension or congestive heart failure. /Corticosteroids/

Because an apparent association has been suggested between use of corticosteroids and left ventricular free-wall rupture after a recent myocardial infarction, corticosteroids should be used with extreme caution in these patients. /Corticosteroids/

Because glucocorticoids increase susceptibility to and mask symptoms of infection, the drugs should not be used, except in life-threatening situations, in patients with viral infections or bacterial infections not controlled by anti-infectives. Manufacturers state that glucocorticoid oral inhalation therapy should be used with caution, if at all, in patients with untreated systemic fungal, bacterial, viral, or parasitic infections. Patients whose susceptibility to infection is high, such as those receiving glucocorticoids as immunosuppressive therapy, are especially likely to develop secondary infections. Patients receiving glucocorticoids who are potentially immunosuppressed should be warned of the risk of exposure to certain infections (e.g., chickenpox, measles) and of the importance of obtaining medical advice if such exposure occurs. Since glucocorticoid therapy can reactivate tuberculosis, treatment of latent tuberculosis infection should be included in the regimen of patients with a history of active tuberculosis undergoing prolonged glucocorticoid therapy. If glucocorticoids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary. Use of glucocorticoids in patients with active tuberculosis should be restricted to those with fulminating or disseminated tuberculosis in which glucocorticoids are used in conjunction with appropriate antimycobacterial chemotherapy. Manufacturers state that glucocorticoid oral inhalation therapy should be used with caution, if at all, in patients with clinical or asymptomatic Mycobacterium tuberculosis infections of the respiratory tract. Since glucocorticoids can reactivate latent amebiasis, any patient who has been in the tropics or who has unexplained diarrhea should be evaluated for amebiasis to exclude these patients prior to initiating therapy. In the treatment of acute or disseminated tuberculosis, glucocorticoids should only be used as part of a total antituberculosis regimen. ... /Corticosteroids/

Corticosteroids should be used with caution in patients with active or latent peptic ulcer, diverticulitis, nonspecific ulcerative colitis (if there is a probability of impending perforation, abscess, or other pyogenic infection), and in those with recent intestinal anastomoses. Manifestations of peritoneal irritation following GI perforation may be minimal or absent in patients receiving glucocorticoids. /Corticosteroids/

Environmental Water Concentrations · 1 Eintrag

While data specific to fludrocortisone were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soil(1).

Antidote and Emergency Treatment · 3 Einträge

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Regulatorische Informationen

FDA Requirements · 1 Eintrag

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fludrocortisone acetate approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Fludrocortisone acetate/

Sicherheitsdaten

risk_code
63
Toxizität
LD50 intraperitoneal in mouse: 170mg/kg
hazard_code
Xn
safety_code
22-26-36
Giftige Stoffe Daten
127-31-1(Hazardous Substances Data)

At the cellular level, corticosteroids diffuse across cell membranes and complex with specific cytoplasmic receptors. These complexes then enter the cell nucleus, bind to DNA (chromatin), and stimulate transcription of mRNA (messenger RNA) and subsequent protein synthesis of various enzymes thought to be ultimately responsible for the physiological effects of these hormones.

Mineralocorticoids act on the distal tubules to increase potassium excretion, hydrogen ion excretion, and sodium reabsorption and subsequent water retention. Cation transport in other secretory cells is similarly affected; excretion of water and electrolytes by the large intestine and by salivary and sweat glands is also altered, but to a lesser extent.

Biological Half-Life · 2 Einträge

The plasma half-life of fludrocortisone has been variably reported to be between 1-3.5 hours, though prescribing information gives an approximate half-life of 18-36 hours.

> or = 3.5 hours (plasma); 18-36 hours (biological).

Metabolism/Metabolites · 2 Einträge

There exists is a paucity of information regarding the specific metabolic pathway _in vivo_ of fludrocortisone. The 9α-fluorination of fludrocortisone appears to greatly simplify its metabolism as compared to other corticosteroids - while oxidation via 11-hydroxysteroid dehydrogenases has been observed, this reaction is greatly impaired as the fluorine moiety appears to confer "protection" from 11β-oxidation by these enzymes. The reduction in 11β-oxidation is thought to be one of the reasons behind fludrocortisone's profound mineralocorticoid potency. An _in vitro_ study generated only two metabolites following incubation in human liver microsomes and cytosol, namely 20β-dihydrofluorocortisol and 6β-hydroxyfluorocortisol, and did not explore in detail the potential enzymes responsible for this reaction. Given that fludrocortisone is a corticosteroid, a class of medications known to be metabolized by the CYP3A family, and is not recommended to be given with strong inhibitors/inducers of CYP3A, it is likely that the CYP3A family of enzymes contributes in some way to its metabolism (though this information does not appear to have been specifically elucidated for fludrocortisone).

STUDIED WERE KIDNEY SLICES, HOMOGENATES, & ISOLATED PERFUSED KIDNEYS. MAJOR METABOLITE: 20(EPSILON)-DIHYDRO-9ALPHA-FLUOROCORTISOL. ONLY 9ALPHA-FLUOROCORTISOL, NO METABOLITES, BOUND TO CYTOSOLIC RECEPTORS.

MeSH Pharmacological ClassificationSubstances that reduce or suppress INFLAMMATION.
Absorption, Distribution and Excretion · 6 Einträge

Absorption of fludrocortisone following oral administration is rapid and complete. Pharmacokinetic studies have estimated the Cmax to be 0.0012 to 0.20 μg/L with a Tmax between 0.5 and 2 hours. The AUC0-∞ of fludrocortisone after oral administration has been variably estimated to be between 1.22 to 3.07 μg.h/L.

Approximately 80% of an administered dose of fludrocortisone shows up in the urine, with the other 20% likely eliminated via fecal or biliary route.

The apparent volume of distribution of fludrocortisone is 80-85 L. Distribution into CSF appears minimal - the observed ratio of CSF drug concentration versus plasma drug concentration is 1:6.

Population pharmacokinetics have estimated the plasma clearance of fludrocortisone to be 40.8 L/h.

Elimination: Renal, mostly as inactive metabolites.

Oral: Rapidly and almost completely absorbed. Parenteral: Intramuscular: Freely soluble esters (sodium phosphate, sodium succinate) - Rapidly absorbed. Poorly soluble derivatives (acetate, acetonide, diacetate, hexacetonide, tebutate) - Slowly but completely absorbed. Local: Freely soluble esters - Less rapidly absorbed than with intramuscular injection. Poorly soluble derivatives - Slowiy but completely absorbed. /Corticosteroids (glucocorticoid effects - systemic)/

Cellular LocationsCytoplasm

Verwendung und Herstellung

Uses · 5 Einträge

For partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison's disease and for the treatment of salt-losing adrenogenital syndrome.

Very important applications include use in treating adrenocortical insufficiency or in other adrenocoritcoid replacement therapies, and in the management of salt-losing forms of congenital adrenogenital syndrome ... desoxycorticosterone acetate (a natural aldosterone precursor) and fludrocortisone are the only clinically significant mineralocorticoidal agents.

... Fludrocortisone is only used in the treatment of postural circulatory dysregulation where other drugs have failed.

THERAP CAT: Mineralocorticoid

For more Uses (Complete) data for FLUDROCORTISONE (7 total), please visit the HSDB record page.

Methods of Manufacturing · 2 Einträge

J Fried, EF Sabo, J Am Chem Soc, 76, 1455 (1954); GB 792224; J Fried, US 2852511 (both 1958 to Olin Mathieson)

One method starts with hydrocortisone acetate, which is first dehydrated to the 4,9-diene. The 9alpha-fluoro and 11beta-hydroxy groups are inserted by a method similar to that used for betamethasone. /Fludrocortisone acetate/

Formulations/PreparationsOral: Tablets: 0.1 mg Florinef Acetate (scored), (Monarch), Fludrocortisone Acetate Tablets (scored), (Barr), Fludrocortisone Acetate Tablets (scored), (Global). /Fludrocortisone acetate/
Use ClassificationPharmaceuticals

Vor- und nachgelagerte Produkte

Vorgelagerte Rohstoffe

hydrogen fluoridePhosphorus oxychloridehypobromous acidHydrocortison-21-acetatFluorwasserstoff

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Glucocorticoids may cause fetal damage when administered to pregnant women. One retrospective study of 260 women who received pharmacologic dosages of glucocorticoids during pregnancy revealed 2 instances of cleft palate, 8 stillbirths, 1 spontaneous abortion, and 15 premature births. Another study reported 2 cases of cleft palate in 86 births. Occurrence of cleft palate in these studies is higher than in the general population but could have resulted from the underlying diseases as well as from the steroids. Other fetal abnormalities that have been reported following glucocorticoid administration in pregnant women include hydrocephalus and gastroschisis. Women should be instructed to inform their physicians if they become or wish to become pregnant while receiving glucocorticoids. If glucocorticoids must be used during pregnancy or if the patient becomes pregnant while taking one of these drugs, the potential risks should be carefully considered. /Corticosteroids/