Fludrocortisone
Vue d'ensemble
Description
La fludrocortisone est un corticostéroïde synthétique aux propriétés minéralocorticoïdes puissantes. Elle est principalement utilisée pour traiter des affections telles que l’insuffisance surrénalienne et le syndrome adrénogénital avec perte de sel . La this compound imite l’action de l’aldostérone, une hormone naturellement présente dans l’organisme, et est structurellement similaire au cortisol .
Mécanisme D'action
La fludrocortisone exerce ses effets en imitant l’action de l’aldostérone sur les récepteurs minéralocorticoïdes du rein . Elle favorise la réabsorption du sodium et l’excrétion du potassium, ce qui entraîne une augmentation du volume du liquide extracellulaire et de la pression artérielle . Les cibles moléculaires impliquées comprennent les canaux sodiques sur la bordure apicale des cellules tubulaires rénales et la Na±K±ATPase sur la membrane basolatérale .
Applications De Recherche Scientifique
La fludrocortisone possède un large éventail d’applications en recherche scientifique :
Chimie : Elle est utilisée comme composé modèle pour étudier les effets de la fluoration sur l’activité des stéroïdes.
Médecine : Elle est utilisée pour traiter des affections telles que la maladie d’Addison et le syndrome adrénogénital avec perte de sel.
Méthodes De Préparation
La fludrocortisone est synthétisée par une série de réactions chimiques à partir du cortisol. La production industrielle de l’acétate de this compound implique l’utilisation de procédés de séchage par pulvérisation pour créer des dispersions solides du composé .
Analyse Des Réactions Chimiques
La fludrocortisone subit diverses réactions chimiques, notamment :
Oxydation : La this compound peut être oxydée pour former la 3-céto-fludrocortisone et ses métabolites tétrahydro et dihydro.
Réduction : Les réactions de réduction peuvent convertir la this compound en métabolites moins puissants.
Substitution : L’introduction d’un atome de fluor en position 9 est une réaction de substitution clé qui renforce son activité minéralocorticoïde.
Les réactifs et les conditions courants utilisés dans ces réactions comprennent les agents oxydants forts pour l’oxydation et les agents réducteurs pour la réduction. Les principaux produits formés à partir de ces réactions sont divers métabolites de la this compound, qui présentent des niveaux de puissance différents .
Comparaison Avec Des Composés Similaires
La fludrocortisone est unique parmi les corticostéroïdes en raison de sa forte puissance minéralocorticoïde. Des composés similaires comprennent :
Hydrocortisone : Un glucocorticoïde présentant une certaine activité minéralocorticoïde, utilisé en association avec la this compound pour traiter l’insuffisance surrénalienne.
Prednisone et prednisolone : Corticostéroïdes à action intermédiaire présentant à la fois une activité glucocorticoïde et minéralocorticoïde.
La particularité de la this compound réside dans sa modification structurelle (fluoration) qui renforce considérablement son activité minéralocorticoïde par rapport aux autres corticostéroïdes .
Propriétés
IUPAC Name |
(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 |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
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 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
AAXVEMMRQDVLJB-BULBTXNYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC12CCC(=O)C=C1CCC3C2(C(CC4(C3CCC4(C(=O)CO)O)C)O)F |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
C[C@]12CCC(=O)C=C1CC[C@@H]3[C@@]2([C@H](C[C@]4([C@H]3CC[C@@]4(C(=O)CO)O)C)O)F |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C21H29FO5 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID7023061 |
Source
|
| Record name | Fludrocortisone | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7023061 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
380.4 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Fludrocortisone | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014825 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
In water, 140 mg/L at 25 °C, 2.24e-01 g/L |
Source
|
| Record name | FLUDROCORTISONE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3332 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Fludrocortisone | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014825 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
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+-K+-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+-H+ 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., 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. |
Source
|
| Record name | Fludrocortisone | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00687 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | FLUDROCORTISONE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3332 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
Crystals | |
CAS No. |
127-31-1 |
Source
|
| Record name | Fludrocortisone | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=127-31-1 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Fludrocortisone [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000127311 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Fludrocortisone | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00687 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | fludrocortisone | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=11318 | |
| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
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| Record name | Fludrocortisone | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7023061 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Fludrocortisone | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.004.395 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | FLUDROCORTISONE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/U0476M545B | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
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| Record name | FLUDROCORTISONE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3332 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Fludrocortisone | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014825 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
Q1: How does fludrocortisone exert its effects in the body?
A1: this compound is a synthetic mineralocorticoid, primarily acting as an analog of aldosterone. It binds to the mineralocorticoid receptor (MR) in the distal tubules of the kidney, promoting sodium reabsorption and increasing the excretion of potassium and hydrogen ions. [, , , ] This action leads to increased plasma volume, contributing to increased blood pressure, making it clinically relevant for managing conditions like postural hypotension and adrenal insufficiency. [, , , ]
Q2: Can this compound's glucocorticoid activity contribute to its clinical effects?
A2: While this compound primarily acts as a mineralocorticoid, it also possesses glucocorticoid activity, though significantly less potent than its mineralocorticoid effects. [, ] This glucocorticoid activity becomes particularly relevant at higher doses, as seen in the treatment of postural hypotension, where it may contribute to side effects like posterior subcapsular cataract formation. []
Q3: How does this compound impact potassium levels?
A3: this compound's interaction with MR in the distal tubules promotes potassium excretion. This effect can lead to hypokalemia, especially with prolonged use or high doses. [, , , , , , ] Monitoring potassium levels is crucial during this compound therapy. [, ]
Q4: What is the chemical structure of this compound?
A4: this compound is a synthetic halogenated derivative of hydrocortisone, specifically 9α-Fluorohydrocortisone. Its chemical formula is C21H29FO5.
Q5: What are the common clinical uses of this compound?
A5: this compound is used in the management of:
- Primary adrenocortical insufficiency (Addison's disease): Supplementing mineralocorticoid deficiency. [, ]
- Postural hypotension (orthostatic hypotension): Increasing blood volume to alleviate symptoms. [, , , , ]
- Cerebral salt wasting syndrome (CSWS): Correcting hyponatremia by promoting sodium reabsorption. [, ]
Q6: Are there differences in the effectiveness of this compound compared to other treatments for orthostatic hypotension?
A7: Evidence comparing this compound to other treatments for orthostatic hypotension, such as midodrine or droxidopa, remains limited. Some studies suggest that while this compound may be effective, it might be associated with a higher risk of side effects, particularly in elderly patients or those with pre-existing conditions like congestive heart failure. [, , , , ]
Q7: Is this compound effective in managing hyperkalemia in hemodialysis patients?
A8: A randomized controlled trial investigated the use of this compound for hyperkalemia in hemodialysis patients. [] While the treatment was safe and well-tolerated, it did not demonstrate clinically significant reductions in serum potassium levels. []
Q8: What is the role of this compound in managing subarachnoid hemorrhage (SAH)?
A9: this compound has been investigated for its potential to prevent hyponatremia and subsequent complications in patients with SAH. [, , ] Some studies suggest that early administration of this compound, particularly in patients with increased urinary sodium excretion, may reduce the incidence of symptomatic cerebral vasospasm. []
Q9: What are the potential adverse effects associated with this compound?
A9: Potential adverse effects of this compound, particularly with prolonged use or high doses, include:
- Hypokalemia: Due to increased potassium excretion. [, , , , , , ]
- Hypertension: Due to increased sodium and water retention. [, , , , ]
- Fluid retention and edema: [, , ]
- Posterior subcapsular cataract formation: Primarily associated with the glucocorticoid activity. []
Q10: Are there any significant drug interactions with this compound?
A10: this compound may interact with various medications, including:
- Potassium-lowering drugs (e.g., diuretics): May increase the risk of hypokalemia. []
- Corticosteroids: May increase the risk of side effects. []
Q11: What factors should clinicians consider when prescribing this compound?
A11: Clinicians should consider the following:
- Patient age: Elderly patients may be more susceptible to adverse effects. []
- Co-existing medical conditions: Conditions like congestive heart failure, hypertension, and renal insufficiency may influence treatment decisions. [, ]
- Concomitant medications: Assess for potential drug interactions. []
- Monitoring: Regular monitoring of blood pressure, electrolytes (particularly potassium), and signs of fluid retention is essential. [, , ]
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