Fludrocortisona
Descripción general
Descripción
La fludrocortisona es un corticosteroide sintético con potentes propiedades mineralocorticoides. Se utiliza principalmente para tratar afecciones como la insuficiencia adrenocortical y el síndrome adrenogenital con pérdida de sal . La this compound imita la acción de la aldosterona, una hormona natural en el cuerpo, y es estructuralmente similar a la cortisol .
Mecanismo De Acción
La fludrocortisona ejerce sus efectos imitando la acción de la aldosterona sobre los receptores mineralocorticoides en el riñón . Promueve la reabsorción de sodio y la excreción de potasio, lo que lleva a un aumento del volumen de líquido extracelular y la presión arterial . Los objetivos moleculares involucrados incluyen los canales de sodio en el borde apical de las células tubulares renales y la Na±K±ATPasa en la membrana basolateral .
Aplicaciones Científicas De Investigación
La fludrocortisona tiene una amplia gama de aplicaciones de investigación científica:
Química: Se utiliza como un compuesto modelo para estudiar los efectos de la fluoración en la actividad de los esteroides.
Medicina: Se utiliza para tratar afecciones como la enfermedad de Addison y el síndrome adrenogenital con pérdida de sal.
Métodos De Preparación
La fludrocortisona se sintetiza a través de una serie de reacciones químicas que comienzan con la cortisol. La producción industrial de acetato de this compound implica el uso de procesos de secado por pulverización para crear dispersiones sólidas del compuesto .
Análisis De Reacciones Químicas
La fludrocortisona se somete a diversas reacciones químicas, que incluyen:
Oxidación: La this compound se puede oxidar para formar 3-ceto-fludrocortisona y sus metabolitos tetrahidro y dihidro.
Reducción: Las reacciones de reducción pueden convertir la this compound en metabolitos menos potentes.
Los reactivos y condiciones comunes utilizados en estas reacciones incluyen agentes oxidantes fuertes para la oxidación y agentes reductores para la reducción. Los principales productos formados a partir de estas reacciones son varios metabolitos de this compound, que tienen diferentes niveles de potencia .
Comparación Con Compuestos Similares
La fludrocortisona es única entre los corticosteroides debido a su alta potencia mineralocorticoide. Los compuestos similares incluyen:
Hidrocortisona: Un glucocorticoide con cierta actividad mineralocorticoide, utilizado en combinación con this compound para tratar la insuficiencia suprarrenal.
Prednisona y Prednisolona: Corticosteroides de acción intermedia con actividad tanto glucocorticoide como mineralocorticoide.
La singularidad de la this compound radica en su modificación estructural (fluoración) que mejora significativamente su actividad mineralocorticoide en comparación con otros corticosteroides .
Propiedades
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. | |
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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. | |
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. | |
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| 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. | |
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| 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: Fludrocortisone 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 fludrocortisone's glucocorticoid activity contribute to its clinical effects?
A2: While fludrocortisone 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 fludrocortisone impact potassium levels?
A3: Fludrocortisone'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 fludrocortisone therapy. [, ]
Q4: What is the chemical structure of fludrocortisone?
A4: Fludrocortisone is a synthetic halogenated derivative of hydrocortisone, specifically 9α-Fluorohydrocortisone. Its chemical formula is C21H29FO5.
Q5: What are the common clinical uses of fludrocortisone?
A5: Fludrocortisone 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 fludrocortisone compared to other treatments for orthostatic hypotension?
A7: Evidence comparing fludrocortisone to other treatments for orthostatic hypotension, such as midodrine or droxidopa, remains limited. Some studies suggest that while fludrocortisone 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 fludrocortisone effective in managing hyperkalemia in hemodialysis patients?
A8: A randomized controlled trial investigated the use of fludrocortisone 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 fludrocortisone in managing subarachnoid hemorrhage (SAH)?
A9: Fludrocortisone has been investigated for its potential to prevent hyponatremia and subsequent complications in patients with SAH. [, , ] Some studies suggest that early administration of fludrocortisone, 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 fludrocortisone?
A9: Potential adverse effects of fludrocortisone, 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 fludrocortisone?
A10: Fludrocortisone 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 fludrocortisone?
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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