RESUMEN
The objective of this case is to describe the pharmacokinetics and toxicity of midodrine in overdose. A 20 year old female ingested up to 350 mg midodrine while recovering in hospital from another overdose. She developed vomiting and severe hypertension (blood pressure [BP], 210/100 mmHg). Remarkable findings included a heart rate with a range of 43-60 beats/min, spontaneous respirations (20 breaths/min), and oxygen saturations of >95 % on FiO2 25 %, and a GS of 8. She was admitted to intensive care and had a normal non-contrast CT brain. She was treated with a glyceryl trinitrate patch (5 mg) and observed for 36 h with subsequent BP reduction to 124/81 mmHg and improved in conscious state. Midodrine and desglymidodrine concentrations were measured with liquid chromatography tandem mass spectrometry and were detected with 2-h post-ingestion at concentrations of 158.4 and 169.7 ng/mL, respectively. The parent drug concentrations rapidly decreased with an elimination of half-life of 1.6 h, and the metabolite initially increased and then decreased. The peak in blood pressure appeared to coincide with peak metabolite concentrations. Midodrine in overdose can potentially cause severe hypertension and reflex bradycardia but given its short half-life treatment with vasodilator agents and supportive care is sufficient.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/envenenamiento , Bradicardia/inducido químicamente , Sobredosis de Droga/terapia , Hipertensión/inducido químicamente , Midodrina/envenenamiento , Presión Sanguínea/efectos de los fármacos , Bradicardia/terapia , Sobredosis de Droga/fisiopatología , Femenino , Escala de Coma de Glasgow , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/terapia , Midodrina/análogos & derivados , Midodrina/sangre , Nitroglicerina/uso terapéutico , Vasodilatadores/uso terapéutico , Adulto JovenRESUMEN
A simple, rapid and sensitive liquid chromatography-tandem mass spectrometry method was developed for quantification of deglymidodrine in human plasma. The plasma samples were pretreated by protein precipitation with trichloroacetate. The chromatographic separation was performed on reversed phase Aquasil C18 column, and the plasma extraction was eluted with a mobile phase solution consisting of acetonitrile (containing 0.02% formic acid) and water (containing 0.02% formic acid). The molecular ion of analyte was detected in positive ionization by multiple reaction monitoring. The mass transitions of m/z 198.4--> 148.1 and m/z 212.4--> 162.3 were used for detection of deglymidodrine and its internal standard, respectively. The assay exhibited linear ranges from 0.25 to 32 ng/ml for the analyte in human plasma. Acceptable precision and accuracy were obtained for concentrations of quality control (QC) samples. The proposed method has been successfully used to analyze human plasma samples for application in oral pharmacokinetic study.
Asunto(s)
Midodrina/análogos & derivados , Adulto , Calibración , Cromatografía Liquida , Humanos , Masculino , Espectrometría de Masas , Midodrina/sangre , Midodrina/farmacocinética , Reproducibilidad de los ResultadosRESUMEN
A specific, rapid, sensitive and selective ultra-performance liquid chromatography - tandem mass spectrometry has been developed for the simultaneous determination of midodrine and desglymidodrine in human plasma. The analytes and its deuterated analogs were quantitatively extracted from 100µL of human plasma by solid phase extraction technique. Separation of analytes was achieved on the Waters Acquity UPLC BEH C18 (50×2.1mm, 1.7µm) column using acetonitrile-4.0mM ammonium formate, pH 2.5(90:10, v/v) as mobile phase. The protonated analytes were quantified by selected reaction monitoring in the positive ionization mode by triple quadrupole mass spectrometer. The calibration plots were linear over the concentration range of 0.050-50.0ng/mL. The intra-batch and inter-batch precision (%CV) across quality control levels was <4.0 and the% mean relative recovery was ≥96%. Various other parameters like stability in different conditions; matrix effect and reproducibility of the method were performed in accordance with the guidelines specified by the USFDA for bioanalytical method development and validation. The developed method was successfully administered to the pharmacokinetics study of 5 mg midodrine tablet in 12 healthy subjects. Reproducibility of assay was proved by reanalysis of 48 incurred samples.
Asunto(s)
Midodrina/análogos & derivados , Midodrina/sangre , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Líquida de Alta Presión/normas , Estudios Cruzados , Humanos , Midodrina/análisis , Espectrometría de Masas en Tándem/normas , Equivalencia Terapéutica , Factores de TiempoRESUMEN
Midodrine (MD) is a prodrug that is converted after oral administration to Desglymidodrine (DMD). In this study, an LC-MS/MS assay was developed and validated for investigation of the pharmacokinetics of MD and DMD in non azotemic patients with liver cirrhosis and tense ascites. Results were compared to those noted with healthy volunteers following the adminstration of a single oral dose of MD. Sample preparation was performed by liquid-liquid extraction using t-butyl methyl ether. HPLC separation was carried out using RP C18 column (4.6mm×50mm, 5µm). Isocratic elution was performed using methanol:0.2% formic acid (70:30, v/v) as the mobile phase, at a flow rate of 0.7mL/min. Tandem mass spectrometric detection was employed at positive electrospray ionization in MRM mode for the determination of MD and DMD. Analysis was carried out within 1.0min over a concentration range of 0.50-40.00ng/mL for the prodrug and its active metabolite. The assay was validated according to FDA guidelines for bioanalytical method validation and satisfactory results were obtained. The applicability of the assay for the determination of the pharmacokinetic parameters of MD and DMD and personalized therapy was demonstrated in healthy volunteers and ascitic patients. Results revealed significant differences in pharmacokinetic parameters among the studied groups. Such differences were explained on the basis of the medical condition and co-adminstered medications exerting possible drug-drug interaction. Results confirmed the need for implementation of reliable analysis tools for therapeutic dose adjustment.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1/sangre , Cromatografía Líquida de Alta Presión/métodos , Midodrina/análogos & derivados , Espectrometría de Masas en Tándem/métodos , Agonistas de Receptores Adrenérgicos alfa 1/metabolismo , Ascitis/tratamiento farmacológico , Monitoreo de Drogas/métodos , Humanos , Límite de Detección , Extracción Líquido-Líquido/métodos , Cirrosis Hepática/tratamiento farmacológico , Midodrina/sangre , Midodrina/metabolismo , Profármacos/metabolismo , Profármacos/farmacocinéticaRESUMEN
Midodrine is an orally active adrenergic agonist useful in the treatment of hypotension. We have investigated the pharmacodynamics of its active metabolite after oral midodrine therapy in nine patients with severe orthostatic hypotension. Peak plasma levels of the metabolite were reached in 60 to 90 minutes and ranged from 25 to 56 ng/ml. The mean values for distribution volume, plasma clearance, and t1/2 were 4.0 L/kg, 23 ml/min/kg, and 2.1 hours, respectively. Heart rate increased after 5 to 10 mg doses and the increases were statistically significant (P less than 0.05) at 120 minutes. An apparent increase in blood pressure was not statistically significant. The patients said that they felt better.
Asunto(s)
Etanolaminas/uso terapéutico , Hipotensión Ortostática/tratamiento farmacológico , Midodrina/uso terapéutico , Administración Oral , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Cromatografía Liquida , Dopamina/sangre , Epinefrina/sangre , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Cinética , Masculino , Persona de Mediana Edad , Midodrina/análogos & derivados , Midodrina/sangre , Midodrina/metabolismo , Norepinefrina/sangre , Síndrome de Shy-Drager/tratamiento farmacológicoRESUMEN
A simple and sensitive fluorometric high-performance liquid chromatographic method was developed for the determination of midodrine in human plasma. After liquid-liquid extraction from plasma, the drug and 2-phenylglycinol (internal standard) were convened into the corresponding fluorescent derivatives by reaction with 3,4-dihydro-6,7-dimethoxy-4-methyl-3-oxoquinoxaline-2-carbonyl chloride, a fluorescence derivatization reagent for amines. The derivatives were separated within 30 min on a reversed-phase column using isocratic elution with acetonitrile-methanol-water (10:30:60, v/v) and were detected spectrofluorometrically at 485 nm with excitation at 400 nm. The detection limit for midodrine was 0.3 pmol (76 pg) per mL plasma at a signal-to-noise ratio of 3.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Midodrina/sangre , Agonistas alfa-Adrenérgicos/administración & dosificación , Agonistas alfa-Adrenérgicos/sangre , Agonistas alfa-Adrenérgicos/aislamiento & purificación , Adulto , Fluorescencia , Humanos , Masculino , Midodrina/administración & dosificación , Midodrina/farmacocinética , Quinoxalinas , Estándares de Referencia , Sensibilidad y EspecificidadRESUMEN
An automated column-switching HPLC system is described for the simultaneous determination of midodrine, an alpha-adrenergic stimulating drug, and its active metabolite, ST-1059. Serum or plasma (850 microliters) is directly injected onto a RP18 (30 micrograms particle size) pre-column (9 x 4 mm ID) which acts as an on-line liquid-solid extractor and analyte enrichment system. The injection is followed by washing steps. The fraction containing the analytes is transferred onto an analytical RP18 column via step gradient elution where the final analysis is performed. Fluorescence detection is used (lambda ex 290 nm and lambda em 322 nm), and method detection limits of 0.8 ng/mL plasma were reached. These were sufficiently low to determine the plasma concentration-time profiles for both compounds following oral administration of 2.5 mg and 5 mg midodrine hydrochloride. The assay in serum or plasma was linear in the range of 1 to 15 ng analyte/mL, the recovery was greater than 95%, and the reproducibility was sufficient. The assay was rugged and was maintained by routinely changing the home-made, dry packed pre-column every 20th serum injection.
Asunto(s)
Etanolaminas/metabolismo , Midodrina/metabolismo , Fenómenos Químicos , Química , Cromatografía Líquida de Alta Presión , Humanos , Midodrina/sangre , Espectrometría de FluorescenciaRESUMEN
The pharmacokinetics of midodrin (alpha-2,5-dimethoxyphenyl-beta-glycinamidoethanol hydrochloride, ST 1085) and its main metabolite ST 1059 (alpha-2,5-dimethoxyphenyl-beta-aminoethanol hydrochloride) have been investigated in 12 male healthy volunteers. 2.5 mg midodrin hydrochloride were applied intravenously, as drinking solution or as tablet (Gutron) according to a randomized cross-over design. Plasma and urine samples collected up to 24 h after application were analyzed by high-performance liquid chromatography with fluorescence detection. The mean maximum concentration in plasma for midodrin was ca. 10 ng/ml 20-30 min after oral administration, for ST 1059 ca. 5 ng/ml after 1 h. Midodrin was eliminated with a terminal half-life of 0.5 h. The half-life of ST 1059 was determined to be 3 h. The mean area under the plasma-level vs. time curve (AUC) of ST 1059 after administration of 2.5 mg midodrin i.v. was 28.7 ng X h/ml, and as drinking solution or as tablet 25.7 and 25.6 ng X h/ml, respectively. The data of 10 volunteers could be used for the calculations of the bioavailability of ST 1059 by the AUC. Assuming an interval of equivalence of 0.75-1.25 because of the relatively small number of volunteers, the three galenical formulations are considered to be equivalent.
Asunto(s)
Agonistas alfa-Adrenérgicos/metabolismo , Etanolaminas/metabolismo , Midodrina/metabolismo , Administración Oral , Agonistas alfa-Adrenérgicos/administración & dosificación , Agonistas alfa-Adrenérgicos/sangre , Adulto , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Humanos , Inyecciones Intravenosas , Cinética , Masculino , Midodrina/administración & dosificación , Midodrina/análogos & derivados , Midodrina/sangreRESUMEN
Midodrine, i.v. or orally administered, causes a prolonged elevation of blood pressure and a reduction in heart rate. These cardiovascular changes are not correlated to the plasma levels of the intact drug. On administration of either midodrine or its metabolite, ST-1059, formed by cleavage of the glycine residue, the elevation of blood pressure and the reduction in heart rate were significantly correlated to the plasma level of ST-1059. The results are in agreement with the assumption that the pressor activity of midodrine is mainly exerted by its metabolite ST-1059.