Prolongación del tiempo QT
Eventos adversos de medicamentos
Variantes ✨Para la evaluación computacionalmente intensiva de las variantes, elija la suscripción estándar paga.
Explicaciones de las sustancias para pacientes.
No existen advertencias adicionales para la combinación de lorazepam y prometazina. Consulte también la información especializada pertinente.
Los cambios informados en la exposición corresponden a los cambios en la curva de concentración plasmática-tiempo [ AUC ]. No esperamos ningún cambio en la exposición a lorazepam, cuando se combina con prometazina (100%). No esperamos ningún cambio en la exposición a prometazina, cuando se combina con lorazepam (100%).
Los parámetros farmacocinéticos de la población media se utilizan como punto de partida para calcular los cambios individuales en la exposición debidos a las interacciones.
La lorazepam tiene una alta biodisponibilidad oral [ F ] del 100 %, por lo que el nivel plasmático máximo [Cmax] tiende a cambiar poco durante una interacción. La vida media terminal [ t12 ] es de 14.3 horas y se alcanzan niveles plasmáticos constantes [ Css ] después de aproximadamente 57.2 horas. La unión a proteínas [ Pb ] es moderadamente fuerte al 100 % y el volumen de distribución [ Vd ] es muy grande a 111 litros. El metabolismo no tiene lugar a través de los citocromos comunes y el transporte activo tiene lugar especialmente a través de UGT2B7.
La prometazina tiene una baja biodisponibilidad oral [ F ] del 100 %, por lo que el nivel plasmático máximo [Cmax] tiende a cambiar fuertemente con una interacción. La vida media terminal [ t12 ] es de 14.5 horas y se alcanzan niveles plasmáticos constantes [ Css ] después de aproximadamente 58 horas. La unión a proteínas [ Pb ] es moderadamente fuerte al 100 %. El metabolismo tiene lugar principalmente a través de CYP2D6.
|Efectos serotoninérgicos a||0||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la lorazepam ni la prometazina aumentan la actividad serotoninérgica.
|Kiesel & Durán b||3||Ø||+++|
Recomendación: Como precaución, se debe prestar atención a los síntomas anticolinérgicos, especialmente después de aumentar la dosis y en dosis en el rango terapéutico superior.
Clasificación: La prometazina aumenta en gran medida la actividad anticolinérgica. El efecto anticolinérgico de la lorazepam no es relevante.
Prolongación del tiempo QT
La prometazina puede aumentar potencialmente el tiempo QT, pero no tenemos conocimiento de arritmias del tipo torsades de pointes. No conocemos ningún potencial de prolongación del intervalo QT de la lorazepam.
Efectos adversos generales
|Efectos secundarios||∑ frecuencia||lor||pro|
|Efecto hangover||1.0 %||+||n.a.|
|Efecto rebote||1.0 %||+||n.a.|
Reducción del umbral de convulsividad: prometazina
Síndrome neuroléptico maligno: prometazina
Depresion respiratoria: lorazepam, prometazina
Con base en sus respuestas e información científica, evaluamos el riesgo individual de efectos secundarios adversos. Estas recomendaciones están destinadas a asesorar a los profesionales y no sustituyen la consulta con un médico. En la versión de prueba restringida (alfa), el riesgo de todas las sustancias aún no se ha evaluado de manera concluyente.
Abstract: No Abstract available
Abstract: Healthy volunteers received single doses of three benzodiazepines (diazepam, 10 mg i.v.; alprazolam, 1.0 mg orally; lorazepam, 2 mg i.v.) on two occasions in random sequence. One trial was a control; for the other, subjects ingested propoxyphene, 65 mg every 6 h, for the duration of the benzodiazepine study. The kinetics of each benzodiazepine were determined from multiple plasma concentrations measured following each dose. For diazepam, propoxyphene produced a small and statistically insignificant prolongation of elimination half-life (43 vs 38 h) and reduction of total clearance (0.41 vs 0.47 ml min-1 kg-1). Propoxyphene significantly prolonged alprazolam half-life (18 vs 12 h, P less than 0.005) and reduced total clearance (0.8 vs 1.3 ml min-1 kg-1, P less than 0.005). Propoxyphene had no apparent influence on lorazepam half-life (13.4 vs 13.5 h) or clearance (1.5 vs 1.4 ml min-1 kg-1). Thus propoxyphene significantly impairs the clearance of alprazolam, biotransformed mainly by the oxidative reaction of aliphatic hydroxylation. Propoxyphene has far less effect on the oxidation of diazepam by N-demethylation, and has no apparent influence on lorazepam conjugation.
Abstract: This article reviews clinical pharmacokinetic data on the H1-receptor antagonists, commonly referred to as the antihistamines. Despite their widespread use over an extended period, relatively little pharmacokinetic data are available for many of these drugs. A number of H1-receptor antagonists have been assayed mainly using radioimmunoassay methods. These have also generally measured metabolites to greater or lesser extents. Thus, the interpretation of such data is complex. After oral administration of H1-receptor antagonists as syrup or tablet formulations, peak plasma concentrations are usually observed after 2 to 3 hours. Bioavailability has not been extensively studied, but is about 0.34 for chlorpheniramine, 0.40 to 0.60 for diphenhydramine, and about 0.25 for promethazine. Most of these drugs are metabolised in the liver, this being very extensive in some instances (e.g. cyproheptadine and terfenadine). Total body clearance in adults is generally in the range of 5 to 12 ml/min/kg (for astemizole, brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, promethazine and triprolidine), while their elimination half-lives range from about 3 hours to about 18 days [cinnarizine about 3 hours; diphenhydramine about 4 hours; promethazine 10 to 14 hours; chlorpheniramine 14 to 25 hours; hydroxyzine about 20 hours; brompheniramine about 25 hours; astemizole and its active metabolites about 7 to 20 days (after long term administration); flunarizine about 18 to 20 days]. They also have relatively large apparent volumes of distribution in excess of 4 L/kg. In children, the elimination half-lives of chlorpheniramine and hydroxyzine are shorter than in adults. In patients with alcohol-related liver disease, the elimination half-life of diphenhydramine was increased from 9 to 15 hours, while in patients with chronic renal disease that of chlorpheniramine was very greatly prolonged. Little, if any, published information is available on the pharmacokinetics of these drugs in neonates, pregnancy or during lactation. The relatively long half-lives of a number of the older H1-receptor antagonists such as brompheniramine, chlorpheniramine and hydroxyzine suggest that they can be administered to adults once daily.
Abstract: Eleven subjects received acetaminophen (650 mg i.v.) on two occasions in random sequence, with and without concurrent administration of probenecid (500 mg) every 6 hr. Nine subjects similarly received lorazepam (2 mg. i.v.) with and without concurrent probenecid. Acetaminophen half-life was prolonged during probenecid treatment (mean +/- S.E., 4.30 +/- 0.23 vs. 2.51 +/- 0.16 hr; P less than .001) due to markedly decreased clearance (178 +/- 13 vs. 329 +/- 24 ml/min; P less than .001) with no change in volume of distribution (65 +/- 4 vs. 69 +/- 3 l; NS). Urinary excretion of acetaminophen glucuronide during 24 hr was decreased (84 +/- 9 vs. 260 +/- 21 mg of acetaminophen as glucuronide; P less than .001) and acetaminophen sulfate excretion was increased (323 +/- 25 vs. 217 +/- 17 mg of acetaminophen as sulfate; P less than .005) during concurrent probenecid treatment. However, the sum of the two conjugated metabolites was not significantly different (407 +/- 28 vs. 476 +/- 20 mg of acetaminophen as glucuronide plus sulfate excreted per 24 hr; NS). Lorazepam half-life was also prolonged during probenecid treatment (33.0 +/- 3.9 vs. 14.3 +/- 1.08 hr; P less than .001) due to decreased clearance (44.7 +/- 5.4 vs. 80.3 +/- 13.2 ml/min; P less than .001) with no change in volume of distribution (111 +/- 5 vs. 111 +/- 7 l; NS). Formation of the ether glucuronides of acetaminophen and lorazepam is impaired markedly by therapeutic doses of probenecid. Sulfate conjugation is not affected.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: No Abstract available
Abstract: The pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories at three dosage strengths and oral syrup were studied. The study had an open-label, randomized, crossover design. At intervals of five to nine days, healthy volunteers were given two 12.5-mg promethazine rectal suppositories, one 25-mg suppository, one 50-mg suppository, or 50 mg (10 mL) of promethazine oral syrup. Blood samples were collected before each dose and at intervals from 0.5 to 48 hours afterward. Promethazine concentration was determined by high-performance liquid chromatography, and pharmacokinetic values were calculated with noncompartmental methods. Thirty-six subjects (18 men and 18 women) completed the study. Absorption was highly variable for all the formulations. On average, absorption was more rapid and the maximum plasma concentration (Cmax) higher for the syrup than for the suppositories. Cmax was significantly lower for the 50-mg suppository (mean, 9.04 ng/mL) than for the syrup (19.3 ng/mL). The time to Cmax (tmax) was significantly shorter for the syrup (mean, 4.4 hours) than for the suppositories (6.7-8.6 hours). There were no significant differences in dose-normalized Cmax among the three suppository treatments. Area under the concentration-versus-time curve (AUC) was comparable between the syrup and the 50-mg suppository and between the treatments with two 12.5-mg suppositories and the 25-mg suppository. Elimination profiles were similar among all treatments (mean half-life [t1/2], 16-19 hours). There were no significant differences in pharmacokinetics on the basis of sex or race. The mean relative bioavailability for the three suppository treatments ranged from 70% to 97%. Individual relative bioavailabilities ranged from 4% to 343%. The pharmacokinetics of promethazine administered in oral syrup and rectal suppositories were highly variable, but, in general, the suppositories produced a lower Cmax and later tmax than the syrup. All formulations were comparable in terms of dose-normalized AUC and t1/2, and the three suppository treatments were comparable in terms of dose-normalized Cmax.
Abstract: OBJECTIVE: To evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point. METHODS: Nine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 microg/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs. RESULTS: The bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins. CONCLUSION: Despite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.
Abstract: The present study investigates the kinetic disposition with focus on the racemization, glucuronidation capacity and the transplacental transfer of lorazepam in term parturients during labor. The study was conducted on 10 healthy parturients aged 18-37 years with a gestational age of 36-40.1 weeks, treated with a single oral dose of 2 mg racemic lorazepam 2-9 h before delivery. Maternal venous blood and urine samples were obtained over a 0-48 h interval and the umbilical cord sample was obtained immediately after clamping. Lorazepam enantiomers were determined in plasma and urine samples by LC-MS/MS using a Chiralcel OD-R column. In vitro racemization of lorazepam required the calculation of the pharmacokinetic parameters as isomeric mixtures. The data were fitted to two-compartment model and the pharmacokinetic parameters are reported as means (95% CI): t(1/2a) 3.2h (2.6-3.7 h), K(a) 0.23 h(-1) (0.19-0.28 h(-1)), t(1/2) 10.4h (9.4-11.3h), beta 0.068 h(-1) (0.061-0.075h(-1)), AUC(0-infinity) 175.3(ngh)/ml (145.7-204.8(ngh)/ml), Cl/F 2.6 ml/(minkg) (2.3-2.9 ml/(minkg)), Vd/F178.8l (146.5-211.1l), Fel 0.3% (0.1-0.5%), and Cl(R) 0.010 ml/(minkg) (0.005-0.015 ml/(minkg)). Placental transfer of lorazepam evaluated as the ratio of vein umbilical/maternal vein plasma concentrations, obtained as an isomeric mixture, was 0.73 (0.52-0.94). Pregnancy changes the pharmacokinetics of lorazepam, with an increase in the apparent distribution volume, an increase in apparent oral clearance, and a reduction of elimination half-life. The increase in oral clearance may indicate an increase in glucuronidation capacity, with a possible reduction in the plasma concentrations of drugs depending on glucuronidation capacity as the major metabolic pathway.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
Abstract: Cases of catatonia in patients with renal failure have been rarely reported. In this report, we describe two renal-insufficient patients with catatonia who had a good response to intramuscular lorazepam whereby the catatonic symptoms were relieved. Case 1 involved a patient with end-stage renal disease and severe pneumonia related respiratory failure. He responded well to intramuscular lorazepam (total dose, 4 mg) whereby the catatonia was elieved. Case 2 involved a patient with alcoholic liver cirrhosis and rhabdomyolysis-related acute renal failure. He showed great improvement with intramuscular lorazepam (2 mg) whereby the catatonia was subsequently relieved. This report demonstrates that intramuscular lorazepam is safe, effective and rapid in relieving catatonia associated with renal function impairment. Neither of the patients had a recurrence of catatonia during a period of 6- months follow-up. In conclusion, intramuscular lorazepam may play an important role in the treatment of catatonia associated with renal insufficiency.
Abstract: The human ether-a-go-go-related gene (hERG) voltage-gated K(+) channels are located in heart cell membranes and hold a unique selectivity filter (SF) amino acid sequence (SVGFG) as compared to other K(+) channels (TVGYG). The hERG provokes the acquired long QT syndrome (ALQTS) when blocked, as a side effect of drugs, leading to arrhythmia or heart failure. Its pore domain - including the SF - is believed to be a cardiotoxic drug target. In this study combining solution and solid-state NMR experiments we examine the structure and function of hERG's L(622)-K(638) segment which comprises the SF, as well as its role in the ALQTS using reported active drugs. We first show that the SF segment is unstructured in solution with and without K(+) ions in its surroundings, consistent with the expected flexibility required for the change between the different channel conductive states predicted by computational studies. We also show that the SF segment has the potential to perturb the membrane, but that the presence of K(+) ions cancels this interaction. The SF moiety appears to be a possible target for promethazine in the ALQTS mechanism, but not as much for bepridil, cetirizine, diphenhydramine and fluvoxamine. The membrane affinity of the SF is also affected by the presence of drugs which also perturb model DMPC-based membranes. These results thus suggest that the membrane could play a role in the ALQTS by promoting the access to transmembrane or intracellular targets on the hERG channel, or perturbing the lipid-protein synergy.
Abstract: BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults.
Abstract: Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd.
Abstract: INTRODUCTION: Postoperative nausea and vomiting (PONV) is a displeasing experience that distresses surgical patients during the first 24 h after a surgical procedure. The incidence of postoperative nausea occurs in about 50%, the incidence of postoperative vomiting is about 30%, and in high-risk patients, the PONV rate could be as high as 80%. Therefore, the study design of this single arm, non-randomized, pilot study assessed the efficacy and safety profile of a triple therapy combination with palonosetron, dexamethasone, and promethazine to prevent PONV in patients undergoing craniotomies under general anesthesia. METHODS: The research protocol was approved by the institutional review board and 40 subjects were provided written informed consent. At induction of anesthesia, a triple therapy of palonosetron 0.075 mg IV, dexamethasone 10 mg IV, and promethazine 25 mg IV was given as PONV prophylaxis. After surgery, subjects were transferred to the surgical intensive care unit or post anesthesia care unit as clinically indicated. Ondansetron 4 mg IV was administered as primary rescue medication to subjects with PONV symptoms. PONV was assessed and collected every 24 h for 5 days via direct interview and/or medical charts review. RESULTS: The overall incidence of PONV during the first 24 h after surgery was 30% (n = 12). The incidence of nausea and emesis 24 h after surgery was 30% (n = 12) and 7.5% (n = 3), respectively. The mean time to first emetic episode, first rescue, and first significant nausea was 31.3 (±33.6), 15.1 (±25.8), and 21.1 (±25.4) hours, respectively. The overall incidence of nausea and vomiting after 24-120 h period after surgery was 30% (n = 12). The percentage of subjects without emesis episodes over 24-120 h postoperatively was 70% (n = 28). No subjects presented a prolonged QTc interval ≥500 ms before and/or after surgery. CONCLUSION: Our data demonstrated that this triple therapy regimen may be an adequate alternative regimen for the treatment of PONV in patients undergoing neurological surgery under general anesthesia. More studies with a control group should be performed to demonstrate the efficacy of this regimen and that palonosetron is a low risk for QTc prolongation. CLINICALTRIALSGOV IDENTIFIER: NCT02635828 (https://clinicaltrials.gov/show/NCT02635828).