RESUMO
INTRODUCTION: Although main antihypertensive drugs are able to efficiently reduce blood pressure, only a third of treated hypertensive patients achieve optimal blood pressure control. Extensive interpatient variability on drug metabolism and oral disposition of blood pressure lowering drugs can contribute to this failure in hypertension management. Areas covered: The aim of the present review is to update the knowledge on the features of hepatic metabolism of the main antihypertensive agents, including ß-blockers, calcium channel blockers, angiotensin receptor blockers, and angiotensin converting enzyme inhibitors. The factors that contribute to the large interindividual variability of main antihypertensive drugs are also covered. Expert opinion: The variability of plasma concentration of antihypertensive drugs due to the involvement of hepatic metabolism can contribute to the inadequate control of blood pressure in the daily clinical practice. Genotype screening of specific hepatic drug-metabolizing enzymes may contribute to optimize dose selection and to increase the rate of blood pressure control in patients treated with specific ß-blockers, calcium channel blockers, and angiotensin receptor blockers.
Assuntos
Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/farmacocinética , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacocinética , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacocinética , Relação Dose-Resposta a Droga , Genótipo , HumanosRESUMO
AIMS: Diabetes mellitus can inhibit cytochrome P450 3A4, an enzyme responsible for the metabolism of nifedipine, used for the treatment of hypertension in pregnant women. We aimed to assess the effect of type 2 diabetes mellitus (T2DM) on the pharmacokinetics, placental transfer and distribution of nifedipine in amniotic fluid in hypertensive pregnant women. METHODS: The study was conducted in 12 hypertensive pregnant women [control group (CG)] and 10 hypertensive pregnant women with T2DM taking slow-release nifedipine (20 mg, 12/12 h). On the 34th week of gestation, serial blood samples were collected (0-12 h) after administration of the medication. At delivery, samples of maternal and fetal blood and amniotic fluid were collected for determination of nifedipine distribution in these compartments. RESULTS: The median pharmacokinetic parameters of CG were: peak plasma concentration (Cmax ) 26.41 ng ml-1 , time to reach Cmax (tmax ) 1.79 h, area under the plasma concentration vs. time curve from 0-12 h (AUC0-12 ) 235.99 ng.h ml-1 , half-life (t½) 4.34 h, volume of distribution divided by bioavailability (Vd/F) 560.96 l, and ClT /F 84.77 l h-1 . The parameters for T2DM group were: Cmax 23.52 ng ml-1 , tmax 1.48 h, AUC0-12 202.23 ng.h ml-1 , t½ 5.00 h, Vd/F 609.40 l, and apparent total clearance (ClT /F) 98.94 l h-1 . The ratios of plasma concentrations of nifedipine in the umbilical vein, intervillous space and amniotic fluid to those in the maternal vein for CG and T2DM were 0.53 and 0.44, 0.78 and 0.87, respectively, with an amniotic fluid/maternal plasma ratio of 0.05 for both groups. The ratios of plasma concentrations in the umbilical artery to those in the umbilical vein were 0.82 for CG and 0.88 for T2DM. CONCLUSIONS: There was no influence of T2DM on the pharmacokinetics or placental transfer of nifedipine in hypertensive women with controlled diabetes.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hipertensão/tratamento farmacológico , Nifedipino/farmacocinética , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Adulto , Líquido Amniótico/química , Líquido Amniótico/efeitos dos fármacos , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/uso terapêutico , Estudos de Casos e Controles , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/uso terapêutico , Feminino , Meia-Vida , Humanos , Nifedipino/uso terapêutico , Placenta/metabolismo , GravidezRESUMO
Novel complexes consisting of Eudragit E100-risedronate are presented. The oral bioavailability of risedronate in rats was determined through its percentage excreted in urine after administration of complexed or free risedronate in fed and fasted conditions. The evaluation of the risedronate gastro-duodenal irritation potential was carried out by macroscopic and histological analyses in an experimental rat model. The degree of counterionic condensation between Eudragit E100 and risedronate was assessed by dialysis with, mechanistic information about the interaction with calcium and the release of risedronate from the complexes being obtained using physiological solution and simulated gastric fluid without pepsin. Non-significant differences were observed in the urinary excretion of risedronate when the complex or free risedronate was administered to fasted rats. However, the urinary excretion of risedronate in the complex group was 4-times higher than in the free risedronate group when animals were concomitantly administered with food. This behavior was related to the high degree of counterionic condensation in the complex (86.5%), which led to a reduction in the calcium induced rate and magnitude of risedronate precipitation and resulted in a decrease in the gastroduodenal damage from the complex, as evidenced by a lower frequency of gastric mucosae hemorrhage. A sustained release of risedronate from the complex was observed toward water, simulated gastric fluid or physiological solution, through an ionic-exchange mechanism. In conclusion, complexation with Eudragit E100 could be a useful strategy to overcome the unfavorable properties of risedronate.
Assuntos
Acrilatos/química , Bloqueadores dos Canais de Cálcio/farmacologia , Química Farmacêutica , Interações Alimento-Droga , Polímeros/química , Ácido Risedrônico/farmacologia , Estômago/efeitos dos fármacos , Administração Oral , Animais , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Ingestão de Alimentos , Jejum , Técnicas In Vitro , Masculino , Ratos , Ratos Wistar , Ácido Risedrônico/química , Ácido Risedrônico/farmacocinéticaRESUMO
OBJECTIVE: To identify patients who were being treated for hypertension with conventional release verapamil (CRV), and to notify the professional responsible for their health care on cardiovascular risk to which they are exposed and achieve a reduction in the number of patients who are treated with this drug. METHODS: A quasi-experimental prospective before and after study without a control group was conducted on 7289 patients diagnosed with hypertension who were on treatment with CRV, between October 1, 2012 and December 31, 2012 in 8 Colombian cities, collected from a database for dispensing medicines. Socio-demographic and pharmacological variables were evaluated. A total of 108 educational interventions were performed on those responsible for their health care, and evaluated within three months with the proportion of suspension of the prescriptions of CRV being evaluated. Multivariate analysis was performed using SPSS 22.0. RESULTS: The mean age of patients was 67.9±11.8 years (range: 26-96 years), of which 70.6% were men. Withdrawal of treatment with CRV was achieved in a total of 1922 patients (26.3% of users), distributed as follows: 1160 (60.4%) were the presentation of 120mg, while 762 (39.6%) the 80mg. The variable being treated in the city of Medellin (OR: 17.6; 95% CI: 11.949 to 25.924; P<.01) was statistically significantly associated with the replacement of CRV for another antihypertensive. CONCLUSIONS: A relatively moderate adherence to recommendations about the proper use of CRV in hypertensive patients, was found. Intervention programs that reduce inappropriate prescribing of potential risks to patients of insurance companies and cities where the change was not achieved, must be enforced.
Assuntos
Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Hipertensão/tratamento farmacológico , Prescrição Inadequada/prevenção & controle , Padrões de Prática Médica/estatística & dados numéricos , Verapamil/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/farmacocinética , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacocinética , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Colômbia , Substituição de Medicamentos , Feminino , Fidelidade a Diretrizes , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Verapamil/efeitos adversos , Verapamil/farmacocinéticaRESUMO
The role of ATP-binding cassette (ABC) transporters in the efflux of the insecticide, temephos, was assessed in the larvae of Aedes aegypti. Bioassays were conducted using mosquito populations that were either susceptible or resistant to temephos by exposure to insecticide alone or in combination with sublethal doses of the ABC transporter inhibitor, verapamil (30, 35 and 40 µM). The best result in the series was obtained with the addition of verapamil (40 µM), which led to a 2x increase in the toxicity of temephos, suggesting that ABC transporters may be partially involved in conferring resistance to the populations evaluated.
Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Aedes/efeitos dos fármacos , Insetos Vetores/efeitos dos fármacos , Resistência a Inseticidas , Inseticidas/farmacologia , Temefós/farmacologia , Transportadores de Cassetes de Ligação de ATP/efeitos dos fármacos , Aedes/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Insetos Vetores/metabolismo , Resistência a Inseticidas/efeitos dos fármacos , Inseticidas/farmacocinética , Larva/efeitos dos fármacos , Larva/metabolismo , Dose Letal Mediana , Temefós/farmacocinética , Verapamil/farmacocinética , Verapamil/farmacologiaRESUMO
The role of ATP-binding cassette (ABC) transporters in the efflux of the insecticide, temephos, was assessed in the larvae of Aedes aegypti. Bioassays were conducted using mosquito populations that were either susceptible or resistant to temephos by exposure to insecticide alone or in combination with sublethal doses of the ABC transporter inhibitor, verapamil (30, 35 and 40 μM). The best result in the series was obtained with the addition of verapamil (40 μM), which led to a 2x increase in the toxicity of temephos, suggesting that ABC transporters may be partially involved in conferring resistance to the populations evaluated.
Assuntos
Animais , Transportadores de Cassetes de Ligação de ATP/fisiologia , Aedes/efeitos dos fármacos , Resistência a Inseticidas , Insetos Vetores/efeitos dos fármacos , Inseticidas/farmacologia , Temefós/farmacologia , Transportadores de Cassetes de Ligação de ATP/efeitos dos fármacos , Aedes/metabolismo , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Insetos Vetores/metabolismo , Resistência a Inseticidas/efeitos dos fármacos , Inseticidas/farmacocinética , Larva/efeitos dos fármacos , Larva/metabolismo , Temefós/farmacocinética , Verapamil/farmacocinética , Verapamil/farmacologiaRESUMO
Nifedipine is embedded in Gelcarin GP-379 to develop a prolonged release matrix. The effect of polymers levels (15, 20, 30 and 50% w/w), diluent type (lactose Fast Flo, DiTab, and Avicel PH-101), and drug levels (13, 20 and 30% w/w) on in vitro release rate of the drug were investigated. The formulation containing 13% nifedipine, 20% Gelcarin GP-379, and lactose Fast Flo controlled the dissolution rate of nifedipine and released approximately 51% drug at 8 h of testing dissolution. The use of different types of diluents, different drug levels, and different rotational speeds during dissolution testing did affect the drug release rate from the swellable matrices. The dissolution data were analyzed according to Higuchi model, zero order, first order, and Peppas kinetic model. Drug release was found to follow the anomalous diffusion model for swellable matrix.
Assuntos
Bloqueadores dos Canais de Cálcio , Preparações de Ação Retardada/química , Composição de Medicamentos , Nifedipino , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Carragenina/química , Química Farmacêutica , Preparações de Ação Retardada/farmacocinética , Difusão , Excipientes/química , Nifedipino/química , Nifedipino/farmacocinética , Polímeros/química , Solubilidade , Comprimidos/química , Fatores de TempoRESUMO
Objetivos Determinar los posibles resultados negativos asociados a la medicación mediante la metodología de búsqueda activa de posibles interacciones medicamentosas en bases de datos de pacientes afiliados al Sistema General de Seguridad Social en Salud. Métodos A partir de las bases de datos de dispensación de medicamentos de Audifarma S.A a unos 4 millones de usuarios del país, se hizo una revisión sistemática de estadísticas de una serie de medicamentos identificados por presentar interacciones de riesgo, dosis diferentes a las recomendadas o dispensación irregular. Los casos son socializados con las EPS responsables. Resultados Se encontró un caso de nefrotoxicidad por ácido zoledrónico; el 37,0 por ciento de los usuarios de clopidogrel recibían concomitantemente omeprazol, que reduce la efectividad del primero; el 29,9 por ciento de los pacientes que toman losartan están recibiendo dosis superiores a las recomendadas para su indicación; el 2,0 por ciento de los pacientes que toman metoprolol o verapamilo, los recibe simultáneamente, con riesgo de generar bradicardia sinusal, bloqueos auriculoventriculares o disfunción sistólica. Todos los casos fueron notificados a los responsables en la EPS que atienden estos pacientes. Discusión La farmacovigilancia activa permite optimizar recursos, prevenir eventos adversos que puedan potencialmente causar morbilidad importante o incluso letalidad o determinar problemas que podrían ser responsables del fracaso terapéutico. Este tipo de estrategia se anticipa a la aparición de posibles riesgos para el paciente por lo que se recomienda considerarla para reforzar los programas de vigilancia de uso de medicamentos en el país.
Objectives Determining negative results associated with medication through an active search of possible drug interactions in databases for patients affiliated to the Colombian general social security/health system. Methods Statistics related to Audifarma S.A. dispensation drug databases for about 4 million Colombian users were systematically reviewed for identifying drugs having known interactions involving risk, doses different from recommended ones or irregular dispensation. The pertinent health-care providing services were made aware of the above. Results There was one case of nephrotoxicity being caused by zoledronic acid. 37 percent of clopidogrel users concomitantly received omeprazole which reduces the former's effectiveness. 29.9 percent of patients who were taking losartan were receiving doses higher than the recommended ones. 2.0 percent of patients who were taking metoprolol or verapamil were simultaneously receiving them, at the risk of generating first-degree heart block, bradycardia, or systolic dysfunction. All these cases were notified to the pertinent health-care services. Conclusions Active pharmacosurveillance leads to resources being optimised, adverse events which can potentially cause morbidity or lethality being prevented or even determining problems which could be responsible for therapeutic failure. This type of strategy anticipates the appearance of possible risks for patients, meaning that drug use monitoring programmes in Colombia should be reinforced.
Assuntos
Humanos , Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Sistemas de Medicação/estatística & dados numéricos , Programas Nacionais de Saúde/estatística & dados numéricos , Sistemas de Notificação de Reações Adversas a Medicamentos/organização & administração , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacocinética , Colômbia , Difosfonatos/efeitos adversos , Interações Medicamentosas , Imidazóis/efeitos adversos , Losartan/efeitos adversos , Sistemas de Medicação/organização & administração , Metoprolol/administração & dosagem , Metoprolol/efeitos adversos , Metoprolol/farmacocinética , Omeprazol/administração & dosagem , Omeprazol/farmacocinética , Estudos Retrospectivos , Previdência Social , Software , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Ticlopidina/análogos & derivados , Ticlopidina/farmacocinéticaRESUMO
Verapamil (VER) is commercialized as a racemic mixture of the (+)-(R)-VER and (-)-(S)-VER enantiomers. VER is biotransformed into norverapamil (NOR) and other metabolites through CYP-dependent pathways. N-hexane is a solvent that can alter the metabolism of CYP-dependent drugs. The present study investigated the influence of n-hexane (nose-only inhalation exposure chamber at concentrations of 88, 176, and 352 mg/m3) on the kinetic disposition of the (+)-(R)-VER, (-)-(S)-VER, (R)-NOR and (S)-NOR in rats treated with a single dose of racemic VER (10 mg/kg). VER and NOR enantiomers in rat plasma was analyzed by LC-MS/MS (m/z = 441.3 > 165.5 for the NOR and m/z 455.3 > 165.5 for the VER enantiomers) using a Chiralpak AD column. Pharmacokinetic analysis was performed using a monocompartmental model. The pharmacokinetics of VER was enantioselective in control rats, with higher plasma proportions of the (-)-(S)-VER eutomer (AUC(0-infinity) = 250.8 vs. 120.4 ng/ml/h; P < or = 0.05, Wilcoxon test). The (S)-NOR metabolite was also found to accumulate in plasma of control animals, with an S/R AUC(0-infinity) ratio of 1.5. The pharmacokinetic parameters AUC(0-infinity), Cl/F, Vd/F, and t(1/2) obtained for VER and NOR enantiomers were not altered by nose-only exposure to n-hexane at concentrations of 88, 176, or 352 mg/m3 (P > 0.05, Kruskal-Wallis test). However, the verapamil kinetic disposition was not enantioselective for the animals exposed to n-hexane at concentrations equal to or higher than the TLV-TWA. This finding is relevant considering that the (-)-(S)-VER eutomer is 10-20 times more potent than R-(+)-VER in terms of its chronotropic effect on atrioventricular conduction in rats and humans.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacocinética , Hexanos/administração & dosagem , Verapamil/farmacocinética , Administração por Inalação , Animais , Área Sob a Curva , Interações Medicamentosas , Ratos , EstereoisomerismoRESUMO
OBJECTIVES: Determining negative results associated with medication through an active search of possible drug interactions in databases for patients affiliated to the Colombian general social security/health system. METHODS: Statistics related to Audifarma S.A. dispensation drug databases for about 4 million Colombian users were systematically reviewed for identifying drugs having known interactions involving risk, doses different from recommended ones or irregular dispensation. The pertinent health-care providing services were made aware of the above. RESULTS: There was one case of nephrotoxicity being caused by zoledronic acid. 37 % of clopidogrel users concomitantly received omeprazole which reduces the former's effectiveness. 29.9 % of patients who were taking losartan were receiving doses higher than the recommended ones. 2.0 % of patients who were taking metoprolol or verapamil were simultaneously receiving them, at the risk of generating first-degree heart block, bradycardia, or systolic dysfunction. All these cases were notified to the pertinent health-care services. CONCLUSIONS: Active pharmacosurveillance leads to resources being optimised, adverse events which can potentially cause morbidity or lethality being prevented or even determining problems which could be responsible for therapeutic failure. This type of strategy anticipates the appearance of possible risks for patients, meaning that drug use monitoring programmes in Colombia should be reinforced.