Metabolism and pharmacokinetics of morphine in neonates: A review

Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml) seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords “morphine metabolism neonate” and “morphine pharmacokinetics neonate”. The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.

CYP2D6 genotype and phenotype relationship in South Indians.

BACKGROUND: Genotypes of the drug-metabolizing enzyme CYP2D6 influence plasma levels of 25% of commonly prescribed drugs. This is the first study in India to investigate the genotype-phenotype relationship of CYP2D6. AIM: To study the influence of some CYP2D6 genotypes on the metabolism of its substrate dextromethorphan in healthy South Indian volunteers and to assess the contribution of the CYP2D6*10 and CYP2D6*4 alleles. MATERIALS AND METHODS: Twenty-six subjects from a previous CYP2D6 genotyping study of healthy volunteers were included for phenotyping in this study. Selected volunteers belonged to any one of three genotype groups:Group I - two normal activity alleles, Group II - one reduced activity allele and one normal activity allele and Group III - one loss of function allele along with either a wild type or reduced activity allele. Volunteers were phenotyped for the CYP2D6 enzyme using dextromethorphan as probe drug. Concentrations of the parent drug and metabolite dextrorphan were estimated using high performance liquid chromatography. Metabolic ratios were calculated as the ratio of parent drug to metabolite in 0-8h urine samples. STATISTICAL ANALYSIS: Metabolic ratios from each genotype group were compared using the Mann-Whitney test at 5% significance, to observe their difference between genotype groups. RESULTS: The mean metabolic ratios+/-SD in Groups I, II and III were 0.0039+/-0.0031, 0.0032+/-0.0017 and 0.0391+/-0.0331 respectively. The mean metabolic ratio of Group III was significantly higher when compared with Groups I or II. In heterozygous individuals, the *1 or *2 alleles compensated for the reduced enzyme activity due to the *10 allele. However, if a heterozygous individual had a *4 allele, the reduced enzyme activity could not be compensated by the *1 or *2 alleles. CONCLUSIONS: The CYP2D6 enzyme activity was found to be decreased in individuals carrying *4 or *5 alleles.The *1 or *2 allele could compensate for the reduced function due to *10 allele, but not for the loss of function due to *4 allele.

Modelagem farmacocinética-farmacodinâmica do propofol em pacientes submetidos à cirurgia cardíaca com anestesia venosa contínua alvo-controlada / Propofol pharmacokinetic-pharmacodynamic modeling in patients submitted to cardiac surgery with continuos venous target controlled anesthesia

O propofol é um sedativo eficiente, largamente empregado em anestesia e geralmente associado a grande números de analgésicos opióides em cirurgias de grande porte, como a cirurgia cardíaca de revascularização do miocárdio (RM) com ou sem circulação extracorpórea (CEC). Devido às suas características farmacocinéticas é administrado através de infusão alvo controlada (TCI) de forma a manter os níveis plasmáticos ótimos para obtenção de sedação e profundidade de anestesia adequadas durante a intervenção cirurgica. O objetivo do presente estudo foi investigar a famacocinética e farmacodinâmica do propofol administrado através de TCI em pacientes submetidos a RM com e sem CEC. Na administração da medicação hipnótica, fez-se necessária a validação do Diprifusor (AstraZeneca), incluindo a bomba de infusão e o software programado com o modelo famacocinético de 3 compartimentos, que necessita apenas da inclusão de dados individuais do paciente, tais como peso corporal...

Propofol is an effective sedative, largely applied in anesthesia and in general it is associated to opioids for analgesia in major surgeries, like the cardiac surgery to coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass (CPB). It is administered by a target controlled infusion system (TCI) to maintain the optimal depth of sedation and anesthesia during the intervention, due to its pharmacokinetic characteristics. The objective of this study was to investigate the influence of CPB in pharmacokinetics and in pharmacodynamics of propofol, applying PK-PD modeling. For drug administration, Diprifusor (AstraZeneca), including pump plus software must enter individual data as body weight from the patient, once pharmacokinetic parameters were included previously. To validate this system of infusion, the prediction error by target controlled infusion must be estimated by comparison between obtained and predict concentration plasma ratio. In the present protocol, 20 patients (10 CONTROL and 10 CPB) were selected based on inclusion criteria for the comparative study. Patients were informed in details about the investigation and before the protocol starts, they signed the informed written consent to participate of the study. Protocol was approved by the local ethical committees of all institutions involved. Rate of infusion and the range of obtained plasma propofol concentrations required to reach 2 µg/mL and to maintain the bispectral index (BIS:40) during cardiac surgery were monitored. Subsequently, at the end of surgery, both rate of infusion and range of obtained plasma propofol concentrations required to reach 1 µg/mL were monitored either. Depth of sedation was assessed with BIS during all period reaching maximum effect in 40 at level of sedation in the operative period. At the end of surgery, the Ramsay score achieved sedation level 6, when the target plasma propofol was adjusted to 1 µg/mL; Additionally, at the end of infusion in the postoperative period, BIS and Ramsay were monitored simultaneously up to 18-20 hours for all patients. Blood samples were collected and propofol plasma levels were monitored during (TCI : 2 µg/mL) and after surgery (TCI: 1 µg/mL). Blood samples also were collected at the end of infusion for pharmacokinetics. Volumes of blood lower than 90 mL were necessary for drug monitoring and pharmacokinetic purposes. Plasma levels were determined by a quite simple, selective, sensitive and robustness analytical method HPLC, using fluorescence detector, C18 column, and binary system at low flow rate. Confidence limits were: 0.1-10 µg/mL (linearity, r2 0.9977), 0.05 µg/mL(LD), 0.1 flg/mL(LQ), 93.9% (absolute recovery), 8.4 and 8.8% (intra and inter day precision), 91.8 and 93.3% (accuracy intra and inter day). Additionally, good stability was shown for the drug and its internal standard (tymol). Plasma levels showed a large fluctuation for the CONTROL compared to CPB in the perioperative period, mainly during the surgical intervention, indicating a higher predicting error for CONTROL group. Pharmacokinetics applying three compartment open model showed significant increases on drug elimination (ClT, ß, γ) for CPB compared to CONTROL, once plasma levels for CPB Group were lower than CONTROL in the period of study.

Efectos respiratorios y usos del remifentanilo: farmacología comparada / Respiratory effects and uses of remifentanil

En la última década, los anestesiólogos incrementaron el uso de opioides sintéticos en el intraoperatorio. Sus principales ventajas son: producir analgesia profunda, mínima depresión cardiovascular, disminuir la respuesta endocrina al estrés, poder ser revertidos por antagonistas competitivos, poseer escasa toxicidad orgánica y no desencadenar hipertermia maligna. Los opioides tienen, como contrapartida, la capacidad de provocar depresión respiratoria postoperatoria importante, dosis-dependiente. Algunas características farmacocinéticas de los opioides utilizados no satisfacen integramente algunos requerimientos de los anestesiólogos. Es por ello que la investigación prosigue, básicamente, en dos direcciones: terminación previsible de su efecto farmacológico y menor depresión respiratoria postoperatoria. El remifentanilo es un agonista de los receptores mu, con una relativa unión a los receptores kappa y delta. Su perfil farmacodinámico es similar a los del fentanilo y el alfentanilo. Su farmacocinética le permite comportarse como una droga de acción corta. Es metabolizado por esterasas sanguíneas y de otros tejidos, permitiendo un extenso y rápido metabolismo, sin participación hepática. Sus características cinéticas permiten pensar que su uso será adecuado en aquellas situaciones en las que se requiere una relación dosis-efecto previsible, rápidos cambios en la profundidad, una rápida desaparición de la depresión respiratoria, un plano anestésico profundo con rápida recuperación y un bloqueo autonómico profundo.