The Maturation of Morphine Clearance and Metabolism

McRorie, Teresa I.; Lynn, Anne M; Nespeca, Mary Kay; Opheim, Kent E.; Slattery, John T.

doi:10.1001/archpedi.1992.02160200094036

Cited by 75 publications

(82 citation statements)

References 22 publications

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“…Dagan and colleagues (8) reported significantly lower clearance in children undergoing the Fontan procedure The morphine steady-state volume of distribution that we observed in this study, 7.3 L/kg, is closer to values reported in cancer patients (35) and patients receiving mechanical ventilation (6,18), 5 L/kg, than to the value reported in post-cardiac surgery patients (8), 13 L/kg. Similar to clearance, distribution volume is not influenced by cardiovascular status.…”

Section: Discussionsupporting

confidence: 74%

“…Despite the documented large inter-individual variability of morphine disposition (7,17), only a few individual studies have addressed the effect of heart disease on morphine pharmacokinetics (PK) in the pediatric population (8,18). The objective of this study is to develop a population PK model for morphine glucuronidation in infants and young children following congenital heart surgery that accounts for the effects of development, cardiac condition, and renal function for possible treatment individualization in this population.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery

Elkomy

Drover

Glotzbach

et al. 2015

AAPS J

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ABSTRACT. The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery

Elkomy

Drover

Glotzbach

et al. 2015

AAPS J

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“…In contrast, rates of morphine clearance in neonates born at term are generally greater, i.e. to 2.0-20 ml/min./kg (Lynn & Slattery 1987;McRorie et al 1992;Pokela et al 1993). It also appears that clearance not only increases with gestational age but also with postnatal age.…”

Section: Morphinementioning

confidence: 93%

Neonatal Hepatic Drug Elimination

Gow

Ghabrial

Smallwood

et al. 2001

Pharmacology & Toxicology

104

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After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.The development of clinical pharmacology has resulted in a more rational approach to drug therapy, as well as a deeper understanding of the factors capable of influencing drug disposition, and hence drug effects. Of these factors, age is of great importance. However, substantial differences in drug disposition not only exist between neonates and adults, but also among premature neonates, term neonates, infants and children.During the last two decades drug disposition in the neonatal period has been studied extensively. A major impetus for these studies seems to have been a series of incidents involving illness or death following the administration of drugs at ratios of dose/body weight innocuous in an adult (Craft et al. 1974;Gershanik et al. 1982). These studies have shown that the transition from neonate to childhood is characterised by the ontogeny of all of the processes of drug absorption, distribution, hepatic metabolism and renal excretion, with the development of hepatic drug metabolism being particularly important.The extent to which the neonatal drug-metabolising en-

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“…Besides, morphine metabolism depends on renal and hepatic function, and residual sedation has been implicated in the delay to extubate those patients. Pharmacokinetic studies of morphine present considerable variability in term newborns and premature neonates, and morphine clearance is reduced in premature neonates 56,57 . Besides, several studies have demonstrated the safety and efficacy of remifentanil in analgesia and anesthesia of newborns, at term and premature 32,33,58 .…”

Section: Resultsmentioning

confidence: 99%

“…Além disso, a morfina apresenta o inconveniente de ter seu metabolismo dependente da função renal e hepática do recém-nascido, podendo manter grau de sedação residual que muitas vezes é implicada no retardo da extubação. Os estudos de farmacocinética da morfina mostraram variabilidade considerável em recém-nascidos de termo e também em prematuros, e o clearance plasmático da morfina está diminuído em recém-nascidos prematuros 56,57 . Assim, vários estudos têm mostrado a segurança e eficá-cia do remifentanil na analgesia e anestesia de crianças e recém-nascidos, assim como em recém-nascidos prematuros 32,33,58 .…”

Section: Conclusãounclassified

Sedação e analgesia em neonatologia

Silva¹,

Gomez²,

Máximo³

et al. 2007

Rev. Bras. Anestesiol.

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JUSTIFICATIVA E OBJETIVOS:A importância do estudo da dor em Neonatologia se deve ao fato de que a sensação de dor e estresse significa sofrimento e desconforto para os recém-nascidos e, apesar desse conhecimento, pouco tem sido feito para minimizá-los. Nessa revisão foram discutidas: a prevenção da dor, as medidas não-farmacológicas e farmacológicas para o seu tratamento e a sedação em recém-nascidos. CONTEÚDO:Várias são as medidas não-farmacológicas que podem ser tomadas com intuito de prevenir a dor nas Unidades de Terapia Intensiva Neonatal e também para tornar o ambiente mais humanizado e menos estressante para os pacientes e seus familiares. O tratamento da dor no recém-nascido consiste em medidas não-farmacológicas (sucção não-nutritiva, glicose) e farmacológicas (analgésicos não-opióides, opióides e anestésicos locais). A sedação em recém-nascidos é produzida por fármacos que agem diminuindo a atividade, a ansiedade e a agitação do paciente, podendo levar à amnésia de eventos dolorosos ou não-dolorosos. A sedação pode ser feita pela administração de hidrato de cloral, barbitúricos, propofol e benzodiazepínicos. CONCLUSÕES:A prevenção da dor e a indicação de analgesia devem ser individualizadas e sempre consideradas em todos os recém-nascidos portadores de doenças potencialmente dolorosas e/ ou submetidos a procedimentos invasivos, cirúrgicos ou não.

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The Maturation of Morphine Clearance and Metabolism

Cited by 75 publications

References 22 publications

Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery

Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery

Neonatal Hepatic Drug Elimination

Sedação e analgesia em neonatologia

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