Neonates drug distribution

In neonates drugs such as various penicillins, pheno-barbital, phenytoin, and theophylline have lower protein-binding affinity than in adults. This may increase the concentration of free or pharmacological active drug in neonates, and may also change the apparent volume of distribution. Thus, neonates may require different doses on a mg/kg basis compared to that for adults for these drugs to achieve appropriate therapeutic serum concentrations. 

Even if a medication is available in multiple formulations and dosage forms, the prescriber must consider the absorption and distribution differences between adult and pediatric patients. Blood supply at injection or infusion site, available blood supply for unit muscle mass, and skeletal muscle mass relative to body mass vary with patient age and size, causing drug absorption to vary, as well. A rapid intravenous bolus in a pediatric patient might result in acute toxicity a slow intravenous infusion, often required in neonates, can cause erratic, unreliable drug delivery in an older child. In addition, the volume of fluid tolerated for intravenous delivery varies significantly with the age and size of the patient. The blood supply and blood flow to and from the injection site are of prime importance since a gradual decrease in blood supply per unit muscle mass is seen with maturation. In addition, the skeletal muscle mass relative to... 

Once absorbed, foreign compounds may react with plasma proteins and distribute into various body compartments. In both neonates and elderly human subjects, both total plasma-protein and plasma-albumin levels are decreased. In the neonate, the plasma proteins may also show certain differences, which decrease the binding of foreign compounds, as will the reduced level of protein. For example, the drug lidocaine is only 20% bound to plasma proteins in the newborn compared with 70% in adult humans. The reduced plasma pH seen in neonates will also affect protein binding of some compounds as well as the distribution and excretion. Distribution of compounds into particular compartments may vary with age, resulting in differences in toxicity. For example, morphine is between 3 and 10 times more toxic to newborn rats than adults because of increased permeability of the brain in the newborn. Similarly, this difference in the blood-brain barrier underlies the increased neurotoxicity of lead in newborn rats. 

Then, given a model for data from a specific drug in a sample from a population, mixed-effect modeling produces estimates for the complete statistical distribution of the pharmacokinetic-dynamic parameters in the population. Especially, the variance in the pharmacokinetic-dynamic parameter distributions is a measure of the extent of inherent interindividual variability for the particular drug in that population (adults, neonates, etc.). The distribution of residual errors in the observations, with respect to the mean pharmacokinetic or pharmacodynamic model, reflects measurement or assay error, model misspecification, and, more rarely, temporal dependence of the parameters. 

Distribution of drugs is influenced by the fact that total body water in the neonate amoimts to 80% as compared to 65% in older children. Consequently ... 

To better understand changes in drug disposition, the pediatric population needs to be categorized into various groups (Table 1) because children vary markedly in their absorption, distribution, metabolism, and elimination of medications. This occurs because neonates, infants, children, adolescents, and adults have different body compositions (i.e., as to their percentages of body water and fat) and have their body organs in different stages of development. 

Lidocaine pharmacokinetics tend to follow a single compartment model in neonates, with an increased half-life, and substantially reduced protein binding, leading to a much larger volume of distribution than in adults, but an increased proportion of unbound drug (56). 

Because disposition refers to the simultaneous effects of distribution and elimination, it is necessary to consider both components of the process when interpreting changes that occur during the neonatal period. Comparison of the disposition kinetics of enrofloxacin (2.5 mg/kg administered intravenously) in 1-day-old and 1-week-old calves shows that the volume of distribution (Vd(ss)) is smaller and the systemic clearance (C/I5) of the drug is lower in the 1-day-old calves, while the half-life does not differ significantly between the age groups... 

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