Neonates blood-brain barrier

Although the CNS is protected from a number of xeno-biotics by the blood-brain barrier, the barrier is not effective against lipophilic compounds, such as solvents or insecticides (Fig. 7.1). Similarly, the peripheral nervous system is protected by a blood-neural barrier. The barriers are less well developed in the immature nervous system, rendering the fetus and neonate even more susceptible to neurotoxicants. Neural tissue susceptibility is due in large part to its high metabolic rate, high lipid content, and for the CNS, high rate of blood flow. 

Pharmacokinetics Rapid, complete absorption after IM administration. Protein binding less than 30%. Widely distributed (doesn t cross the blood-brain barrier low concentrations in cerebrospinal fluid (CSF). Excreted unchanged in urine. Removed by hemodialysis. Half-life 2-4 hr (increased in impaired renal function and neonates decreased in cystic fibrosis and febrile or burn patients). 

Changes in pharmacodynamics further complicate the pharmacology of many drugs in the neonate and infant. The blood-brain barrier is poorly developed, allowing more rapid transfer of drugs into the central nervous system (CNS). However, the response to higher brain concentrations may be tempered by an inadequate response due to lack of receptor maturation. 

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. 

Schlachetzki F, Zhu C, Pardridge WM. Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier. J Neurochem 2002 81(l) 203-6. 

The toxin 6-OHDA does not cross the blood brain barrier after peripheral administration in the adult animal, and so must be administered centrally in order to yield effective lesions. This restriction does not apply in neonates. Thus, 6-OHDA can produce profound depletions of central catecholamines when administered subcutaneously or intracisternally to neonatal rats or mice (Breese and Traylor, 1971). Moreover, greater selectivity for individual amine pathways can be achieved by refinements of the route of delivery or by pharmacological manipulation, and different protocols of administration can allow relatively selective depletions. For example, several small repeated injections of 6-OHDA spare dopamine and preferentially deplete dopamine, whereas dopamine toxicity after a single large injection can be enhanced by pargyline treatment, in particular if the noradrenaline depletion is concurrently blocked with pargyline (Breese and Traylor, 1971 Cooper et al., 1973 Smith et al., 1973 Luthman et al., 1989). 

Kernicterus (that may result from hyperbihrubinaemia) manifests as various neurological deficits, seizures, abnormal reflexes and eye movements. The blood-brain barrier of the neonate is not fully developed and unconjugated bilirubin can freely pass into the brain interstitium. Some medications, such as the antibiotic co-trimoxazole (a combination of trimethoprim and sulphamethoxazole) may induce this disorder in the infant, either when taken by the mother or if given directly to the infant, due to a displacement of bilirubin from binding sites on serum albumin, thus allowing unconjugated bihrubin to pass across the blood-brain barrier. 

Kernicterus may occur as the result of immaturity of the blood-brain barrier in severe neonatal icterus and can occasionally be found in premature infants as well, with bilirubin levels usually higher than 20 mg/dl. Unconjugated bilirubin is deposited in the basal ganglia of the hippocampus and the hypothalamus nuclei as bilirubin-phosphatidylcholine precipitate, where it gives rise... 

Cornford EM, Braun LD, Oldendorf WH, Hill MA (1982) Comparison of lipid-mediated blood-brain-barrier penetrabihty in neonates and adults. Am J Physiol 243 C161-C168. 

A drug is more likely to cross into the central nervous system (CNS) of a neonate rather than an older child or an adult. This most likely occurs because its CNS is less mature and the blood-brain barrier is less formed. This is an important consideration when antimicrobial therapy is needed for the treatment of bacterial meningitis or anticonvulsant for seizures. 

Today the predominant if not the sole source of methylmercury is derived from the methylation of inorganic mercury in aquatic sediments and soils. Methylmercury is well absorbed from the diet and distributes within a few days to all tissues in the body. It is present in the body as water-soluble complexes mainly, if not exclusively, attached to the sulfur atom of thiol ligands, and crosses the blood—brain barrier without hindrance, entering the endothelial cells of the blood—brain barrier as a complex with L-cysteine. The principal target tissue of MeHg is the brain, and its major toxic effects are on the central nervous system. Whereas adult poisoning affects the visual cortex and the cerebellum, in neonatal infants the outcome can be much more serious, ranging in its effects from cerebral palsy to developmental retardation. 

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