Neonates drug absorption

Drug absorption is highly variable in neonates and infants [21,22]. Older children appear to have absorption patterns similar to adults unless chronic illness or surgical procedures alter absorption. Differences in bile excretion, bowel length, and surface area probably contribute to the reduced bioavailability of cyclosporine seen in pediatric liver transplant patients [22a]. Impaired absorption has also been observed in severely malnourished children [22b]. A rapid GI transit time may contribute to the malabsorption of carbamazepine tablets, which has been reported in a child [23]. Selection of a more readily available bioavailable dosage form, such as chewable tablets or liquids, should be promoted for pediatric patients. 

Table 1. Summary of drug absorption in neonates, infants and children ...

Developmental differences in drug absorption between neonates, infants and older children are summarized in Table 1. It must be recognized that the data contained therein reflect developmental differences which might be expected in healthy pediatric patients. Certain conditions and disease states might modify the function and/or structure of the absorptive surface area(s). GI motility and/or systemic blood flow can further impact upon either the rate or extent of absorption for drugs administered by ex-travascular routes in pediatric patients. 

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... 

Table 59-3 Oral Drug Absorption (Bioavailability) of Various Drugs in the Neonate Compared with Older Children and Adults. ...

Absorption of i.m. administered medications depends on the injection site because perfusion of individual muscle groups differs. For example, drug absorption from the deltoid muscle is faster than that from the vastus lateralis that is more rapid than from the glu-teus. In addition, lower perfusion or hemostatic decompensation, frequently observed in ill neonates and young infants, may reduce i.m. absorption. It may also be decreased in neonates who receive a skeletal muscle-paralyzing agent such as pancuronium because of decreased muscle contraction. In addition, the smaller muscle mass of neonates and young infants provides a small absorptive area. 

The variability associated with drug absorption from the gastrointestinal tract can be overcome by using a parenteral preparation (dosage form). It should preferably be administered either by intravenous infusion or slow intravenous injection to avoid circulatory overload. Intraosseous administration is a useful alternative to intravenous injection of some antimicrobial agents (e.g. sodium ampicillin or amoxycillin, cefotaxime, ceftriaxone, gentamicin or amikacin sulphate) in neonatal foals (Fig. 7.1) (Golenz et al, 1994) and puppies (Lavy et al, 1995). This particularly applies when the neonate is in a state of septic shock and/or dehydration. Total plasma protein concentration is an inaccurate index of hydration status unless monitored (repeatedly measured) and interpreted in conjunction with packed cell volume (PCV). 

Drug ahsorption from an intramuscular site also may he altered in premature infants. Differences in relative muscle mass, poor perfusion to various muscles, peripheral vasomotor instability, and insufficient muscular contractions in premature infants compared with older children and adults can influence drug absorption from the intramuscular site. The net effect of these factors on drug absorption is impossible to predict phenobarbital has been reported to be absorbed rapidly, whereas diazepam absorption may be delayed." Thus intramuscular dosing is used rarely in neonates except in emergencies or when an intravenous site is inaccessible. 

Another, though less well-characterised, determinant of oral drug absorption is biliary function, which affects the ability to solubilise and absorb lipophilic drugs. Immature transportation and secretion of biliary salts in the neonatal period may affect drug absorption. 

Variable rates of colonisation of gastrointestinal microflora and beta-glucuronidase activity may also add to the variation and unpredictability of oral drug absorption in neonates and young infants. 

Drugs absorbed by active transport mechanisms appear to have a delayed rate, but not extent of absorption, in the neonatal period [20]. The absorption of vitamin K depends, to some extent, on the development of intestinal flora. 

The renal excretion of drugs depends on glomerular filtration, tubular secretion, and tubular absorption. A twofold increase in glomerular filtration occurs in the first 14 days of life [36], The glomerular filtration rate continues to increase rapidly in the neonatal period and reaches a rate of about 86 mL/min per 1.73 m2 by 3 months of age. Children 3-13 years of age have an average clearance of 134 mL/min per 1.73 m2 [37]. Tubular secretion approaches adult values between 2 and 6 months [11], There is more variability observed in maturation of tubular reabsorption capacity. This is likely linked to fluctuations in urinary pH in the neonatal period [38],... 

Gastrointestinal enzyme activities tend to be lower in the newborn than in the adult. Activities of -amylase and other pancreatic enzymes in the duodenum are low in infants up to 4 months of age. Neonates also have low concentrations of bile acids and lipase, which may decrease the absorption of lipid-soluble drugs. 

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