Neonatal Pharmacology

Diagnosis

Effective treatment begins with an accurate diagnosis and assessment of symptoms. Although this applies to all areas of therapeutics, treatment in newborns presents specific challenges. Their small size and fragility may preclude useful, but inordinately invasive, diagnostic procedures. For example, newborns with chronic lung disease are treated for “bronchospasm” on the basis of the findings of decreased air entry, desaturation, and abnormal breath sounds. Relief of these symptoms with aerosolized bronchodilators may be interpreted as confirming this diagnosis. Although this may be correct, increased humidity or movement of the endotracheal tube bevel away from a pliable tracheal wall during aerosol treatment may also result in improvement. A similar argument can be made for suspected neonatal infection, the clinical diagnosis of a patent ductus arteriosus, neonatal pain management, drug-related renal or hepatic toxicity, or the claimed link between gastroesophageal reflux and apnea. Therefore, evaluation of an ineffective therapy should include reconsideration of the diagnosis, in the same way as conclusions about why a therapy succeeded should be made cautiously.

Absorption

Absorption is the movement of a drug into the systemic circulation. It generally requires the crossing of membranes or membrane barriers and is characterized by rate (time to peak) and extent (percentage of dose). The most commonly used route in neonates is intravenous administration . However, even this route of administration has challenges related to neonatal pathophysiology and limitations of intravenous infusion systems (e.g., low flow, small volume, dead space volume, limited flush volume). Consequently, drugs should be infused into the patient as close as possible to the site of the venous access. If a drug is injected farther away from the infant and at a low rate, the drug may reach the patient far too slowly or incompletely to achieve effective concentrations. Infusion solution filters may further hamper drug delivery by blocking large molecules, by adsorption of the drug to the filter, or by allowing a heavier drug to settle in the filtration chamber and mix slowly. For drugs in which the peak concentration matters (e.g., aminoglycosides) or when the driving force for tissue penetration is a concentration gradient between circulation and tissue (e.g., meningitis), these limitations may result in suboptimal therapy.

Intramuscular administration of drugs is used for slow release (e.g., vitamin A or K, palivizumab) but is a poor substitute for intravenous access and should be avoided for multiple doses. Absorption following intramuscular injection relates to muscle blood flow and depends on maturation and disease characteristics (e.g., hypothermia, shock). Furthermore, intramuscular administration may result in tissue sclerosis, causing sterile abscesses, or create large intramuscular collections, which are subsequently absorbed slowly, producing a “depot effect” in which serum concentrations evolve slowly (both rise and fall) over time.

Oral administration of drugs is preferred for treatment of chronic illnesses in newborns, but this route is not very well studied in acutely ill preterm neonates. Maturation affects gastric and intestinal pH and motility, pancreatic activity and bile acid secretion, or pre-systemic drug metabolism and transport (first pass) in the intestinal wall. The gastric fluid composition (bile salts, osmolarity, pH) displays age-dependent changes, further affected by type and frequency of feeding. Many newborns experience gastroesophageal reflux and delayed gastric emptying. This prolongs and delays absorption, which reduces the peak concentration and may also reduce the total dose absorbed. Passive intestinal venous congestion caused by elevated right atrial pressure decreases drug absorption in adults and may do so in premature infants with severe bronchopulmonary dysplasia. Co-administration of medications to newborns with small volumes of milk or during continuous gastric or duodenal feedings may also alter absorption. Volumes can affect drug solubility in the intestinal lumen while milk can affect bioavailability (e.g., iron or quinolone absorption when combined with milk).

Buccal, lingual, or rectal administrations are additional enteral routes that are all associated with variability. For clinicians, this means that if enteral drug therapy fails, the impact of the route or feeding patterns on drug absorption must be considered. Finally, unanticipated absorption of drugs or excipients intended for topical effects (e.g., cutaneous, inhalation, perineural) should be considered, as these can also be associated with relevant side effects.

Distribution

Distribution is the partitioning of drugs among various body fluids, organs, and tissues. The distribution of a drug within the body is determined by several factors, including organ blood flow, pH and composition of body fluids and tissues, physical and chemical properties of the drug (e.g., lipid solubility, molecular weight, and ionization constant), and drug transporter activity but also by the extent of drug binding to plasma proteins (albumin, α ₁ -acid glycoprotein) and other macromolecules.

Physiologic differences between fetuses, preterm neonates, children, and adults affect drug distribution. Total body water content ranges from 85% in premature newborns to 75% in term newborns to 65% in adults. Conversely, body fat content ranges from 0.7% or less in extremely premature newborns to 12% in term newborns. These differences affect distribution of water-soluble (e.g., aminoglycosides, acetaminophen), lipophilic (e.g., propofol) or nonpolar drugs (e.g., fentanyl). The protein-binding capacity of drugs in the circulation is lower in early infancy because of lower circulating plasma protein concentrations (e.g., albumin, α ₁ -acid glycoprotein) and less binding affinity. Competitive binding with bilirubin is another specific issue to be considered in neonates. With rare exceptions, only the free (unbound) drug crosses membranes, exerts pharmacologic actions, and undergoes metabolism and elimination. However, measurements of drug concentrations usually reflect total circulating drug concentrations, which consist of both free and protein-bound drug concentrations. Thus even when total circulating drug concentrations in the newborn may be low by adult standards, the free drug concentrations may still be equivalent or even higher than those in the adult because of decreased protein binding. Disease (sepsis) or therapeutic interventions (extracorporeal circulation) can further affect distribution.

Metabolism

Drug-metabolizing enzymes are crucial in the extent of drug biotransformation. Although the liver is considered the major organ responsible for drug biotransformation, other organs such as the intestines, lungs, and kidneys also contribute to drug metabolism. These metabolizing enzymes can be classified as participating in non-synthetic phase I reactions (e.g., oxidation, reduction, hydrolysis) or synthetic phase II reactions (e.g., glucuronidation, sulfation, acetylation). Their metabolites can subsequently be eliminated by renal, biliary, or other elimination routes and may also be therapeutically active or contribute to adverse effects.

The primary type of enzymes involved in phase I reactions are cytochromes P450 (CYPs). CYPs mature at different rates and in different patterns with the highest impact in early infancy. In addition, single nucleotide polymorphisms (SNPs) or substitutions in the DNA sequence for a CYP may reduce its metabolizing activity or completely eliminate it if the polypeptide cannot be formed (cf. PGx). Conversely, some individuals inherit multiple copies of a CYP, producing “supermetabolizers” (CYP2D6). The phase II conjugation enzymes, such as the uridine 5-diphosphoglucuronosyltransferases (UGTs) have several forms with different substrate specificity (e.g., UGT1A1 for bilirubin, UGT2B7 for morphine) although they are not as absolutely selective as the CYPs.

All enzymes display isoenzyme specific maturation, and this affects drug metabolism throughout infancy. Consequently, the clearance of almost all drugs is decreased in neonates compared with older children and adults, but important variations in rates of maturation occur among drug classes and among individuals, which prevents simple generalization. Three patterns can be identified with (a) most CYPs being low at birth and increasing to adult levels in the first months or years (e.g., CYP2D6, UGT1A1), (b) high at birth and decreasing thereafter (e.g., CYP3A7), and (c) stable expression (e.g., plasma esterase, sulfation). Although this classification is very helpful to explain and even predict maturational drug disposition, it should be used cautiously. We cannot simply miniaturize “major” and “minor” routes of elimination as documented in adults to (pre)term neonates. In the absence of an adult major route, a minor route, either metabolic or primary elimination, may be a more relevant route of clearance in neonates (e.g., caffeine elimination is renal in neonates and metabolic [CYP1A2] in adults). A similar argument can be made for acetaminophen. Glucuronide conjugation is usually low at birth. In contrast, conjugation through sulfation is usually active at birth. These different patterns are reflected in the developmental changes in acetaminophen metabolism in early life.

Besides age-driven maturation, other factors such as nutrition, disease characteristics, PGx, or drug–drug interactions further affect the phenotypic activity of enzymes and organs responsible for drug metabolism in the newborn. Maturational changes in hepatic blood flow, drug transport into hepatocytes, synthesis of serum proteins, protein binding of drugs, and biliary secretion further confound accurate predictions about drug metabolism after birth.

Elimination

Drug elimination can occur through several mechanisms. Elimination occasionally occurs by the hepatobiliary route, transcutaneously, or by the lungs, but is most commonly by the kidneys. Renal elimination is the most important pathway for unchanged drugs or metabolites, either by glomerular filtration or by renal tubular transport (reabsorption, secretion).

Glomerular function increases steadily after birth, whereas tubular function matures more slowly, causing a glomerular-to-tubular imbalance. Based on pooling of GFR estimates (polyfructose, Cr-EDTA, mannitol or iohexol), a quantitative description using weight and postmenstrual age (PMA) showed that half of the adult value is reached at 48 weeks PMA. In a very recent analysis on differences between preterm and term neonates, Salem et al. documented that both postnatal and gestational age (GA) are relevant for GFR until 1.25 years. This postnatal increase in glomerular function relates to higher cardiac output, reduced renal vascular resistance, redistribution of intrarenal blood flow, and changes in intrinsic glomerular basement membrane permeability. These age-dependent dynamics of neonatal renal function markedly influence drug elimination. Similar to drug metabolism, however, the variability in renal elimination capacity and drug clearance is further affected by other covariates, such as hypoxemia, nephrotoxic drugs, hypoperfusion, hypothermia, and intercurrent renal diseases.

The maturation of biliary elimination capacity appears to be fast, attaining adult activity within the first months of life. Drugs that are conjugated within the liver may also be eliminated, excreted through bile only to enter the intestinal tract, where they may be deconjugated and undergo enterohepatic recirculation, similarly to bilirubin. Although biliary elimination is not well studied in newborns, clinical conditions such as parenteral nutrition-associated cholestasis suggest that it may be quite variable among specific patients and conditions.

Transporters play important roles in the uptake or removal of drugs. Compared with enzymes, the ontogeny is still not well documented, although patterns have been described and incorporated in physiologically based PK models. A recent review suggests that different developmental patterns for individual transporters are emerging. Organic anion transporter polypeptides provide facilitated transport of anions in many tissues, including the kidney and liver. P-glycoprotein (PGP), the permeability glycoprotein, is an efflux transporter that belongs to the adenosine triphosphate-binding cassette/multiple drug resistance family of transporters and prevents absorption of many compounds across the intestinal wall or into the brain. PGP expression has been described as limited at birth, reaching adult levels at 3 to 6 months of age. To put these findings into perspective, the limited PGP efflux activity increases opioid concentrations in the central nervous system of newborns and likely explains the higher incidence of apnea in neonates following opioid exposure.