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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
TABLE 11.1
Throughout the years, it has been repeatedly shown that newborns are
more prone to adverse drug reactions (Table 11.1), while some of these
events could have been anticipated based on the available knowledge on
neonatal pharmacology. A knowledge-driven approach requires understanding
of human developmental biology and insights in the ontogeny of drug
absorption, distribution, metabolism, and excretion (PK). In addition, there
must be a rigorous appreciation of the developmental aspects of drug–
receptor (number, affinity, modulation, and regulation) interactions (PD). The
purpose of this chapter is to provide information on the foundations for
neonatal drug therapy, based on their physiologic characteristics. This chapter
focuses on absorption and distribution as PK determinants in neonates, since
the impact of hepatic and renal function (metabolism and elimination) is
discussed in Chapters 4 and 12. This is followed by a reflection on the need
to also assess maturational PD.
Illustrations of Adverse Drug Reactions in Neonates with the Mechanisms
Involved and the Clinical Relevance
TABLE 11.2
ABSORPTION
Absorption describes the movement of a drug into the systemic circulation.
Drugs administered by nonintravenous (e.g., sublingual, oral, rectal, buccal)
routes may not enter the systemic circulation completely and intact. Although
the primary focus of interest is on absorption, these barriers can have effects
on distribution, metabolism, and excretion. This is because barriers (like
intestinal mucosa and skin) can avoid, delay, or limit, but also drugs during
passage by first-pass metabolism, and are not just filters.
Absorption describes the concentration–time profile following
nonintravenous administration, captured by the rate of absorption and
bioavailability (translocation). The absorption rate is most commonly
reflected by the time to reach the peak concentration (t
max
).2 To assess
bioavailability, the area under the drug concentration–time curve (AUC) is a
measure of the total amount of drug that reaches the systemic circulation, as
absolute bioavailability (compared to intravenous administration) or—when
compared to a nonintravenous route—relative bioavailability. Absorption
depends on physicochemical (drug specific) factors and host factors (patient
specific) (Table 11.2).
Factors Affecting Gastrointes tinal Drug Absorption
Physicochemical factors = issues likely not specific to neonates
Formulation characteristics
Disintegration of tablets or solid phase
Dissolution of drug in gastric or intestinal fluid
Release from sustained-release preparations
Molecular weight
pKa and number of ionizable groups
Degree of lipid solubility
Patient factors = issues more specific to neonates
Gastric content and gastric emptying time: frequent feeding, delayed gastric emptying
Gastric and duodenal pH: frequent feeding, delayed gastric emptying
Intestinal surface area: intestinal growth and maturation (like enzymes, transporters)
Tube feeding: potential adherence to the plastic tubing used
Size of bile salt pool: maturational changes
Bacterial colonization of the lower intestines: microbiome patterns depend on nutrition (formula
vs. human milk), perinatal antibiotic exposure, and type of delivery
Underlying disease states: necrotizing enterocolitis, short-bowel syndrome, intestinal motility
including drug-related changes (opioids, erythromycin)
ONTOGENY OF GASTRIC ACID PRODUCTION
The gastric and duodenal pH affect drug solubility and ionization, as well as
gastrointestinal motility, and this will also affect absorption and
bioavailability.
7–9
An acid pH favors absorption of acid drugs (low pKa)
because the drug will largely be unionized and more lipid soluble. In contrast,
a relatively high pH (as in achlorhydria) enhances translocation of basic drugs
and restricts acidic drug absorption. The relevance of maturational changes in
gastric acid production has been illustrated by Huang and High, documenting
that oral penicillin G absorption is much more pronounced in the newborn
when compared to infants or children because less penicillin G is destroyed
by the lower amount of gastric acid in the neonate.
10
At birth, gastric pH is neutral,
6–8
but falls rapidly to 1.5 to 3 within
hours.11 This gastric pH fall is quite variable, but appears to be independent
of birth weight or age. Data on gastric fluid composition (reflecting gastric
acid production and feeding pattern) throughout childhood were recently
reported, and these authors confirmed that differences were most prominent in
preterm and term neonates when compared to other pediatric subpopulations
or adults.
6,12
In this context, the fact that neonates are rarely fasted because of
frequent feedings affects the gastric fluid composition. When we focus on the
ontogeny of gastric acid production, Kelly et al. described the presence of
gastric acid secretion in preterm infants from 24 to 29 weeks of gestational
age.13 All 22 preterm infants studied on multiple occasions (71 recordings)
from 1 to 17 days’ postnatal life were able to produce and maintain an
intragastric median pH less than 4, with an inverse relationship between age
and initial acid production.13 Grahnquist et al. documented gastric H,Kadenosine triphosphatase activity in stomach biopsies from infants of 25 to 42
weeks’ gestation, with increasing activity with age.14 The initiation of gastric
acid production likely relates to extrauterine factors (such as nutrition) and
correlates with postnatal age.
7–9
Its subsequent pattern is still somewhat controversial. Initial descriptions
suggested that the acid secretion capacity displays a biphasic pattern with an
initial low gastric pH in the first 8 to 10 days, followed by relatively higher
pH values between the first and fourth week of postnatal life. Using betazole
stimulation, Agunod et al. confirmed these patterns since the gastric fluid
TABLE 11.3
volume and its acidity are related to postnatal age to reach the lower limit of
adult values by 3 months of age. Secretion of pepsin and intrinsic factor was
also found to parallel that of gastric acid.15 In contrast, the longitudinal data of
Kelly et al. suggest a more constant intragastric pH (0.6 to 3.9) over the first 2
weeks of life in very premature infants.13 As mentioned earlier, this is likely
because gastric fluid composition reflects both gastric acid production and the
feeding pattern.
6,16
GASTRIC EMPTYING
The stomach serves as a reservoir, with subsequent titrated emptying to the
duodenum and small intestines. Because most orally administered drugs are
absorbed in the small intestines, the rate of gastric emptying is an important
determinant of the rate and extent of absorption. Assuming intestinal motility
and absorption capacity remain stable, slower gastric emptying will result in
delayed and lower peak serum drug concentrations. In contrast, nasoduodenal
tube feeding bypasses the stomach and may result in earlier and higher peak
serum drug concentrations shortly after administration.
2,6
Observations on
maturational changes should be interpreted cautiously because maturational
changes display collinearity with the type of feeding (milk for neonates;
different types of foods for infants, and beyond), so observations on
maturation of peristalsis do not always reflect the phenotypic gastric emptying
patterns. An overview on the covariates of faster or slower gastric emptying
is provided in Table 11.3.
Factors Affecting Gastric Emptying Rate in Neonates
Faster Slower No Effect
Human milk > formula
Hypocaloric feedings
Drugs: erythromycin
Prematurity
Gastroesophageal reflux
Respiratory distress syndrome
Congenital heart disease
Long-chain fatty acids
Congenital malformations:
esophageal atresia, congenital
diaphragmatic hernia
Drugs: opioids, feed thickeners
Osmolality
Posture
When based on peristaltic activity, the gastric emptying rate in neonates is
variable and characterized by irregular and unpredictable peristaltic
activity.
8,16–19
It is prolonged relative to adults and appears to be affected by
gestational and postnatal age, as well as by type of feeding to attain adult
values at 6 to 8 months.
16,17,19–21
An inverse relationship between gestational
age and the amount of gastric retention 30 minutes after a 5% glucose feeding
has been demonstrated. Similar, slower gastric emptying times have been
reported with increasing caloric density in premature infants (age 25 to 35
weeks). Significant differences were noted between formulas containing 0,
6.5, 13, or 20 calories per 100 g. These differences were significant at all
times (20, 40, 60, 80, and 100 minutes) after feeding. Interestingly, although
reduction in emptying rate is observed with higher caloric density substrates,
the quantity of calories delivered to the duodenum from the stomach increased
with increasing formula concentration.
8,9
Long-chain compared to mediumchain fatty acids result in slower gastric emptying, whereas osmolality is not
relevant.
8,17
In contrast, when based on breath tests, gastric emptying in
neonates is mainly driven by the type of food (regular formula < partially
hydrolyzed < extensively hydrolyzed < human milk), with the fastest gastric
emptying for human milk.19 Consequently, when using mean gastric residence
time (MGRT) of age-adjusted liquid and solid food, Bonner et al. concluded
that the meal type and not the maturational changes determines gastric
emptying.
6,20
EXOCRINE PANCREATIC FUNCTIONS, SECRETION OF
BILE ACIDS, AND INTESTINAL MOTILITY
The ontogeny of other intestinal physiologic processes can further influence
the gastrointestinal absorption of drugs and other compounds.
7,8,21,22
At birth, pancreatic enzyme activity is low and is even lower in premature
neonates. Interestingly, at 1 week of postnatal age, pancreatic fluid output and
enzyme activity are higher in preterm than those in full-term neonates. Lipase
activity is present by 34 to 36 weeks of gestation. This increases fivefold
during the first week and 20-fold during the first 9 months.
7,8,16,21,22
Importantly, human milk also has lipase activity (bile salt–stimulated lipase,
or BSSL) that disappears when pasteurized. However, substitution by
recombinant BSSL formulation had no effect on lipid absorption, growth, or
weight gain.23 Human milk and colostrum also contain bile salts,
predominately cholate and chenodeoxycholate.24 In contrast, amylase activity
has been detected as early as 23 weeks of gestation but remains very low
even after birth (10% of adult values). Decreased duodenal amylase activity
in fasting and fed infants has been observed in the first year of life. This is
only in part compensated by salivary amylase. It has been documented that
salivary amylase produces significant glucose polymer digestion in the
stomach and small intestine (acid resistant), but falls substantially short of that
accomplished by pancreatic amylase.25 Trypsin secretion in response to
pancreozymin and secretin administration is blunted in term infants to develop
throughout infancy.
7,8,16,21,22
The pool size, the rate of synthesis, and the intestinal reabsorption of bile
acids are lower in neonates than in adults.
22,26,27
These factors result in overall
lower duodenal bile acid concentrations and can affect the dissolution and
solubility of lipophilic drugs.
28,29
Duodenal contractions in term neonates
appear to occur at rates similar to those observed in fasting adults, although
the number of contractions per burst may be less, while fasting or
interdigestive motor activity also appears to be shorter.
9,27
MATURATION OF INTESTINAL BARRIERS,
INTESTINAL DRUG-METABOLIZING ENZYM ES, AND
TRANSPORTERS
The intestinal barrier is not a passive filter, but an active organ that displays
maturation for permeability, enzymes, and transporter activities.
Permeability
The potential age-related changes in the intestinal paracellular and
transcellular permeability of drugs did not receive the necessary attention they
deserved for a long time.28 Using lactulose/rhamnose as a biomarker of
intestinal permeability in preterm neonates, the intestinal barrier maturation
related to gestational and postnatal age was investigated. This permeability
was influenced by feeding and showed an age-driven maturational effect, with
additional effects related to exposure to human milk or antibiotics, two of the
covariates that affect the microbiome.30 The same lactulose/rhamnose
biomarker has also been used to assess intestinal permeability after
necrotizing enterocolitis.
31
Drug-Metabolizing Enzymes
There are preliminary data on age-related patterns for several drugmetabolizing enzymes and transporter proteins in the intestines, but the exact
ontogeny still remains to be elucidated. Although the liver is commonly
considered to be the main organ for drug metabolism, first-pass effects are not
limited to the liver but also involve the gut. Even more relevant for neonates,
the ontogenic profile of drug-metabolizing enzymes varies across organs.
32
Cytochrome P-450 enzymes (CYPs) are also expressed in the intestinal wall,
and this can alter the oral bioavailability of drugs such as midazolam.
33
CYP3A4/5 accounts for 80% of the total immuno-quantifiable intestinal
CYPs, with its expression decreasing from duodenum to ileum.33 The clinical
relevance of these ontogenic processes has been illustrated by the ontogeny of
oral midazolam bioavailability: this is substantially higher in preterm infants
when compared to adults, because of the more limited intestinal drug
metabolism.
34
Transporters
The ontogeny of P-glycoprotein (P-gp) and other transporters like breast
cancer resistance protein (BCRP), multidrug resistance proteins 1 to 3
(MRP1, MRP2, MRP3), organic anion transporting polypeptide (OATP)2B11A2, organic cation transporter (OCT)1, or peptide transporter (PEPT1) has
recently been summarized.35 Multidrug resistance (MDR) 1 P-gp (P-gp
ABCB1) is the intestinal transport protein for which most data are available.
35
Initially considered to be responsible for primary drug resistance in tumors
(cellular resistance to “cancer” chemotherapeutics), studies subsequently
confirmed that P-gp is expressed in the cellular membranes of the intestinal
tract (duodenum, ileum, jejunum, and colon), apical hepatic membranes, renal
proximal tubular cells, and on the luminal side of the capillary endothelial
cells of the blood–brain barrier. The overall developmental pattern of
intestinal P-gp expression revealed a change from undetectable expression in
the first trimester of fetal life to being present from approximately 12 weeks
of gestation onward. Very limited data suggest that P-gp expression
TABLE 11.4
subsequently increases slowly to reach adult levels at or very shortly after
birth.35 In contrast, Lam et al. documented that P-gp expression on the
meningeal endothelial cells (blood–brain barrier) is limited at birth and
reaches an adult level of expression at 3 to 6 months.
36
BEYOND MATURATIONAL CHANGES IN INTESTINAL
ABSORPTION
Absorption-related changes are not only affected by age (i.e., maturation) but
are also driven by nonmaturational covariates such as disease, microbiologic
flora, or the type and extent of enteral nutrition. These nonmaturational
covariates interrelate as nutrition or exposure to antibiotics will both affect
the intestinal flora.
Disease States
Table 11.4 provides an illustrative list of disease states affecting
gastrointestinal drug absorption. The diseases that likely have the greatest
impact on oral drug absorption are those affecting the total intestinal surface
area, such as short-bowel syndrome.37 This syndrome results from massive
bowel resection complicating necrotizing enterocolitis, from volvulus, or
from congenital anomalies like gastroschisis or multiple intestinal atresia.
Multiple systemic diseases may also affect gastrointestinal drug absorption.
Congestive heart failure may cause mucosal edema or—by means of various
hemodynamic compensations—affect drug absorption by delaying gastric
emptying or by shunting blood flow away from visceral organs.
Hypothyroidism or hyperthyroidism also influences drug absorption by its
effects on the intestinal transit.
Selected Disease States Affecting Gastrointes tinal Absorption of Drugs
Affected Factor Disease State
Decreased surface area Short-bowel syndrome
Protein-calorie malnutrition
Delayed gastric emptying Pyloric stenosis
Congestive heart failure
Protein-calorie malnutrition
Bile salt excretion Cholestatic liver disease
Extrahepatic biliary obstruction
Intestinal transit time Protein-calorie malnutrition
Thyroid disease
Diarrheal disease
Gastric acid secretion Proximal small-bowel resection
Microbiologic Flora
The microbiologic flora affects bile salt metabolism, intestinal motility,
intestinal barriers, intestinal drug-metabolizing enzymes and transporter
proteins.
30,38
To further illustrate this, the production of secondary bile acids
requires enzymatic modification by colonic bacteria. This is, therefore,
affected by the development of the microbiologic flora.38 Besides age-driven
maturation, there is an increasing interest in the metabolic activity of the
intestinal tract through intestinal drug-metabolizing enzymes, the gut
microflora, and the interaction between both of these.39 These interactions are
not limited to drug metabolism but may also affect drug transporter activity, as
well as bioactivation, biotransformation, or biodegradation.
Type and Extent of Enteral Nutrition
A gastrointestinal growth spurt occurs in early neonatal life, mainly driven by
the trophic effects of enteral nutrition. Early feeding with a non-nutritive (like
water alone) delays the enteric motor activity, impairs gastrointestinal growth,
and slows clinical progress.38. This has also resulted in the practice of
minimal enteral feeding to enhance enteral feeding tolerance in preterm
neonates.40 It has been reported that the type of feeding, either human milk or
formula, affects both the intestinal bacterial flora and drug metabolism.
2,6
Using in vivo probe drugs, the type of feeding (human milk vs. formula) also
affected CYP3A4 (dextromethorphan) and CYP1A2 (caffeine) metabolism.
2,6
Formula feeding appears hereby to accelerate maturation.
2,6,38
Similarly,
enteral nutrition affects the duration and extent of hyperbilirubinemia, whereas
parenteral nutrition is associated with an increased likelihood to develop
cholestasis, including an elevated conjugated bilirubin.
TABLE 11.5
ABSORPTION FOLLOWING NONORAL ROUTES OF
ADMINISTRATION
When oral therapy is precluded because of maturational- or disease-related
causes, or when the bioavailability of an oral formulation is too poor,
parenteral or nonoral routes are used. Parenteral (i.e., intravenous) route is
the most commonly used in neonates and is preferred over intramuscular
injection. Other routes are percutaneous or rectal. Irrespective of the
extravascular route used, the physiochemical and physiologic constraints
mentioned in Table 11.2 will affect the rate and/or extent of drug
bioavailability and absorption. This also includes unintentional and
inadvertent absorption.
Absorption of Intramuscular Drugs
The serum concentration–time profile following intramuscular drug
administration depends on factors related to the drug, the site of
administration, the presence of concomitant pathophysiology, and the
developmental status of the neonate (Table 11.5). These differences may
result in differences in bioavailability and PK and, therefore, should be
considered when this route is used in neonates. Lipophilicity of a drug favors
rapid diffusion into the capillaries. However, the drug must retain some water
solubility at physiologic pH to prevent precipitation at the injection site. The
impact of these characteristics on absorption is used in clinical care like for
intramuscular vitamin K injection to prevent neonatal bleeding (delayed, to
attain sufficient exposure over 2 to 3 months),41 or for respiratory syncytial
(palivizumab and nevirapine, respectively).
2,42
In contrast, intramuscular
aminoglycoside administration is effective in the AFRINEST studies in
neonates with suspected infection in limited-resource settings.
43
Considerations for Extravascular Route s , Nongastrointestinal Route s of
Drug Administration that May Affect Drug Absorption
Physicochemical factors = issues likely not specific to neonates
Molecular weight
pKa and degree of ionization
Lipid-water partition coefficient