Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
pH and viscosity at the site(s) membrane translocation
Particle size
Physiologic factors = issues likely more specific to neonates
Membrane permeability, “leakiness”
Thickness and surface area of membranes at the site(s) of translocation
Relative differences in solute concentration around membranes
Presence or absence of facilitated or active transport mechanisms
Relative surface area at the site(s) of membrane translocation
Volume of fluid at administration site
Presence or absence of metabolic pathways and/or enzymes necessary for biotransformation
Determination of residence time at absorptive sites (like gastrointestinal motility, bulk flow of
cerebrospinal fluid)
Blood supply to the site(s) of membrane translocation
Affinity of drug for binding to plasma and/or tissue constituents
Concomitant pathophysiology, like cutaneous lacerations, inflammation at the site of administration
(conjunctiva, nasal, buccal, or retinal), muscular activity (in the setting of muscular administration), or
bronchial tree and alveolar surface (inhalation)
A relevant physiologic factor that influences drug absorption from an
intramuscular injection site is the blood flow to and from the injection site and
the muscle mass. As a consequence, the muscle activity and its
microcirculation matters.2 This may be compromised in newborns with poor
peripheral perfusion with low cardiac output states or respiratory distress.
The absorption rate and extent from an intramuscular injection site is also
influenced by the total surface area of muscle coming into contact with the
injected solution, similar to the dependence of oral absorption on the
absorptive intestinal area. The ratio of skeletal muscle mass to body mass is
lower in neonates.2 The muscle activity may also display both maturational
(age) and nonmaturational (critical illness, neuromuscular diseases, muscle
relaxants) covariates. This may affect the absorption rate and, therefore, the
peak concentration.
Percutaneous Absorption
Postnatal life accelerates the skin barrier functions (e.g., stratum corneum
thickness and hydration, pH, sebum) so that even preterm neonates have
barrier functions similar to term neonates from 2 to 3 weeks of postnatal age
onward, although there are differences between anatomic regions.44 Nachman
and Esterly studied the blanching response to topical 10% phenylephrine in
(pre)term neonates. At 28 to 34 weeks of gestational age, there was a rapid
(30 minutes) and lasting (6 to 8 hours) response, no longer observed at 21
days of postnatal age. In near-term newborns at birth, there was a blunted
response with a longer latency period, and term infants failed to demonstrate
any blanching response.45 This suggests that neonatal skin adjusts to
extrauterine life, irrespective of the age at birth.
45,46
Antenatal glucocorticoid
exposure is another covariate of neonatal skin maturation.47 Obviously, if the
skin integrity is compromised, percutaneous translocation will be enhanced,
as illustrated for topical timolol to treat infantile hemangiomas.
48
Besides skin maturation, the larger body surface area to weight (BSA per
kg) ratio in (pre)term neonates is also relevant. Using the Mosteller formula,
the BSA per kg ratio in neonates of 26, 30, 34, and 38 weeks is 0.090, 0.087,
0.075, and 0.064, respectively, as compared to infants (0.046) or adults
(0.025).2 Based on this BSA per kg ratio, the systemic availability per
kilogram of body weight is 3.6 to 2.5 (0.09 to 0.064/0.025) times greater in
the newborn, if both receive the same percutaneous dose per kg.
Because of this permeability and the BSA/kg ratio, the skin represents an
often overlooked but important organ for drug absorption in neonates.49 There
are numerous reports on neonatal toxicity related to cutaneous drug exposure.
These reports include cases on hexachlorophene, pentachlorophenolcontaining laundry detergents, excipients, hydrocortisone, lidocaineprilocaine, and iodine- or aniline-containing disinfectant solutions–related
toxicity.
2,49
Extreme caution should be exercised in using topical therapy in
newborns.
Rectal Absorption
Rectal absorption is erratic with unpredictable absorption that depends on the
formulation (liquid or solid suppository) and retention time within the rectal
vault. The predominant mechanism for rectal absorption is passive diffusion,
with faster absorption from aqueous or alcoholic solutions than from
suppositories.
50,51
Acetaminophen observations illustrated that the rectal route
results in more limited bioavailability and more extensive variability.
52
Compared to oral, the relative bioavailability was 0.67 (30%) and 0.61
(21%) for triglyceride base elixir and capsule suppositories, respectively.
52
This necessitates higher doses to attain a similar median plasma
concentration, be it with still poor predictability, making the rectal route less
suitable for repeated administration.
The inferior and middle rectal veins drain the anus and lower rectum,
connected to the systemic circulation by the inferior vena cava. In contrast, the
superior rectal vein drains the upper part of the rectum to empty into the portal
vein by the inferior mesenteric vein. Therefore, drugs administered into the
upper rectal part will undergo hepatic first-pass, whereas drugs administered
in the lower rectal part will initially bypass the liver.51 Because of these
anatomic findings, rectal administration is associated with higher and earlier
peak concentrations of lipophilic compounds (pKa values 7 to 8) like
thiopentone, methohexitone, or benzodiazepines.
2,51
The rapid attainment of
effective systemic drug concentrations after rectal administration has been
applied to treat seizures, although this recently has shifted to the buccal or
nasal route.
53
Observations on Other Routes Involved in Absorption
Alternative routes reported in neonates cover—among others—the
endotracheal, epidural, intrathecal, intraperitoneal, buccal, nasal, or
intravitreal route. Overall, there is still limited knowledge on drug absorption
via these routes, although some drug-specific observations have been
reported.
2,51,54
Inhalational absorption is of relevance for inhalational anesthetic agents.
Their absorption relates to the functional residual capacity and alveolar
surface area. This results in faster absorption in neonates.54 Conjunctival
absorption is commonly nonintentional, but mydriatics (for retinopathy of
prematurity screening) have been associated with cardiorespiratory events,
feeding intolerance, and paralytic ileus in preterm neonates.55 Absorption
after intravitreal injection of anti–vascular epithelial growth factor (VEGF)
results in systemic appearance. This may be relevant because preterm infants
treated with bevacizumab had higher odds of severe neurodevelopmental
disability.56 The buccal route for midazolam (buccolam) has been mentioned
earlier,53 although there is increasing interest in the nasal route.57 Finally,
locoregional anesthesia techniques (epidural, intrathecal) result in lower but
quantifiable systemic exposure to analgesics or adjuvants, such as clonidine.
54
TABLE 11.6
For any extravascular route, the physiochemical and physiologic
constraints will affect the absorption rate and extent.51 In neonates, this is even
the case for the intravenous route.58 To attain a target exposure, any method
should enable the drug to reach its site of action at the desired time and
concentration. Appreciation of the substantial delay and variability in the rate
of drug delivery from the intravenous line is often lacking. Other challenges
relate to slow intravenous flow rates, small drug volumes, dead space
volumes, and limitations of the flush volume in neonates.58 The lack of
awareness to critical aspects of drug administration techniques can lead to
therapeutic misadventures (Table 11.6).
Potential Errors in Drug Administration Techniques
Factors Involved Potential Errors
Drug (dose) preparation Inappropriate dilutions
Similarity in appearance of dose units
Loss of potentially large amounts of drug dose in the dead
space of a syringe or infusion Y site
Unsuitable drug formulations for administration
Unlabeled or undesirable ingredients in dose forms
Undesirable drug concentrations and/or osmolality
Errors in interpreting drug orders and/or dose calculations
Intravenous drug administration Loss of drug consequent to routine changing of intravenous
sets
Reduction in serum concentration for drugs with rapid
plasma clearance that are infused slowly
Extreme increase in plasma drug concentrations
consequent to rapid infusion with small central
compartment volume of distribution
Delayed infusion of total dose when intravenous line is not
flushed
Inadvertent admixture of drugs by the manual intravenous
retrograde method
Large distance between the site of drug infusion into an
intravenous line and the insertion of the line in the patient
Potential loss of large volume doses in the overflow syringe
with the intravenous retrograde technique
Possible loss of drug because of binding to tubing
Use of large intraluminal diameter tubing for small patients
Infiltrations not detected by pump alarms
Infusion of multiple medications/fluids at different rates by
a single access
Oscillations in fluid/dose rate of potent medication infused
with piston-type pumps
Other routes of drug administration Loss in delivery (nasogastric tube dead space) or from oral
cavity
Leakage of drug from intramuscular or subcutaneous
injection site
Expulsion of drug from the rectum
Misapplication to external sites (i.e., ophthalmic ointment in
young infants)
DISTRIBUTION
Distribution describes the passage of compounds in the systemic circulation
and to other compartments. Distribution depends on maturational (e.g., body
composition), drug (e.g., molecular size, ionization, lipophilicity, protein
binding), or disease factors (e.g., regional perfusion, membrane
permeability).
6,59
Mathematically, the distribution volume (Vd) describes the
relationship between the amount of drug in the body and its plasma
concentration. Although affected by physiologic covariates, Vd does not
necessary reflect a physiologic compartment, since Vd is the volume needed to
contain the total body store of drug if the concentration in the whole body
were the same as in plasma. This is described by the following equation:
where D = dose administered, F = bioavailability, and C0 is derived by
extrapolating the slope of the curve of plasma concentration versus time to
time 0. Several factors, including plasma protein concentration and tissue
binding, affect Vd. This is described by the following equation:
TABLE 11.7
where Vb= blood volume, Vt = tissue volume, fB = unbound blood drug
fraction, and ft = unbound tissue drug fraction. Therefore, any factor that
increases the blood volume or the unbound blood drug fraction, or reduces
the unbound tissue drug fraction will increase Vd. Differences in drug-specific
distribution are mainly driven by differences in protein binding or body
composition.
DEVELOPMENTAL ASPECTS OF PROTEIN BINDING IN
NEONATES
Drug binding of plasma proteins depends on the protein concentrations, the
affinity constant of the relevant protein(s), the number of available binding
sites, and the presence of pathophysiologic conditions or endogenous
compounds that may alter the drug–protein-binding interaction.60 Table 11.7
provides an overview on to what extent these variables are different in
neonates. Total plasma protein increases in early infancy to reach adult levels
at 10 to 12 months.61 Albumin may reach adult levels earlier, while the
albumin concentration is proportional to gestational age. Within the neonatal
age range, albumin significantly increases with postmenstrual age, but this
only explained 20% of the variability, illustrating that there are also
nonmaturational covariates.
59,62
Albumin is not the only plasma protein that
binds drugs. Basic drugs are bound by plasma proteins like α1-acid
glycoprotein, and a sigmoidal maturational pattern for this glycoprotein has
recently been described.63 The significant lower concentrations result in
lower binding capacity and higher free concentrations for drugs like lidocaine
or propranolol.
Physiologic Variables Influencing Drug–Prote in Binding in Ne onates ,
Compared to Infants or Children, Re lative to Adult Values
Table 11.8 provides data on comparative protein binding (newborns to
adults) for eight specific drugs. Differences are not only driven by the protein
concentration (Table 11.7) but are also explained by other mechanisms like
(a) displacement of drugs from binding sites by bilirubin, (b) different binding
properties of albumin, (c) different binding properties of globulins, and (d)
decreased binding properties of albumin because of interaction with globulins
in newborns.
Comparative Protein Binding of Some Repres e ntative Drugs
TABLE 11.8
Percentage Bound
Drug Newborn Adult
Ampicillin 10 18
Cefazolin 60 80
Diazepam 84 99
Lidocaine 20 70
Phenytoin 80 90
Propranolol 60 93
Theophylline 36 56
Vancomycin 10 40
INFLUENCE OF ENDOGENOUS SUBSTANCES ON
PROTEIN BINDING
There are different endogenous compounds that also bind to plasma proteins
and may displace (competitive binding) drugs from these binding sites, or
alter the protein structure, and its binding places and affinity (allosteric
effects). If the drug is displaced, this results in an increase in distribution
volume. More relevant, the increased free drug concentration may result in a
transient intensified pharmacologic response at the same serum total drug
concentration and may also affect clearance.
60,63
The clinical significance of
protein displacement-related drug–compound interactions is usually very
limited owing to the increased Vd and concurrent change in body clearance.
64
However, in neonates, this interaction may be of greater importance because
of their immature clearance.
60,63,64
Clinically significant protein-binding displacement reactions occur when
(a) a drug is more than 80% to 90% protein (un)bound, (b) the clearance is
capacity limited, (c) the clearance is binding sensitive, and (d) the Vd is small,
usually less than 0.15 L per kg. Above this value, only a small percentage of
total drug in the body is present in plasma. Under these conditions, the
following sequence of events may occur: displacement increases the free drug
concentration, which may result in a heightened pharmacologic response if the
drug’s concentration–effect curve is reasonably steep. Such intensified
pharmacologic effect is often transient because the displacement increases the
amount of free drug available for clearance. Once a steady state is achieved,
the result is a decreased total and an unchanged free drug concentration.
61
FREE FATTY ACIDS AND UNCONJUGATED BILIRUBIN
Free fatty acids (FFAs) and unconjugated bilirubin are both illustrations of
endogenous compounds that can display competitive binding and drug
displacement at the albumin sites. This can affect the variability in binding
capacity, especially in neonates.
65,66
Nonesterified fatty acids are reversibly bound to albumin and may have
allosteric effects.67 FFA is present at relatively high concentrations in
neonatal plasma. Significant reductions in albumin binding of phenylbutazone,
dicoumarol (bishydroxycoumarin), and phenytoin have been demonstrated at
high serum levels of FFAs and at a FFA-to-albumin molar ratio of greater than
3.5. Although these values are rarely attained, they have been observed under
certain pathophysiologic conditions, such as Gram-negative septicemia.
Bilirubin is also noncovalently bound to albumin and can display competitive
binding. The bilirubin-binding affinity of albumin at birth is independent of
gestational age and is lower in the newborn than in the adult to reach adult
capacity by approximately 5 months of age.
68,69
The lower bilirubin-binding
affinity of albumin in neonates is believed to be a contributing factor in their
susceptibility to kernicterus.
68,69
However, other covariates like hypothermia,
acidosis, hypoglycemia, hypoxemia, sepsis, birth asphyxia, and hypercapnia,
and their effect on bilirubin–albumin binding and on the blood–brain barrier
permeability must be considered.70 The apparent importance of P-gp
maturation on the blood–brain barrier to bilirubin transport has recently been
described.36 A number of drugs are thought to be able to compete with and
displace bilirubin from the albumin-binding sites, increasing the risk to
develop kernicterus. This includes not only sulfonamides, ceftriaxone,
ibuprofen, or indomethacin but also some X-ray contrast agents.
68,70,71
TABLE 11.9
DEVELOPMENTAL ASPECTS OF BODY
COMPARTMENTS
Alterations in body water compartments affect the distribution volume,
especially when drugs are water soluble. Age-dependent changes in the
various body water compartments are summarized in Table 11.9.
72,73
This
reflects the very high body water content in fetal and neonatal life (75% to
90%), with a subsequent decrease to reach adult values (50% to 60%) after
the first year of life. This decrease is almost completely explained by a
simultaneous decrease in extracellular water, partially mirrored by a
proportional increase in body fat.
72,73
Body Water Compartment Sizes (Pe rce ntage of Body We ight, Median
Estimates) as a Function of Age
a