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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
γ-Aminobutyric acid (GABA) is the most prevalent inhibitory
neurotransmitter in the mature brain interacting with postsynaptic GABA
receptors. However, it has a different role during early development, acting as
a trophic factor influencing proliferation, migration, differentiation, synapse
maturation, and cell death.
20
There are two types of GABA receptors: GABA-A and GABA-B. The
GABA-A receptor incorporates binding sites not only for GABA but also for
benzodiazepines, barbiturates, steroid anesthetics, volatile general
anesthetics, and possibly alcohols. These agents are allosteric modulators at
the receptors, resulting in increased GABA affinity and increased frequency
of chloride channel opening.
3,4
Studies in nonhuman primates and, more recently, in children with seizure
disorders have shown that major changes in GABA-A receptor binding and
subunit expression occur during postnatal development. During early
development, the chloride concentration in nerve cells is high. Opening of the
chloride channels by GABA results in a depolarization (i.e., excitation).
During maturation, possibly because of changes in the GABA-A receptor
subunit composition, the intracellular chloride concentration decreases, so
that the effect of GABA to open up the chloride channels causes the cell to
become hyperpolarized, thus interrupting impulse conduction (i.e., inhibition).
In this way, GABA switches from excitatory to an inhibitory neurotransmitter.
This switch occurs around 1 to 2 weeks postnatally in the rat, but it is not
known when it occurs in humans.
3,4
A change in the density and distribution of GABA-A receptor with age has
been shown in humans.21 By applying positron emission tomography using the
tracer [11C] flumazenil, a ligand that binds to a subunit of the GABA-A
receptor complex, all brain regions showed the highest distribution of the
tracer at 2 years of age (which was the youngest age measured) and the values
subsequently decreased with age. The greatest differences between children
and adults occur in the temporal lobe, visual cortex, and thalamus. The
developmental changes in GABA-A receptor subunit composition,
distribution, or abundance, therefore, could have a significant impact on the
efficacy of anticonvulsant drugs in the pediatric population. Increased
apoptotic death and reduced neurogenesis are observed in 1-week-old rats
exposed to benzodiazepines or phenobarbital. Similar findings were observed
with other anticonvulsant drugs, suggesting that the immature brain may be
more dependent upon a higher level of neuronal activity for survival than the
adult brain is. Midazolam is reported to decrease the mechanical reflex
threshold and increase the magnitude of mechanical and thermal reflexes in
neonatal rats, but had no effect in juvenile rats. In the same study, midazolam
had sedative effects in postnatal age day 10 and 21 rats, but not in postnatal
age day 3 rats.
4
Excitatory mode of GABA-A receptors may help to explain seizures
experienced by preterm infants and newborns after exposure to
benzodiazepines. The hypothesis could also be extended to febrile
convulsions in young children. Although differences in anticonvulsant doses
between adults and children are largely because of PK, the requirement for
larger doses in children may also be partly attributed to changes in receptor
density and subunit composition (which affect binding affinity) during
maturation.
Since GABA has a trophic role during early brain development, it is
important that future studies in preterm and young infants evaluate how
interference with the function of GABAergic transmission during this period
affects the development of neuronal wiring, plasticity of neuronal network,
and neuronal organization, all of which could have long-term behavioral
effects.
20
DRUGS ACTING ON THE CARDIOVASCULAR
SYSTEM
RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM
The renin–angiotensin–aldosterone system (RAAS) plays a major role in
pathophysiology of cardiovascular disease and organ damage across the
cardiovascular continuum. It controls cardiovascular, renal, and adrenal
function by regulating body fluids, electrolyte balance, and arterial pressure.
It is a commonly used target for pharmacotherapy of cardiovascular diseases
in adults. However, the efficacy of this pharmacotherapy can only be inferred
in children in a limited way. The vast collection of information on physiologic
and therapeutic effects of drugs acting on the RAAS derived from adult
populations may not be entirely applicable to children.
22
Comprehensive knowledge of the peptides acting in the pediatric RAAS
(e.g., angiotensin I, angiotensin II, angiotensin 1 to 7, angiotensin III, and
angiotensin IV) might facilitate a more effective and rational pharmacotherapy
in children. Age has a major impact on circulating angiotensin I and
angiotensin II, with both being significantly elevated at birth and decreasing
into adolescence, from a median of 302 to 98 pg per mL
.22
The sex hormones
that are believed to play a regulatory role in the adult RAAS do not appear to
be influential in children, suggesting that the gender-specific differences in the
RAAS develop after childhood. The effect of addition of antihypertensive
medication appears to increase angiotensin I and decrease angiotensin II,
whereas cardiac and renal surgery seems to decrease both angiotensin I and
angiotensin II.22 Elevated levels of aldosterone and 18-hydroxycorticosterone
have also been reported in children.
23,24
Angiotensin-converting enzyme (ACE) inhibitors are known to play a role
in cardiovascular remodeling and, in adults, have shown to regress left
ventricular hypertrophy and improve systolic function. Such effects are
beneficial in patients with ventricular hypertrophy who have achieved most of
their somatic growth potential. But there is concern that similar effects may be
detrimental in young children.25 A study of the newborn pig heart shows that
rapid growth of the left ventricle can be diminished by ACE inhibitors.
26
Thus, in the actively growing child with other etiologies of congestive heart
failure, inhibiting hypertrophy, the mechanism by which the heart grows in
humans beyond the age of 6 months, could limit cardiac growth potential. The
findings of a large randomized controlled trial (RCT) in children with single
ventricle physiology did not support the routine use of enalapril.
27
There also appears to be an age influence on the expression of two main
angiotensin receptor subtypes: AT1 and AT2. AT1 is believed to mediate the
classic actions of angiotensin II, such as vasoconstriction, sodium and water
retention, and cardiovascular remodeling. AT2 is highly and transiently
expressed in fetal tissues, with receptor density falling significantly in all
tissues soon after birth and AT1 becoming dominant by 3 months of age. This
has led to the speculation that the AT2 receptor has an important role in cell
growth, differentiation, and adhesion. The neonatal decrease and
simultaneously higher AT2 receptor density is a point of concern with regard
to the use of angiotensin receptor blockers in the developing child.
28,29
CARDIAC ELECTROPHYSIOLOGY
The developing heart demonstrates significant differences in calcium
regulation mechanisms and in responses to physiologic and pharmacologic
interventions.
30
Digoxin
Children appear to require and tolerate higher doses of digoxin to achieve
therapeutic endpoints comparable with adults.
31–33
The developmental PD
effects of digoxin have been demonstrated in the myocardium of various
species.
34–36
One possible explanation for the relative resistance of children to
digoxin may lie in the developmental changes in Na K-ATPase isoform
expression (the binding site of digoxin), which have been shown to alter
electrophysiologic properties and cardiac glycoside sensitivity.
37
QT Interval Prolongation
The QT interval reflects ventricular repolarization on an electrocardiogram,
and prolongation is associated with ventricular arrhythmias. During infancy, it
has been shown that the QT interval is related to postmenstrual age and
progressively increases after birth, reaching a maximum value in the second
month of life, and thereafter progressively decreases until 6 months of age to
reach values similar to those of adults.38 The changes in QT interval
according to postmenstrual age may be due to developmental changes in
repolarizing potassium currents.39 Another possible mechanism of QT
developmental changes is the maturation of the autonomic nervous system.
40
These data suggest that electrocardiogram monitoring should be implemented
in premature newborns who have reached 30 to 32 weeks’ postmenstrual age
and are exposed potentially to QT lengthening.
38
There is actual evidence that infants are more sensitive to drugs with
proarrhythmic tendencies. Cisapride, a prokinetic agent widely used in the
1980s and early 1990s for gastrointestinal disorders, especially esophageal
reflux, was withdrawn from the market after publication of multiple reports of
QT prolongation in children and adults.41 A PK–PD study of sotalol in the
treatment of children with supraventricular tachycardia (SVT) showed that
neonates exhibited a higher sensitivity toward QTc interval prolongation
compared with older children.42 In a study of oral domperidone in neonates,
advanced gestational age and serum potassium at the upper limit of normal
were two risk factors associated with QT prolongation.
43
DOPAMINERGIC SYSTEM
Studies in several animal species have demonstrated an important difference
in cardiovascular response to dopamine between newborn and mature
animals.44 Dopamine does not elicit D1-mediated renal vasodilatation in the
newborn as it does in the adult animal. In fact, low doses of dopamine that
produce renal vasodilatation in the adult actually may induce vasoconstriction
in the newborn from stimulation of α-adrenergic receptors, which are well
developed at term. Likewise, the natriuretic response to D1 agonists is blunted
in the newborn. It is unclear whether the decreased response to dopamine in
immature animals is due to differences in receptor density, affinity for the
agonist, coupling to second messengers, or distal intracellular mechanisms. In
addition, the ontogenic profile of the different dopamine receptor subgroups in
various organs and tissues beyond the newborn period is not known.
However, differences in response to dopamine between the newborn and the
adult animal do not appear to translate to humans. A number of studies in
premature neonates show that a dose-dependent increase in urine output is
observed with dopamine infusions.
45
HEMOSTATIC SYSTEM
The hemostatic system is a dynamic, evolving, age-dependent system.
46
Synthesis of clotting factors by the fetus starts during the fifth week of
gestation for fibrinogen, and blood is capable of clotting after 11 weeks. At
birth, the plasma levels of most coagulation proteins are around half that
measured in adults, preterm neonates having lower levels than term neonates.
Although there is continuous maturation of the hemostatic system postnatally,
it is still significantly different from adults at 6 months of age. For example,
plasma concentrations of vitamin K–dependent coagulation factors (FII, FVII,
FIX, FX) are approximately 20% lower than the corresponding values in
adults until the late teenage years. Plasma prothrombin concentrations during
childhood are 10% to 20% lower than adults. In addition, plasma
concentrations of the thrombin inhibitor, α-2-macroglobulin was twice the
adult value in early childhood and remained elevated throughout childhood. In
contrast, mean plasma concentrations of protein C and heparin cofactor II
were significantly lower than for adults until early teenage years.
Primary hemostasis is far less studied, but the platelet count is usually
normal or elevated at birth, reaching adult values within 1 year.46 Platelets are
hyporeactive in neonates, but despite this, the bleeding time and the platelet
closure time (platelet function assay) were found to be shorter in newborns
and normalized before the end of the first month of life. Levels of von
Willebrand factor appear to be associated with the physiologic development
of the ABO(H) and I blood group system and are reported to be significantly
higher in newborns and decreasing to adult values after 1 year of life.
46
The effect of these developmental differences on the relationship between
anticoagulants and the hemostatic system has been explored in a limited
number of studies.
Warfarin
An ex vivo study revealed that the capacity of plasma to generate thrombin
was decreased and delayed in children receiving warfarin therapy compared
to adults with similar international normalized ratio (INR) values. Increased
inhibition of thrombin was attributed to elevated α-2-macroglobulin levels in
children. The in vivo relevance of these observations was highlighted with
decreased plasma concentrations of prothrombin fragment 1 + 2 in children
compared to adults at equivalent doses of warfarin.47 The increased
sensitivity of children to warfarin has also been reported in an in vivo PK–PD
study. Children and adults (age range 1 to 76 years) on a constant maintenance
dose of warfarin for at least 1 month were investigated for plasma
concentrations of unbound warfarin, CYP2C9 genotype, vitamin K, and
various coagulation parameters. Accounting for the developmental changes in
PK and genotype, comparable unbound concentrations of (S)-warfarin,
showed significantly lower plasma concentrations for protein C and
prothrombin fragments 1 + 2 and greater INR in children.
48
Heparin
Unfractionated heparin (UFH), an antithrombin activator, remains one of the
most commonly used drugs in pediatric secondary care. Neonates have low
antithrombin levels, high levels of α-2-macroglobulin, and an increased
volume of distribution because of increased binding of UFH to heparinbinding proteins. The overall effect, at least at lower doses, appears to be
heparin resistance, with UFH dosage usually higher in neonates and younger
children than in older children or adults. Because activated partial
thromboplastin time (aPTT) ratio is physiologically prolonged in the younger
patients, treatment with UFH should preferably be monitored using anti-FXa
activity.
46
Age dependency of the dose of low-molecular weight heparin (LMWH)
has also been observed. Younger patients required higher doses of enoxaparin
to achieve target anti-FXa level on a per-kg basis: 1.5 to 2.0 mg per kg in
infants versus 1.0 mg per kg in older children and adults. Similarly, pediatric
doses for tinzaparin administered once daily decrease with age: 280 IU per kg
between 0 and 2 months, 245 IU per kg between 2 and 12 months, 240 IU per
kg between 1 and 5 years, 200 IU per kg between 5 and 10 years, and 175 IU
per kg (adult dosage) between 10 and 16 years.
46
Antiplatelets
There are limited literature data on the use of antiplatelet agents in children.
46
Aspirin antiplatelet doses (1 to 5 mg per kg per d) appear to have been
extrapolated linearly from adults, although there are no supporting data. In
contrast, the antiplatelet effects of clopidogrel have been evaluated in a study
of children aged 0 to 24 months and appeared to exhibit age-dependent PD
with a lower dose of 0.2 mg per kg per d, achieving a platelet inhibition level
similar to that in adults taking 75 mg per d.49 This dose was subsequently
evaluated in a randomized, double-blind, placebo-controlled trial in neonates
and infants with cyanotic congenital heart disease. The study concluded that
clopidogrel treatment of young infants with cyanotic congenital heart disease
does not reduce all-cause mortality or shunt-related morbidity. Consequently,
there have been some question marks around whether the 0.2 mg per kg per d
dose was actually too low dose.
50,51
DRUGS ACTING ON/WITH THE IMMUNE
SYSTEM
The normal neonatal immune response is relatively hypoinflammatory,
characterized by the production of anti-inflammatory cytokines, negative
regulators of Toll-like receptor signaling, and decreased innate-adaptive
immune system communication.52 This functional immaturity of the immune
system in neonates, especially preterm neonates, makes them susceptible to
bacterial and viral infections often presenting as sepsis.
In the early postnatal immune system, neonates have lower numbers and/or
decreased functional capacity of leukocytes (T and B lymphocytes, natural
killer cells, and myeloid-lineage cells). There is a predisposition in the
perinatal period to Th-2 skewed immunity and suboptimal Th1 responses so
that early-life adaptive T-cell immunity is characterized by tolerogenic
reactivity, reduced alloantigen recognition, and poor responses to foreign
antigens. Suboptimal B-cell response contributes to blunted humoral immune
responses with incomplete immunoglobulin class switching. The ability of B
cells to produce various immunoglobulins matures at different rates. Serum
immunoglobulin M (IgM) concentrations are only approximately 10% of adult
levels at birth and do not reach adult levels until 1 to 2 years of age.
Similarly, concentrations of IgG in serum do not reach adult levels for 4 to 6
years after birth.
53
Compared to adult innate cells, neonatal cells are much less
polyfunctional, and each individual cell produces fewer cytokines. Neonatal
cells produce high levels of superoxide and display an increased production
of chemotactic interleukin-8 (IL8). In contrast, a low production of classic
pro-inflammatory cytokines is detected. Monocytes from children have the
capacity to produce tumor necrosis factor (TNF) and IL6 to the same levels as
adult monocytes around the age of 3 years, but a number of other cytokines
such as interferon-γ (IFNγ) and IL12 remain low until the teenage years.
54
Low cytokine production in response to infectious stimulus continues for
years and increases children’s susceptibility to microbial infections.
Newborn serum concentrations of almost all circulating components of the
complement system are 10% to 80% lower than in adults, with diminished
biologic activity. Complement levels increase after birth, with some serum
factors reaching adult concentration within a month (e.g., factor B), but others
evolve more slowly.
55
IMM UNOSUPPRESSANTS
There is some evidence that lymphocyte ontogeny corresponds to a variable
and age-related response to immune-modulating agents. In humans, it has been
shown that there is a difference in sensitivity of adult and infant T cells to
inhibition of their proliferative response by dexamethasone. T cells from cord
blood of preterm and term neonates are more sensitive to inhibition by
dexamethasone than were adult peripheral blood cells. The heightened
sensitivity to dexamethasone gradually decreases throughout infancy, and the
adult response pattern is reached at 1 year of age.56 Similarly, an ex vivo
study investigating the effect of age on the immunosuppressive effects of
cyclosporine revealed markedly enhanced sensitivity in infants compared
with older children and adults. The concentration at which 50% inhibition
occurs (IC50) for peripheral blood monocyte proliferation was less than half
that in older children and adults. In addition, inhibition of IL2 expression by
peripheral blood monocytes was significantly greater in infants than that in
adults. This is likely related to immaturity of the T-lymphocyte response in the
infant and has important therapeutic implications for dosing cyclosporine in
infants independent of PK differences.
57
Perturbation of the developmental sequence of events can lead to immune
dysfunctions that may be life-threatening. Studies in mice suggest that
administration of certain drugs during early postnatal life can also result in
altered immune function later in life. For example, 1-day-old mice exposed to
cortisol or hydrocortisone displayed thymic atrophy and reduced antibody
responses to sheep red blood cells.
58
ANTIMICROBIALS AND VACCINES
Despite the general recognition of the important role of the host’s defense in
contributing to clearance of microorganisms, most clinical studies focus
almost exclusively on the PK/PD of the antimicrobial drug and microorganism
and neglect the contribution of the immune system.59 Therefore, the exposure
that yields the desired microbiologic and clinical cure in adults is assumed to
be similar in all pediatric age categories, and adjusting doses in children to
achieve equivalent exposure to that observed in adult studies is the main
objective.
60
TABLE 3.2
This, however, ignores the possibility that, particularly in neonates due to
their immature immune function, to achieve microbiologic and clinical cure,
age-specific exposure in children may differ from the exposure needed in
adults. Currently, no prospective data exist in children to validate the
exposures required for microbiologic and clinical cure.
The immaturity of the neonatal immune system is also relevant to
vaccination development programs because infants are the target age group
for many of the vaccines in development, including tuberculosis (TB),
malaria, and HIV vaccines. A better understanding of the intrinsic factors
influencing maturation and development of the neonatal immune system can
inform the development of effective and safe vaccines, which can elicit
protective responses against these organisms.
GROWTH, DEVELOPMENT, AND DRUG
TOXICITY
Age-dependent PD, of course, does apply not only to the desired
pharmacologic response but also to adverse effects. The complex processes
involved in growth and development frequently make the child uniquely
vulnerable to mechanisms of toxicity that are not present in mature
individuals. There are periods of vulnerability in the developing infant, when
they are much more sensitive to toxic effects of drugs than later in life. This
phenomenon is particularly relevant to the nervous, endocrine, reproductive,
immune, and visual systems.61 This may have the consequence of narrowing or
widening the therapeutic window so that for a given exposure, an adverse
effect is more or less likely to occur in children compared to adults (Table 3.2
and Fig. 3.2).
Examples of Age-Dependent Toxicity