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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
The clinical relevance of this gradual reduction in the size of body water
compartments and a gradual increase in body fat with age cannot be
overemphasized. To achieve comparable plasma and tissue concentrations of
TABLE 11.10
drugs distributed into the extracellular fluid, higher doses per kilogram of
body weight must be given to neonates, as compared to children or adults for
water-soluble drugs, such as acetaminophen or aminoglycosides, whereas the
reverse occurs for highly lipophilic drugs, such as propofol (Table 11.10).
74–77
This is reflected in the higher dose (mg per kg) for aminoglycosides to attain a
similar peak concentration, with a subsequent further extended time interval
between doses to enable sufficient time for clearance.
75,76
Besides
maturational changes, fluid retention related to diseases (such as sepsis and
respiratory distress) or treatment modalities (such as extracorporeal
membrane oxygenation) further contributes to the inter- and intrapatient
variability in drug distribution.
73,78
Impact of Maturational Changes in Body Composition on Distribution
Volume (L/kg) of Frequently Used Drugs
METABOLISM
Drug removal from the body occurs by metabolism or primary (renal)
elimination. The primary organ for drug metabolism is the liver, but kidneys,
intestine, lungs, or skin may contribute.
59,79
Although metabolism generally
results in pharmacologically weaker, inactive, and water-soluble compounds,
parent compounds may be transformed into active metabolites (like
theophylline to caffeine, codeine to morphine) or prodrugs may be converted
to their active moiety (like chloramphenicol-succinate or chloramphenicolpalmitate to chloramphenicol base).
Hepatic metabolism commonly determines the PK and PD properties of a
drug. The PK parameter of estimated clearance describes the overall rate of
drug removal and can be described as plasma clearance, organ clearance, or
total body clearance. Plasma clearance is the volume of plasma from which a
drug is completely removed per unit of time. Drugs can be cleared by several
mechanisms, with hepatic biotransformation, renal excretion, and exhalation
representing the primary routes. Drug clearance (CL) by an individual organ
depends on the organ-specific blood flow (Q). The organ’s extraction ratio
(E) can be described as follows:
CL = Q × E
where E is the ratio of the arteriovenous concentration difference, divided
by the arterial concentration, expressed by:
where Ca and Cv are the arterial and venous concentration, respectively.
Hepatic clearance depends on hepatic blood, plasma free drug concentration,
cellular uptake, hepatic metabolism, and biliary excretion. The hepatic drug
clearance can be expressed by the following equation:
where CLH = hepatic clearance, Q = hepatic blood flow, fB = fraction of free
drug, and CL
int
= intrinsic clearance, as measure of hepatocellular
metabolism. Drugs that are primarily cleared by the liver can be classified as
flow limited or capacity limited. If a drug displays a high CL
int
and E, then
doubling the CL
int
will have little effect on CLH, whereas a change in blood
flow will produce a proportional CLH change. In other words, for drugs that
are highly extracted (>80%) and undergo hepatic metabolism, CLH reflects the
amount and rate of drug delivered to the liver. High extraction ratios drugs
will be subjected to the first-pass effect when administered orally. This
signifies that a drug is rapidly metabolized or altered when passing through
the intestinal mucosa or liver after absorption. Therefore, the parent
compound is found in lower concentrations in the systemic circulation
compared to intravenous administration, whereas metabolites are the
predominant form of the drug retrieved in the circulation. Examples of drugs
that exhibit high extraction are lidocaine, propranolol, acetylsalicylic acid,
and isoproterenol.
In contrast, capacity-limited drugs display low extraction ratios (<20%)
and low intrinsic metabolic clearance. Hepatic clearance depends on the
degree of hepatic uptake and metabolism, independent of hepatic blood flow.
Capacity-limited drugs can be further subdivided into binding-sensitive and
binding-insensitive drugs. For binding-sensitive drugs (such as clindamycin),
extraction ratios approach the free drug concentration (E = fB). Therefore,
factors that increase fB, such as decreased protein binding, will increase
hepatic clearance. In contrast, other drugs may display extraction ratios that
are much less than that of the free drug, and therefore, the hepatic clearance is
only a function of the intrinsic clearance, independent of protein binding.
These drugs are referred to as binding insensitive (such as chloramphenicol).
Ontogenetic and pathophysiologic changes in hepatic blood flow, portal
oxygen tension, developmental alterations in protein binding, and
metabolizing enzyme activities all affect processes associated with hepatic
clearance. Significant developmental changes in the physiologic and
biochemical processes that govern drug disposition occur during infancy. The
description of the ontogeny of hepatic drug–related functions, including
cytochrome P-450 hepatic enzymes (phase I) and conjugation (phase II), is
addressed in Chapter 4.
ELIMINATION CLEARANCE
Most drugs and their metabolites are eliminated by the kidneys or, more
rarely, by exhalation or biliary excretion. Renal excretion depends not only on
glomerular filtration but also on tubular reabsorption and tubular secretion.
The amount of drug that is cleared is influenced by the extent of protein
binding and the renal plasma flow. If the latter is constant, then greater protein
binding will result in a smaller fraction that is filtered. The influence of renal
function maturation and its covariates on drug clearance is addressed in
Chapter 12.
1.
2.
3.
DEVELOPMENTAL PHARMACODYNAMICS
We do not give drugs to neonates to reach a given concentration–time profile,
but with the intention to treat or prevent a specific disease or risk, while
avoiding disproportional side effects. Consequently, the concentration–effect
profile is the real target.
80,81
Assumptions are hereby commonly made that a
systemic drug exposure similar to that associated with desired drug action in
adults will produce the same response in neonates. A review of the literature
suggests that this assumption may—frequently—be wrong.82 As discussed
earlier in this chapter, most of the variability observed relates to differences
in PK. In addition to these PK differences, differences in neonatal physiology
may also result in population-specific PD. There is little information on how
human development and growth, and its intersection with disease, have its
impact on PD. This may result in differences in efficacy, potency, or toxicity,
because age-related developmental changes in the functionality and
expression of receptors and differences in disease status may alter the
response to a given drug concentration.
6,80–82
Perhaps, the greatest obstacle
and challenge in characterizing developmental PD aspects is to measure drug
effects, using valid outcome measurements or biomarkers.
SUMMARY
There are relevant differences in drug disposition in newborns compared to
adults with respect to all PK processes. Besides age, (patho)physiologic
covariates also contribute to the variability in drug disposition. In this
chapter, we mainly have focused on absorption and distribution to illustrate
its relevance for neonatal pharmacotherapy.
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