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You have lunch with a colleague in Pediatric Critical Care. He is excited about a
new antibiotic (of low molecular weight) that he has been using with excellent
coverage for bacterial pathogens that both of you are observing in your respective
units. He is particularly impressed about the bactericidal concentrations with oral
administration and suggests that you try it on your babies. You are interested
primarily in studying this new antibiotic since there are no data in premature and
term newborn infants. One of the first questions for the oral preparation would be
how the timing and efficiency of absorption in the newborn compares to that of
older individuals. You are aware that, in general, newborns absorb drugs from the
gastrointestinal tract less efficiently than older people. You review the
mechanisms of absorption for drugs administered enterally to help design your
study.
Of the following, the MOSTcommon mechanism for the absorption of a drug
administered enterally to a newborn infant is:
active transport
facilitated diffusion
filtration through aqueous pores
pinocytosis
simple diffusion
You selected
, the correct answer is
.
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Because illness can lead to poor circulation and gastrointestinal motility problems,
the preferred route for drug administration to sick newborn infants is intravenous.
However, it is helpful to have drugs that can be administered enterally for use in
stable newborn infants. New drugs, on the other hand, should be administered
with caution or on a research basis when there are few data available on their use
in this population. Therapeutic misadventures have occurred in the past (eg,
chloramphenicol, dexamethasone, benzyl alcohol) when assumptions were made
about the absorption, distribution, metabolism, and excretion of drugs that were
not systematically studied in the premature and term newborn infants.
The most common mode of absorption for low-molecular-weight drugs is passive
diffusion. This mechanism follows Fick's Law in that the rate of diffusion (dQ/dt)
is directly proportional to the concentration gradient (C o - C i), times the product of
the partition coefficient of the drug (K), the diffusion coefficient of the membrane
(D), and the surface area of the membrane (A), and indirectly proportional to the
thickness of the membrane (H). The formula for Fick's Law is:
http://emb.aap.org/courseprodv2/Index.asp[4/4/2012 3:55:29 PM]
Education Module Learner
dQ/dt = DAK(C o - C i)/H.
A drug that is highly water soluble would have a low value for K, and a membrane
that is highly permeable to a drug would have a high value for D. With a particular
drug and infant, the factors other than the inside and outside concentrations are
constants; therefore, the formula can be simplified to:
dQ/dt = P(Co - C i)
where P is a composite constant representing DAK/H. Because the membrane
being traversed is a lipid bilayer, the more lipid-soluble the drug is, the higher the
value of K.
If the drug is ionizable, then another factor that affects the rate of diffusion is the
pH of the lumen. A weak acid, such as furosemide, would diffuse across the
membrane well when the luminal pH is low (as it is in older children and adults).
Newborns, however, produce less stomach acid and tend to have higher gastric pH
values, which would make the concentration of the ionized (water-soluble) form of
an acidic drug higher and reduce the rate of passive diffusion.
In addition, protein binding of a drug tends to 1) reduce the concentration of free
or active drug in circulation, thus decreasing its effect(s), and 2) increase the size
of the gradient between outer and inner membrane concentrations of the free
drug, thus increasing the rate of absorption.
Active transport is an energy-consuming process in which a substance is carried
selectively across a membrane. With active transport, substrates may accumulate
intracellularly against a concentration gradient. This mechanism is saturable,
meaning that the maximum rate of transfer is unrelated to the concentration
gradient. Active transport most often takes place with drugs that are similar to
naturally occurring compounds in the body. These drugs are usually absorbed from
the small intestine. Active transport processes have been identified for various
ions, vitamins, sugars, amino acids, and related compounds.
In facilitated diffusion, a carrier molecule (usually a protein) combines reversibly
with the drug at the cell surface, and the carrier-drug complex diffuses across the
membrane more readily than the drug alone, releasing the drug to the interior.
Carrier-mediated diffusion is also selective and saturable: the carrier transports
only substrates with specific molecular configurations, and the transfer rate is
limited by the availability of carrier. This mechanism does not require chemical
energy, however, so transport against a concentration gradient does not occur.
Filtration through aqueous pores is a specialized mechanism that allows a small
water-soluble compound or ion, such as bromide, to pass through a portion of the
membrane that is occupied by a gated through-and-through tubular channel or
pore constructed of protein(s). These channels are highly regulated.
Pinocytosis (also known as phagocytosis or vacuolar transport) occurs when the
cell membrane in contact with the luminal surface invaginates and physically
engulfs a portion of the liquid at the surface containing the drug. A subsurface
vacuole is pinched off and travels to the inner cell membrane to be disgorged. This
mechanism costs chemical energy, too. Pinocytosis is not a common mechanism
for drug transport. It can be the only way to absorb large-molecular-weight drugs
(more than 900 daltons), such as protein drugs and biologicals.
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References:
http://emb.aap.org/courseprodv2/Index.asp[4/4/2012 3:55:29 PM]
Education Module Learner
Aranda JV, Edwards DJ, Hales BF, Rieder MJ. Developmental pharmacology. In:
Fanaroff AA, Martin RJ. Neonatal-Perinatal Medicine: Diseases of the fetus and
infant. 7 th ed. St. Louis, Mo: Mosby; 2002:144-166
Beals M, Gross L, Harrell S. Diffusion through a cell membrane. Available at:
http://www.tiem.utk.edu/~gross/bioed/webmodules/diffusion.htm. Accessed
October 18, 2005
Beals M, Gross L, Harrell S. Permeability of molecules. Available at:
http://www.tiem.utk.edu/~gross/bioed/webmodules/permeability.htm.
Accessed October 18, 2005
Chemtob S. Basic pharmacologic principles. In Polin RA, Fox WW, Abman SH. Fetal and
Neonatal Physiology. 3 rd ed. Philadelphia, Pa: Saunders; 2004:179-190
Membrane structure and function. Human biology: lecture 9 notes Web site.
Available at: http://members.aol.com/Bio50/LecNotes/lecnot09.html. Accessed
October 18, 2005
Content Specification(s):
Understand the factors that influence drug absorption
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