DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

are γ-carboxylated in the primary sequence of the Gla domain, C-
terminal to the propeptide. The Glu→Gla conversion enables the
factors to interact well with Ca 2+ and thence with phospholipids of
platelet membranes, positioning the factors in the proper conformations
for interacting with their substrates and modulators. In the
absence of vitamin K (or in the presence of a coumarin derivative),
newly synthesized vitamin K-dependent clotting factors lack Gla
residues and are inactive because the molecular conformations
needed for their interactions are not achieved.
Human Requirements. The human requirement for vitamin K has
not been defined precisely. In patients made vitamin K deficient by
a starvation diet and antibiotic therapy for 3-4 weeks, the minimum
daily requirement is estimated to be 0.03 μg/kg of body weight
(Frick, 1967) and possibly as high as 1 μg/kg, which is approximately
the recommended intake for adults (70 μg/day).
Symptoms of Deficiency. The chief clinical manifestation of
vitamin K deficiency is an increased tendency to bleed (see the
discussion of hypoprothrombinemia in the section on “Oral
Anticoagulants,” earlier in the chapter). Ecchymoses, epistaxis,
hematuria, GI bleeding, and postoperative hemorrhage are common;
intracranial hemorrhage may occur. Hemoptysis is uncommon. The
discovery of a vitamin K-dependent protein in bone suggests that
the fetal bone abnormalities associated with the administration of
oral anticoagulants during the first trimester of pregnancy (“fetal
warfarin syndrome”) may be related to a deficiency of the vitamin.
Considerable evidence indicates a role for vitamin K in adult
skeletal maintenance and the prevention of osteoporosis. Low concentrations
of the vitamin are associated with deficits in bone mineral
density and fractures; vitamin K supplementation increases the
carboxylation state of osteocalcin and also improves bone mineral
density, but the relationship of these two effects is unclear (Feskanich
et al., 1999). Bone mineral density in adults is not changed by therapeutic
use of vitamin K antagonists (Rosen et al., 1993), but new
bone formation may be affected.
Toxicity. Phytonadione and the menaquinones are nontoxic to animals,
even when given at 500 times the recommended daily allowance.
However, menadione and its derivatives (synthetic forms of vitamin K)
have been implicated in producing hemolytic anemia and kernicterus
in neonates, especially in premature infants (Diploma and Ritchie,
1997). For this reason, menadione should not be used as a therapeutic
form of vitamin K.
Absorption, Fate, and Excretion. The mechanism of intestinal absorption
of compounds with vitamin K activity varies with their solubility.
In the presence of bile salts, phytonadione and the menaquinones are
adequately absorbed from the intestine, almost entirely by way of the
lymph. Phytonadione is absorbed by an energy-dependent, saturable
process in proximal portions of the small intestine; menaquinones are
absorbed by diffusion in the distal portions of the small intestine and in
the colon. Following absorption, phytonadione is incorporated into chylomicrons
in close association with triglycerides and lipoproteins. In a
large survey, plasma phytonadione and triglyceride concentration were
well correlated (Sadowski et al., 1989). The extremely low phytonadione
levels in newborns may be partly related to very low plasma
lipoprotein concentrations at birth and may lead to an underestimation
of vitamin K tissue stores. After absorption, phytonadione and
menaquinones are concentrated in the liver, but the concentration of
phytonadione declines rapidly. Menaquinones, produced in the lower
bowel, are less biologically active than phytonadione due to their long
side chain. Very little vitamin K accumulates in other tissues.
Phytonadione is metabolized rapidly to more polar metabolites,
which are excreted in the bile and urine. The major urinary
metabolites result from shortening of the side chain to five or seven
carbon atoms, yielding carboxylic acids that are conjugated with glucuronate
prior to excretion.
Apparently, there is only modest storage of vitamin K in the
body. Under circumstances in which lack of bile interferes with
absorption of vitamin K, hypoprothrombinemia develops slowly
over several weeks.
Therapeutic Uses. Vitamin K is used therapeutically to
correct the bleeding tendency or hemorrhage associated
with its deficiency. Vitamin K deficiency can result from
inadequate intake, absorption, or utilization of the vitamin,
or as a consequence of the action of a vitamin K
antagonist.
Phytonadione (AQUAMEPHYTON, KONAKION, MEPHYTON, generic)
is available as tablets and in a dispersion with buffered polysorbate
and propylene glycol (KONAKION) or polyoxyethylated fatty acid
derivatives and dextrose (AQUAMEPHYTON). KONAKION is administered
only intramuscularly. AQUAMEPHYTON may be given by any route;
however, oral or subcutaneous injection is preferred because severe
reactions resembling anaphylaxis have followed its intravenous
administration.
Inadequate Intake. After infancy, hypoprothrombinemia due to dietary
deficiency of vitamin K is extremely rare: The vitamin is present in
many foods and also is synthesized by intestinal bacteria. Occasionally,
the use of a broad-spectrum antibiotic may itself produce a hypoprothrombinemia
that responds readily to small doses of vitamin K and
reestablishment of normal bowel flora. Hypoprothrombinemia can
occur in patients receiving prolonged intravenous alimentation. It is
recommended to give 1 mg of phytonadione per week (the equivalent
of about 150 μg/day) to patients on total parenteral nutrition.
Hypoprothrombinemia of the Newborn. Healthy newborn infants show
decreased plasma concentrations of vitamin K-dependent clotting
factors for a few days after birth, the time required to obtain an adequate
dietary intake of the vitamin and to establish a normal intestinal
flora. In premature infants and in infants with hemorrhagic disease of
the newborn, the concentrations of clotting factors are particularly
depressed. The degree to which these changes reflect true vitamin K
deficiency is controversial. Measurements of non-γ-carboxylated prothrombin
suggest that vitamin K deficiency occurs in about 3% of live
births (Shapiro et al., 1986).
Hemorrhagic disease of the newborn has been associated with
breast-feeding; human milk has low concentrations of vitamin K
(Haroon et al., 1982). In addition, the intestinal flora of breast-fed
infants may lack microorganisms that synthesize the vitamin
(Keenan et al., 1971). Commercial infant formulas are supplemented
with vitamin K.
In the neonate with hemorrhagic disease of the newborn, the
administration of vitamin K raises the concentration of these clotting
factors to the level normal for the newborn infant and controls the
bleeding tendency within about 6 hours. The routine administration
of 1 mg phytonadione intramuscularly at birth is required by law in
the U.S. This dose may have to be increased or repeated if the mother
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CHAPTER 30
BLOOD COAGULATION AND ANTICOAGULANT, FIBRINOLYTIC, AND ANTIPLATELET DRUGS