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

tablets and as a lyophilized powder for injection.
Concerns have been raised regarding variations in therapeutic
effectiveness among the branded and generic
levothyroxine products and the standards used to establish
bioequivalence (Hennessey, 2006). More recently,
the focus has been on improving uniformity among
preparations in tablet content of levothyroxine and stability
(Burman et al., 2008). Table 39–3 lists drugs and
other factors that may influence levothyroxine dosage
requirements.
The potency standards of levothyroxine have been narrowed
from the previous standard of 90-110% to 95-105%, and the content
must be stable at this level for the designated shelf life. Absorption
of thyroxine occurs in the stomach and small intestine and is incomplete
(~80% of the dose is absorbed). Absorption is slightly increased
when the hormone is taken on an empty stomach, and it is associated
with less variability in the TSH when taken this way regularly (Bach-
Huynh et al., 2009). The serum T 4
peaks 2-4 hours after oral ingestion,
but changes are barely discernable with once-daily dosing due
to the 7-day plasma t 1/2
of the T 4
. Given this long t 1/2
, omission of one
day’s dose does not materially affect the serum TSH or FT 4
, but to
maintain consistent dosing the patient should be instructed to take a
double dose the next day. For any given serum TSH, the serum T 4
/T 3
ratio is higher in patients taking levothyroxine than in patients with
endogenous thyroid function, due to the fact that ~20% of circulating
T 3
normally is supplied by direct thyroidal secretion (Jonklaas
et al., 2008). Occasionally this may result in a levothyroxine-treated
patient having a marginally elevated free T 4
and a normal TSH,
which is acceptable. Follow-up blood tests typically are done
~6 weeks after any dosage change due to the 1-week plasma t 1/2
of
T 4
. Dosages are discussed subsequently under specific indications.
In situations where patients cannot take oral medications or
where intestinal absorption is in question, levothyroxine may be
given intravenously once a day at a dose ~80% of the patient’s daily
oral requirement.
Liothyronine. Liothyronine sodium (L-T 3
) is the salt of
triiodothyronine and is available in tablets (CYTOMEL)
and in an injectable form (TRIOSTAT, others).
Liothyronine absorption is nearly 100% with peak serum levels
2-4 hours following oral ingestion. Liothyronine may be used
occasionally when a more rapid onset of action is desired such as in
the rare presentation of myxedema coma or if rapid termination of
action is desired such as when preparing a thyroid cancer patient for
131
I therapy. Liothyronine is less desirable for chronic replacement
therapy due to the requirement for more frequent dosing (plasma t 1/2
=
0.75 days), higher cost, and transient elevations of serum T 3
concentrations
above the normal range. In addition, organs that express the
type 2 deiodinase use the locally generated T 3
in addition to plasma
T 3
, and hence there is theoretical concern that these organs will not
maintain physiological intracellular T 3
levels in the absence of
plasma T 4
. Ten to 15 μg of liothyronine sodium three times per day
typically yields a normal serum free T 3
in an athyreotic individual.
However, normalization of circulating TSH may require higher levels
of free T 3
, perhaps because negative feedback normally relies in
part on the local generation of T 3
from circulating T 4
(Koutras et al.,
1981, Saberi and Utiger, 1974).
Other Preparations. A mixture of thyroxine and triiodothyronine 4:1
by weight is marketed as liotrix (THYROLAR). Desiccated thyroid
preparations such as (ARMOUR THYROID, others), with a similar T 4
:T 3
ratio, also are available. A 60-mg (1 grain) desiccated thyroid tablet
is approximately equivalent in activity to 80 μg of thyroxine. This
conversion can be used when changing a patient from replacement
therapy with desiccated thyroid to levothyroxine, but typically such
patients can be dosed with levothyroxine using dosing guidelines
based on age and weight.
Thyroid Hormone Replacement Therapy in Hypothyroidism.
Thyroxine (levothyroxine sodium) is the hormone of
choice for thyroid hormone replacement therapy due to
its consistent potency and prolonged duration of action.
With this therapy, one relies on the types 1 and 2 deiodinases
to convert T 4
to T 3
to maintain a steady serum
level of free T 3
.
The average daily adult replacement dose of levothyroxine
sodium is 1.7 μg/kg body weight (0.8 μg/lb), although the variation
about this average is substantial. Dosing should generally be based
on lean body mass (Santini et al., 2005). Although not ideal, oncea-week
dosing can be used in situations where compliance is otherwise
not possible (Grebe et al., 1997). The goal of therapy is to
normalize the serum TSH (in primary hypothyroidism) or free T 4
(in
secondary or tertiary hypothyroidism) and to relieve symptoms of
hypothyroidism. In primary hypothyroidism, generally it is sufficient
to follow TSH without free T 4
. A patient with mild primary
hypothyroidism will achieve a normal TSH with substantially less
than a full replacement dose, but as the endogenous thyroid function
declines, the dose will need to be increased. Thus, especially in
young healthy patients, it can be simpler to begin with nearly a full
replacement dose. In individuals >60 years of age and those with
known or suspected cardiac disease or with areas of autonomous
thyroid function, institution of therapy at a lower daily dose of
levothyroxine sodium (12.5-50 μg per day) is appropriate. The dose
can be increased at a rate of 25 μg per day every 6-8 weeks until the
TSH is normalized.
Combination therapy with levothyroxine plus liothyronine
seems attractive superficially because the thyroid
gland secretes T 4
and T 3
. However, the T 4
:T 3
ratio in
human thyroid secretion is ~11:1, compared with 4:1 in
the currently available combination pills. Furthermore,
the short plasma t 1/2
of T 3
would necessitate multiple
daily dosing to achieve steady circulating T 3
levels.
Importantly, randomized blinded controlled trials have
failed to uncover evidence of a better therapeutic
response to combination therapy with T 4
plus T 3
, versus
T 4
alone (Grozinsky-Glasberg et al., 2006). Although
occasional patients find that they feel better on combination
therapy, this is usually short lived. The data indicate
that monotherapy with levothyroxine most closely
mimics normal physiology and generally is preferred.
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CHAPTER 39
THYROID AND ANTI-THYROID DRUGS