PHARMACOKINETICS

[Pharmacology A – J2]
Aug. 20, 2019

TOLEDO, Erjen C.
TUNGBABAN, Thea Vera C.
VALENCIA, Shaira Nicole D.
VALLE, Joshua M.
VALLEJO, Chamomile P.
VASQUEZ, Arvee Jacob M.
VEGERANO, Kristine Mae J.
VILLALON, Joash C.
VILLANUEVA, Grace T.
VILLACRUZ, Angelo David P.
ZAMORA, Roselle Isabela N.
 CASE #
A female patient of
3
child-bearing age has hyperthyroidism and is currently
maintained on methimazole. When she discovers that she is pregnant, she is concerned
about the safety of methimazole during pregnancy. Upon consult with her OB-GYN, she
was told to shift to propylthiouracil during the first trimester.

OVERVIE
free
W by hypermetabolism and elevated serum levels of
Hyperthyroidism is characterized
thyroid hormones. It results from increased synthesis and secretion of thyroid
hormones, thyroxine (T4) and triiodothyronine (T3), from the thyroid, caused by thyroid
stimulators in the blood or by autonomous thyroid hyperfunction.

Generally, there are four (4) steps in the synthesis of thyroid hormones, namely,
Iodide uptake, oxidation, organification and coupling. Iodide is trapped by thyroid follicle
with the aid of secondary active transport Na-Iodide symporter (NIS), then oxidized into
Iodine. With the action of Thyroid Peroxidase enzyme, it combines with thyroglobulin to
form monoiodotyrosine (MIT) and diiodotyrosine (DIT). Afterwhich, two molecules of DIT
combine within the thyroglobulin molecule to form thyroxine (T4) and one molecule of MIT
and one molecule of DIT combine to form T3.

Figure 1. Biosynthesis of thyroid hormones

Reduction of thyroid activity and hormone effects can be accomplished by agents that
interfere with the production of thyroid hormones. Anti-thyroid drugs, such as
propylthiouracil and methimazole, prevent hormone synthesis by inhibiting the thyroid
peroxidase-catalyzed reactions and blocking iodine organification. Since the synthesis
GUIDE
rather than the release of hormones is affected, the onset of these agents is slow, often
requiring 3–4 weeks before stores of T4 are depleted.

QUESTIONS
1
1. Differentiate the pharmacokinetics (absorption, distribution, metabolism,
excretion) of methimazole and propylthiouracil.

PROPYLTHIOURACIL METHIMAZOLE

ABSORPTION ● About 80% absorbed rapidly ● Absorbed rapidly

and readily from GI tract. from the GI tract
with 80% to 95%
bioavailability.

DISTRIBUTION ● Appears to be concentrated ● Drug is

in the thyroid gland. Readily concentrated in the
crosses the placental thyroid. Readily
barrier; distributed into crosses the
breast milk. 75% to 80% placental barrier
protein-bound. and is distributed
into breast milk. It
is not protein-
bound.

METABOLISM ● Undergoes Hepatic ● Undergoes Hepatic

Metabolism Metabolism

EXCRETION ● 35% is excreted renally ● About 80% of drug

● Less than 10% is excreted and its metabolites
Unchanged are excreted
● Half life is 1 to 2 hours renally;
● 7% is excreted
unchanged.
● Half-life is between
5 and 13 hours.

2. What is the basis of shifting methimazole to propylthiouracil in the first

trimester?

Either surgery or thioamides are the treatment of choice for hyperthyroidism

in pregnant patient. During the other two trimesters, thioamides, such as
methimazole (MMI) and propylthiouracil (PTU), are preferred because surgery can
precipitate spontaneous abortion.
Both thioamides are equally effective, demonstrate similar placental crossing
properties, and produce similar thyroid hormone concentrations in fetal umbilical
cord blood samples. However, of the two, PTU is more strongly protein-bound and,
therefore, crosses the placenta less readily, making it more preferable. Also,
propylthiouracil partially inhibits the peripheral deiodination of T4 to T3. On the
other hand, methimazole does not have this effect, thus it is the rationale for the
selection of propylthiouracil over other anti-thyroid drugs in the treatment of severe
hyperthyroid state where a decreased rate of T4 to T3 conversion would be
beneficial.

2
 PTU is preferable during the first trimester because of rare reports of
teratogenicity from methimazole, but methimazole is preferred thereafter to reduce
the risks of PTU-associated hepatitis.
Methimazole has been associated with anecdotal reports of congenital scalp
defects (e.g. aplasia cutis) and embryopathy syndrome (esophageal and choanal
atresia). However, these risks of reversible aplasia cutis were not greater in women
receiving methimazole (e.g. 2.7%) compared with PTU (e.g. 3%) or hyperthyroid
controls (e.g. 6%). Therefore, methimazole can be considered throughout the
pregnancy if there is intolerance or non-adherence to PTU.

3. What are the general recommendations in the management of

hyperthyroidism during pregnancy?

If thyrotoxicosis or hyperthyroidism does develop during pregnancy,

Radioactive Iodine (RAI) is contraindicated because it crosses the placenta and may
injure the fetal thyroid. Propylthiouracil (fewer teratogenic risks than methimazole)
can be given in the first trimester, and then methimazole can be given for the
remainder of the pregnancy in order to avoid potential liver damage.
The dosage of propylthiouracil must be kept to the minimum necessary for
control of the disease (ie, <300 mg/d), because it may affect the function of the
fetal thyroid gland. In pregnant women who are being treated for hyperthyroidism,
serum TSH and FT4 should be measured every two weeks until the patient is on a
stable medication dosage.
Alternatively, a subtotal thyroidectomy can be safely performed during the
mid trimester. It is essential to give the patient a thyroid supplement during the
balance of the pregnancy.

REFERENC
ESThe Pharmacological Basis of Therapeutics. 12th ed. USA:
Brunton, L. (2011). Goodman & Gilman’s
McGraw-Hill Education.
Katzung, B. (2018). Basic & Clinical Pharmacology. 14th ed. USA: McGraw-Hill Education.
Methimazole. Retrieved from: <https://www.glowm.com/resources/glowm/cd/pages/drugs/m030.html>