Antithyroid Drugs

New England Medical Journal

David S. Cooper, M.D
March 3, 2005 Number 9
Volume 352:905-917
by R4 馮漢賢

.
 Introduction
use for more than half a century
the treatment of choice for most young
people with Graves' disease
 Mechanism of Action
simple molecules :thionamides, contain a
sulfhydryl group and a thiourea moiety within a
heterocyclic structure
Propylthiouracil and methimazole: United States
Methimazole: Europe and Asia
Carbimazole: United Kingdom
actively concentrated by thyroid gland against a
concentration gradient.
inhibit thyroid hormone synthesis by interfering
with thyroid peroxidase–mediated iodination of
tyrosine residues in thyroglobulin
Figure 2. Synthesis of Thyroxine and Triiodothyronine.
In Panel A, thyroid peroxidase (TPO), a heme-containing glycoprotein, is anchored within the thyroid follicular-cell
membrane at the luminal side of the thyroid follicle. In Panel B, the first step in thyroid hormone synthesis involves
generation of an oxidized enzyme promoted by endogenously produced hydrogen peroxide. In Panel C, the oxidized enzyme
reacts with trapped iodide to form an "iodinating intermediate" (TPO–Iox), the nature of which is not entirely understood.
Some investigators favor the formation of a heme-linked iodinium ion (TPO–I+), whereas others suggest the formation of
hypoiodite (TPO–O–I–).
. Panel D, in the absence of an antithyroid drug, the iodinating intermediate reacts with specific tyrosine residues in
thyroglobulin (Tg) to form monoiodotyrosine and diiodotyrosine. Subsequent intramolecular coupling of MIT and DIT
forms triiodothyronine, and the coupling of two DIT molecules forms thyroxine. In the presence of an antithyroid drug (e.g.,
methimazole, shown in Panel E), the drug serves as an alternative substrate for the iodinating intermediate, competing with
thyroglobulin-linked tyrosine residues and diverting oxidized iodide away from hormone synthesis. The drug intermediate
with a sulfur-linked iodide is a theoretical reaction product.6 In Panel F, the oxidized drug forms an unstable drug disulfide7
that spontaneously degrades to an inactive desulfurated molecule, shown as methylimidazole. Antithyroid drugs also impair
the coupling reaction in vitro, but it is uncertain whether this occurs in vivo.
 Mechanism of Action-2
PTU block the conversion of T4 to T3 within the
thyroid and in peripheral tissues
immunosuppressive effects:
1) antithyrotropin-receptor antibodies
2) intracellular adhesion molecule 1
3) soluble interleukin-2 and interleukin-6 receptors
decrease with time
may induce apoptosis of intrathyroidal
lymphocytes, and decrease HLA class II
expression
↑circulating suppressor T cells
↓ helper T cells, natural killer cells and activated
intrathyroidal T cells
Figure 3. Effects of
Antithyroid Drugs.
inhibition of thyroid hormone
synthesis and a reduction in
both intrathyroidal immune
dysregulation and the
peripheral conversion of T4 to
T3.
Tyrosine-Tg denotes tyrosine
residues in thyroglobulin,
I+ the iodinating intermediate,
TPO thyroid peroxidase.
 Mechanism of Action-3
analyses of animal data and human studies
suggested that changes in the immune
system may not be predicated solely on
changes in thyroid function.
 Clinical Pharmacology
rapidly absorbed from GI tract
peak within one to two hours
Serum levels have little to do with
antithyroid effects, which typically last
from 12 to 24 hours for PTU
methimazole  long duration once-
daily
Methimazole is essentially free in serum,
whereas 80 to 90 percent of PTU is bound
to albumin
 Clinical Pharmacology -2

doses do not need to be altered in

children ,elderly, renal failure and liver
disease, although the clearance of
methimazole (but not PTU) may be
decreased.
 Clinical Use of Drugs
two ways: primary treatment for
hyperthyroidism or preparative therapy
before radiotherapy or surgery
Graves' disease, "remission“ is possible.
(euthyroid for one year after cessation)
not primary therapy for toxic multinodular
goiters and solitary autonomous nodules,
because spontaneous remissions rarely
occur
 Clinical Use of Drugs-2

primary treatment in pregnant and most

children and adolescents
preferable in severe Graves' eye disease
radioiodine therapy has been associated
with worsening ophthalmopathy
 severe Mild to moderate
Figure 4. Radioiodine may be eye
preferable as initial therapy for
adults in the United States1 but not
for those in the rest of the world.2 I

Subtotal or near-total thyroidectomy

is also an option for some patients
after treatment with antithyroid
drugs.

In adults who have a relapse,

definitive radioiodine therapy is the
preferred strategy.

Some patients prefer a second

course of antithyroid-drug therapy,
and this strategy is preferable for
children and adolescents.
 Clinical Use of Drugs-3

antithyroid drugs, radioiodine, and

surgery :patient satisfaction > 90%
costs lowest : drug
also used to normalize thyroid function
before the administration of radioiodine,
caused by a rise in stimulating
antithyrotropin-receptor antibodies
 Choice of Drugs

methimazole>PTU, by better adherence

and more rapid improvement in T3 and T4,
and side-effect
propylthiouracil : during pregnancy.
 Practical Considerations
starting dose of methimazole : 15 to 30 mg
qd,
PTU : 300 mg daily tid
many patients can be controlled with
smaller doses of methimazole, suggesting
that the accepted potency ratio of 10:1 for
methimazole as compared with PTU is
underestimated .
if methimazole is overly aggressive
iatrogenic hypothyroidism with relatively
mild hyperthyroidism may result
 Practical Considerations-2

follow-up every four to six weeks, until

thyroid function is stable or the patient
becomes euthyroid
Maintenance : 5 to 10 mg of methimazole
or 100 to 200 mg of PTU daily.
hypothyroidism or goiter can develop if the
dose is not decreased appropriately
 Practical Considerations-3
After the first three to six months, follow-
up intervals can be increased to every two
to three months and then every four to six
months.
Serum TSH levels remain suppressed for
weeks or even months, despite a
normalization of thyroid hormone levels, so
a test of TSH is a poor early measure
 Practical Considerations-4

patients sometimes continue to have

elevated serum T3 levels despite normal or
even low T4 or FT4, increase, not
decrease, the antithyroid drug dose
 Low Remission

severe hyperthyroidism
large goiters
T3-to-T4 ratio >20
higher baseline levels of antithyrotropin-
receptor antibodies
 Remission-2

age, sex, and smoking

Ophthalmopathy
duration of symptoms before diagnosis
risk factors for relapse depression,
hypochondriasis, paranoia, mental fatigue
after an average of three years of
antithyroid-drug therapy
 Remission-3
TSHR at the end of a course of treatment
predictive value -->positive : relapse often
However, even those patients whose
antibody titers have normalized have a
fairly high rate of relapse (30 to 50 percent)
 Remission-4
Since immunosuppressive effects, a higher
dose or longer treatment duration might
enhance the chances of remission.
prospective trials >4y follow-up do not
indicate that treatment for >1 year has any
effect on relapse rates
treatment for 12 to 18 months is the usual
practice
 Remission-5

a Japanese study showed that a

combination of an antithyroid drug plus
thyroxine for 1year, followed by
thyroxine alone for 3 years, decreased
the relapse rate significantly
 Discontinuation of Drug
Treatment
children and adolescents, are often for
many years,
relapse is increased in normal FT4 and T3 but
suppressed TSH.
Relapse usually occurs within the first
three to six months after medication is
stopped
 Discontinuation of Drug
Treatment-2
overall recurrence rate 50 to 60
percent.
About 75 percent of women in
remission who become pregnant will
have a postpartum relapse of Graves'
disease or the development of
postpartum thyroiditis.
 Discontinuation of Drug
Treatment-3
When used before radioiodine therapy,
PTU (but not methimazole), increases the
failure rate of the radioactive iodine
This "radioprotective" effect of PTU may
be related to its ability to neutralize
iodinated free radicals produced by
radiation exposure, can be overcome by
increasing the radioiodine dose.
 Side Effects
methimazole are dose-related, (PTU less
clear )
cutaneous reactions (usually urticaria or
macular rashes), arthralgia, and GI upset
5% of patients, with equal frequency for
both drugs
 Side Effects-2
cross-reactivity between the two agents
may be as high as 50 percent. the use of the
alternative antithyroid drug is
contraindicated
arthralgias, should prompt drug
discontinuation, : may be a harbinger of a
severe transient migratory polyarthritis
known as "the antithyroid arthritis
syndrome”
 Side Effects-3 Agranulocytosis
an absolute granulocyte count of less than
500 per cubic millimeter
0.37 % in PTU and 0.35 % methimazole
must be distinguished from the transient,
mild granulocytopenia (<1500 per cubic
millimeter) in Graves' disease, African
descent, and occasionally in patients treated
with antithyroid drugs.
baseline differential white-cell count
Side Effects-4 Agranulocytosis
Occur within 90 days of treatment, but can
occur >1 year
greater in older patients
A higher rate of death
can develop after a prior uneventful course,
a relapse and a second course of therapy.
 Side Effects-5
Fever and sore throat are the most common
sepsis :very rapid onset of fever, chills, and
prostration
Pseudomonas aeruginosa most common
G-CSF may shorten the time to recovery
and length of hospitalization
 Side Effects-6
Hepatotoxicity 0.1 to 0.2 %
30 % with normal baseline GPT treated with
PTU, transient increases ranging from 1.1 to 6
times normal —resolve while therapy is
continued.
asymptomatic elevations in GPT occur frequently
in untreated patients with hyperthyroidism and are
not predictive of further increases after PTU
therapy.
 Side Effects-7
The average duration of PTU therapy
before the onset of hepatotoxicity is
approximately three months
allergic hepatitis
Pathology: submassive or massive hepatic
necrosis
case fatality rate of 25 to 50 %
Liver transplantation may be required
 Side Effects-8
methimazole and carbimazole are typical of
a cholestatic process
alternative agent could be used cautiously
 Side Effects-8 Vasculitis
PTU >methimazole
drug-induced lupus
perinuclear antineutrophil cytoplasmic
antibodies, antimyeloperoxidase
antineutrophil cytoplasmic antibodies.
Mechanism: PTU can react with
myeloperoxidase to form reactive
intermediates promote autoimmune
inflammation
 Side Effects-9 Vasculitis
acute renal dysfunction, arthritis, skin
ulcerations, vasculitic rash, and upper and
lower respiratory symptoms, including
sinusitis and hemoptysis.
Although resolves after drug cessation,
high-dose glucocorticoid or
cyclophosphamide in severe cases
short-term hemodialysis
 Pregnancy and Lactation
Thyrotoxicosis occurs in 1 /1000 to 2000
pregnancies
an antithyroid drug should be started at the
time of diagnosis
PTU in North America because cross the
placenta minimally as compared with
methimazole
However, recent studies suggest that PTU
does, in fact, cross the placenta
 Pregnancy and Lactation-2
congenital anomalies with methimazole,
particularly aplasia cutis, (single or multiple
lesions of 0.5 to 3 cm at the vertex or occipital
of scalp)
very rare "methimazole embryopathy,"
choanal or esophageal atresia.
2 of 241 children of women exposed to
methimazole, (spontaneous rate of 1 in 2500 to
1 in 10,000 for esophageal atresia and choanal
atresia, respectively).
 Pregnancy and Lactation-3

If allergy to PTU, methimazole can be

substituted
class D agents (i.e., drugs with strong
evidence of risk to the fetus)
If the maternal FT4 level is maintained at or
slightly above the upper limit of normal, the
risk of fetal hypothyroidism is negligible.
 Pregnancy and Lactation-4

By the third trimester, approximately

30 % of women can discontinue
therapy and still remain euthyroid
For nursing mothers, both drugs are
considered safe
 Thyroid Storm
PTU preferred : inhibit conversion of T4 to
T3, (but no evidence that it is more
efficacious than methimazole)
A high dose of either drug should be used,
60 to 120 mg of methimazole
600 to 1200 mg of PTU per day in divided
doses
 Thyroid Storm-2

A CBC/DC obtained immediately and

discontinued if granulocyte count <1000 per
cubic millimeter