Obat antithiroid

New England Medical Journal

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

Ganguan thyroid
Sistem

hiper

hipo

kardiovascular

Tachicardi, AF, ggl

jantung

bradkardia

Kulit

Hangat, lembab,
karingat, tak tahan panas

Mata/wajah

exopthalmus

Edem preorbital, ptosis

GIT

diare

Konstipasi

CNS

Nervous, hiperkinesia,
labil

letargia

Muskuler, metabolik,
hormonal

Weakness, hiperrefleksia, Fatique, penurunan

peningkatan BMR, mens BMR, hipermenore,
ireguler
libido turun

Hormon thyroid
Sediaan
Levothyroxine(T4): 50 mg. 100mg/tab
Liothyronine(T3): 5,25,50 mg/tab
Liothrix(rasio T3/T4)

Indikasi
Replacement therapy pada hipothyroidesm
&kretinism
Terapi supresi untuk goiter non toksik

antitiroid
Thionamides
Anion inhibitors
Iodida dan iodonated contras media
Iodine radioactived
Penghambat reseptor adrenergik

Thionamides
Prophylthiourasil
Methymazole
carbimazole

Thionamides
Mekanimse kerja
Inhibisi thiroxine peroxidase
Inhibisi oksidasi iodida menjadi iodine
Inhibisi iodinasi thyroglobulin
Inhibisi pembentukan T3&T4

PTU(metimazole tidak) menghmabat

deiodinasi T4 diperifer
Tidak mempengaruhi uptake iodia oleh tyroid

Thionamides
Farmakokinetik
Absorbsi GIT
FPEbioavalabilitas 50-80%
Metabolisme: glukoronidasi di hati
Distribusi:
terkonestrasi di tyroid
Menembus plasenta: methimazole>>PTU. PTU bis auntuk
wanita hamil
Eksresi: urin, sedikit ASI
PTU dalam jumlah kecil diekskresi di ASI

T1/2:
PTU 75 menit1-4X/hari
Methimazole 4-6 jam1x/hari

Efek samping(relatif rendah)

Agranulositosis (methimazole>PTU)
Rash, arthralgia

Sediaan
PTU: tab 100mg
Methimazole: 5 & 10 mg
Carbimazole:

Thionamides
Indikasi
Terapi hiperthiroidism( gravess disease,
thyroid storm, terapi supresi sebelu
pembedahan)
Supresi TSH pd non toxic goiter

Ionic blocker
Menghambat trnasport aktif iodida ke thyroid
Jarang digunakan
Sediaan
Thiocianate
Perchlorate
Nitarte
Pertechnetate
fluoroborate

Iodide & iodinated contrast

media
Iodide: antitiroid tertua
Diperlukan dalam jumlah kecil untuk
sintesis TH
Dalam dosis besar inhibisis sekresi TH
Efek samping: alergi, iritasi GI, metalic
taste,erupsi kulit
NaI & KI: tersidia oral

Radioactive iodine
I131
Cepat terkonsentrasi ditirod

terutama pada

kondisis hipertoroid
T1/2 8 hari

Ekskresi : urin
Hipotirod: 85-90% diekskresi dlm 24 jam
Eutiroid: 65%
Hipertiroid 5%

Radioactive iodine
Indikasi:
Hipertiroidism
Graves disease
Toxic noduler goiter
Ca tiroid metatastik

Kntraindikasi: hamil, pasien muda

Efek samping: hipotiroidism, resiko
perubahan neoplastik

Radioactive iodine
Dosis
O,o3 mcg dosis tunggal

Sediaan
NaI131 kapsul untuk po dan solution unuk
pemberian IV

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" (TPOI ox), the nature of which is not entirely understood.
Some investigators favor the formation of a heme-linked iodinium ion (TPOI +), whereas others suggest the formation of
hypoiodite (TPOOI).

. 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 disulfide 7
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.

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.

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
eye

Figure 4. Radioiodine may be

preferable as initial therapy for
adults in the United States1 but not
for those in the rest of the world.2
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

Remission
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
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
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, highdose 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