antithyroid drugs new england medical journal
TRANSCRIPT
Antithyroid DrugsNew 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 centurythe 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 StatesMethimazole: Europe and AsiaCarbimazole: 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-2PTU block the conversion of T4 to T3 within the thyroid and in peripheral tissuesimmunosuppressive effects:
1) antithyrotropin-receptor antibodies 2) intracellular adhesion molecule 1 3) soluble interleukin-2 and interleukin-6 receptors
decrease with timemay 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 surgeryGraves' 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 adolescentspreferable in severe Graves' eye diseaseradioiodine therapy has been associated with worsening ophthalmopathy
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.
severe Mild to moderate
I
eye
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 tidmany 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 euthyroidMaintenance : 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 >20higher baseline levels of antithyrotropin-receptor antibodies
Remission-2
age, sex, and smokingOphthalmopathyduration of symptoms before diagnosisrisk 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 oftenHowever, 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 ratestreatment 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 iodineThis "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 contraindicatedarthralgias, 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 % methimazolemust 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 deathcan 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 prostrationPseudomonas aeruginosa most common G-CSF may shorten the time to recovery
and length of hospitalization
Side Effects-6Hepatotoxicity 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-7The 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 processalternative agent could be used cautiously
Side Effects-8 Vasculitis PTU >methimazole
drug-induced lupusperinuclear 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 casesshort-term hemodialysis
Pregnancy and Lactation Thyrotoxicosis occurs in 1 /1000 to 2000 pregnanciesan antithyroid drug should be started at the time of diagnosisPTU 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 substitutedclass 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 euthyroidFor 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
