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 peroxid30777
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1. Antithyroid Drugs New England Medical Journal
David S. Cooper, M.D
March 3, 2005 Number 9
by R4 ???
2. Introduction use for more than half a century
the treatment of choice for most young people with Graves' disease
3. 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
7. Mechanism of Action-2 PTU block the conversion of T4 to T3 within the thyroid and in peripheral tissues
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
9. 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.
10. 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
11. 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.
12. 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
13. 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
15. 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
16. Choice of Drugs methimazole>PTU, by better adherence and more rapid improvement in T3 and T4, and side-effect
propylthiouracil : during pregnancy.
17. 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
18. 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
19. 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
20. 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
21. Low Remission severe hyperthyroidism
T3-to-T4 ratio >20
higher baseline levels of antithyrotropin-receptor antibodies
22. Remission-2 age, sex, and smoking
duration of symptoms before diagnosis
risk factors for relapse ?depression, hypochondriasis, paranoia, mental fatigue after an average of three years of antithyroid-drug therapy
23. 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)
24. 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
25. 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
26. 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
27. 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.
28. 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.
29. 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
30. 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”
31. 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
32. 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.
33. 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
34. 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.
35. Side Effects-7 The average duration of PTU therapy before the onset of hepatotoxicity is approximately three months
Pathology: submassive or massive hepatic necrosis
case fatality rate of 25 to 50 %
Liver transplantation may be required
36. Side Effects-8 methimazole and carbimazole are typical of a cholestatic process
alternative agent could be used cautiously
37. Side Effects-8 Vasculitis PTU >methimazole
perinuclear antineutrophil cytoplasmic antibodies, antimyeloperoxidase antineutrophil cytoplasmic antibodies.
Mechanism: PTU can react with myeloperoxidase to form reactive intermediates ?promote autoimmune inflammation
38. 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
40. 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
41. 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).
42. 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.
43. 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
44. 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
45. Thyroid Storm-2 A CBC/DC obtained immediately and discontinued if granulocyte count <1000 per cubic millimeter