Antithyroid Drugs

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Antithyroid Drugs

• New England Medical Journal
• David S. Cooper, M.D
• March 3, 2005 Number 9
• Volume 352905-917
• by R4 ???
• .

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Introduction

• use for more than half a century
• the treatment of choice for most young people
  with Graves' disease

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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 peroxidasemediated iodination of
  tyrosine residues in thyroglobulin

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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" (TPOIox), 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).
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. 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.
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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

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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.
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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.

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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

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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.

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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

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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

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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.
I
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Clinical Use of Drugs-3

• antithyroid drugs, radioiodine, and surgery
  patient satisfaction gt 90
• costs lowest drug
• also used to normalize thyroid function before
  the administration of radioiodine, caused by a
  rise in stimulating antithyrotropin-receptor
  antibodies

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Choice of Drugs

• methimazolegtPTU, by better adherence and more
  rapid improvement in T3 and T4, and side-effect
• propylthiouracil during pregnancy.

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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 101 for methimazole as
  compared with PTU is underestimated .
• if methimazole is overly aggressive iatrogenic
  hypothyroidism with relatively mild
  hyperthyroidism may result

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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

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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

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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

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Low Remission

• severe hyperthyroidism
• large goiters
• T3-to-T4 ratio gt20
• higher baseline levels of antithyrotropin-receptor
  antibodies

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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

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Remission-3

• TSHR at the end of a course of treatment
  predictive value --gtpositive relapse often
• However, even those patients whose antibody
  titers have normalized have a fairly high rate of
  relapse (30 to 50 percent)

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Remission-4

• Since immunosuppressive effects, a higher dose or
  longer treatment duration might enhance the
  chances of remission.
• prospective trials gt4y follow-up do not indicate
  that treatment for gt1 year has any effect on
  relapse rates
• treatment for 12 to 18 months is the usual
  practice

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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

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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

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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.

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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.

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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

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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

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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 (lt1500 per cubic millimeter) in
  Graves' disease, African descent, and
  occasionally in patients treated with antithyroid
  drugs.
• baseline differential white-cell count

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Side Effects-4 Agranulocytosis

• Occur within 90 days of treatment, but can occur
  gt1 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.

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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

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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.

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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

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Side Effects-8

• methimazole and carbimazole are typical of a
  cholestatic process
• alternative agent could be used cautiously

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Side Effects-8 Vasculitis

• PTU gtmethimazole
• drug-induced lupus
• perinuclear antineutrophil cytoplasmic
  antibodies, antimyeloperoxidase antineutrophil
  cytoplasmic antibodies.
• Mechanism PTU can react with myeloperoxidase to
  form reactive intermediates ?promote autoimmune
  inflammation

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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

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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

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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).

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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.

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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

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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

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Thyroid Storm-2

• A CBC/DC obtained immediately and discontinued if
  granulocyte count lt1000 per cubic millimeter

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