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At present, drug treatment is still the most basic and most common treatment for hyperthyroidism, and it is suitable for hyperthyroidism patients with mild disease and mild to moderate thyroid enlargement. Drugs should be treated if they are under 20 years of age, pregnant with hyperthyroidism, frail elderly or have severe heart, liver and kidney disease intolerance.

Clinically used anti-thyroid drugs (ATD) are mainly methimazole (MMI) and propylthiouracil (PTU), so how to choose when treatment?

Both belong to the same thiourea drug, have the same mechanism of action, can inhibit the peroxidase system in the thyroid, block the oxidation of ionic iodine concentrated in the thyroid to active iodine, so that tyrosine can not be iodized, and hinder The condensation of iodinated tyrosine, in turn, inhibits the synthesis of triiodothyronine (T3) and thyroxine (T4) and exerts an antithyroid effect. However, they have their own characteristics in terms of clinical efficacy and adverse reactions.

 

I. The curative effect

MMI 5mg is equivalent to PTU 50mg drug dose, but related studies have found that, although the dose is equivalent, the efficacy is not the same in clinical application of hyperthyroidism.

The study believes that the therapeutic effect of MMI is better than PTU, we explain from the following aspects:

Methimidazole (MMI) contains a sulfhydryl group

Studies have found that patients with untreated Graves’ hyperthyroidism have increased serum lipid peroxidation, decreased plasma sulfhydryl and sulfhydryl lysate levels, increased intracellular antioxidant enzyme activity, and insufficient extracellular free radical scavenging system. Indole imidazole treatment can reverse these abnormalities.

Propylthiouracil (PTU) has a relatively high molecular weight

The relative molecular weight of propylthiouracil is 170.24, while the methimazole is only 114.16. The large molecular weight makes propylthiouracil difficult to pass through the placenta tissue, and the concentration in breast milk is also low, which is its advantage; but it also affects its Absorption in the body and through the thyroid follicular cell membrane.

Although high doses of propylthiouracil also inhibit the activity of deiodinase in the thyroid and peripheral tissues, reducing the conversion of thyroxine to triiodothyronine, and reducing the triiodothyronine in the blood, can not completely offset Due to the short-term plasma half-life, large molecular weight and other effects.

 

II. Adverse reactions

In general, anti-thyroid drug treatment is safe and effective, but its clinical adverse reactions are more common, generally less severe, if you can stop the drug in time, you can recover. However, rare and serious side effects may occur in the treatment, and there may be a potentially fatal danger, so it is necessary to pay attention.

The adverse effects of MMI were significantly lower than PTU, and the adverse effects of MMI were dose-dependent, and PTU was not clearly associated with drug dose.

 

1. Granulocyte deficiency

Absolute counts of peripheral blood granulocytes below 0.5 x 109/L are defined as agranulocytosis. The incidence of granulocytosis caused by antithyroid drugs is between 0.1% and 0.5%. The incidence of treatment with PTU and MMI was 0.37% and 0.35%, respectively.

Most of the agranulocytosis occurs during the first 3 months of treatment and also occurs 1 year or more after treatment. It should be noted that there is no neutropenia in the initial treatment, and it may still occur during retreatment. The most typical clinical manifestations of agranulocytosis are fever and sore throat, which may have respiratory, digestive tract, genitourinary tract infections or severe sepsis, sepsis.

If clinically determined to use anti-thyroid drugs, patients should be routinely examined before taking the drug to confirm that the patient has no other problems, and can also be compared with the blood routine after administration.

During the anti-thyroid drug treatment, white blood cells should be regularly detected in order to detect asymptomatic agranulocytosis early. If the neutrophils are less than 1.5×109/L, the drug should be stopped immediately. Treatment of agranulocytosis should actively control infection, combined with granulocyte colony-stimulating factor, glucocorticoids or lithium carbonate.

It should be noted that there is a cross-reactivity between MMI and PTU in the adverse reactions of agranulocytosis, so it is not recommended to replace them.

 

2. Liver damage

The clinical manifestations of liver damage caused by anti-thyroid drugs are lack of specificity, and may include abdominal distension, nausea, vomiting, yellow urine, yellow staining of the skin and sclera. Upper abdominal pain and hepatomegaly are rare; laboratory tests usually have significant elevations in ALT, and pathology suggests non-specific hepatocyte necrosis.

Both MMI and PTU can cause liver damage, but the liver damage caused by MMI is lighter. It is mainly caused by intrahepatic cholestatic. It usually occurs about 2 weeks after administration. It is mainly characterized by elevated bilirubin and jaundice. Laboratory examination It can be seen that serum bilirubin is elevated, liver enzymes are mild and moderately elevated, and liver biopsy indicates the presence of hepatocyte structure, accompanied by cholestasis in the tubules and mild periportal inflammation.

Liver damage caused by PTU is heavier than MMI, and liver damage mainly occurs in patients treated with PTU. The general incidence rate is 0.1%-0.2%, mainly hepatocyte damage, most of which occur in the initial stage of PTU treatment. 1-2 months. It should be noted that 30% of patients treated with PTU will have a transient acute increase in ALT, which can be as high as 1.1-6.0 times the upper limit of normal. This increase in ALT can be resolved while continuing to take the drug.

The mechanism of liver damage is still unclear and is generally thought to be related to the heterogeneous response of the body. The incidence of severe liver damage caused by antithyroid drugs is very low and there are no predictors.

It is recommended to test liver function before antithyroid drug treatment. If ALT or serum bilirubin is slightly elevated, it is recommended to use hepatoprotective or anti-yellow drugs at the same time as anti-thyroid drugs; if ALT or serum bilirubin is significantly elevated, it is recommended to take liver or yellowing drugs first. After the indicators improved to a slight increase, anti-thyroid drugs were treated, and liver function was continuously observed.

Liver damage occurs after antithyroid drug treatment, should be immediately discontinued, symptomatic liver protection, hyperthyroidism can be treated with 131I.

There is no report of liver toxicity between MMI and PTU, so when using one of the drugs to cause liver damage, another drug can be carefully selected.

 

3. Vasculitis

Vasculitis is generally rare, and PTU causes more than MMI.

Anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis is more common in middle-aged women. Clinical manifestations include fever, rash, joint muscle pain, acute renal insufficiency, upper respiratory tract involvement (eg pharyngitis, rhinitis, nasopharynx). Ulcers, nosebleeds, etc.) and lower respiratory tract involvement (such as cough, hemoptysis, pulmonary hemorrhage, non-infectious lung shadows, and severe respiratory failure).

Once vasculitis occurs, the drug should be discontinued immediately, and most patients can recover, but some serious cases should be based on their clinical manifestations, organ involvement and antibody titer to determine whether to use glucocorticoids, immunosuppressants, hemodialysis or plasma. Replacement and other treatments.

 

4. Skin adverse reactions

Mainly for rash and itchy skin, the incidence rate is 10%, more anti-histamine drugs can be corrected; if the rash is serious, the drug should be discontinued to avoid exfoliative dermatitis.

 

5. Joint pain

The incidence of joint pain is 1%-5%. When joint pain occurs, you should consider the possibility of anti-thyroid arthritis syndrome, usually within 2 months of anti-thyroid drug treatment, can be relieved after stopping the drug, it is recommended to switch to other therapies for the treatment of hyperthyroidism, and use non-steroidal Symptomatic treatment of anti-inflammatory drugs or glucocorticoids.

 

6. Gastrointestinal reactions

Gastrointestinal reactions are one of the mild adverse reactions of antithyroid drugs, which occur between 1% and 5%. Usually manifested as stomach discomfort, loss of appetite and nausea. Generally do not cause serious harm, only symptomatic treatment can be.

 

7. Hypoglycemia syndrome

Hypoglycemia syndrome, also known as insulin autoimmune syndrome or Hirata disease, is currently reported in the world more than 200 cases of the syndrome, more common in Asian populations, especially Japanese. The syndrome can be seen in patients treated with MMI, and there is currently no report of this syndrome caused by PTU.

Most patients discontinue their own MMI and their condition resolves within 3 months. The treatment is to eat multiple times a day to avoid high-sugar foods (except when hypoglycemia occurs). Studies have shown that the use of alpha-glucosidase inhibitors may reduce the immune response to insulin in postprandial serum. It is also possible to use an immunosuppressive agent such as glucocorticosteroid, azathioprine or 6-mercaptopurine or to remove antibodies in serum by plasma exchange.

 

8. Hypocalcemia

The study found that T3 may inhibit the release of bone calcium, and may also be related to the changes in the function of parafollicular cells that secrete calcitonin in thyroid tissue.

 

9. Other adverse reactions

In addition to the above adverse reactions, anti-thyroid drugs can also cause taste or olfactory abnormalities, mumps, thrombocytopenia, aplastic anemia, hypoprothrombinemia, alopecia, drug fever, acute necrotizing gingivitis, pancreatitis, There are few adverse reactions such as methimazole dependence. Among them, taste or olfactory abnormality and mumps are only seen in patients who are treated with MMI.

 

III. Special circumstances

1. Pregnant patients

The goal of antithyroid drugs for the treatment of hyperthyroidism during pregnancy is to use the minimum effective dose of anti-thyroid drugs to achieve and maintain the upper limit of serum FT4 in the shortest possible time, to prevent the anti-thyroid drugs from affecting the fetal brain development through the placenta.

PTU preferred in early pregnancy

PTU is preferred, and MMI is a second-line option. Because of the high ratio of PTU to plasma protein binding, the placental pass rate is lower than MMI, and the amount of PTU through the placenta is only 1/4 of MMI; while MMI may cause fetal skin hypoplasia and methimazole-induced embryo disease (including retronasal pores) And congenital malformations such as esophageal atresia, facial deformity).

MMI is preferred in the third trimester of pregnancy

The preferred MMI is recommended because of the risk of severe liver damage, including liver failure and death.

The initial dose of PTU 50-100mg, 3 times a day or MMI 10-20mg, once a day, monitor thyroid function, and reduce the dose in time. Thyroid function was examined every 2-4 weeks at the beginning of treatment and later extended to 4-6 weeks.

 

2. Lactating patients with hyperthyroidism

The choice of lactam drug in lactation is still controversial

Nearly 20 years of research have shown that the use of anti-thyroid drugs during lactation is safe for offspring. PTU 150mg/d or MMI 10mg/d has no significant effect on infant brain development, but thyroid function should be monitored in infants; anti-thyroid should be applied during lactation Mothers who were treated with drugs did not find complications such as neutropenia and liver damage. The mother should take anti-thyroid medication after breastfeeding, and then take the next breastfeeding interval 3 to 4 hours. MMI’s milk excretion is 7 times that of PTU.

3. Hyperthyroid crisis patients

PTU is preferred. Compared with MMI, PTU can inhibit the synthesis of thyroid hormone in addition to inhibiting the transformation of T4 into T3 with higher biological activity in peripheral tissues, so it has a faster onset and can quickly control hyperthyroidism. Therefore, the PTU is preferred when rescuing a hyperthyroid crisis, but the MMI can be replaced without a PTU.

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