What Are Thionamides?

Thionamides are antithyroid drugs that inhibit thyroid hormone synthesis by blocking thyroid peroxidase-mediated iodination of tyrosine residues in thyroglobulin—the critical step in producing thyroxine (T4) and triiodothyronine (T3). 1, 2, 3

Chemical Structure and Available Agents

Thionamides are relatively simple molecules containing a sulfhydryl group and a thiourea moiety within a heterocyclic structure 1
The two primary thionamides used clinically are:
- Methimazole (MMI): 1-methyl-2,3-dihydro-1H-imidazole-2-thione 1
- Propylthiouracil (PTU): 6-propyl-2-sulfanylidene-1,2,3,4-tetrahydropyrimidin-4-one 1
Carbimazole, a methimazole analogue, is used in the United Kingdom and parts of the former British Commonwealth 1, 2

Mechanism of Action

Primary Mechanism: Inhibition of Thyroid Hormone Synthesis

Thionamides are taken up by the thyroid gland as anions similar to iodide (like perchlorate, thiocyanate, and pertechnetate) 3
Their primary target is thyroid peroxidase, where they block:
- Iodination of tyrosine residues in thyroglobulin 1, 2, 3
- Coupling of iodotyrosines into iodothyronines (T3 and T4) 3, 4

Additional Mechanisms

Propylthiouracil (but NOT methimazole or carbimazole) blocks peripheral conversion of T4 to T3 1
Thionamides possess clinically important immunosuppressive and immunomodulatory effects 1, 3
Proposed immunomodulatory mechanisms include:
- Thyroid depletion of iodine, which reduces antigen expression 3
- Scavenging of reactive free radicals generated from oxygen and/or iodide during peroxidation 3
- Significant decrease in antithyroid antibody titers in most patients treated for at least 12 months 3

Clinical Indications

Primary Indication: Hyperthyroidism

Thionamides are the mainstay of treatment for:
- Graves' disease in both children and adults 2, 4
- Hyperthyroidism during pregnancy, postpartum period, and lactation 2, 4
- Thyrotoxic children and adolescents 4
- Toxic multinodular goiter (long-term low-dose maintenance therapy) 2

When Thionamides Are Preferred Over Radioiodine

Methimazole is the preferred first-line agent in most situations due to better efficacy, fewer adverse effects, once-daily dosing (long half-life), and similar cost 2
Thionamides remain the treatment of choice when radioiodine or surgery are contraindicated or not appropriate 5

Dosing and Administration

Methimazole Dosing

Initial therapy: Higher doses during the initial phase of treatment 1
Maintenance therapy: Low maintenance doses for long-term therapy in Graves' disease and toxic multinodular goiter 2
Once-daily dosing is possible due to methimazole's long half-life 2

Propylthiouracil Dosing

Typically requires multiple daily doses (shorter half-life than methimazole) 2
Dose of 400 mg results in only 0.025% excretion in breast milk over 4 hours 5

Monitoring During Therapy

Thyroid function tests should be monitored periodically during therapy 6, 5
Once clinical hyperthyroidism resolves, a rising serum TSH indicates the need for a lower maintenance dose 6, 5
Prothrombin time should be monitored, especially before surgical procedures, as thionamides may cause hypoprothrombinemia and bleeding 6, 5

Pregnancy and Lactation Considerations

First Trimester

Propylthiouracil is recommended over methimazole in the first trimester because methimazole is linked to congenital anomalies including aplasia cutis congenita and choanal or esophageal atresia 7
PTU may be the preferred agent during pre-pregnancy months and the first 16 weeks of gestation due to methimazole's more severe teratogenic effects 2

Second and Third Trimesters

Methimazole is preferred during the second and third trimesters because propylthiouracil carries a higher risk of severe hepatotoxicity 7
It may be preferable to switch from PTU to methimazole for the second and third trimesters 6, 5

Pregnancy Monitoring

Maintain free T4 or free thyroxine index (FTI) in the high-normal range to avoid fetal hypothyroidism 8
Check free T4 or FTI every 2-4 weeks during acute management 8
Assess thyroid function in newborns of mothers treated during pregnancy, as neonatal thyroid dysfunction can occur 8

Lactation

Both methimazole and propylthiouracil are considered safe for use while breastfeeding 7
Methimazole is present in breast milk but studies found no effect on clinical status in nursing infants 6
A long-term study of 139 thyrotoxic lactating mothers failed to demonstrate toxicity in infants nursed by mothers receiving methimazole 6
Propylthiouracil is present in breast milk to a small extent, resulting in clinically insignificant doses to the nursing infant 5

Adverse Effects

Minor and Common Side Effects

Side effects are usually mild and occur in 3-5% of patients, more frequently during initial phases when daily doses are higher 1, 9
Common minor effects include:
- Skin rash and itching 9
- Mild leukopenia 9
- These are typically transient 9

Major and Serious Adverse Effects

Agranulocytosis

The most dangerous effect, occurring in 0.1-0.5% of patients 9
This life-threatening condition can now be effectively treated with granulocyte colony-stimulating factor 9
Patients should report immediately: sore throat, skin eruptions, fever, headache, or general malaise 5
Monitor for agranulocytosis symptoms (sore throat, fever) even with alternative therapies 8

Hepatotoxicity

Propylthiouracil carries a higher risk of severe hepatotoxicity than methimazole 7
Postmarketing reports of severe liver injury including hepatic failure requiring liver transplantation or resulting in death have been reported in the pediatric population 5
Patients should report symptoms suggestive of hepatic dysfunction: anorexia, pruritus, right upper quadrant pain 5
If patients develop tiredness, nausea, anorexia, fever, pharyngitis, or malaise, PTU should be discontinued immediately, a physician contacted, and white blood cell count, liver function tests, and transaminase levels obtained 5

Vasculitis

Cases of vasculitis resulting in severe complications and death have occurred with propylthiouracil 5
Patients should promptly report symptoms: new rash, hematuria, decreased urine output, dyspnea, or hemoptysis 5

Other Rare Major Effects

Aplastic anemia 9
Thrombocytopenia 9
Lupus erythematosus-like syndrome 9
These are exceedingly rare 9

Drug Interactions

Anticoagulants (Oral)

Due to potential inhibition of vitamin K activity, the activity of oral anticoagulants (e.g., warfarin) may be increased 6, 5
Additional monitoring of PT/INR should be considered, especially before surgical procedures 6, 5

Beta-Adrenergic Blocking Agents

Hyperthyroidism causes increased clearance of beta-blockers with high extraction ratio 6, 5
A reduced dose of beta-blockers may be needed when a hyperthyroid patient becomes euthyroid 6, 5

Digitalis Glycosides

Serum digitalis levels may increase when hyperthyroid patients on stable digitalis regimens become euthyroid 6, 5
A reduced dosage of digitalis glycosides may be needed 6, 5

Theophylline

Theophylline clearance may decrease when hyperthyroid patients on stable theophylline regimens become euthyroid 6, 5
A reduced dose of theophylline may be needed 6, 5

Pediatric Considerations

Because of postmarketing reports of severe liver injury in pediatric patients treated with propylthiouracil, methimazole is the preferred choice when an antithyroid drug is required for a pediatric patient 6
Propylthiouracil is NOT recommended for use in the pediatric population except in rare instances where methimazole is not well-tolerated and surgery or radioactive iodine therapy are not appropriate 5
Parents and patients should be informed of the risk of liver failure when PTU is used in children 5

Alternative Treatments When Thionamides Are Unavailable

Immediate Symptom Management

Administer a beta-blocker (e.g., propranolol) to control ventricular rate and reduce hyperthyroid symptoms such as tachycardia, tremor, and heat intolerance 8
Beta-blockers are particularly critical in thyroid storm, where high doses may be required to prevent maternal heart failure 8
Use calcium channel antagonists (diltiazem or verapamil) to control ventricular rate when beta-blockers are contraindicated 8

Definitive Treatment Options

Surgical thyroidectomy should be reserved for patients who do not respond to medical therapy or when thionamides are unavailable and other options are unsuitable 8
Surgery is the definitive treatment when radioactive iodine is contraindicated (pregnancy) and medical management is impossible 8
Thyroidectomy provides immediate resolution but requires careful perioperative management to prevent thyroid storm 8

Critical Pitfalls

Never use radioactive iodine in pregnant patients 8
Reserve thyroidectomy for the second trimester when absolutely necessary 8
Avoid calcium channel blockers, digitalis, or beta-blockers in patients with Wolff-Parkinson-White syndrome and atrial fibrillation, as these can accelerate ventricular response 8

Long-Term Efficacy and Safety

Thionamides cure 50% of Graves' disease patients provided they are maintained for at least 12 months 3
Recent studies confirm the efficacy, safety, and cost-benefit properties of long-term methimazole therapy with low maintenance doses for Graves' disease and toxic multinodular goiter 2, 4
Continuous thionamide treatment shows acceptable efficacy and safety profiles in treatment of hyperthyroidism, especially Graves' disease in both children and adults 2

Carcinogenesis Concerns

Laboratory animals treated with propylthiouracil for >1 year demonstrated thyroid hyperplasia and carcinoma formation 5
In a 2-year rat study, methimazole at doses 2 and 12 times the maximum human maintenance dose caused thyroid hyperplasia, adenoma, and carcinoma 6
The clinical significance of these animal findings is unclear, as similar findings occur with continuous suppression of thyroid function by various antithyroid agents, dietary iodine deficiency, subtotal thyroidectomy, and autonomous thyrotropic hormone-secreting pituitary tumors 6, 5

What are thionamides (the antithyroid drug class) and how are they used, including mechanism, indications, dosing, pregnancy considerations, and adverse effects?

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