Methimazole (Thiamazole) and Propyl hysteractyl (PTU)

Mechanism

Pharmacological Class and Group

Derivatives of Thionamides (synthetic antithyroids)..

Mechanism of Action

Thyroid hormones are synthesized in the thyroid follicle through iodination and incorporation of tyrosine residues into thyroglobulin. This process is catalyzed exclusively by the transmembrane enzyme Thyroperoxidase (TPO) in the apical membrane of the colonocyte.

Enzyme Inhibition Mechanism

1. Thyroperoxidase (TPO) Inhibition: Methimazole and propylthiouracil act as alternative competitive substrates for the TPO enzyme. By binding covalently, they inactivate the enzyme and terminally prevent:

• The oxidation of iodine ions from the circulation to active neutral iodine (I^- → I⁰).
• The iodination of the tyrosyl residues of the thyroglobulin protein to form Monoiodotyrosine (MIT) and Diiodotyrosine (DIT).
• The phenolic coupling reaction of MIT and DIT to synthesize Thyroxine (T4) and Triiodothyronine (T3).

2. Extra-thyroid Inhibition of Deiodinase Type 1 (D1) (Exclusive effect of PTU): Propylthiouracil (but not methimazole) has the additional property of peripherally blocking the enzymatic conversion of T4 to T3 in the liver, kidney and muscle:

PTU Peripheral blockade of D1 deiodinase ↓ Rapid serum levels of active T₃

This property makes PTU the priority drug of choice during an acute decompensated thyrotoxic storm.

Pharmacokinetics

High Resolution Pharmacokinetics

Indicators and dose

Clinical Indications and Off-Label Uses

• Primary hyperthyroidism (Graves-Basedow Disease): To induce medical remission after 12-18 months of continuous therapy.
• Prior preparation for Thyroidectomy or Radioactive Iodine Therapy: To achieve the previous euthyroid state and prevent thyroid discharge crises induced by physical manipulation.
• Thyroid Storm (Thyrotoxic Crisis): Acute life support treatment of choice (preferably with PTU).

Dosage and Clinical Adjustment

Methimazole (Thiamazole) (General choice for greater convenience of taking):

• Initial Dose (Moderate Hyperthyroidism): 15 mg to 30 mg per day orally, dosed in a single dose or divided into two doses.
• Initial Dose (Severe Hyperthyroidism / Bulky Goiter): 40 mg to 60 mg per day.
• Maintenance Phase (after achieving euthyroidism, typically at 4-8 weeks): Gradually reduce to a stable maintenance dose of 5 mg to 15 mg once a day.

Propilchain (PTU):

• Initial Dose: 300 mg to 450 mg per day orally, strictly divided into three separate doses (every 8 hours).
• Dose in Thyroid Storm: 200 mg every 4 hours orally or by nasogastric tube.

Adjustment in Liver / Kidney Failure: There are no pre-established dose reduction guidelines, but due to the high hepatic metabolism and increased risk of toxicity in extreme organ failure, a prudent reduction of the dose by 25-50% is recommended.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to thionamides.
• Documented history of severe systemic adverse reactions (such as previous agranulocytosis, vasculitis, or severe antithyroid-induced toxic hepatitis).

Relative Contraindications

• Severe baseline neutropenia prior to the start of treatment (absolute neutrophil count < 1500/mm³).
• Pre-existing liver failure (methimazole is less hepatotoxic than PTU).

Adverse Effects (ADR) and Specific Toxicity

• Frequent (1%-10%): Skin itching, maculo-papular skin eruptions, symmetrical migratory arthralgias, gastric dyspepsia, headaches, temporary alteration of taste or smell.
• Uncommon (0.1%-1%): Moderate elevation of serum transaminases of hepatocellular origin or cholestatic pattern.
• Rare (0.01%-0.1%): ANCA antibody vasculitis, drug-induced lupus erythematosus syndrome, thrombocytopenia.
• Very rare (<0.01%): Acute idiopathic agranulocytosis, fulminant hepatitis or massive hepatic necrosis (severe ADR linked to the use of PTU).

Critical Toxicity: Agranulocytosis and Neutropenia Alert

Agranulocytosis (absolute neutrophil count < 500/mm³) is an idiosyncratic and unpredictable antibody-mediated complication of autoimmune origin, with an incidence rate of approximately 0.2 to 0.5% of patients exposed to thionamides. It manifests clinically abruptly with sudden onset fever, chills and severe odynophagia/necrotizing oral ulcers.

Appearance of fever or odynophagia Immediate performance of a complete blood count Urgent suspension of Thionamides

The patient must receive strict and unequivocal instructions: if there is any fever or sore throat, the medication must be stopped and a blood count must be performed immediately. You should not re-expose yourself to thionamides.

Drug Interactions of Clinical Relevance

• Oral anticoagulants (Vitamin K Antagonists / Warfarin): As the hyperthyroid state is progressively corrected, the clearance of endogenous coagulation factors decreases, reducing the clinical effect of warfarin and requiring close monitoring of the INR value.
• Digoxin: Hyperthyroidism increases renal clearance of digoxin. When euthyroidism is reestablished, plasma digoxin levels can rise abruptly to digitalis toxicity ranges.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Uncontrolled maternal hyperthyroidism is associated with intrauterine growth retardation and preeclampsia. A dual regimen of thionamides should be managed during pregnancy:
  • First Trimester of Pregnancy: Mandatory use of Propylthiouracil (PTU). Methimazole freely crosses the placenta and is causally associated with methimazole embryopathy (aplasia cutis congenita, choanal or esophageal atresia, facial dysmorphia).
  • Second and Third Trimester: Recommended rotation of PTU to Methimazole due to the severe cumulative risk of maternal fulminant hepatic necrosis induced by prolonged PTU in the pregnant woman.
• Breastfeeding: Compatible. Both thionamides are excreted in low concentrations in breast milk. The use of methimazole at low doses (maximum 20 mg/day) with periodic monitoring of the infant's thyroid function is preferred.