Methimazole

Methimazole is an anti-thyroid agent belonging to the pharmacological class of Thyroid Function Modulator.

Methimazole is approved by FDA for the treatment of hyperthyroidism due to Graves' disease or toxic multinodular goitre.

Methimazole is rapidly absorbed through the gastrointestinal tract, concentrating in the thyroid gland, crossing the placenta, and entering breast milk. The liver extensively metabolizes it, excreting mainly via urine.

The most common side effects of methimazole include skin rash, nausea, vomiting, joint pain, paresthesia, loss of taste, loss of hair, muscle pain, headache, and drowsiness.

Methimazole is available as a tablet.

The molecule is available in India, the United States, Canada, the United Kingdom, Australia, Germany, France, Italy and Japan.

Methimazole is an anti-thyroid agent belonging to the pharmacological class of Thyroid Function Modulator.

The primary mechanism of action of methimazole is interference with thyroid peroxidase (TPO), an early step in synthesising thyroid hormone. The precise mechanism by which methimazole inhibits TPO is unknown. TPO and hydrogen peroxide typically work together to catalyze the transformation of iodide into iodine, which is subsequently incorporated into the 3 and/or 5 positions of the phenol rings of tyrosine residues in thyroglobulin. The primary hormones produced by the thyroid gland, thyroxine (T4) or tri-iodothyronine (T3), are created when these thyroglobulin molecules break down inside thyroid follicular cells.

Methimazole has the potential to inhibit TPO directly. Still, in vivo studies have demonstrated that it functions as a competitive substrate for TPO, causing it to become iodinated and disrupting thyroglobulin's iodination process. An alternative hypothesis suggests that the sulfur moiety of methimazole could directly interact with the iron atom located at the centre of TPO's heme molecule, thereby impeding the molecule's capacity to iodinate tyrosine residues. Weaker evidence supports two other proposed mechanisms: direct inhibition of thyroglobulin or direct binding of methimazole to thyroglobulin.

The onset of action for methimazole is generally 12-18 hr after oral administration.

The peak plasma time of methimazole occurs around 1-2 hours after oral administration.

The duration of methimazole is typically around 36-72 hours after oral ingestion.

Methimazole is available as a tablet.

Tablet: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally thrice daily for as directed.

• Hyperthyroidism
• Graves Disease
• Thyrotoxicosis (Off-label)

Methimazole effectively treats hyperthyroidism by preventing the thyroid gland from producing too many hormones, which is especially useful in Graves' disease. It lessens hyperthyroidism-related symptoms like tremors, anxiety, rapid heartbeat, and weight loss. Methimazole is frequently used off-label for thyrotoxicosis despite not having FDA approval because of how well it inhibits the synthesis of thyroid hormones. This medication significantly reduces the symptoms of hyperthyroidism by controlling thyroid hormone levels. Methimazole is an essential pharmaceutical for treating thyrotoxicosis and Graves' disease because it can treat the underlying cause of thyroid disorders, which means that patients with these conditions will have better control over their hormone levels and overall health.

Methimazole is indicated as follows:

• Effective in hyperthyroidism by reducing excessive thyroid hormone production.
• It is commonly administered to manage the symptoms associated with Graves Disease, an autoimmune condition causing hyperthyroidism.
• Methimazole might be indicated off-label to treat or manage thyrotoxicosis, a condition of excessive thyroid hormone levels.

Orally: Patients take methimazole orally as tablets, swallowing them whole with water, preferably at consistent times daily for optimal effectiveness, after meals, is advisable, preferably at consistent times daily. Adhering actively to these instructions is crucial, as ensuring regularity in dosage, timing, and handling potential food interactions enhances the medication's efficacy and safety profile. Ensuring strict adherence to prescribed guidelines allows for the best possible management of the condition while minimizing the risk of complications.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablets: 5mg, 10mg.

Methimazole is available in the form of tablets.

Dose Adjustment in Adult Patients:

Hyperactive thyroid

Mild: 15 mg PO daily divided every 8 hours at first

Moderate: at first, 30–40 mg PO divided every 8 hours

Severe: start with 60 mg PO divided every 8 hours.

Maintenance: 5–30 mg PO divided every eight hours

The Graves Disease

10–20 mg/day PO once; after reaching euthyroidism, cut the dosage in half and take for 12–18 months; if TSH levels return to normal, you can then taper or stop.

Off-label thyrotoxicosis

As a first-day adjunct to other agents, take 15-20 mg PO every 4 hours; after the patient is stable, reduce the frequency to qDay or q12 hours.

While taking methimazole, specific dietary guidelines should be followed to ensure optimal effectiveness and safety. Excessive consumption of iodine-rich foods like seaweed, seafood, and iodized salt should be avoided, as they can worsen thyroid-related issues. Consume non-iodized salt, tea, egg whites, and specific fruits and vegetables to limit iodine intake. Ensure adequate calcium, vitamin D, zinc, iron, and selenium for optimal thyroid function. Additionally, maintaining a balanced diet with consistent Vitamin K-rich foods like leafy greens is recommended due to methimazole's impact on blood clotting. Moderating alcohol and caffeine intake and discontinuing smoking are advisable to prevent adverse health effects.

The dietary restriction should be individualized as per patient requirements.

Hypersensitivity to methimazole or any container component or ingredient in the formulation.

• Reports have surfaced about a lupus-like syndrome.
• Bleeding risk and hypoprothrombinemia are possible, especially before surgical procedures; vigilant monitoring is essential.
• Immediate discontinuation is advised upon the presence of ANCA-positive vasculitis.
• Exercise caution when concurrently using drugs known to cause agranulocytosis.
• Prolonged usage may result in hypothyroidism; monitor and adjust doses for thyroid balance.
• There’s a risk of significant bone marrow suppression; be cautious when using myelosuppression-inducing agents and discontinue if severe conditions occur.
• Discontinue use promptly upon hepatitis occurrence or significant elevation in hepatic enzyme levels.
• Terminate use if unexplained fever arises.
• Severe dermatologic reactions, though rare, may happen; discontinue if exfoliative dermatitis occurs.

It is unsafe to consume alcohol.

Methimazole passes into the breast milk when used by a lactating mother. Caution is recommended.

Due to clear evidence of risk to the developing fetus, it is not safe to use during pregnancy.

Limit iodine-rich foods; ensure nutrients; balance diet; avoid smoking and alcohol.

The adverse reactions related to Methimazole can be categorized as:

• Common Adverse Effects: Nausea, vomiting, upset stomach, alterations in taste perception, skin rash, and itching.
• Less Common Adverse Effects: Joint pain, hair loss, tingling sensations in the extremities, drowsiness, and muscle weakness.
• Rare Adverse Effects: Agranulocytosis, hepatitis, vasculitis, severe skin reactions like exfoliative dermatitis or Stevens-Johnson syndrome, and the onset of lupus-like syndrome.

Reports on post-marketing

Severe liver injury, including hepatic failure requiring liver transplantation or death, has been reported (pediatric population).

The clinically relevant drug interactions of Methimazole are briefly summarized here.

• Warfarin Interaction: Methimazole may potentiate the anticoagulant effect of warfarin, increasing the risk of bleeding. Close monitoring of international normalized ratio (INR) and warfarin dosage adjustments may be necessary.
• Beta-Blockers: Concurrent use with beta-blockers can enhance cardiovascular effects, such as bradycardia. Adjustments to beta-blocker dosage may be required to prevent excessive cardiac suppression.
• Theophylline Interaction: Methimazole may increase theophylline levels, potentially leading to theophylline toxicity. Regular monitoring of theophylline levels and adjustments to its dosage are advisable.
• Digitalis Glycosides: Methimazole can enhance the effects of digitalis glycosides, potentially causing cardiac arrhythmias. Careful monitoring of heart function and dosage adjustments may be necessary.

• Lithium Interaction: Concurrent use with lithium may increase lithium levels, resulting in toxicity. Regular monitoring of lithium levels and adjustment of lithium dosage is recommended when used concomitantly with methimazole.

The common side effects of Methimazole include:

• Headache
• Upset stomach
• Nausea
• Vomiting
• Minor skin irritation or rash
• Unusual hair loss
• Taste loss atypical feelings (prickling, tingling, Burning, constriction, and pulling)
• Bloating
• Pain in the muscles and joints
• Drowsiness
• Lightheadedness
• Reduced platelet concentration, or thrombocytopenia

• Pregnancy

Pregnancy Category D (FDA): Use in situations where there is no safer medication available and life is in danger. Evidence that human fetal risk exists.

When treating hyperthyroidism in pregnant women, especially during the first trimester (during organogenesis), other medications may be preferred due to the uncommon incidence of congenital abnormalities linked to methimazole use.

Patients should be informed that they should contact their physician right away about their therapy if they get pregnant or plan to become pregnant while taking an antithyroid medication.

Reducing the amount of antithyroid treatment may be feasible because thyroid dysfunction often improves during pregnancy in many pregnant women. Sometimes, antithyroid medication can be stopped two or three weeks before birth. Methimazole can induce fetal goitre and cretinism in pregnant women due to its high transplacental membrane crossing ability.

During pregnancy, it is crucial to administer a dose that is enough but not overly high.

• Nursing Mothers

Breast milk absorbs methimazole through excretion. That being said, several studies have reported no effect on the clinical state of nursing infants whose mothers take methimazole; this is especially true if the mother's thyroid function is continuously evaluated (every week or every two weeks).

There was no evidence of toxicity in the infants nursed by women receiving methimazole medication in a long-term trial of 139 thyrotoxic breastfeeding mothers and their children.

• Pediatric Use

As per FDA, the safety and efficacy of Methimazole in Pediatric patients have not been established. However, when using this population, utmost caution should be taken.

Dose Adjustment in Pediatric Patients:

Hyperactive thyroid

Initial: divided every eight hours or 0.5–0.7 mg/kg/day PO

Maintenance: divided every eight hours or 0.2 mg/kg/day PO

Not exceeding 30 mg per day

Graves Disease

0.2–0.5 mg/kg/day PO; after attaining euthyroidism, reduce the dosage in half and continue to use the medication for a year or two.

Off-label thyrotoxicosis: 0.5–1 mg/kg/day PO divided every 8 hours; modify dosage and duration of treatment according to patient response.

• Geriatrics (> 65 years old)

As per the FDA, the safety and efficacy of Methimazole in elderly patients above 65 have not been extensively studied or established. Insufficient data from Methimazole studies involve subjects aged 65 or older. Clinical experience hasn't shown differences between elderly and younger patients. Caution in dose selection for elderly patients is essential, considering potential hepatic, renal, or cardiac function declines and other concurrent medical conditions or medications.

Dose Adjustment

The initial daily dosage is three doses of 0.4 mg/kg of body weight, approximately eight hours apart. About half of the initial dose is the maintenance dosage.

Dose Adjustment in Kidney Impairment Patients:

Kidney impairment: Cautiously start methimazole with lower doses; dosage adjustment is required.

Dose Adjustment in Hepatic Impairment Patients:

Hepatic Impairment: Dosage adjustment may be required.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Methimazole.

Signs and Symptoms

Overconsumption of Methimazole could lead to nausea, vomiting, headache, fever, epigastric distress, joint pain, pruritus, and oedema. Aplastic anemia (pancytopenia) or agranulocytosis can emerge within hours to days. Less common occurrences involve hepatitis, nephrotic syndrome, exfoliative dermatitis, neuropathies, and CNS stimulation or depression.

Management

There is no specific antidote or treatment for overdosage of methimazole, so treatment typically involves symptomatic and supportive measures. Methimazole should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

Gastric lavage, activated charcoal administration, and symptomatic relief constitute essential supportive measures. Hospitalization may be necessary in severe toxicity cases. Addressing symptoms such as nausea and vomiting is part of symptomatic treatment. Agranulocytosis can be managed with glucocorticoids. Regular blood cell count assessments are crucial for monitoring complications. Beta-blockers may be administered for symptom management, including tachycardia and tremors. Consider granulocyte colony-stimulating factor (G-CSF) in cases of bone marrow suppression. Extreme situations may warrant plasmapheresis or hemodialysis for methimazole elimination. Ensuring immediate medical attention and adopting an individualized treatment approach is vital for favourable outcomes in methimazole overdosage cases.

Pharmacodynamics

Methimazole reduces the production of thyroid hormones, which lessens hyperthyroidism. Its duration of action is 36 to 72 hours, with a start within 12 to 18 hours. This is probably because methimazole and specific metabolites accumulate in the thyroid gland following administration.

Patients should be instructed to report any symptoms of agranulocytosis, such as fever or sore throat, as they are the most severe potential side effect of methimazole therapy. During methimazole therapy, other cytopenias might also manifest. Additionally, there is a risk of severe hepatic toxicity when using methimazole. As such, patients utilizing this therapy should be closely monitored for symptoms of hepatic dysfunction, including jaundice, anorexia, pruritus, and elevated liver transaminases.

Pharmacokinetics:

• Absorption:After oral treatment, methimazole is rapidly and widely absorbed, with an approximate absolute bioavailability of 0.93.
• Distribution:The apparent volume of distribution of methimazole has been shown as approx 20 L and exhibits little-to-no protein binding, existing primarily as a free drug in the serum.

• Metabolism: The liver rapidly and extensively metabolised methimazole, mostly using the CYP450 and FMO enzyme systems.

Researchers have identified substances such as 3-methyl-2-thiohydantoin and linked them to antithyroid action in rats, even if the precise enzyme isoforms responsible for producing methimazole metabolites are yet unknown. Methimazole-induced hepatotoxicity may result from cytotoxic glyoxal and N-methyl thiourea; residual sulfenic and sulfinic acid is thought to be the ultimate toxicants, potentially arising from methimazole oxidation through FMO or N-methyl thiourea downstream.

• Excretion: Reported urinary excretion of unchanged methimazole ranges between 7% and 12%, while limited faecal elimination accounts for 3%. Methimazole and its metabolites show enterohepatic circulation, which is evident in bile post-administration.

Half-life: 4-6 hr

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