METHIMAZOLE

ANTITHYROID DRUG

PRESENTED BY:MEENAKSHIM.Sc. 1st Year

HISTORY• Antithyroid drugs were developed as derivatives of

thiourea, which was discovered to goiter in rats.• Thiourea was the first drug used in man, followed by �

thiouracil (after testing hundreds of compounds in rats) (JAMA 1943)

• Both compounds caused agranulocytosis in �approximately 1% of patients

• Propylthiouracil was found to have a lower risk of �agranulocytosis, and methimazole, introduced a few years later, in 1949, seemed to have a lower rate still

HYPERTHYROIDISM

The over production of thyroid hormones.Symptoms include fatigue, weight lose, rapid heart beat, anxiety,

swollen eyes, and sensitivity to hot temperatures.Causes:

Grave’s disease, and autoimmune disorder in which antibodies serve as agonists to the THS receptors on the thyroid’s surface, causing thyroid growth and activation of hormone synthesis and secretion.Thyroid tumors which cause the uncontrolled synthesis and secretion of thyroid hormones.Thyroiditis, inflammation of the thyroid typically caused by infection.

Symptoms:

Anti-thyroid drugs

Drugs used for the treatment of hyperthyroidism :Inhibition of hormone synthesis : THIOAMIDES

• Propylthiouracil and Methimazole.Blockade of hormone release :• Iodides, Iodinated contrast media. Radioactive Iodine 131Anion Inhibitors :• Perchlorates, Thiocynates.Beta blocking drugs : Propranolol

Anti-thyroid agents

THIOAMIDES : • Methimazole • Propylthiouracil (PTU), Carbimazole• MOA: – inhibit synthesis by acting against iodide

organification – coupling of iodotyrosines – Blocks peripheral conversion of T4 to T3 (PTU)

Anti-thyroid drugs: THIOAMIDES

The thiocarbamide group is essential for antithyroid activity

THIOAMIDES :

• Pharmacokinetics:– almost completely absorbed in the GIT– serum half life: 90mins(PTU) ; 6 hours

(methimazole)– excretion: kidney – 24 hours (PTU) ; 48 hours

(Methimazole)– can cross placental barrier (lesser with PTU)– Methimazole 10x more potent than PTU– PTU more protein-bound

Pharmacological action:

Inhibition of the synthesis of T3 & T4

• Mechanism• All thioamides inhibit peroxidase-catalyzing reactions• Iodine organification• Iodotyrosines condensation

• Propylthiouracil also inhibit T4 converting to T3 Characteristics① Result appears slowly: in 3-4 w hyperthyroid ameliorated, and in 2-3 months BMR normalized;② Long-term use leads to thyroid hyperplasia③ Methimazole is 10 times as potent as propylthiouracil

• Clinical use

• treatment of hyperthyroid

• 1. Mild hyperthyroid and surgery & 131I not permitted;

• 2. Operation preparation;

• 3. Thyroid crisis (comprehensive therapy).

• Adverse reactions

• 1. Long-term use leads to thyroid hyperplasia;

• 2. Pruritic maculopapular rash is the most common adverse raaction

• 3. The severe adverse reaction is agranulocytosis

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Iodides (NaI, KI)

Pharmacological action Inhibition of T3 & T4 release and synthesis Decrease of size & vascularity of the hyperplastic gland

Clinical use Ministrant treatment of hyperthyroid 1. Operation preparation; 2. Thyroid crisis.

Adverse reactions 1. Acneiform rash (similar to that of bromism); 2. Swollen salivary glands, mucous membrane ulcerations, and etc.

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Radioactive iodine (131I)

131I is the only isotope for treatment of thyrotoxicosis. Its therapeutic effect depends on emission of β rays with an effective half-life of 5 days & a penetration range of 0.4-2 mm.Woman in pregnancy or lactation is forbidden!

β-adrenoceptor blockers

βblockers are effective in treatment of thyrotoxicosis.

Propranolol is the most widely studied and used.

ANION INHIBITORS :• Monovalent ions like perchlorate, pertechnetate,

thiocyanate can competitively block the uptake of iodine.• Anion inhibitors are uncommon in use because of

aplastic anemia.• These are effective in iodine induced hyperthyroidismIODINATED CONTRAST MEDIA: Diatrizoate / Iohexol :• They are valuable in hyperthyroidism and as adjunctive in

thyroid storm.• They inhibit the peripheral conversion of T4 into T3.• Inhibition of hormone release is an additional mechanism

Other Anti-thyroid drugs :• Propranolol is used in the management of

cardiac symptoms of thyrotoxicosis.• Lithium is known to inhibit synthesis and release

of thyroid hormones.• Amiodarone can also result in hypothyroidism.

Mechanism of action of anti thyroid drugs

METHIMAZOLE

• IUPAC name: 1-methyl-3H-imidazole-2-thioneI• Formula:C4H6N2S• Mol. mass114.17 g/mol• Melt. point146 °C (295 °F)

• Trade Name(s): India- Methimez . International- Mercazole, Thyrozole

• Brands: Tapazole , Metizol• Routes: Oral

• PHARMACOKINETIC DATA: • Bioavailability 93% Metabolism: Hepatic• Half-life 5-6 hours• Excretion: Renal

METHIMAZOLE• INDICATIONS:• Methimazole is indicated in the medical treatment of

hyperthyroidism. Long-term therapy may lead to remission of the disease.

• Category: D There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans.

• Can also be taken before thyroid surgery to lower thyroid hormone levels.

PHARMACOKINETICSABSORPTION: Bioavailability : Readily and rapidly absorbed from the GI tract following oral

administration.Peak plasma concentrations attained within about 1 hour.Distribution Extent: • Readily crosses the placenta.• Distributed into milk (in concentrations approximately equal to those in

maternal serum).Metabolism: Metabolized in the liver.Elimination Route: Excreted in urine; approximately 12% of dose excreted in

urine within 24 hours.Half-life : 5–6 hours.Storage: 15–30°C.

• DOSAGE• Adult: The initial daily dosage is 15 mg.• It may be increased upto 60 mg, divided into 3 doses at 8-hour

intervals.• The maintenance dosage is 5 to 15 mg daily. • Pediatric: Initially, the daily dosage is 0.4 mg/kg, divided into 3 doses

and given at 8-hour intervals.• ADMINISTRATION: Oral, with or without food• Warnings and Precautions : Caution should be exercised in

patients with history of decrease in blood cells, liver disease, any allergy, who are taking other medications, during pregnancy and breastfeeding. It may cause drowsiness, dizziness, or lightheadedness, do not drive a car or operate machinery while taking this medication

• SIDE EFFECTS: Skin - Rash, hives, abnormal loss of hair, itching and skin pigmentation. Gastrointestinal - Nausea, vomiting and stomach upset. Musculoskeletal - Joint/muscle pain. Central Nervous System - Tingling, headache, drowsiness, dizziness and fainting. Miscellaneous - Loss of taste, swelling and jaundice.

Other Precautions : Avoid excess dosage.

Storage Conditions : Store it at controlled room temperature (15° to 30°C), and in an airtight container. Keep away from children.

COMMON ADVERSE EFFECTS:• skin rash• itching• abnormal hair loss• upset stomach• vomiting• loss of taste• abnormal sensations (tingling, prickling, burning, tightness, and pulling)• swelling• joint and muscle pain• drowsiness• dizziness• decreased white blood cells• decreased platelets

• List of Contraindications• Methimazole and Pregnancy• Contraindicated in pregnancy

USFDA pregnancy category D. Methimazole can harm an unborn baby. Perform pregnancy tests before using Methimazole. Use effective contraceptive modes to prevent unintended pregnancies while taking Methimazole.

• Methimazole and Lactation• Methimazole can pass into breast milk and harm a breast-

feeding baby. Consult a physician before taking Methimazole.

• Storage• Store at 20-25°C.

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