65. Thyroid hormones, antithyroid drugs

From greek.doctor

Pharmacological therapy of hypothyroidism

  • L-thyroxine
  • Liothyronine
  • Iodine

Indication

The most frequently used drug to treat hypothyroidism is L-thyroxine (levothyroxine).

Liothyronine is used when rapid effect is needed, or if it’s desirable that the effect should go over quickly after stopping the drug. This can be beneficial in the treatment of myxoedema coma. It’s never used alone and should always be combined with L-thyroxine.

Iodine is used to treat iodine deficiency hypothyroidism.

Mechanism of action

L-thyroxine is a synthetic form of T4. It is converted into T3 in the periphery.

Liothyronine is a synthetic form of T3.

Pharmacokinetics

L-thyroxine is orally absorbed, but the oral bioavailability varies significantly based on many factors, like the bacterial flora, the gastrointestinal motility and the simultaneous intake of caffeine, iron, aluminium or calcium.

L-thyroxine has strong plasma protein binding. It is metabolized in the periphery to active T3 and to inactive rT3, and it is conjugated in the liver.

Iodine is well absorbed and distributed. It’s eliminated through the kidneys.

Dosing

The drugs are taken orally, except in emergency cases like in myxoedema coma, where IV administration is used.

Due to the variable oral bioavailability levothyroxine should be taken before meals. The daily amount should be divided into three doses. A normal maintenance dose of levothyroxine is 75 – 150 µg per day.

The daily requirement of iodine is 0.1 mg.

Interactions

L-thyroxine interacts with many drugs. These interactions occur on multiple levels:

  • L-thyroxine is metabolized by the liver and is subject to interactions with drugs that induce liver enzymes
  • L-thyroxine has strong plasma protein binding and is subject to interactions with other drugs which have strong plasma protein binding
  • The oral absorption of L-thyroxine is reduced by some drugs

Here is a list of some drugs that interact with L-thyroxine and how the L-thyroxine dose should be adjusted accordingly (don't memorise):

Drug/condition Mechanism of interaction The dose of L-thyroxine should be:
Phenytoin Induction of liver metabolism Increased
Carbamazepine Induction of liver metabolism Increased
Oestrogen Plasma protein binding Increased
Tamoxifen Plasma protein binding Increased
Glucocorticoids Plasma protein binding Decreased
Androgens Plasma protein binding Decreased
Beta blockers Decreased peripheral conversion of T4 to T3 Increased
Calcium carbonate Decreased absorption Increased
PPIs Decreased absorption Increased
Liver disease Decreased liver metabolism Decreased

Adverse effects

  • Tachycardia/palpitation
  • Atrial fibrillation
  • Weight loss
  • Anxiety
  • Osteoporosis

Therapy of hyperthyroidism

  • Thioamides
    • Carbimazole (Neo-Mercazole®)
    • Methimazole
    • Propylthiouracil
  • Iodine
  • Beta blockers
    • Propranolol
  • Old drugs
    • Lithium-carbonate
    • Perchlorate

Indications

Thioamides, especially carbimazole is the first-line treatment for hyperthyroidism.

Propylthiouracil is the preferred treatment for thyroid storm and for hyperthyroidism in pregnant women.

Iodine can be used as adjunctive therapy.

Beta blockers, especially propranolol, are used to treat the symptoms of hyperthyroidism.

Mechanism of action

Thioamides inhibit the thyroid peroxidase, the enzyme which catalyses the addition of iodine onto thyroglobulin. Carbimazole is a prodrug which is metabolised into methimazole. Propylthiouracil also inhibits the peripheral conversion of T4 to T3.

High amounts of iodine (300 – 600 mg daily) inhibits the proteolytic cleavage of T3 and T4 from thyroglobulin.

Pharmacokinetics

Methimazole has 100% oral bioavailability, negligible plasma protein binding and a half-life of 4 – 6 hours. Propylthiouracil has 50 – 70% oral bioavailability, significant plasma protein binding and a half-life of 75 minutes. Both are metabolized in the liver and excreted by the kidneys.

Propylthiouracil doesn’t significantly cross the placenta and is therefore the drug of choice in pregnant women. It also acts quicker and is therefore the choice in thyroid storm, when it should be given IV. However, due to the unfavourable pharmacokinetics and the side effects it’s not a first choice for non-pregnants.

The thioamides take 3 – 4 weeks to have effect. Iodine has effect within a week.

Adverse effects

  • Thioamides
    • Hypersensitivity reactions
      • More common with methimazole
      • Rash
      • Rarely severe
    • Agranulocytosis
      • Rare
    • Hepatotoxicity
      • Only with propylthiouracil
    • Teratogenicity
      • Only with methimazole
    • Goitre
      • Due to increased TSH
  • Iodine
    • Side effects are rare and mild
    • Hypersensitivity reactions
    • Fever
  • Perchlorate
    • Agranulocytosis

Radioiodine ablation

Radioiodine ablation uses radioactive iodine (I131) to destroy the excess thyroid tissue. This isotope only gives off beta radiation, which penetrates only 0.5 mm into tissues. The radioactive iodine is taken up by the thyroid and the beta radiation will destroy only parts of the thyroid.

Patients should be euthyroid before the procedure. This can be accomplished with the antithyroid drugs outlined above.