Drugs used in the treatment of thyroid disorders – Pharmacology

What is the largest endocrine gland?

Thyroid gland

What is an enlarged thyroid gland called?

Goiter

What is the functional unit of the thyroid gland?

Follicle (acinus)

Describe the structure of a thyroid follicle.

A cavity surrounded by epithelial cells and filled with thick colloid called thyroglobulin

What is thyroglobulin?

A large glycoprotein present in thyroid follicular colloid

How many tyrosine residues does a thyroglobulin molecule contain?

115 tyrosine residues

Which thyroid hormones are produced by thyroid follicles?

Triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine)

Which cells produce calcitonin?

Parafollicular C cells

What is the function of calcitonin?

Regulates calcium metabolism

What are the major steps in thyroid hormone synthesis?

Uptake of plasma iodide, oxidation of iodide and iodination of tyrosine residues of thyroglobulin, coupling, secretion of thyroid hormone, peripheral conversion of T4 to T3

How do thyroid hormones exert their effects?

T3/T4 bind to nuclear thyroid hormone receptors (TR) to induce or repress T3-target gene expression

What is the role of TRE in thyroid hormone action?

Thyroid hormone response element that mediates regulation of gene expression by TR-bound thyroid hormones

How do T3 and T4 regulate their own secretion?

Through negative feedback on the hypothalamic-pituitary-thyroid axis

What is the Wolff-Chaikoff effect?

High intracellular iodine prevents release of thyroid hormones and inhibits the Na/I pump

What are the main physiological functions of thyroid hormones?

Growth and development, metabolic and calorigenic effects, cardiovascular effects, CNS effects

Why do hyperthyroid patients develop heat intolerance, tremor, palpitations and nervousness?

Increased sensitivity to catecholamines

Define hypothyroidism.

A condition where there is deficiency of thyroid hormones

What are the key symptoms of hypothyroidism?

Weight gain, cold intolerance, easy fatigability, constipation, muscle cramps, menorrhagia, depression

What are the key physical signs of hypothyroidism?

Coarse rough dry skin, puffy face/hands/feet (myxedema), hoarse voice, slow reflexes, possible goiter, muscle weakness, bradycardia

What is myxedema?

Puffy face, hands and feet seen in hypothyroidism

How is hypothyroidism treated?

By replacing deficient thyroid hormones with levothyroxine (T4) or liothyronine (T3)

What are the thyroid hormone replacement drugs?

Levothyroxine (T4) and liothyronine (T3)

Why is liothyronine (T3) used less frequently than levothyroxine (T4)?

More expensive, shorter half-life, requires multiple daily doses, more difficult to monitor, and T4 is converted intracellularly to T3

What is the route of administration of liothyronine (T3)?

Oral or parenteral

What is the half-life of liothyronine (T3)?

Approximately 24 hours

What happens to serum T3 levels after liothyronine administration?

Serum T3 rises quickly

How is levothyroxine activated in tissues?

Converted intracellularly to liothyronine (T3) by deiodinases

Why is levothyroxine the drug of choice for chronic hypothyroidism?

Lower cost, longer half-life and prolonged duration of action

What is the route of administration of levothyroxine?

Oral

What is the half-life of levothyroxine?

Approximately 7 days

What is a pharmacokinetic advantage of levothyroxine over liothyronine?

Increase in serum T3 is not rapid, producing prolonged action

What is the oral absorption of T4?

50-80%

What is the oral absorption of T3?

95%

How is T4 metabolized?

Peripheral deiodination (80%) and hepatic metabolism (20%)

How is T3 metabolized?

Deiodination (90%) and hepatic metabolism (10%)

Which hormone has a greater free fraction in circulation, T3 or T4?

T3 is more in free form compared with T4

Which thyroid hormone replacement drug is preferred in elderly and cardiac patients?

Levothyroxine (T4)

Which thyroid hormone replacement drug may be useful in myxedema coma?

Liothyronine (T3)

How is thyroid replacement therapy monitored?

By serum TSH levels

How long does TSH take to return to euthyroid levels after treatment?

About 4 weeks

What adverse effects can occur with levothyroxine or liothyronine overreplacement?

Symptoms resembling hyperthyroidism including nervousness, anxiety, tremor, heat intolerance, weight loss with increased appetite, arrhythmias and palpitations

What is a contraindication to liothyronine (T3)?

Heart disease due to cardiotoxicity risk

What are the characteristic symptoms of hyperthyroidism?

Weight loss with increased appetite, heat intolerance and sweating, palpitations, fatigue, weakness, diarrhea, polyuria, amenorrhea/oligomenorrhea

What are the characteristic physical signs of hyperthyroidism?

Tachycardia, atrial fibrillation in elderly, tremor, goiter, warm moist skin, muscle weakness, thyroid eye disease, hair loss

How can hyperthyroidism be treated by reducing functional thyroid tissue?

Thioamides, iodides, radioactive iodine, or surgery

How can sympathetic overstimulation be reduced in hyperthyroidism?

Non-selective beta blockers

Which drugs are classified as thioamides in this lecture?

Carbimazole and propylthiouracil (PTU)

What is the major mechanism of action of thioamides?

Inhibit thyroid peroxidase-catalyzed reactions and block iodine organification

What additional step of thyroid hormone synthesis is inhibited by thioamides?

Coupling of iodotyrosines

Do thioamides affect release of preformed thyroid hormones?

No, they have no effect on release of preformed hormones already synthesized and stored in colloid

Which thioamide inhibits peripheral conversion of T4 to T3?

Propylthiouracil (PTU)

Which enzyme involved in peripheral T4 to T3 conversion is inhibited by PTU?

Deiodinase D1

How is carbimazole absorbed?

Well absorbed orally

What is the half-life of carbimazole?

4-6 hours

How is carbimazole usually dosed?

Once daily

How is PTU absorbed?

Incompletely absorbed

What is the half-life of PTU?

1-2 hours

How is PTU usually dosed?

Every 6-8 hours

Why is carbimazole preferred over PTU?

About 10 times more potent, slower metabolism, longer half-life, and once-daily dosing

How long does it take thioamides to produce a euthyroid state?

3-6 weeks after onset of therapy

Why does it take weeks for thioamides to produce a euthyroid state?

They inhibit new hormone synthesis but do not affect release of preformed hormones stored in colloid

How long may be required to achieve remission with thioamide therapy?

Several months (18-24 months) of therapy

What is the relapse rate after thioamide therapy?

Greater than 50%

What is the drug of choice for Graves' hyperthyroidism?

Carbimazole

Why is carbimazole preferred in Graves' hyperthyroidism?

Longer duration of action and more rapid achievement of euthyroid state

Why is PTU preferred in thyroid storm?

It blocks peripheral conversion of T4 to T3

Why is PTU preferred in pregnancy?

Less freely crosses the placenta than methimazole and is less associated with increased birth defects

What is the most common adverse effect of thioamides?

Maculopapular rash (4-6% of patients)

What is the most serious adverse effect of thioamides?

Agranulocytosis

What is the incidence of thioamide-induced agranulocytosis?

0.1-0.5%

Is thioamide-induced agranulocytosis reversible?

Usually reversible after discontinuation of the drug

What monitoring is recommended in patients receiving thioamides?

Bone marrow status monitoring

Which thioamide is more commonly associated with hepatitis?

PTU

Why is carbimazole contraindicated in nursing mothers?

It is found in breast milk

What is the pregnancy risk category of carbimazole?

Category D

Why is carbimazole contraindicated in pregnancy?

Crosses the placenta, causes fetal hypothyroidism, and is associated with congenital malformations

Which iodide preparations are discussed in the lecture?

Saturated solution of potassium iodide (SSKI) and Lugol's solution

What is the major mechanism of action of iodides in hyperthyroidism?

Inhibit release of thyroid hormones from the thyroid gland via the acute Wolff-Chaikoff effect

How do iodides affect thyroid hormone synthesis?

Inhibit thyroidal peroxidase within the thyroid gland

Why are iodides only given for a few days?

The thyroid gland escapes from iodide block in 2-3 weeks

What are the indications for iodides?

Hyperthyroidism, thyroid storm, Graves' disease, goiter, and preoperative reduction of thyroid vascularity

Are iodides commonly used as sole therapy for hyperthyroidism?

No, they are rarely used as sole therapy

Why are iodides used before thyroid surgery?

To decrease vascularity of the thyroid gland

What is the major contraindication to iodide therapy?

Pregnancy

Why are iodides contraindicated in pregnancy?

They cross the placenta and can cause fetal goiter

What are the adverse effects of iodides?

Acne-like rash, swollen salivary glands, ulcerations of mucous membranes, sore mouth, conjunctivitis

What beta blocker is specifically mentioned for symptomatic management of hyperthyroidism?

Propranolol

How does propranolol help hyperthyroid patients?

Blunts sympathetic stimulation and provides symptomatic relief

Why are non-selective beta blockers preferred in hyperthyroidism?

They relieve increased cardiac activity, hypermetabolic state, and related symptoms

How is radioactive iodine (131I) administered?

Oral administration

What happens to radioactive iodine after administration?

Rapidly absorbed and concentrated in the thyroid gland

How does radioactive iodine destroy thyroid tissue?

Emits beta rays that destroy thyroid parenchyma

What percentage of radioactive iodine is excreted in urine?

Up to 80%

When are clinical benefits of radioactive iodine first seen?

6-12 weeks

How long does it take for radioactive iodine-treated patients to become euthyroid?

4-6 months

What are the advantages of radioiodine therapy?

Usually effective with a single dose, very low relapse/failure rate, and safe

What are the disadvantages of radioiodine therapy?

Requires special facilities and post-treatment precautions

What precautions are required after radioiodine therapy?

Avoid close contact for about 2 weeks, especially during the first 48 hours

Who should not receive radioactive iodine therapy?

Pregnant women, lactating mothers, and children

What is the most important adverse effect of radioactive iodine therapy?

Hypothyroidism