Thyroid andAnti-thyroid Drugs

Ass. Prof. Dr. Naza M. AliLec 3-414 Nov 2019

Objectives:

• Thyroid physiology and function

• Regulation of synthesis

• Biosynthesis of thyroid hormones

• Mechanism of action

• Pharmacokinetics

• Hypothyroidism and treatment

• Hyperthyroidism and treatment

Thyroid Gland Physiology

• Consists of two lobes & is situated in the lower

neck

• Both T4 & T3 are produced within the follicular

cells in the thyroid.

• The gland is made up of multiple follicles that

consist of a single layer of epithelial cells

surrounding a lumen filled with thyroglobulin,

which is the storage form of thyroid hormone.

Consists of two lobes & is situated in the lower neck

Thyroid gland

• Thyroid hormones are :

➢ Triiodothyronine ( T3 most active )

➢ Tetraiodothyronine ( T4 )

• These hormones contain 59% and 65% of iodine as an essential part of the molecule.

➢ Calcitonin hormone is important in the regulation of calcium metabolism

• Regulation of hormone

synthesis is by TSH

from the anterior

pituitary.

• TSH is regulated by

hypothalamic secretion

of TRH

Regulation of Hormone Synthesis

• Feedback inhibition of TRH occurs with high

levels of circulating thyroid hormone.

• At pharmacologic doses, dopamine,

somatostatin, or glucocorticoids can also

suppress TSH secretion

• Most of T3 and T4 is bound

to thyroxine-binding globulin in the plasma.

Biosynthesis of Thyroid Hormones

• Once taken up by the thyroid gland,

• iodide undergoes a series of enzymatic reactions that incorporate it into active thyroid hormone

1. The first step is the transport of iodide into the thyroid gland by the sodium/iodide symporter (NIS).

• This can be inhibited by thiocyanate (SCN−)

2. Oxidation to iodine ( I2 ) by a peroxidase

3. Followed by iodination of tyrosines on thyroglobulin.

4. Condensation of two diiodotyrosine residues gives rise to T4,

whereas condensation of a monoiodotyrosine residue with a

diiodotyrosine residue generates T3

5.The hormones are released following proteolytic cleavage of the thyroglobulin.

Biosynthesis of thyroid hormones

Mechanism of action of thyroid hormone

• Most circulating T3 & T4 is bound to thyroxine-binding globulin in the plasma.

• The hormones must dissociate from thyroxine-binding globulin prior to entry into cells.

Mechanism of action of thyroid hormone

• In the cell, T4 is enzymatically deiodinated to T3, which enters the nucleus and attaches to specific receptors.

• The activation of these receptors promotes the formation of RNA and subsequent protein synthesis, which is responsible for the effects of T4

Pharmacokinetics

• Both T4 and T3 are absorbed after oral administration.

• Food, calcium preparations, iron salts, and aluminum containing antacids can decrease the absorption of T4 .

• Deiodination is the major route of metabolism of T4.

• T3 also undergoes sequential deiodination.

• The hormones are also metabolized via conjugation with glucuronides and sulfates and excreted into bile.

• Thyroxine should be administered on an empty stomach ( 60 minutes before meals, or at bedtime).

• Drugs that induce the P450 enzymes:

Phenytoin,

Rifampin,

Phenobarbital

accelerate metabolism of thyroid hormones

Hypothyroidism

• A deficiency of thyroid hormones and a reversible

slowing down of all body functions

• In infants and children, there is striking retardation

of growth and development that results in dwarfism

and irreversible mental retardation.

• Hypothyroidism can occur with or without thyroid

enlargement (goiter).

• The laboratory diagnosis is made by the combination of

low free thyroxine and elevated serum TSH levels

• The most common cause of hypothyroidism is

Hashimoto’s thyroiditis, an immunologic disorder

In hypothyroidism

• bradycardia,

• poor resistance to cold,

• mental and physical slowing (In children, this can cause mental retardation and dwarfism).

Treatment of hypothyroidism

• It is treated with levothyroxine (T4)

• is given once daily because of its long half-life.

• Steady state is achieved in 6 to 8 weeks.

• Dosage will vary depending on age and weight.

• Infants and children require more T4 per kilogram

of body weight than adults.

Toxicity

• Nervousness, heart palpitations and tachycardia,

intolerance to heat, weight loss.

Special Problems in Management of Hypothyroidism

Myxedema Coma

• is an end state of untreated hypothyroidism.

• is a medical emergency, treated in the intensive care unit

• treatment of choice is to give a loading dose of

levothyroxine IV 300–400 mcg initially,

followed by 50–100 mcg daily

Hypothyroidism and Pregnancy

• Hypothyroid women have anovulatory cycles

• So the widespread use of thyroid hormone for infertility

• In a pregnant hypothyroid patient receiving thyroxine,

• It is important that the daily dose of thyroxine be

adequate because early development of fetal brain

depends on maternal thyroxine .

Hyperthyroidism (thyrotoxicosis)

• Is the clinical syndrome that results when tissues are exposed to high levels of thyroid hormone

• Most patients T3 & T4 are elevated / TSH is suppressed

• Tachycardia , cardiac arrhythmias,

• Body wasting,

• Nervousness,

• Tremor,

• Excess heat production

Graves disease

• An autoimmune disease that affects the thyroid, is the most common cause of hyperthyroidism.

• which a defect in suppressor T lymphocytes stimulates B lymphocytes to synthesize antibodies to thyroidal antigens.

Treatment of hyperthyroidism

The goal of therapy is to decrease synthesis and/or release of additional hormone.

• This can be accomplished by:

I. Removing of the thyroid gland

II. Inhibiting of thyroid synthesis

III. Blockade of hormones release from the follicle.

I. Removal of the thyroid:

• either surgically or by destruction of the gland

• by radioactive iodine 131

I

• is selectively taken up by the thyroid follicular cells.

• Most patients become hypothyroid as a result and

require treatment with levothyroxine.

II. Inhibition of thyroid hormone Synthesis:

• The thioamides, methimazole & propylthiouracil are cocentrated in thyroid

• Carbimazole, which is converted to methimazole

• Methimazole is the drug of choice in adults and children.

Mechanism of action of PTU & methimazole

• They inhibit both:

➢ the oxidative processes required for iodination

of tyrosyl groups and

➢the condensation (coupling) of iodotyrosines to

form T3 and T4

➢PTU also inhibit peripheral deiodination

T4 & T3

• PTU & methimazole are concentrated in the

thyroid

• [These drugs have no effect on the

thyroglobulin already stored in the gland].

• Observation of any clinical effects of these drugs may be delayed until thyroglobulin stores are depleted.

• The thioamides are well absorbed from GIT

• they have short half-lives.

• PTU is given each 6-8 hours

• Methimazole is administered in 3 equally divided doses each 8-hour intervals.

• Both thioamides cross the placental barrier and are concentrated by the fetal thyroid

• Because of the risk of fetal hypothyroidism, both thioamides are classified as FDA pregnancy category D.

• PTU is preferable during the first trimester of pregnancy because it is more strongly protein-bound.

• PTU should be reserved for use during the first

trimester of pregnancy.

• Due to a black box warning about severe hepatitis

• Carbimazole is associated with congenital malformations:

aplasia cutis (skin defect).

• Both thioamides are secreted in low concentrations in breast milk

• are considered safe for the nursing infant.

Adverse effects:

• Agranulocytosis, rash, and edema.

• liver toxicity or liver failure

Thyroid storm

• Presents with extreme symptoms of hyperthyroidism.

• The therapeutic options for thyroid storm

are the same as those for hyperthyroidism,

except that the drugs are given in higher

doses and more frequently.

• β-Blockers ( propranolol) are effective

• IV is effective in treating thyroid storm.

• An alternative in patients suffering from severe heart failure or asthma is the calcium-channel blocker, diltiazem.

• Other agents used in the treatment of thyroid storm include:

• PTU,

• iodides,

• iodinated contrast media (which rapidly inhibits the conversion of T4 to T3) and glucocorticoids (to protect against shock).

III. Blockade of Hormone Release:

• A pharmacologic dose of iodide inhibits the iodination of tyrosines ,

• but this effect lasts only a few days.

• iodide inhibits the release of thyroid hormones from thyroglobulin by mechanisms not yet understood.

• It is used to treat potentially fatal

thyrotoxic crisis (thyroid storm) or

prior to surgery, because it decreases

the vascularity of the thyroid gland.

• Iodide is not useful for long-term

therapy, because the thyroid ceases to

respond to the drug after a few weeks.

• Iodide is administered orally.

Adverse effects

• Sore mouth and throat,

• Swelling of the tongue or larynx,

• Rashes, ulcerations of mucous membranes

• A metallic taste in the mouth.

Thyrotoxicosis during pregnancy

• Treated with PTU with a dose of a minimum necessary for control of the disease (< 300mg/ d) , because it may effect the fetal thyroid gland.

• Methimazole is an alternative but possible fetal scalp defects.

Amiodarone-Induced Thyrotoxicosis

• About 3% of patients receiving will develop hyperthyroidism .

Two types of amiodarone-induced thyrotoxicosis

• Iodine-induced (type I)

• An inflammatory thyroiditis (type II) that occurs in patients without thyroid disease due to leakage of thyroid hormone into the

circulation.

Treatment of type I requires therapy with thioamides,

while

type II treatment responds best to glucocorticoids.

• it is not always possible to differentiate between the two types,

• thioamides and glucocorticoids are often administered together.