Drugs used in thyroid disorders and their mechanism of action

1. Dr. Aqsa Mushtaq
R.Ph. Ph.D Pharmacology
Department of Pharmacology
Dow College of Pharmacy

2. Drugs that inhibit thyroid hormone production
Thioamides
Propylthiouracil
•Mathimazole
Anion Inhibitors
Thiocyanate Ion
•Perchlorate Ion
Iodides
Radioactive Iodine
Anti-thyroid drugs
Mechanism of Action
inhibition of iodide transport
Inhibition of organification and
coupling
Inhibition of hormone release
Inhibition of deiodinated of T4 to T3
Compound
Perchlorate
Thioamides
(propylthiouracil,methimazole)
Iodide
Thioureylenes (propylthiouracil)
•b-adrenergic receptor blockers
•Glucocorticoids
ANTITHYROID DRUGS

3. ANTITHYROID DRUGS MECHANISM
OF ACTION

4. Anion Inhibitors(Thiocyanate Ion & Perchlorate
Ion)
Mechanism of Action:
 Competitive inhibition----Inhibition of the Iodide Trapping Mechanism
 Thyroglobulin formation is not stopped--only prevents its iodination--no thyroid hormone
Adverse effect:
 Thyroid hormone secretion decrease ---increase secretion of TSH---overgrowth of thyroid
gland --cause Goiter
 Rarely used due to its association with Aplastic anemia
Thioamides (Propylthiouracil & Methimazole)
Mechanism of Action:
 blocks iodine organification (the major mechanism of action)
 blocks coupling of iodotyrosines
 inhibits the peripheral deiodination of T4 to T3 (only PTU)
 Methimazole ~10 times more potent than propylthiouracil (PTU)
Indication:
 thyrotoxicosis (high doses must be used if used to treat thyroid storm)

5. Drug Route of
administration
Oral absorption Plasma protein
binding
Propylthiouracil Oral Good 82%
Methimazole Oral Good 8%
Pharmacokinetics:
Since synthesis rather than release of thyroid hormone is effected, there is a slow
onset of observable effects, often taking 3-4 weeks before stores of T4 are depleted
Side Effects:
 rash (common)
 Edema
 Agranulocytosis (rare, 0.1-0.5%), usually reversible upon drug withdrawal
 hepatitis (rare, but potentially fatal)
 cholestatic jaundice (rare,but potentially fatal); more common with methimazole)
 nausea, GI distress, altered taste or smell
Pregnancy:
 PTU is more strongly protein-bound compared to methimazole, and therefore PTU is
preferred in pregnancy if either are indicated for treatment of maternal hyperthyroidism

6. Inorganic Iodides (in high concentration)
Mechanism of Action:
 A major action of iodide is to inhibit hormone release from the thyroid gland. This may result
from inhibition of thyroglobulin proteolysis (which is necessary for production or
excocytosis of thyroid hormones)
 Interferes with the synthesis of thyroid hormones by inhibiting thyroidal peroxidase inside the
thyroid gland
 The thyroid gland will “escape” from iodide block in 2-8 weeks.
Indications:
 Hyperthyroidism & thyroid storm: Graves' disease, toxic adenoma, goiter, thyroiditis
 Used prior to thyroid gland surgery to decrease the vascularity of the thyroid gland
Contraindications:
 Pregnancy - iodide can cross the placenta & cause fetal goiter.
Side Effects:
 acne-like rash
 metallic taste in the mouth
 swollen salivary glands
 ulcerations of mucous membranes (sore mouth)
 conjunctivitis

7. Radioactive Iodine
( Sodium Iodide 131 ®)
Mechanism of Action:
 I-131 is rapidly absorbed & is concentrated in the thyroid where it is incorporated into
storage follicles
 It's therapeutic effect depends on emission of beta rays (Penetration range-400-2000µm
)with an effective half-life of ~56 days
 Beta particles act on secretary cells of thyroid gland with little damage to surrounding
tissue
Indications: dose
 Radioactive iodide uptake test to evaluate thyroid function
 Thyrotoxicosis - multinodular hyperthyroidism & toxic adenomas
Contraindications:
 Children, pregnancy or nursing mothers
Side Effects:
 delayed hypothyroidism
Iodine131 Advantages
 Easy administration
 Effectiveness
 Low expense
 Absence of pain

8. Thyroid dysfunctions
 Hyperthyroidism
Hyperthyroidism is a condition in which an overactive thyroid gland is
producing an excessive amount of thyroid hormones that circulate in the
blood. ("Hyper" means "over" in Greek). This may cause the “speeding-up”
of metabolic activity in body cells.
 Hypothyroidism
Hypothyroidism is a condition characterized by abnormally low thyroid
hormone production. There are many disorders that result in hypothyroidism.
These disorders may directly or indirectly involve the thyroid gland.

10. Hyperthyroidism Causes
Some common causes of hyperthyroidism include:
 Graves' Disease
 Functioning adenoma ("hot nodule") and toxic
multinodular goiter (TMNG)
 Excessive intake of thyroid hormones
 Abnormal secretion of TSH
 Excessive iodine intake
 Thyroiditis (inflammation of the thyroid gland)
• can lead to the release of excess amounts of thyroid hormones that are
normally stored in the gland.
• the painful inflammation of the gland is believed to be caused by a virus,
and the hyperthyroidism lasts a few weeks

11. Graves' Disease
 Most common cause of hyperthyroidism
 Graves' disease is often called diffuse
toxic goiter because the entire thyroid gland is
enlarged, usually moderately enlarged,
sometimes quite big.
 Graves' disease tends to run in families
 Graves' disease is uncommon over the age of
50 (more common in the 30s and 40s)
 Graves' disease is an Autoimmune disease
 Up to five times more common among females
than males.
 The triggers for Graves' disease include
stress, smoking, radiation to the neck,
medications, and infectious organisms such as
viruses.
 Immunoglobin Antibody—continual activation
of cAMP system of cells—development of
hyperthyroidism—called Thyroid Stimulating
Immunoglobulin (TSI)—prolonged stimulating
effect on thyroid gland lasting for 12 hours (1
hour for TSH)

12. Exophthalmos
 Graves' disease may be
associated with eye disease,
Exophthalmos
 Cause of protruding eyes is
edematous swelling of Retro-
orbital tissues & degenerative
changes in extraocular muscles.
 Eyes become dry, irritated &
infected.

13. Functioning Adenoma and Toxic
Multinodular Goiter
 Hyperthyroidism can also be caused by a single nodule
within the thyroid instead of the entire thyroid.
 thyroid nodules usually represent benign (non-cancerous) lumps
or tumors in the gland. These nodules sometimes produce
excessive amounts of thyroid hormones. This condition is called
"toxic nodular goiter."
 The picture on the right is an iodine scan (also simply called a
thyroid scan)
 This scan is abnormal because a solitary "hot" nodule is located in
the lobe on the left. This single nodule is comprised of thyroid
cells which have lost their regulatory mechanism that dictates how
much hormone to produce.
 the nodule is larger than 3 cm. When there is
 a single nodule that is independently producing thyroid
hormonesm called a functioning nodule.
 If there is more than one functioning nodule, the term toxic
multinodular goiter is used.
 Functioning nodules may be readily detected with a thyroid scan.

14. Symptoms & Diagnosis
Diagnostic tests for
hyperthyroidism
 Direct measurement of
concentration of free thyroxine in
plasma –radioimmunoassay
procedure
 concentration of TSH in plasma—
thyrotoxicosis case—comletely
supressed
 Concentration of TSI is measured by
radioimmunoassay—high in
thyrotoxicosis—low in thyroid
adenoma
 a thyroid scan using radioactively-
labelled iodine (which concentrates
in the thyroid gland) can help
diagnose the underlying thyroid
disease.

15. Treatment of hyperthyroidism
The options for treating hyperthyroidism include:
 Antithyroid drugs
 Radioactive iodine
 Surgery
o The most direct treatment for hyperthyroidism—
surgical removal of most of thyroid gland.
o Prepare patient for surgical removal of gland:
o By administering Propylthiouracil for several
weeks—until basal metabolic of patient rate has
returned to normal
o Then high Concentration of iodides for 1 to 2 weeks
administered immediately before operation

16. Causes of Hypothyroidism
 Hashimoto's thyroiditis
 Lymphocytic thyroiditis (which may occur after hyperthyroidism)
 Endemic colloid goiter
 cretinism
 Thyroid destruction (from radioactive iodine or surgery)
 Pituitary or hypothalamic disease
 Abnormality of enzyme system (thyroid gland)
o Deficient iodide-trapping mechanism
o Deficient peroxidase system
o Deficiency of deiodinase enzyme
o Deficient coupling of iodinated tyrosine
 Medictions e.g. goitrogenic substances

17. Hashimoto's Thyroiditis
 common cause of hypothyroidism in the United States—inherited
condition
 the thyroid gland is usually enlarged (goiter)—decreased ability to make
thyroid hormones.
 an autoimmune disease in which the body's immune system
inappropriately attacks the thyroid tissue.
 5 to 10 times more common in women than in men.
 Blood samples drawn from patients with this disease reveal an
increased number of antibodies to the enzyme, thyroid peroxidase (anti-
TPO antibodies).
 Hashimoto's can be identified by detecting anti-TPO antibodies in the
blood and/or by performing a thyroid scan.

18. Lymphocytic thyroiditis
 Thyroiditis refers to inflammation of the thyroid gland.
 inflammation is caused by a particular type of white blood cell known as a
lymphocyte, the condition is referred to as lymphocytic thyroiditis.
 particularly common after pregnancy and can actually affect up to 8% of
women after they deliver.
 there is usually a hyperthyroid phase (in which excessive amounts of
thyroid hormone leak out of the inflamed gland)—followed by a
hypothyroid phase that can last for up to six months.
 The majority of affected women eventually return to a state of normal
thyroid function, although there is a possibility of remaining hypothyroid.

19. Endemic Colloid Goiter
 Caused by dietary iodide deficiency (0mg of iodine/year)
 Insufficient iodide—in soil for foodstuffs—even minute quantity—certain areas
of world Andes & Great Lakes region of US.
 Thyroid hormone secretion decrease –increase secretion of TSH—stimulates
thyroid cells to secrete large amount of Thyroglobulin colloid into follicles—
overgrowth of thyroid gland—cause Goiter(thyriod gland size increase 10-20
times)
Cretinism:
 Caused by extreme hypothyroidism during fetal life, infancy or childhood.
 Failure of body growth & mental retardation
 Types:
 Congenital cretinism
 Endemic cretinism

20. Symptoms & Diagnosis
Myxedema:
• Almost total lack of thyroid hormone funtion
• Bagginess under eyes & swelling of face
• Increased quantities of hyaluronic acid & chondrointin sulfate—bound with
protein—excessive tissue gel in interstitial spaces—intrestitial fluid to increase—
immobile edema is nonpitting type
Diagnostic tests for
hyperthyroidism:
 Free thyroxine in blood is low
 Basal metabolic rate in myxedema
ranges between -30 to -50
 Increase TSH secretion

21. Treatment of hypothyroidism
 Hormone replacement therapy
 Thyroid Dosage specific to individual and is determined by their TSH serum
levels.
 Typically 1.5µg T4 per kg body weight.
 Administering too high of a dosage leads to hyperthyroid symptoms
Drug Route of
administration
Oral
absorption
Half-
Life(euthyroid
state)
Disposition Plasma
protein
binding
Thyroxine (T4) Oral, IV Fair (50%-
80%)
7 days Metabolism,
enterohepatic
circulation
>99%
Triiodothyronine
(T3)
Oral Good 24 hours Metabolism,
enterohepatic
circulation
>99%