Thyroid and Antithyroid Drugs

Anatomy of the Thyroid Gland

 The thyroid gland is located anterior and caudal to the cartilages of the
larynx and situated in the lower part of the front and sides of the neck.
 It is the largest endocrine gland in adults.
 It is a small, butterfly-shaped bilateral organ with 2 lobes. Each lobe is about
4 cm long.
 The normal weight of a nongoitrous adult thyroid is about 20 g, depending
on body size and iodine supply.
 Thyroid glandular tissue is comprised of spherical follicles that vary in size.
Each follicle is lined with follicular epithelium that encircle the inner colloid
space (colloid lumen).
• The thyroid gland is supplied by the superior and the inferior thyroid arteries.
• The thyroid follicles are the functional, secretory units of the thyroid gland; are multiple, variable-
sized, formed by a single layer of epithelial cells.
• Follicular cells (thyroid epithelial cells) produce thick, protein colloid that fills the lumen.
• Colloid serves as store house of materials for thyroid hormone production & is composed primarily
of thyroglobulin (Tg), Thyroglobulin is a high-molecular weight glycoprotein that facilitates the
assembly of thyroid hormones within the thyroid follicular lumen.
• The amino acid tyrosine, which is incorporated within the molecular structure of Tg,1 becomes
iodinated.
• Iodine is bound to tyrosine residues in Tg at the apical surface of the follicle cells to form, in turn,
monoiodotyrosine (MIT) and diiodotyrosine (DIT).
• MIT and DIT combine to form the 2 biologically active thyroid hormones, thyroxine (T4) and
triiodothyronine (T3).
• In addition to providing the matrix for thyroid hormone synthesis, the Tg molecule also stores a
large supply of iodine and thyroid hormone for secretion at a steady rate or on demand.

Normal human thyroid secretes 60-90 micrograms of T4 and 10-30 micrograms of T3 daily.
Calcitonin is produced by interfollicular C cells; chemically and biologically different from T3 and T4.
 Thyroid Hormones
•Two biologically active hormones types released:
• Thyroxine (tetraiodothyronine) and triiodothyronine
• Calcitonin

Two principal hormones:

• Thyroxine (T4 ) and triiodothyronine (T3) is required for homeostasis of all cells
• Normal thyroid function is required for the maintenance of pregnancy and lactation.
• Influence cell differentiation, essential for normal growth and development, and
metabolism, maintaining normal body temperature
• Considered the major metabolic hormones because marked effect on lipid, carbohydrate,
and protein metabolism
• responsible for increasing the Basal Metabolic Rate (BMR) by stimulation of cellular
metabolism
 CALCITONIN
• The plasma calcium level is precisely regulated by 3
hormones; parathormone, calcitonin and calcitriol.
These regulators control its intestinal absorption,
exchange with bone and renal excretion.
• Calcitonin is a 32 amino-acid single chain polypeptide
produced by parafollicular cells.
• Synthesis and secretion of calcitonin is regulated by
plasma Ca2+ concentration itself; rise in plasma
calcium increases while fall in plasma calcium
decreases calcitonin release.
• The physiological role of calcitonin in regulating
plasma calcium appears to be minor.
 ACTIONS OF THYROID HORMONES
• Calcitonin inhibits bone resorption by direct action on osteoclasts-
decreasing their ruffled surface which forms contact with the resorptive
cell.
• As the level of calcium in the blood rises, the amount of calcitonin secreted
by the C cells of the thyroid increases. Calcitonin stimulates osteoblasts to
form bone taking calcium out of the circulation. At the same time,
calcitonin inhibits the mobilization of bone (and calcium) by osteoclasts.
The end result is a decrease in the level of calcium in the blood thus helping
to maintain proper blood calcium levels.
Thyroid Hormones

• Thyroid hormones are unique biological molecules, in that, they

incorporate iodine in their structure.
• Thus, adequate iodine intake (diet, water) is required for normal
thyroid hormone production.
• These hormones contain 59% (T3) and 65% (T4) of iodine as an
essential part of the molecule.
• Calcitonin, the second type of thyroid hormone, is important in the
regulation of calcium metabolism .
Mechanism of action

• Both T4 and T3 must dissociate from thyroxine-binding plasma

proteins prior to entry into cells, either by diffusion or by active
transport.
• 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, and aluminum-containing antacids can
decrease the absorption of T4 but not of T3.
• T4 is converted to T3 by deiodinases
• The hormones are metabolized through the microsomal P450 system,
conjugation with glucuronides and sulphate and excreted into bile
 IODINE METABOLISM
•Dietary iodine is absorbed in the GI tract, then taken up by the thyroid
gland (or removed from the body by the kidneys).
•The transport of iodide into follicular cells is dependent upon a Na+/I-
cotransport system.
•Iodide taken up by the thyroid gland is oxidized by peroxide in the lumen
of the follicle:

• Oxidized iodine (I2) undergoes iodination of tyrosines on thyroglobulin

which is used in production of thyroid hormones.
 Thyroid-Stimulating Hormone (TSH)

• TSH regulates thyroid hormone production and secretion

• Pituitary produces TSH, which binds to follicle cell receptors.
• The follicle cells of the thyroid produce thyroglobulin. Thyroglobulin is
released into the colloid space, where it’s tyrosine residues are
iodinated by I+.
• This results in tyrosine residues which have one or two iodines attached
(monoiodotyrosine or diiodotyrosine).
• Secretion of TSH by the pituitary is stimulated by hypothalamic TRH.
Feedback inhibition of TRH occurs with high levels of circulating
thyroid hormone (T4 and T3 ).
• As blood concentrations of thyroid hormones increase, they inhibit both
TSH and TRH, leading to "shutdown" of thyroid epithelial cells.
• Consequently, when blood levels of thyroid hormone have decayed, the
negative feedback signal diminishes, and the system wakes up again.
Biosynthesis of T4 and T3
• The process includes
• Dietary iodine (I) ingestion
• Active transport and uptake of iodide (I-) by thyroid gland
• Oxidation of I- to I+ then I2 and iodination of thyroglobulin (Tg) tyrosine residues
• Coupling of iodotyrosine residues (MIT and DIT) to form T4 and T3
• Proteolysis *of Tg with release of T4 and T3 into the circulation

• * =(degradation of proteins)
Iodine Sources

• Available through certain foods (eg, seafood, bread, dairy products),

iodized salt, or dietary supplements, as a trace mineral. shellfish
• The recommended daily adult iodide (I–)* intake is 150 mcg (200 mcg
during pregnancy).
THYROID DISORDERS
What does the thyroid gland do?
• The primary function of the thyroid gland is to control body’s metabolism.
• A normal thyroid gland would maintain correct levels of thyroid hormones in
the body.
• The regulation of thyroid hormones is done by the anterior pituitary and the
hypothalamus. (Recall – Negative feedback)
• Women are 5 – 8 times more likely to get affected than men.
• When the thyroid produces too much hormone the body uses energy faster
than it should – Hyperthyroidism.
• When the thyroid doesn’t produce enough hormone – the body uses energy
slower than it should – Hypothyroidism.
Overview of Thyroid Disease States

• Hypothyroidism
• Hyperthyroidism
Hypothyroidism
Hypothyroidism is a disorder with multiple causes in which the thyroid
fails to secrete an adequate amount of thyroid hormones
• The most common thyroid disorder
• Usually caused by primary thyroid gland failure
• Also may result from diminished stimulation of the thyroid gland by TSH
• Hypothyroidism can occur with or without thyroid enlargement (goiter).
• Hypothyroidism usually results from autoimmune destruction of the
gland or the peroxidase and is diagnosed by elevated TSH.
Hypothyroidism: Deficiency in Thyroid Hormones

• Primary: Abnormality in the thyroid gland itself

The most common forms include Hashimoto's thyroiditis (an autoimmune
disease)
• Secondary: Results when the pituitary gland is dysfunctional and does not
secrete TSH usually caused by damage to the pituitary gland, as by a tumor,
radiation, or surgery
• Tertiary: Results when the hypothalamus gland does not secrete TRH
(Thyrotropin-Releasing Hormone) , which stimulates the release of TSH
• Others: Thyroiditis (inflammation), Postpartum thyroiditis (after giving birth –
temporary), Iodine deficiency, a non-functioning thyroid gland (one in 4000
newborns)
Hypothyroidism
Cretinism
• Hyposecretion of thyroid hormone during youth
• Low metabolic rate, retarded growth and sexual development,
possibly mental retardation
Hypothyroidism

Myxedema
• Hyposecretion of thyroid hormone during
adulthood
• Decreased metabolic rate, loss of mental
and physical stamina, weight gain, loss of
hair, edema
• Myxedema coma is a rare but life-
threatening condition
 Hypothyroidism
Goiter
• Enlargement of the thyroid gland (thyromegaly)
• Results from overstimulation by elevated levels of TSH
CLASS II GOITER
• TSH is elevated because there is little or no thyroid (NODULAR)
hormone in circulation
• Also thyroid cancers and pituitary disease cause goiter.
• 3 types of goiters: Class I (cannot be seen only found by
palpitation), Class II (can be easily seen), class III (whole
thyroid appearing to be enlarged)

CLASS III GOITER

(DIFFUSE)
Hypothyroidism
Common symptoms:
• Constipation
• Lethargy
• Anorexia
• Fatigue
• Cold intolerance
• Slowing of intellectual and motor activity
• Lessened appetite
• Increased weight
• Dry skin
• Dry hair & hair loss
• Deeper, hoarser voice
Hyperthyroidism (THYROTOXICOSIS)

• A clinical syndrome that results when the tissues are exposed to high
levels of thyroid hormone.
• Hyperthyroidism refers to excess synthesis and secretion of thyroid
hormones by the thyroid gland, which results in accelerated
metabolism in peripheral tissues.
• The most common form of hyperthyroidism is Grave’’s disease or
diffuse toxic goiter
Hyperthyroidism: Excessive Thyroid
Hormones
Caused by several diseases
• Graves’ disease (auto immune, bug eye looks)
• Toxic multinodular goiter
• Excessive iodine intake
• Intake of thyroid hormones
• Medications like excessive iodine containing drugs (Amiodarone,
• Lugol’s solution and some cough syrups).)
• Thyroiditis(The inflammation of the thyroid)
Graves’ disease
• Graves disease is a thyroid disorder characterized by goiter, exophthalmos, "orange-peel" skin,
and hyperthyroidism.
• It is caused by an antibody-mediated auto-immune reaction. A genetic defect in suppressor T
Lymphocytes. Helper T Lymphocytes stimulate B lymphocytes to synthesize antibodies to
thyroidal antigens.
• It is the most common cause of hyperthyroidism.
• Laboratory diagnosis includes elevation of T3, T4 whereas TSH is suppressed.
Exophthalmos :Abnormal protrusion of the eyeball

Toxic multinodular goiter

• Toxic multinodular goiter (also known as toxic nodular goiter) is a form of hyperthyroidism -
where there is excess production of thyroid hormones.
• It is characterized by functionally autonomous nodules. It emerges insidiously from nontoxic
multinodular goiter.
• It is the second most common cause of hyperthyroidism after Graves disease.
• Occurs in age of 50 years
• May present wit atrial fibrillation, palpitation, tachycardia, nervousness, tremors, weight
loss.
• Low TSH, elevated T3, T3>T4
Hyperthyroidism
Common symptoms:
• Diarrhea
• Flushing
• Increased appetite
• Muscle weakness
• Sleep disorders
• Altered menstrual flow
• Fatigue
• Palpitation
• Nervousness
• Heat intolerance
• Irritability
 Treatment of Hypothyroidism Thyroid Preparations

• For the majority of patients with hypothyroidism, thyroid hormone

replacement (synthetic or natural, pill or liquid, etc) will make the "thyroid
function tests" return to the normal range. This is accompanied by a general
improvement in symptoms making the patient feel better.
• Levothyroxine (T4 ) , Liothyronine (T3)
• Activation of nuclear receptors results in gene expression with RNA
formation and protein synthesis
• Maximum effect seen after 6–8 weeks of therapy
• Side effects: Symptoms of thyroid excess
Preparations of choice: Synthetic
levothyroxine
• Low-cost
• Non-allergenic (no foreign protein)
• Long half-life (seven days) -- supports once-daily dosing
• Since T4 is converted to T3 inside the cell, T4 administration produces both
hormones
• Levothyroxine - once a day, preferably in the morning, a pure synthetic form
of T4 is an exact replacement for the T4 that the human thyroid gland
normally secretes.
• Steady state is achieved in 6 to 8 weeks
Synthetic levothyroxine
• Levothyroxine (T4) is preferred over T3 (liothyronine or T3/T4
combination products for the treatment of hypothyroidism.
• It is better tolerated than T3 preparations and has a longer half-life.
• Toxicity is directly related to T4 levels and manifests as nervousness,
palpitations and tachycardia, heat intolerance, and unexplained weight
loss.
• Drugs that induce the cytochrome P450 enzymes, such as phenytoin,
rifampin, and phenobarbital, accelerate metabolism of the thyroid
hormones and may decrease the effectiveness.
Liothyronine
More active than levothyroxine but not recommended because of:
• Shorter half-life (multiple dosing)
• More costly
• Higher hormonal activity enhances cardiotoxicity (T3 :
contraindicated in patients with cardiac disease)
• Most appropriate use: Short-term TSH suppression
 Anti-thyroid Agents
Treatment of hyperthyroidism
Purpose: Reduction of thyroid activity and hormone effects
Approach:
• by glandular destruction with radiation or surgery.
• by agents that interfere with the production of thyroid hormones,
• by agents that modify the tissue response to thyroid hormones,

• Antithyroid drug therapy is with large divided doses, shifting to maintenance

therapy with single daily doses when the patient becomes clinically euthyroid.
• Goitrogens are agents that suppress secretion of T3 and T4 to subnormal levels and thereby increase TSH, which in
turn produces glandular enlargement (goiter).
1.Removal of part or all of the thyroid:
• This can be accomplished either surgically or by destruction of the
gland with radioactive iodine (131I), which is selectively taken up by
the thyroid follicular cells.
• Most patients become hypothyroid as a result of this drug and require
treatment with levothyroxine.
 2. Inhibition of thyroid hormone synthesis:
• The thioamides, propylthiouracil (PTU) and methimazole , are concentrated in the
thyroid, where 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 blocks the peripheral conversion of T4 to T3.
• Methimazole is preferred over PTU because it has a longer half-life, allowing for once-
daily dosing, and a lower incidence of adverse effects.
• However, PTU is recommended during the first trimester of pregnancy due to a greater
risk of teratogenic effects with methimazole.
• PTU has been associated with hepatotoxicity and, rarely, agranulocytosis.

Note: These drugs have no effect on thyroglobulin already stored in the gland. Therefore, clinical effects of
these drugs may be delayed until thyroglobulin stores are depleted
Thioamides

Methimazole & Propylthiouracil

• Major drugs for treatment of thyrotoxicosis
• Carbimazole, which is converted to methimazole, is
widely used.
• Methimazole is about ten times more potent than
propylthiouracil.
• The thiocarbamide group is essential for antithyroid
activity.
Thioamides :Mechanism of action
• Prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and
blocking iodine organification.
• Block coupling of the iodotyrosines.
• They do not block uptake of iodide by the gland.
• Propylthiouracil and (to a much lesser extent) methimazole inhibit the peripheral
deiodination of T4 and T3 .
• These drugs have no effect on thyroglobulin already stored in the gland.
• Since the synthesis rather than the release of hormones is affected, the onset of these
agents is slow, therefore, clinical effects of these drugs may be delayed until
thyroglobulin stores are depleted often requiring 3–4 weeks before stores of T4 are
depleted.
Hyperthyroidism therapy can be started with;
• Propylthiouracil (PTU), 100–150 mg every 6 or 8 hours, followed after
4–8 weeks by gradual reduction of the dose to the maintenance level of
50–150 mg once daily.
• Propylthiouracil also inhibits the conversion of T4 to T3, so it brings the
level of activated thyroid hormone down more quickly than does
methimazole. The best clinical guide to remission is reduction in the
size of the goiter.

Methimazole is preferred over PTU because it has a longer half-life, allowing for once-daily dosing, and
a lower incidence of adverse effects.
PTU is recommended during the first trimester of pregnancy due to a greater risk of teratogenic
effects with methimazole.
Thioamides : Side effects

Occur in 3–12% of treated patients.

• Nausea, gastrointestinal distress, rash, agranulocytosis, hypothyroidism, allergic reaction
• The most dangerous complication is agranulocytosis (granulocyte count < 500 cells/mm3),
an infrequent but potentially fatal adverse reaction in those receiving high dose
methimazole (reversible upon discontinuation)
• An altered sense of taste or smell may occur with methimazole
• The most common adverse effect )(4–6%), is a maculopapular pruritic rash (kind of skin
disease that is characterized by the appearance of small and red spots on the skin ).
• Hepatitis (more common with propylthiouracil)
• Cholestatic jaundice (more common with methimazole)
• The cross-sensitivity between propylthiouracil and methimazole is about 50%; therefore,
switching drugs in patients with severe reactions is not recommended.
• Cross-sensitivity :a sensitivity to one substance that predisposes an individual to sensitivity
to other substances that are related in chemical structure.
Anion Inhibitors
• Monovalent anions such as perchlorate (ClO4–), pertechnetate (TcO4–), and
thiocyanate (SCN–) can
• Mechanism of action: block uptake of iodide by the gland through competitive
inhibition of the iodide transport mechanism.
• Since these effects can be overcome by large doses of iodides, their effectiveness is
somewhat unpredictable.
• The major clinical use : Potassium perchlorate block thyroidal reuptake of I– in patients
with iodide-induced hyperthyroidism (eg, amiodarone-induced hyperthyroidism).
• Side effects: Potassium perchlorate is rarely used clinically because it is associated with
aplastic anemia.
 3. Blockade of hormone release:
• A pharmacologic dose of iodide inhibits the iodination of tyrosines (“Wolff-Chaikoff
effect”), but this effect lasts only a few days.
• More importantly, iodide inhibits the release of thyroid hormones from thyroglobulin
by mechanisms not yet understood.
• Iodide is employed to treat 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 include sore mouth and throat, swelling of the tongue or larynx,
rashes, ulcerations of mucous membranes, and a metallic taste in the mouth.
 Iodides
Lugol solution , Potassium iodide
• Rarely used now as monotherapy
Mechanism of action: Iodides have several actions on the thyroid. They inhibit organification and
hormone release and decrease the size and vascularity of the hyperplastic gland.
Clinical usage:
• Improvement in thyrotoxic symptoms occurs rapidly—within 2–7 days—hence the value of iodide
therapy in thyroid storm.
• In addition, iodides decrease the vascularity, size, and fragility of a hyperplastic gland, making the drugs
valuable as preoperative preparation for surgery.
• In radiation emergencies, the thyroid-blocking effects of potassium iodide can protect the gland from
subsequent damage if administered before radiation exposure.

Disadvantages of iodide therapy include:

• An increase in intraglandular stores of iodine, which may delay onset of thioamide therapy or prevent
use of radioactive iodine therapy for several weeks.
• Chronic use of iodides in pregnancy should be avoided, since they cross the placenta and can cause fetal
goiter.
Adverse effects: Iodides

• Adverse reactions to iodine (iodism) are uncommon and in most cases

reversible upon discontinuance.
• Rash
• Swollen salivary glands
• Conjunctivitis (inflammation of the conjunctiva)
• Rhinorrhea (the free discharge of a thin nasal mucus)
• Metallic taste
 Radioactive Iodine
• 131I is the radioactive isotope used for treating thyrotoxicosis.
Mechanism of Action:
• Rapidly absorbed, concentrated in the thyroid
• Destruction of the gland by beta particles emitted by radioactive
iodine which is selectively taken up with thyroid follicular cells.
Contraindication:
• 131I: Not administered to pregnant women or nursing
mother;131I crosses placental barrier and excreted in breast milk
Side effects : Sore throat, hypothyroidism
Beta blockers
• Propranolol
• Mechanism of action: Inhibition of adrenoreceptors/ inhibit T4 to T3
conversion
• Usage: Hyperthyroidism, especially thyroid storm adjunct to control
tachycardia, hypertension, and atrial fibrillation (the most common cardiac
arrhythmia)
• Propranolol, 20–40 mg orally every 6 hours, manage tachycardia, hypertension,
and atrial fibrillation. Propranolol is steadily withdrawn once serum thyroxine
levels come back to normal.
• Side effects: Asthma, hypotension, bradycardia
Adjuncts to antithyroid therapy

• Diltiazem, 90–120 mg three or four times daily, can be used to control

tachycardia in patients in whom - blockers are contraindicated, eg,
those with asthma.
• Adequate nutrition and vitamin supplements are vital.
• Barbiturates accelerate T4 breakdown (by hepatic enzyme induction)
and may be helpful both as sedatives and to lower T4 levels.
Drug Effects and Thyroid Function

Change in thyroid hormone synthesis

• Inhibition of TRH or TSH secretion without induction of hypothyroidism or
hyperthyroidism:

Dopamine, levodopa, corticosteroids, somatostatin, metformin,

bexarotene
• Inhibition of thyroid hormone synthesis or release with the induction of
hypothyroidism (or occasionally hyperthyroidism):

Iodides (including amiodarone), lithium, aminoglutethimide, thioamides,

ethionamide
Effect of thyroid function on drug effects
Anticoagulation
• Lower doses of warfarin required in hyperthyroidism, higher doses in hypothyroidism

Glucose control
• Increased hepatic glucose production and glucose intolerance in hyperthyroidism;
impaired insulin action and glucose disposal in hypothyroidism

Cardiac drugs
• Higher doses of digoxin required in hyperthyroidism; lower doses in hypothyroidism

Sedatives; analgesics
• Increased sedative and respiratory depressant effects from sedatives and opioids in
hypothyroidism; converse in hyperthyroidism
 Thyroid storm

• 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.
Treatment:
• β-Blockers propranolol, is effective in blunting the widespread sympathetic
stimulation that occurs in hyperthyroidism. Intravenous administration 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).
Monitoring of Thyroid Function
• Thyroid disorders are common and so thyroid function testing in blood samples
is also common with approximately 10 million requests each year in the UK at an
estimated cost of £30 million.
• The most commonly performed tests in serum are used to establish if there is
thyroid dysfunction or to monitor the response to therapy.
• These tests include thyroid stimulating hormone (TSH), free thyroxine (FT4), and
free tri-iodothyronine (FT3). A range of other tests is also available to determine
the specific causes of thyroid disease.
• Routine thyroid function monitoring is not recommended in asymptomatic
adults.
• Monitoring of thyroid function may be indicated when;
a) non-specific signs and symptoms are present in patients and
b) for patients who are at risk for thyroid disease.
Monitoring of Thyroid Function
High risk individuals are:
• Individuals having personal history of thyroid disease.
• Individuals having strong family history of thyroid disease.
• Having history of autoimmune disease.
• Having past history of neck irradiation.
• Patients on drug therapies such as lithium and amiodarone.
• Women over age 50.
• Elderly patients.
Laboratory Investigations
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