Thyroid and Antithyroid Drugs

THYROID PHYSIOLOGY
• The normal thyroid gland secretes sufficient amounts
of the thyroid hormones—triiodothyronine (T3) and
tetraiodothyronine (T4,
• thyroxine)—to normalize growth and development,
body temperature, and energy levels. These
hormones contain 59% and 65%
• (respectively) of iodine as an essential part of the
molecule. Calcitonin, the second type of thyroid
hormone, is important in the regulation
• of calcium metabolism
 Iodide Metabolism
• The recommended daily adult iodide (I−)* intake is
150 mcg (200 mcg during pregnancy and lactation).
• Iodide, ingested from food, water, or medication, is
rapidly absorbed and enters an extracellular fluid
pool. The thyroid gland removes
• about 75 mcg a day from this pool for hormone
synthesis, and the balance is excreted in the urine. If
iodide intake is increased, the
• fractional iodine uptake by the thyroid is diminished
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
• The first step is the transport of iodide into
the thyroid gland by an intrinsic follicle cell
basement membrane protein called the
sodium/iodide symporter (NIS)
• This can be inhibited by such anions as thiocyanate
(SCN−), pertechnetate (TcO4−), and
perchlorate(CIO4−)
• At the apical cell membrane a second I− transport
enzyme called pendrin controls the flow of iodide
across the membrane.Pendrin is also found in the
cochlea of the inner ear. If pendrin is deficient or
absent (PDS or SLC26A4 mutation), a hereditary
syndrome of goiter and deafness, called Pendred’s
syndrome, ensues.
• At the apical cell membrane, iodide is oxidized by
thyroidal peroxidase (TPO) to iodine, in which form
it rapidly iodinates tyrosine residues within the
thyroglobulin molecule to form monoiodotyrosine
(MIT) and diiodotyrosine (DIT). This process is
called iodide organification. Thyroidal peroxidase
is transiently blocked by high levels of
intrathyroidal iodide and blocked more persistently
by thioamide drugs. Gene expression of TPO is
stimulated by thyroid-stimulating hormone (TSH).
• Two molecules of DIT combine within the
thyroglobulin molecule to form L-thyroxine
(T4).
• One molecule of MIT and one molecule of DIT
combine to form T3
• In addition to thyroglobulin, other proteins
within the gland may be iodinated, but these
iodoproteins do not have hormonal activity.
• Thyroxine, T3, MIT, and DIT are released from
thyroglobulin by exocytosis and proteolysis of
thyroglobulin at the apical colloid border.
• The MIT and DIT are then deiodinated within
the gland, and the iodine is reutilized. This
process of proteolysis is also blocked by high
levels of intrathyroidal iodide
 Transport of Thyroid Hormones
• Thyroxine and T3 in plasma are reversibly bound
to protein, primarily thyroxine-binding globulin
(TBG). Only about 0.04% of total T4 and
• 0.4% of T3 exist in the free form (as FT4 and
FT3). Many physiologic and pathologic states
and drugs affect T4, T3, and thyroid transport.
• However, the actual levels of free hormone
generally remain normal, reflecting feedback
control.
 Peripheral Metabolism of Thyroid
Hormones
• The primary pathway for the peripheral
metabolism of thyroxine is deiodination by three
5′deiodinase enzymes (D1, D2, D3).
• Deiodination of T4 may occur by monodeiodination
of the outer ring, producing 3,5,3′-triiodothyronine
(T3), which is three to four times more potent than
T4
• The D1 enzyme is responsible for most of the
circulating T3 while D2 regulates T3 levels in the
brain and pituitary.
• D3 deiodination produces metabolically
inactive 3,3′,5′-triiodothyronine (reverse T3
[rT3])
• The low serum levels of T3 and rT3 in normal
individuals are due to the high metabolic
clearances of these two compounds.
 THYROTOXICOSIS (HYPERTHYROIDISM
• PATHOPHYSIOLOGY
• Thyrotoxicosis results when tissues are exposed to
excessive levels of T4, T3, or both.
• TSH-secreting pituitary tumors release biologically
active hormone that is unresponsive to normal
feedback control. The tumors may cosecrete
prolactin or growth hormone; therefore, patients
may present with amenorrhea, galactorrhea, or
signs of acromegaly.
• In Graves disease, hyperthyroidism results from
the action of thyroid-stimulating antibodies
(TSAb) directed against the thyrotropin receptor
on the surface of thyroid cell.
• An autonomous thyroid nodule (toxic adenoma)
is a thyroid mass whose function is independent
of pituitary control. Hyperthyroidism usually
occurs with larger nodules (>3 cm in diameter).
• In multinodular goiter, follicles with
autonomous function coexist with normal or
even nonfunctioning follicles. Thyrotoxicosis
occurs when autonomous follicles generate
more thyroid hormone than is required.
 CLINICAL PRESENTATION
• Symptoms of thyrotoxicosis include
• nervousness, anxiety, palpitations, emotional
lability, easy fatigability, heat intolerance,
weight loss concurrent with increased
appetite, increased frequency of bowel
movements, proximal muscle weakness
(noted on climbing stairs or arising from a
sitting position), and scanty or irregular
menses in women.
 HYPOTHYROIDISM
• The vast majority of patients have primary
hypothyroidism due to thyroid gland failure from
chronic autoimmune thyroiditis (Hashimoto’s
disease).
• Defects in suppressor T lymphocyte function lead
to survival of a randomly mutating clone of helper
T lymphocytes directed against antigens on the
thyroid membrane.
• The resulting interaction stimulates B lymphocytes
to produce thyroid antibodies.
• Physical signs include warm, smooth, moist skin
and unusually fine hair; separation of the ends of
the fingernails from the nail beds (onycholysis);
retraction of the eyelids and lagging of the upper
lid behind the globe upon downward gaze (lid lag);
tachycardia at rest, widened pulse pressure, and
systolic ejection murmur; occasional
• gynecomastia in men; fine tremor of the protruded
tongue and outstretched hands; and hyperactive
deep tendon reflexes.
• Secondary hypothyroidism due to pituitary
failure is uncommon. Pituitary insufficiency
may be caused by destruction of thyrotrophs
by pituitary tumors, surgical therapy, external
pituitary radiation, postpartum pituitary
necrosis (Sheehan syndrome), trauma, and
infiltrative processes of the pituitary (eg,
metastatic tumors, tuberculosis).
 CLINICAL PRESENTATION
• Symptoms of hypothyroidism include dry skin,
cold intolerance, weight gain, constipation,
• weakness, lethargy, fatigue, muscle cramps,
myalgia, stiffness, and
• loss of ambition or energy.
• In children, thyroid hormone deficiency may
manifest as growth or intellectual retardation
• Physical signs include coarse skin and hair, cold or
dry skin, periorbital puffiness,
• bradycardia, and slowed or hoarse speech.
Objective weakness (with proximal muscles
affected more than distal muscles) and slow
relaxation of deep tendon reflexes are common.
Reversible neurologic syndromes such as carpal
tunnel syndrome,
• polyneuropathy, and cerebellar dysfunction may
also occur
 TREATMENT
• Goals of Treatment: Eliminate excess thyroid
hormone; minimize symptoms
• long-term consequences; and provide
individualized therapy based on the type and
• severity of disease, patient age and gender,
existence of nonthyroidal conditions, and
response to previous therapy
 Nonpharmacologic Therapy
• Surgical removal of the thyroid gland should
be considered in patients with a large gland
(>80 g), severe ophthalmopathy, or lack of
remission on antithyroid drug treatment
• If thyroidectomy is planned, propylthiouracil
(PTU) or methimazole is usually
• given until the patient is biochemically
euthyroid (usually 6–8 weeks), followed by
• addition of iodides (500 mg/day) for 1–14
days before surgery to decrease vascularity of
the gland.
• Levothyroxine may be added to maintain the
euthyroid state while thionamides are
continued.
• Propranolol has been used for several weeks
preoperatively and 7 to 10 days after
• surgery to maintain pulse rate less than 90
beats/min. Combined pretreatment with
• propranolol and 10 to 14 days of potassium
iodide also has been advocated.
 Drugs Used in the preparation of thyroid disease
Subclass, Drug Mechanism of Indications Pharmacokinetics,
action toxicity and
interaction
Thyroid Activation of Hypothyroidism Maximum effect is
preparations nuclear receptors seen after 6-8
•Levithyroxine(T4) result in gene weeks of therapy
•Liothyronine(T3) expression with
RNA Formation and
protein synthesis
Antithyroid agents •Inhibit thyroid Hyperthyroidism Oral- duration of
THIOAMIDES peroxidase action is 24
•Methimazole reactions hrs(methimazole),P
•Propylthiouracil •Block iodine TU(6-8hrs)
organification Toxicity-Nausea,GIT
•Inhibit peripheral distress,rash,hepatit
deiodination T3 and s,hypothyroidism,ag
T4 ranulocytosis
Subclass,Drugs MOA Indications Pharmacokinetics,to
xicities and
interactions
IODIDES •Inhibit Preparation for Oral-acute onset
•Lugol’s solution organification and surgical within 2-7 days
•Potassium Iodide hormone release thyroidectomy Toxicity-rare
•Reduce the size and
vascularity of the
gland

BETA BLOCKERS Inhibition of beta Hyperthyroidism( es Onset within

•Propanolol adrenoreceptors pecially thyroid hours( duration 4-6
•A few other storm) hrs) in case of oral
blockers which lack Inhibit conversion of Adjunct control of propanolol
partial agonist T4 to T3 tachycardia Toxicity- asthma, AV
activity Hyoertension and blockade,
atrial fibrilation hypotension and
bradycardia
Radioactive Iodine Radiation destroys Hyperthyroidism Avoid in pregnancy
the thyroid Patients should be and nursing
parenchyma suthyroid or on beta Orally given( onset in
blockers before RAI 6-12 weeks)
maximum effect in 3-
6 months, Toxicity-
sore throat, sialitis
and hypothyroidism
Pharmacologic Therapy
Thyroid Drugs

Levothyroxin(T4)

Liothyronine(T3)

Liotrix(T3=T4)
Pharmacokinetics of Thyroid drugs
• Easily orally absorbed
• Biolavaliability of T4 is 80% and T3 is 95%
• The following drugs which induce hepatic
microsomal enzymes improve their
metabolism
• Such as ( rifampin,phenobarbital and
phenytoin etc)
 ANTITHYROID AGENTS
• Reduction of thyroid activity and hormone effects can be
accomplished by agents that interfere with the production
of thyroid hormones,
• by agents that modify the tissue response to thyroid
hormones, or by glandular destruction with radiation or
surgery.
• Goitrogens are agents that suppress secretion of T3 and T4
to subnormal levels and thereby increase TSH, which in
turn produces glandular enlargement (goiter).
• The antithyroid compounds used clinically include the
thioamides, iodides, and radioactive iodine
 THIOAMIDES
• The thioamides methimazole and
propylthiouracil are major drugs for
treatment of thyrotoxicosis. In the United
Kingdom,
• carbimazole, which is converted to
methimazole in vivo, is widely used.
Methimazole is about ten times more potent
than propylthiouracil and is the drug of
choice in adults and children
 Mechanism of action
• Prevent thyroid hormone synthese by inhibiting
thyroid peroxidase catalyzed recations and
blocking iodine organification
• Blocks the coupling of iodotyrosines
• PTU and methimazole block the peripheral
deiodination of T3 and T4
• Cabamazole can cross the placental barrier
hence it needs to be used carefully in
pregnancy
• Methimazole can cause congenital
malformations
• PTU is indicated during pregnancy as it doesn’t
cross the placental barrier and is not found in
breast milk
Propylthiouracil Carbimazole

Thiourea derivative Imidazole derivative

Less potent More potent

Highly plasma protein bound Not so

Less transported across placental barrier Can cross the barrier

Multiple dose needed Single dose needed

No active metabolites Methimazole is the active metabolite

 Pharmacokinetics
• Methimazole is completely absorbed but at variable
rates. It is readily accumulated by the thyroid gland and
has a volume of distribution similar to that of
propylthiouracil.
• Excretion is slower than with propylthiouracil; 65–70% of
a dose is recovered in the urine in 48 hours.
• The bioavailability of 50–80% may be due to incomplete
absorption or a large first-pass effect in the liver
• Most of an ingested dose of propylthiouracil is excreted
by the kidney as the inactive glucuronide within 24
hours
• The short plasma half-life of these agents (1.5 hours for
propylthiouracil and 6 hours for methimazole) has little influence
on the duration of the antithyroid action or the dosing interval
because both agents are accumulated by the thyroid gland
• For propylthiouracil,
• giving the drug every 6–8 hours is reasonable since a single 100
mg dose can inhibit iodine organification by 60% for 7 hours.
Since a
• single 30 mg dose of methimazole exerts an antithyroid effect for
longer than 24 hours, a single daily dose is effective in the
management
• of mild to severe hyperthyroidism
• Both thioamides cross the placental barrier and are
concentrated by the fetal thyroid, so that caution must be
employed when using these drugs in pregnancy
• Toxicity
• Adverse reactions to the thioamides occur in 3–12% of treated
patients. Most reactions occur early, especially nausea and
• gastrointestinal distress. An altered sense of taste or smell
may occur with methimazole. The most common adverse
effect is a
• maculopapular pruritic rash (4–6%), at times accompanied by
systemic signs such as fever. Rare adverse effects include an
urticarial
 Contd.
• The most dangerous complication is
agranulocytosis (granulocyte count < 500
cells/mm3), an infrequent but potentially fatal
adverse
• reaction. It occurs in 0.1–0.5% of patients
taking thioamides, but the risk may be
increased in older patients and in those
receiving more
• than 40 mg/d of methimazole
 ANION INHIBITORS
• Monovalent anions such as perchlorate (ClO4), pertechnetate
(TcO4−), and thiocyanate (SCN−) can 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 for potassium perchlorate is to block
thyroidal reuptake of I− in patients with iodide-induced
hyperthyroidism
• (eg, amiodarone-induced hyperthyroidism). However,
potassium perchlorate is rarely used clinically because it is
associated with aplastic anemia
 IODIDES
• Iodides have several actions on the thyroid. They inhibit
organification and hormone release and decrease the size and
vascularity of the hyperplastic gland.
• In susceptible individuals, iodides can induce hyperthyroidism (Jod-
Basedow phenomenon) or precipitate hypothyroidism.
• In pharmacologic doses (> 6 mg/d), the major action of iodides is to
inhibit hormone release, possibly through inhibition of thyroglobulin
proteolysis.
• 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.
 Mechanism of action of iodides
• They inhibit organifiaction
• Hormone release
• Decrease the size and vascularity of
hyperplastic gland
 Iodinated contrast media
• These drugs can rapidly inhibit the conversion
of T4 to T3 in pituitary gland, kidney, liver and
brain
• Relatively non toxic
• Adjuvant therapy in thyroid storm
• Safely can be used in pregancy
• Can be used as an alternative therapeutic
regimen in case of iodides and thioamides
 Clinical Use of Iodide
• 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. Thus, iodides should
be initiated after onset of thioamide therapy and avoided if treatment
with radioactive iodine seems likely.
• Iodide should not be used alone, because the gland will escape from the
iodide block in 2–8 weeks, and its withdrawal may produce severe
exacerbation of thyrotoxicosis in an iodine-enriched gland.
• Chronic use of iodides in pregnancy should be avoided, since they cross
the placenta and can cause fetal goiter.
• In radiation emergencies involving release of radioactive iodine isotopes,
the thyroid-blocking effects of potassium iodide can protect the gland
from subsequent damage if administered before radiation exposure.
 Toxicity
• Adverse reactions to iodine (iodism) are
uncommon and in most cases reversible upon
discontinuance.
• They include acneiform rash (similar to that of
bromism), swollen salivary glands, mucous
membrane ulcerations, conjunctivitis,
rhinorrhea, drug fever, metallic taste,
• bleeding disorders, and rarely, anaphylactoid
reactions
 RADIOACTIVE IODINE
• 131I is the only isotope used for treatment of thyrotoxicosis (others are used in
diagnosis).
• Administered orally in solution as sodium 131I,
• it is rapidly absorbed, concentrated by the thyroid, and incorporated into
storage follicles.
• Its therapeutic effect depends on emission of β rays with an effective half-life of
5 days and a penetration range of 400–2000 μm.
• Within a few weeks after administration, destruction of the thyroid
parenchyma is evidenced by epithelial swelling and necrosis, follicular
disruption, edema, and leukocyte infiltration.
• Advantages of radioiodine include easy administration, effectiveness, low
expense, and absence of pain. Fears of radiation-induced
• genetic damage, leukemia, and neoplasia have not been realized after more
than 50 years of clinical experience with radioiodine therapy
• for hyperthyroidism. Radioactive iodine should not be administered to
pregnant women or nursing mothers, since it crosses the placenta
• to destroy the fetal thyroid gland and it is excreted in breast milk.
 ADRENOCEPTOR-BLOCKING AGENTS
• Beta blockers without intrinsic sympathomimetic activity (eg,
metoprolol, propranolol, atenolol) are effective therapeutic
adjuncts in the management of thyrotoxicosis since many of
these symptoms mimic those associated with sympathetic
stimulation.
• Propranolol has been the β blocker most widely studied and
used in the therapy of thyrotoxicosis. Beta blockers cause
clinical improvement of hyperthyroid symptoms but do not
typically alter thyroid hormone levels.
• Propranolol at doses greater than 160 mg/d may also reduce
T3 levels approximately 20% by inhibiting the peripheral
conversion of T4 to T3
 SPECIAL PROBLEMS
• Thyroid Storm
• Thyroid storm, or thyrotoxic crisis, is sudden acute
exacerbation of all of the symptoms of thyrotoxicosis,
presenting as a life-threatening
• syndrome. Vigorous management is mandatory.
Propranolol, 60–80 mg orally every 4 hours, or
intravenous propranolol, 1–2 mg slowly
• every 5-10 minutes to a total of 10 mg, or esmolol,
50–100 mg/kg/min, is helpful to control the severe
cardiovascular manifestations
 Ophthalmopathy
• Although severe ophthalmopathy is rare, it is
difficult to treat. Exacerbations of severe eye
disease may occur following RAI, especially
• in those who smoke. Management requires
effective treatment of the thyroid disease,
usually by total surgical excision or 131I
ablation of
• the gland plus oral prednisone therapy
 Dermopathy
• Dermopathy or pretibial myxedema will often respond to
topical corticosteroids applied to the involved area and covered
with n occlusive dressing.
• Thyrotoxicosis during Pregnancy
• If thyrotoxicosis does develop
• during pregnancy, RAI is contraindicated because it crosses the
placenta and may injure the fetal thyroid. Propylthiouracil
(fewer
• teratogenic risks than methimazole) can be given in the first
trimester, and then methimazole can be given for the
remainder of the
• pregnancy in order to avoid potential liver damage.
 Neonatal Graves’ Disease
• Graves’ disease may occur in the newborn infant,
either due to passage of maternal TSH-R Ab [stim]
through the placenta, stimulating
• the thyroid gland of the neonate, or to genetic
transmission of the trait to the fetus. Laboratory
studies reveal an elevated free T4, a
• markedly elevated T3, and a low TSH—in contrast to
the normal infant, in whom TSH is elevated at birth.
TSH-R Ab [stim] is usually
• found in the serum of both the child and the mother.
Summary