Thyroid and Antithyroid Drugs

Fig: The thyroid gland & its regulation by the hypothalamic - anterior pituitary axis.
Fig: Biosynthesis of thyroid hormones
Fig: Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis.
 Actions of Thyroid Hormones

• Thyroid hormone action is mediated largely by the binding of T3 to

thyroid hormone receptors (TRs)

• T3 binds to TRs with ~10-fold greater affinity than does T4

• T4 is not thought to be biologically active in normal physiology.

• T3 and T4 are qualitatively similar

 Actions of Thyroid Hormones

• The physiological actions of the thyroid hormones fall into two

categories:
Those affecting metabolism and
Those affecting growth and development.
 Actions of Thyroid Hormones

• Effects on metabolism
 Thyroid hormones produce a general increase in the metabolism of carbohydrates,
fats and proteins, and regulate these processes in most tissues.

The calorigenic action is important as part of the response to a cold

environment.

 There is an increase in oxygen consumption and heat production

 Administration of thyroid hormone results in augmented cardiac rate and output,

and increased tendency to dysrhythmias such as atrial fibrillation.
 Actions of Thyroid Hormones

• Effects on growth and development

• Thyroid hormones have a critical effect on growth, partly by a direct action on
cells, and also indirectly by influencing growth hormone production and
potentiating its effects on its target tissues.

• The hormones are important for a normal response to parathormone and

calcitonin as well as for skeletal development

• They are also essential for normal growth and maturation of the CNS.
 Actions of Thyroid Hormones….

• The thyroid hormones are responsible for optimal growth,

development, function, and maintenance of all body tissues.

• Excess amounts: hyperthyroidism

• Inadequate amounts: hypothyroidism

 Hypothyroidism
• A decreased activity of the thyroid results in hypothyroidism, and in severe
cases myxedema
• In adults the common symptoms include fatigue (or easy fatigability), sensitivity
to cold, weight gain, constipation, muscle cramps & menstrual abnormalities
• Etiology: Immunological in origin (most commonly), destruction of thyroid
tissue following treatment with radioactive iodine and Secondary forms of
hypothyroidism can result from disorders of the anterior pituitary or
hypothalamus resulting in impaired TSH release.
• The prevalence of autoimmune hypothyroidism is 4 to 6-fold more common in
women (up to 2% of adult women), and increases with age.
Table 1: Features of Hypothyroidism in Adults*
 Hyperthyroidism (thyrotoxicosis)
• By definition Hyperthyroidism is an over-activity of the thyroid gland.

• Hyperthyroidism, in turn, results in a state of thyroid hormone excess that is

referred to as “thyroidtoxicosis”.

• While hyperthyroidism (thyroid gland overactivity) is the most common cause of

thyroidtoxicosis, thyroidtoxicosis can also be caused by an overdose of
thyroxine, or excessive release of stored thyroid hormone during a viral
infection.
Table: Features of Hyperthyroidism in Adults
 Treatment of hypothyroidism
• Drugs used
Levothyroxine(T4)

T3 (liothyronine) or

T3/T4 combination products (liotrix)

• Drugs that induce the cytochrome P450 enzymes accelerate metabolism

of the thyroid and may decrease the effectiveness.
• E.g., phenytoin, rifampin, and phenobarbital
 Treatment of hypothyroidism
 Levothyroxine or Thyroxine (T4)
• Mechanism of Action:
• T4 is converted to T3 (the active form) inside cells by one of two distinct deiodinases, depending on
the tissue
• T3 binds to specific receptor proteins (alpha & beta) in the nucleus, resulting in altered gene
expression, and increased formation of RNA and protein
• Systemic effects include increased oxygen consumption by most tissues of the body and increases
the basal metabolic rate and the metabolism of carbohydrates, lipids and proteins

• Indications:
• Hypothyroidism
• Pituitary TSH Suppression (in the treatment or prevention of various types of euthyroid goiters)
 Treatment of hypothyroidism
 Levothyroxine or Thyroxine (T4)
• Pharmacokinetics:
• Taken orally
• T4 has a longer half life (7 days) compared to T3 (1 day)

• Side Effects:
• Symptoms resembling hyperthyroidism: nervousness, anxiety, tremor, heat intolerance, weight loss
w/ increased appetite and arrhythmias (palpitations)
• Hyperthyroidism will increase the metabolic clearance and decrease the half life of T3 (& T4).

• Notes:
• The lower cost & longer half-life of T4 make it a drug of choice for chronic treatment of
hypothyroidism (e.g. compared to T3 which is more expensive & produces transient effects)
 Treatment of hypothyroidism
 Liothyronine or Triiodothyronine (T3)
• Mechanism of Action: see T4

• Indications:
• Replacement therapy or supplement in patients with hypothyroidism

• For short term suppression of the pituitary thyroid-stimulating hormone (TSH) in the treatment
or prevention of various types of euthyroid goiters, including Hashimoto's goiter

• As diagnostic agents in suppression tests to differentiated suspected mild hyperthyroidism or

thyroid gland autonomy

• Contraindications: heart disease (T3 can cause cardiotoxicity)

 Treatment of hypothyroidism
 Liothyronine or Triiodothyronine (T3)
• Pharmacokinetics:
• Taken orally or parenterally

• Short half life (24hrs) compared to T4 (7 days), requiring multiple daily doses

• Notes:
• T3 is not used very frequently compared to T4 because it:
• Costs more than T4

• Has a shorter t1/2 (requiring multiple daily doses) compared to T4

• Is more difficult to monitor using conventional lab tests

• T4 is converted to T3 intracellularly
 Treatment of hyperthyroidism (thyrotoxicosis)

I. Removal of part or all of the thyroid:

 Surgically

 Destruction of the gland with radioactive iodine (131I): selectively taken up

by the thyroid follicular cells.
• Most patients become hypothyroid as a result of this drug and require treatment
with levothyroxine.
 Radioactive I -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 with an effective half-life of ~56 days

• Beta particles act on parenchymal cells with little damage to surrounding tissue

• Indications:
• Radioactive iodide uptake test to evaluate thyroid function

• Thyrotoxicosis - multinodular hyperthyroidism & toxic adenomas

• Contraindications: pregnancy or nursing mothers

• Side Effects: delayed hypothyroidism

 Treatment of hyperthyroidism (thyrotoxicosis)…

II. Inhibition of thyroid hormone synthesis:

• Drugs: Propylthiouracil (PTU) and methimazole
• Concentrate in the thyroid
• 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.
• 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.
 Propylthiouracil (PTU)
• Mechanisms of Action:
• Prevents thyroid hormone synthesis by
inhibiting the thyroid peroxidase-
catalyzed reactions & blocking iodine
organification (the major mechanism of
action)
• Blocks coupling of iodotyrosines
• Inhibits the peripheral deiodination
(deiodinase D1) of T4 to T3
• Indications:
• Thyrotoxicosis (thyroid storm) (high doses must be used to
treat thyroid storm)
• PTU is favored over methimazole for this indication because of
its effect to block T4 to T3 conversion
• 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
 Propylthiouracil or PTU
 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)
 Propylthiouracil or PTU

 Pregnancy:
• Risk Category D: PTU can cross the placental barrier & cause fetal hypothyroidism.

 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

• PTU has been considered preferable to methimazole in nursing mothers, since it may

not accumulate in breast milk to the same extent (but both are considered relatively

safe due to low levels of secretion into breast milk)

 Methimazole vs PTU during pregnancy
 Methimazole causes a specific pattern of rare teratogenic effects after first
trimester exposure, while PTU therapy may be followed by rare but severe
hepatotoxic sequelae. It is therefore appropriate to use PTU to treat
maternal hyperthyroidism during the first trimester of pregnancy, and to
switch to MMI for the remainder of the pregnancy
 Reference: (Hackmon R, Blichowski M, Koren G. The safety of methimazole and
propylthiouracil in pregnancy: a systematic review. J Obstet Gynaecol Can 2012
Nov;34(11):1077-1086).
 Methimazole
 Mechanism of Action:
• ~10 times more potent than propylthiouracil (PTU)

• Prevents thyroid hormone synthesis by inhibiting the thyroid peroxidase-catalyzed

reactions & blocking iodine organification (the major mechanism of action)

• It mechanism of action on the thyroid gland is the same as PTU, however methimazole

does not effectively block peripheral deiodinase D1 that converts T4 to T3.

 Methimazole
• Indications: treatment of hyperthyroidism (long-term treatment may lead to remission of the disease)

• In non-pregnant adults, methimazole is the primary drug used to treat Grave's hyperthyroidism.

• Compared to propylthiouracil, methimazole has a longer duration of action (allowing for once a day dosing),

and more rapidly results in a euthyroid state (normal T4 & T3 levels) after onset of therapy (Ross 2016).

• to reduce the degree of hyperthyroidism in preparation for subtotal thyroidectomy or radioactive iodine

therapy

• used when thyroidectomy is contraindicated or is not advisable

• Contraindications: pregnancy (category D) & nursing mothers -

• Methimazole can cross the placental barrier & cause fetal hypothyroidism
 Methimazole
 Pharmacokinetics:

• Patients treated with methimazole require 3-8 weeks to become euthyroid

because it blocks the synthesis of new thyroid hormone, and any already

formed T3 & T4 that are stored in the thyroid gland must be secreted and

metabolized before a clinical improvement can occur.

• This is also true for propylthiouracil (PTU)

 Methimazole
 Side Effects:
• Maculopapular rash (4-6% of patients); the most common side effect, sometimes
associated with fever

• Agranulocytosis; dangerous but very rare (0.1-0.5%)

• usually reversible when drug is discontinued

• patients should have their bone marrow status monitored

• Hepatitis (more common with PTU)

• Cholestatic jaundice has been reported, and can be fatal

• Nausea, GI distress, altered taste or smell

 Treatment of hyperthyroidism (thyrotoxicosis)…

 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.

 PTU has been associated with hepatotoxicity and, rarely, agranulocytosis.

 Treatment of hyperthyroidism (thyrotoxicosis)…

III. Blockade of hormone release:

A pharmacologic dose of iodide acutely inhibits the iodination of tyrosines and
release of thyroid hormones and decrease the size and vascularity thyroid gland

Iodide is not useful for long-term therapy, because the thyroid ceases to respond to
the drug after a few weeks.

Saturated potassium iodide solutions (SSKI)

Potassium iodide-iodine (Lugol's solution)

 Potassium Iodide
• Mechanism of Action: Iodine has several effects on thyroid function:
• A major action of iodide is to inhibit hormone release from the thyroid gland.
• This is the most acute effect of iodine on thyroid status, and occurs within hours after starting therapy

• This effect may result from inhibition of thyroglobulin proteolysis (which is necessary for
production/excocytosis of thyroid hormones)

• Interferes with the synthesis of thyroid hormones by inhibiting thyroidal peroxidase inside the
thyroid gland. This decreases thyroid hormone biosynthesis.

• Maximal effect of iodine on thyroid hormone conc.~10 days of Rx

• Iodine therapy is typically given only for a few weeks because the thyroid gland will
commonly “escape” from iodide block in 2-8 weeks.
 Potassium Iodide
• Indications:
• Hyperthyroidism & thyroid
storm: Graves' disease, toxic
adenoma, goiter, thyroiditis
• Rarely used as sole therapy for
hyperthyroidism
• 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:
• Hypersensitivity reactions: skin rashes, drug
fever, rhinitis, conjunctivitis
• Iodism: metallic taste, burning mouth and throat,
sore teeth and gums, symptoms of a head
cold, and sometimes stomach upset and diarrhea
• Salivary gland swelling
• Gynecomastia.
 Treatment of hyperthyroidism (thyrotoxicosis)…

• Adrenoceptor-blocking agents: eg, metoprolol, propranolol, atenolol

Are effective therapeutic adjuncts in the management of thyrotoxicosis since many

of these symptoms mimic those associated with sympathetic stimulation.

Beta blockers cause clinical improvement of hyperthyroid symptoms but do not

typically alter thyroid hormone levels.
 Propranolol
• Mechanism of Action: Competitively blocks both β1 and β2 adrenergic receptors.

• Indications:
• Hypertension.
• Angina pectoris.

• Cardiac arrhythmias: thyrotoxicosis

• Prevention of sudden death and reinfarction after an MI.
• Prophylactic treatment for the prevention of migraine headaches.
• Treatment of systolic & diastolic forms of heart failure
• management of hypertrophic subaortic stenosis
• Adjunct therapy with alpha blockers in treatment of pheochromocytoma
• Management of familial or hereditary essential tremor
 Propranolol
 Contraindications:  Side Effects:

• Cardiogenic shock • Bradycardia

• Congestive heart failure (a dose-dependent effect; low doses are

• Sinus bradycardia and greater
used to treat heart failure)
than first degree block
• Intensification of AV block
• Bronchial asthma
• Hypotension

• Paresthesia of hands

• Light-headedness

• Mental depression manifested by insomnia, lassitude, weakness,

fatigue; sexual dysfunction in men
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