I do not have any conflicts.

Anti-thyroid drugs Sean Thatcher, PhD

sean.thatcher@temple.edu

At the end of the lecture, the student should be to:

1. Explain the regulation and the key steps in thyroid hormone synthesis and peripheral conversion.
2. Identify the mechanisms by which thyroid hormones regulate cellular function (e.g. cardiomyocyte).
3. Identify the signs and symptoms of hypothyroidism (myxedema) and the consequences of the disease that can alter drug therapy for
other concurrent diseases.
4. Explain the relationship between thyroid hormones and the actions of catecholamines and the rationale for the use of propranolol in the
treatment of hyperthyroidism.
5. Identify the best index of adequate replacement therapy with thyroid hormone.
6. Explain the pharmacokinetic rationale (half-life and absorption) for selecting the most appropriate form of thyroid hormone as
replacement therapy.
7. Describe potential adverse effects of replacement therapy with levothyroxine.
8. Outline the adverse effects of antithyroid medications and identify those that are potentially life threatening.
9. Explain the necessary cautions when replacing thyroid hormone in a patient with a history of coronary artery disease.
10. Explain the rationale and the administration of drugs given to treat thyroid storm.
11. Explain the rationale for the uses of drugs/radioiodine in treating hyperthyroidism; explain their mechanism of action, and consequences
of radioiodine use.
Iodide intake levels and functions of thyroid hormone
• Recommended daily iodide intake:
• 150 µg adults
• 200 µg pregnancy and lactation
• 250 µg children

• Thyroid hormone is necessary for:

• Growth and development, especially
CNS/skeleton
• Maintain body temperature
• Maintain energy levels

• Calcitonin is a hormone produced by Image taken from cusabio

the parafollicular cells (C-cells) of the

thyroid gland
 Thyroid hormone production
• Symporter  sodium-iodide (Na+/I-) TSH stimulates gene transcription of TPO
transporter responsible for getting iodide +
into the thyroid gland.
• Thyroid peroxidase (TPO) oxidizes I- to (storage)
make it I0
• This will allow for organification of iodide to
make MIT and DIT.

• There are multiple steps where excess

iodide can block the production and
release of T4/T3 (Wolff-Chaikoff effect).
This effect can last around 10 days. After
this, an escape mechanism will occur and
some thyroid hormone can be produced.
Endocrine positive and negative
feedback loops for thyroid hormone
• TRH/TSH/T3 and T4 are released in a
circadian manner (highest at night).

• Stress and the use of corticosteroids will

block TRH or TSH, respectively.
Thyroid-stimulating
immunoglobulin (TSI)
• Thyroid hormone helps in thermogenesis (Graves’ disease)
++
and cold can activate the release of TRH.

• Somatostatin blocks growth hormone and

thyroid hormone signaling. It blocks TSH
release.
Thyroid hormone signaling exerts both
genomic and non-genomic effects Non-genomic effects

• Thyroid hormone
signaling is tightly
associated with
cardiovascular function.
• Because it is a hormone,
it has both acute and
long-term effects.
• Can influence calcium
handling, contractile
function, and adrenergic Positive
sensitivity. inotropic effect
and lusitropic
effect
Taken from Barreto-Chaves MLM et al., Endocrine Connections, 2020
T3 versus T4 effects
• T3 is 3-4 times more potent
T4 5
than T4. T3
=
1
• Primarily bound to in circulation
(T4)
thyroxine-binding globulin D1 & D2 D3
(TBG).
• 80% of T3 comes from T4
peripheral metabolism
through deiodination.
• 0.04% total T4 and 0.4% of T3
exist as free forms.
Peripheral metabolism of thyroxine

• Of the 80% that is metabolized,

40% is by D1 & D2, and 40% is by
D3. The remaining 20% is
metabolized in other pathways.
• D1 ↑ hyperthyroidism
• D1 ↓ hypothyroidism
• D1 is inhibited by propylthiouracil
(PTU)(one of the MOA).
• T4 induces ubiquitination and
degradation of D2.
 Thyroid hormone kinetics
Variable T4 T3
Volume of distribution 10 L 40 L
Daily production 75 µg 25 µg
Half-life 7 days 1 day
Total levels 4.8-10.4 µg/dl 60-181 ng/dl 102 order of magnitude difference
Free levels 0.8-2.7 ng/dl 230-420 pg/dl in total and free levels.
Amount bound to TBG 99.96% 99.6%
Potency 1 4
Oral absorption 70-80% 95%

L-forms of thyroid hormones are the natural and bioactive forms. D-isomers have very little activity.

Thyroid hormones can be given orally or through IV (parenteral).

 Factors that can influence thyroxine binding
to thyroxine-binding globulin
Increase binding Decrease binding
Drugs
Estrogens, tamoxifen Corticosteroids, androgens, danazol
Methadone, heroin L-Asparaginase, furosemide
Clofibrate, 5-fluorouracil Salicylates, mefenamic acid
Antiseizure medications (phenytoin, carbamazepine)
Systemic factors
Liver disease, porphyria Acute and chronic illness
HIV infection Inheritance
Inheritance
Pregnancy
From Table 38-3 in Katzung textbook

Drugs that can increase thyroxine binding to TBG will result in a decrease in the free fraction, initially.
Drugs that can decrease thyroxine binding to TBG will result in an increase in the free fraction, initially.
There are also effects of drugs on thyroid
hormone synthesis
Inhibition of TRH or TSH secretion without induction *Inhibition of thyroid hormone synthesis or release
of hypo- or hyperthyroidism (FYI) with induction of hypothyroidism (occasionally can
be hyperthyroidism)
Dopamine, levodopa Amiodarone
Somatostatin Lithium
Metformin Thioamides (PTU/methimazole)
Heroin HIV protease inhibitors
Interleukin-6 Tyrosine kinase inhibitors (chemotherapy)

From Table 38-3 in Katzung textbook

*Just know the second column, the first column is FYI.

Effects of thyroid function on other drug classes
From Table 38-3 in Katzung textbook

Effect of thyroid function

on drug classes
Anticoagulation Lower doses of warfarin required in hyperthyroidism; higher doses with hypo-
Other drugs that work as inhibitors of thrombin (e.g. dabigatran) or Factor Xa
inhibitors (e.g. rivaroxaban) would also require lower dosing in hyperthyroid
patients.
Glucose control Increased hepatic glucose production and glucose intolerance in hyper- (insulin
resistance); impaired glucose disposal in hypo-
Cardiac drugs Higher doses of digoxin required in hyper-; lower doses in hypo-
Sedatives and analgesics Increased sedative and respiratory depressant effects in hypo-; decreased sedative
effects in hyper-

Increased dosages of drugs are needed to treat glucose intolerance, cardiac issues, or CNS depressants if the
patient has hyperthyroidism. All of this is due to increased metabolic rate or increased clearance of the drug.

For warfarin, hyperthyroidism causes a decrease in vitamin K-dependent clotting factor production while
catabolism of the clotting factors increases. Therefore, you will need lower doses of warfarin for patients with
hyperthyroidism.
Myxedema coma does not require the patient to be
in a coma

One year post-

treatment of
thyroid hormone
(Panels C and D).

56 yo woman who had not received medical care for 30 years presented to the ER with progressively worsening fatigue and
confusion. On physical exam, she was disoriented but conversant. Vital signs were notable for hypothermia (93°F), heart
rate of 50 BPM, and respiration of 12 breaths per minute. She had edema for the face, coarse skin, thin hair, brittle nails.
Biochemical eval showed a TRH level of 258 mIU/L. (normal range is 0.4-4.2) and a free thyroxine level of 0.1 ng/dl (normal
range is 0.8-2.2 ng/dl). Serum sodium was 130 mM (normal range is 136-146 mM). Patient was admitted to receive IV
repletion of thyroid hormone. IV administration was given since there may be edema of the GI which would limit drug
absorption. Joyce Kim, NEJM, 2015.
 Clinical parameters for a patient that has hypothyroidism
Organ system Hypothyroidism
Skin and appendages Pale, cool, puffy, yellowish skin, face, and hands; dry and brittle hair; brittle nails
Eyes, face Drooping of eyelids, periorbital edema, puffy, nopitting facies, large tongue, tooth imprints
on tongue
Cardiovascular system Increased peripheral vascular resistance, decreased heart rate, stroke volume, cardiac output
Respiratory system Hypoventilation and CO2 retention; sleep apnea
GI system Decreased appetite, constipation, ascites
CNS Lethargy/fatigue, slowing of mental processes, weakness and muscle cramps
Musculoskeletal system Stiffness and muscle fatigue; carpal tunnel syndrome, decreased deep tendon reflexes,
increased lactose dehydrogenase (LDH)
Renal system Impaired water excretion, decreased GFR
Hematopoietic system Decreased erythropoiesis; could have normochromic, hyper- or hypochromic due to
decreased production rate, decreased iron/folic acid absorption
Reproductive system Decreased gonadal steroid metabolism, infertility, decreased libio; menorrhagia
Metabolic system Decreased metabolic rate, decreased drug metabolism, increased warfarin requirement

Taken from Table 38-4 of Katsung textbook

 Levothyroxine (Synthroid®), a synthetic form of
thyroxine (T4), is used to treat hypothyroidism
• Pharmacotherapeutic uses:
• Congenital or acquired hypothyroidism (replacement therapy in thyroidal, pituitary, and hypothalamic)
• Adjunct to surgery for patients with thyroid cancer (hypo-related cancers)

• Pharmacokinetics
• Therapeutic index is low. Must be careful in administration.
• Dose of levothyroxine should be titrated slowly and yearly measures of TSH should be performed.
• Should be taken on an empty stomach. Certain foods (bran, soy, coffee) and drugs can interfere with
absorption. Celiac disease and H. pylori gastritis can also interfere if not treated.

• Adverse effects include:

• Angina, arrhythmias (particularly in elderly), increased bone resorption (could suppress parathyroid
hormone (PTH)), may worsen glycemic control in diabetics.

• Will need to lower dose in elderly with a history of cardiovascular disease.

Triiodothyronine (Liothyronine, T3) is not
recommended for routine replacement therapy
• Pharmacotherapeutic uses
• As an adjunct therapy to surgery and radioiodine in the management of thyroid cancer.
• As a diagnostic agent in suppression tests for mild hyperthyroidism

• Pharmacodynamics in comparison to levothyroxine

• More potent and has a faster onset of action
• Pharmacokinetics
• Half-life of 1 day
• Typically given IV, but can be given orally
• Route of elimination is mainly renal, small portion can be part of enterohepatic
recirculation.
• Adverse effects
• Must be careful in administration to patients with cardiovascular disease.
Amiodarone-induced hypothyroidism
• Amiodarone is an anti-arrhythmic drug (class III).
• Used to treat atrial fibrillation (off-label), ventricular fibrillation, and unstable
ventricular tachycardia.
• Long half life approx. 58 days (range 9-100 days)
• Effects on thyroid hormone
• Blocks peripheral conversion of T4 to T3

• 3% of patients that receive amiodarone can develop thyrotoxicosis.

• Iodine-induced (type I)  administer thioamides
• Inflammatory thyroiditis (type II)  administer glucocorticoids
• In some cases, if you cannot differentiate, then both drugs will be administered.
Lithium has been associated with
hypothyroidism
• Lithium is used in the treatment of mood disorders including bipolar
disease.
• Study found there was an increased risk among women less than 60
years of age.
• Should not use Lithium if patient presents with a goiter or has a
strong family history.
• Lithium impairs uptake of iodine, blocks organification, and impairs
release of T4/T3 from thyroid gland.
• Lithium has been used off-label to treat refractory hyperthyroidism.
Summary for hypothyroidism and drugs for
treatment
• TRH from the hypothalamus causes release of TSH from anterior
pituitary which will result in mainly the release of T4 from thyroid gland.
• T4 and T3 can bind to TBG and there are drugs and systemic factors that
can influence the binding of thyroid hormones to TBG.
• Patients that develop severe hypothyroidism can become myxedemic.
For children, cretinism can develop which can influence growth and
mental status.
• Hypothyroidism can result in a number of clinical manifestations.
Levothyroxine is a synthetic form of T4 and is used in replacement
therapy.
Graves’ disease is an autoimmune disorder
leading to overactivity of the thyroid gland
• Autoimmune disease where body produces
thyroid stimulating immunoglobulin (TSI).
Has a greater affinity for receptor than TSH.
• Treatments include:
• Radioactive iodine
• Propylthiouracil (PTU) or methimazole
• Surgery
• Beta-blockers to provide symptomatic relief
(Calcium channel blockers if beta-blockers are
contraindicated)
• Rituximab may also be given to treat
orbitopathy (blocks CD20 on B-lymphocytes)
• If left untreated, Graves’ disease can cause Taken from www.uspharmacist.com

severe thyrotoxicosis or thyroid storm.

Clinical parameters for a patient with hyperthyroidism
Organ system Hyperthyroidism (or thyrotoxicosis)
Skin and appendages Warm, excessive sweating, heat intolerance, thin hair, Plummer’s nails
Eye and face Retraction of upper lid with wide stare; exopthalmos
Cardiovascular Decreased peripheral vascular resistance, increased heart rate, cardiac output
Respiratory Dyspnea, decreased vital capacity
GI Increased appetite, increased frequency of bowel movements; hypoproteinemia
CNS Nervousness, hyperkinesia, agitation
Musculoskeletal Increased deep tendon reflexes, tremors, hypercalcemia, osteoporosis
Renal Mild polyuria, increased GFR
Hematopoietic Increased erythropoiesis, increased RBC turnover so patient could be anemic
Reproductive Amenorrhea, increased gonadal steroid metabolism
Metabolic Increased basal metabolic rate, negative nitrogen balance, hyperglycemia, increased
drug metabolism, decreased warfarin requirement
Taken from Table 38-4 of Katsung textbook
Radioactive iodine (I131)
• Because iodine is preferentially taken
up by the thyroid gland, ingestion of I131
is the preferred treatment for most
patients over 21 years of age.

• If patients have heart disease or severe

thyrotoxicosis, then use of methimazole
is preferred until patient is euthyroid.

• 6-12 weeks following administration,

the gland will shrink in size. If not, a
second dose may be administered.
 Propylthiouracil (PTU) inhibits the synthesis of
thyroxine and inhibits peripheral conversion via D1
• Pharmacotherapeutic uses:
• Overactive thyroid gland (e.g., Graves’ disease)
• First trimester of pregnancy
• Mechanism of action
• PTU binds to thyroid peroxidase inhibiting it. It also blocks D1 to prevent
deiodination to go from T4 to T3. Therefore, it blocks the production of T3.
• Onset of action is slow due to not blocking release of T4 from thyroid
gland. Takes 3-4 weeks before stores of T4 are depleted.
• Pharmacokinetics
• Rapidly absorbed, peak after 1 hour
• High volume of distribution, however short half-life (1.5 hours) due to high
clearance and biotransformation.
• Accumulates in the thyroid gland and typically is dosed every 6-8 hours.
• Adverse effects
• Agranulocytosis, elevations in AST/ALT (liver enzymes)
• Has a black box warning to induce severe hepatitis.
Methimazole has a longer half-life and there is less
potential for hepatic toxicity compared to PTU
• Pharmacotherapeutic uses:
• Mild to moderate severe thyrotoxicosis
• Second and third trimester of pregnancy

• Mechanism of action
• Inhibition of thyroid peroxidase (TPO)
• Pharmacokinetics
• Has longer half-life than PTU (5-7 hours) therefore can dose once per day

• Adverse effects
• Pruritic rash, nausea, and GI distress, altered sense of taste or smell
• Agranulocytosis (e.g., neutropenia)
• Jaundice, anorexia, pruritus, and elevation in liver AST/ALT
• There is a potential for hepatic toxicity, but it is lower than PTU
Thyroidectomy is the treatment of choice if the
patient has very large glands or multinodular goiters
• Patients will be treated
with PTU or methimazole
for 6 weeks to control
thyroid hormone levels.

• Two weeks before surgery,

patients receive potassium
iodide to diminish
vascularity of the gland and
to simplify surgery.
 Iodide salts and potassium iodide
• Different preparations  Lugol’s solution, potassium iodide, iodide
salts
• Inhibits organification and T4/T3 release
• Reduces the size and vascularity of the thyroid gland
• Rarely used as sole therapy
• Should be avoided if using radioactive iodine.
• Since iodide therapy can increase intraglandular stores of iodine, it
should be initiated after onset of thioamide therapy.

• Adverse effects
• Acneiform rash (similar to bromism), swollen salivary glands, metallic taste, Image taken from Wikipedia

mucous membrane ulcerations, conjunctivitis, bleeding disorders

Thyroid storm is a sudden acute exacerbation
that can be life threatening
• Must control cardiac output by giving a beta-blocker. If beta-blockers
are contraindicated, then give calcium channel blocker.
• Give PTU by mouth or rectally to block endogenous thyroid hormone
production.
• Give potassium iodide to block synthesis and release of thyroid
hormones.
• Hydrocortisone should also be given to protect against shock and will
help block the conversion of T4 to T3 and release of TSH.
• Can also give oral bile sequestrants (e.g., cholestyramine) to lower
levels of circulating thyroxine.
The 5 B’s
Block synthesis, block release, block T4 to T3, block peripheral effects, block enterohepatic recirculation
Propranolol and metoprolol are beta-adrenergic receptor
antagonists used in the treatment of thyroid storm
• Used in the treatment of thyroid storm
(thyrotoxicosis)
• Beneficial in patients over 60 yo with
cardiovascular disease
• Used to treat tachycardia, hypertension, Chemical structure of propranolol (Wikipedia)

and atrial fibrillation.

• Can use calcium channel blockers
(diltiazem, verapamil) if beta-blockers
are contraindicated (e.g., asthmatics).

Chemical structure of metoprolol (Wikipedia)

Summary of hyperthyroidism and drugs for
treatment
• A common cause for hyperthyroidism is Graves’ disease.
• Use of radioactive iodine is the preferred choice for an adult who is not
pregnant or have a history of cardiovascular disease.
• Use of antithyroid medications, such as PTU and methimazole, are used to
block the production of thyroid hormone. These have a slow onset of
action and require 3-4 weeks before stores are diminished and patient
becomes euthyroid.
• Thyroid storm can be life threatening and require a regiment of different
drugs to treat patient (remember the 5 B’s).
• Beta-blockers are given as adjuncts to antithyroid therapy to help lower
heart rate and cardiac output.
 Drugs utilized in the treatment of thyroid disease

Should also know about drugs that can induce hypo- or hyperthyroidism (e.g. amiodarone, lithium)
 Poll everywhere
TEXT SEANTHATCHER068 to 22333
Question #1 Respond with letter choice

Which of the following drugs would be influenced by a patient taking

levothyroxine with an elevated serum T4 and how would dosing of the
drug be adjusted?
A. Dabigatran; higher dosing
B. Aspirin; higher dosing
C. Warfarin; lower dosing
D. Allopurinol; lower dosing
E. 5-flurouracil; lower dosing
Question #2
The mechanism by which thiocyanate reduces synthesis of thyroid
hormones is by inhibition of which of the following?
A. Iodine oxidation by thyroid peroxidase
B. Iodide transport
C. TSH biosynthesis
D. Thyroid receptor-beta
Question #3
A 33-year-old man is noted to have tachycardia, heat intolerance,
weight loss, and an enlarged thyroid gland. Which of the following is
the probable ultimate treatment for this patient?
A. Long-term corticosteroid therapy
B. Propranolol therapy
C. Radioactive iodine
D. Surgical resection
FYI
Hyperthyroidism versus hypothyroidism
(clinical symptoms)
 FYI
Metabolic steps with inhibitors for the
production of thyroid hormone
FYI

Black box warning for PTU

 The End
Thank you for your attention!
Any questions?