Drugs For Thyroid Disorders

Question 1

List 4 pro-thyroid agents

Answer 1

Levothyroxine [T4]
Liothyronine [T3]
Liotrix [4:1 ratio of T4:T3]
Thyroid desiccated

Question 2

List 4 antithyroid agents

Answer 2

Radioactive iodine (131I) sodium
Methimazole
Potassium iodide
Propylthiouracil (PTU)

Question 3

During thyroid hormone biosynthesis, an intrinsic cell basement membrane protein called the sodium/iodide symporter (NIS) transports iodide into the thyroid gland.

______, an apical iodide transport enzyme, controls the flow of iodide across the membrane (this transporter is also found in the cochlea). Iodide is then oxidized by ____________ at the apical cell membrane before rapidly iodinating _______ residues within the thyroglobulin molecule to form MIT and DIT.

T4, T3, MIT, and DIT are released from the thyroid gland by exocytosis and proteolysis at the apical cell border. Most of the hormone released is in the ____ form

Answer 3

Pendrin; thyroid peroxidase; tyrosine

T4

Question 4

T3 and T4 are reversibly bound to _____ in plasma. Free levels of thyroid hormone are low, with only 0.04% total T4 and 0.4% total T3 existing in the free form.

During peripheral metabolism, T4 is primarily deiodinated to ______ or _____. T4 may be inactivated by deamination, decarboxylation, or conjugation

Answer 4

Thyroxine-binding globulin (TBG)

T3 (3,5,3’-triiodothyronine); reverse T3 (3,3’5’-triiodothyronine)

[T3 is 4x more potent than T4; reverse T3 is metabolically inactive]

Question 5

Oral bioavailability of T3 vs T4

Answer 5

Oral bioavailability of T3 is 95% with half life of 1 day

Oral bioavailability of T4 is 80% with half life of 7 days — best absorbed in duodenum and ileum; affected by food, drugs, gastric acidity, intestinal flora, etc.

Question 6

T4 and T3 may be affected by myxedema with _____ but not by mild hypothyroidism (IV route is preferred parenteral administration for T4 and T3 if necessary)

Answer 6

Ileus

Question 7

How is clearance and half life of T3 and T4 affected in pts with hyperthyroidism vs. hypothyroidism?

Answer 7

Hyperthyroidism: clearance increased, half life decreased

Hypothyroidism: clearance decreased, half life increased

Question 8

Agents that inhibit the conversion of T4 to T3 and increase reverse T3 levels

What is the clinical purpose of these agents?

Answer 8

Radiocontrast agents: iopanoic acid and ipodate
Amiodarone
Beta-blockers
Corticosteroids

Administered in patients who are experiencing thyroid storm (thyrotoxic crisis)

Question 9

Drugs that decrease T4 absorption

Answer 9

Antacids (aluminum hydroxide, calcium carbonate)
Ferrous sulfate
Cholestyramine
Colestipol
Ciprofloxacin
PPI’s
Bran
Soy
Coffee

Question 10

What effect do drugs like rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, imatinib, and protease inhibitors have on T3 and T4?

Answer 10

These drugs are Cyp450 inducers — they increase the metabolism of T3 and T4

Question 11

Iopanoic acid, ipodate, amiodarone, beta blockers, corticosteroids, propylthiouracil, and flavonoids exhibit inhibition of ___________, thus decreasing T3 and increasing the metabolically inactive reverse T3

Answer 11

5’-deiodinase

Question 12

Drugs that induce autoimmune thyroid disease with hypothyroidism or hyperthyroidism

Answer 12

IFN-a
IL-2
IFN-b
Lithium
Amiodarone

Question 13

General functions of thyroid hormones

Answer 13

Maturation and differentiation
Neurologic function
Growth
Metabolism
SNS function
Skeletal muscle
CV system
Reproduction

Question 14

Describe the thyroid hormone receptor

Answer 14

The thyroid receptor (TR, a member of the nuclear receptor superfamily) is bound to DNA at the thyroid hormone response element (TRE, a DNA sequence selectively recognized by the TR DNA-binding domain)

In the absence of hormone, the TR homodimer is bound to corepressor proteins and is inactive

Question 15

Describe the MOA of thyroid hormone via interaction with its receptor

Answer 15

T4 and T3 enter the cell by active transport and T4 is converted to T3 by 5’-deiodinase

T3 enters the nucleus where it binds to the TR, the corepressor is released and a coactivator binds, the homordimer separates, TR binds to RXR (retinoid X receptor), and gene transcription occurs

The action of thyroid hormone is manifested in vivo with a lag time of hours to days after administration due to effects at the level of gene transcription

Question 16

T/F: the affinity of the TR for T4 is roughly 10x higher than that for T3

Answer 16

False, it is roughly 10x lower

Question 17

Thyroid preparations may be synthetic or of animal origin (desiccated versions, which are rarely used). Of the T4 and T3 preparations available, _______ is the preparation of choice for thyroid replacement therapy due to its stability, low cost, lack of allergic foreign protein, easy lab measurement of serum levels, and long half-life, which permits once daily administration

Answer 17

Levothyroxine (T4)

Question 18

T3 is 3-4x more potent than T4, so why isn’t T3 recommended for routine thyroid replacement therapy?

Answer 18

Because of its short half-life (requires multiple daily doses), higher cost, and difficulty monitoring its adequacy of replacement by conventional lab tests

Thus, T3 is best used for short-term suppression of TSH

Question 19

Thioamids used as anti-thyroid agents

Answer 19

Methimazole

Propylthiouracil (PTU)

Question 20

Pharmacokinetics of PTU

Answer 20

Rapidly absorbed; peak serum after 1 hour
50-80% bioavailability (incomplete absorption, first-pass effect)
Renal excretion (all metabolites w/i 24 hrs)
Accumulates in thyroid gland
Half-life 1.5h
3-4 doses/day

Question 21

Pharmacokinetics of methimazole

Answer 21

Completely absorbed
Accumulates in thyroid gland
Slower renal excretion than PTU (65% dose recovered in 48 hrs)
Half life 6 hours
Once daily dosing

Question 22

T/F: Thioamides are relatively contraindicated in pregnancy

Answer 22

True — they cross the placental barrier and are concentrated by the fetal thyroid; not recommended in pregnant females. They can be taken while breastfeeding because only released in breast milk at low concentrations

Question 23

If treatment with thioamides is required in pregnancy, _____ is the drug of choice in first trimester and _____ is the drug of choice in second and third trimesters

Answer 23

PTU; methimazole

Question 24

MOA of thioamides (PTU and methimazole)

Answer 24

Inhibits thyroid peroxidase-catalyzed reactions and blocks iodide organification (i.e., inhibits the synthesis of thyroid hormones by blocking the oxidation of iodide in the thyroid gland)

Also inhibits coupling of MIT and DIT to form T3 and T4

PTU blocks peripheral conversion of T4 to T3; a significantly greater fall in T3 concentration and the T3:T4 ratio may occur with PTU and iodine compared to methimazole and iodine

Does not block thyroid gland iodide uptake

Hormone synthesis, rather than release, is inhibited; requires 3-4 weeks of therapy before stores of T4 and T3 are depleted

Question 25

Most serious complication of treatment with thioamides

Answer 25

Agranulocytosis (granulocyte count <500 cells/mm)

Occurs in 0.1-0.5% of patients and can be reversed with drug discontinuation and colony-stimulating factors (risk increased in older patients and those receiving high-dose methimazole therapy)

Question 26

AEs of thioamides

Answer 26

Most commonly macolopapular pruritic rash, at times accompanied by systemic signs such as fever, nausea, and GI distress

Rare effects include urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy, hypoprothrombinemia, acute arthralgia

Hepatitis (more common with PTU) and cholestatic jaundice (more common with methimazole) can be fatal

Question 27

Anion inhibitors used to tx hyperthyroid

Answer 27

Monovalent anions: perchlorate (ClO4-), pertrechnetate (TcO4-), and thiocyanate (SCN-)

Question 28

MOA of anion inhibitors

Answer 28

Block thyroid gland uptake of iodide by competitively inhibiting the iodide transport mechanism

Question 29

T/F: effects of anion inhibitors can be overcome by large doses of iodides; and effects in general can be unpredictable so clinical usefulness is limited

Answer 29

True

Question 30

MOA of iodides used to tx hyperthyroidism

Answer 30

Inhibit organification and hormone release; decrease the size and vascularity of the hyperplastic thyroid gland

Question 31

Clinical use of iodides

Answer 31

Thyroid storm — thyrotoxic sxs improve rapidly (w/i 2-7 days)

Preoperative reduction of a hyperplastic thyroid gland

Block thyroidal uptake of radioactive isotopes of iodine in a radiation emergency or other exposure to radioactive iodine

Question 32

AEs of iodides

Answer 32

Adverse reactions are uncommon, but include acneiform rash, swollen salivary glands, mucous membrane ulcerations, conjunctivitis, metallic taste

Question 33

Recommendations of iodides in pregnancy

Answer 33

Should be avoided in pregnancy since iodides can cross the placenta and cause fetal goiter

Question 34

______ is the only isotope used for the tx of thyrotoxicosis. It is administered orally, rapidly absorbed, and concentrated by the thyroid before being incorporated into storage _____

Answer 34

131-I; follicles

Question 35

Effects of radioiodine’s beta-ray radiation

Answer 35

Destruction of thyroid parenchyma, evidenced by epithelial swelling and necrosis, follicular disruption, edema, and leukocyte infiltration

Question 36

Advantages and contraindications associated with radioiodine

Answer 36

Advantages: ease of administration, effectiveness, low expense, and absence of pain

Contraindicated in women who are pregnant or breast feeding

Question 37

Clinical indications for beta blockers in thyroid conditions

Answer 37

Beta blockers without sympathomimetic activity (e.g., metoprolol, propranalol, atenolol) are effective adjunctive agents in the management of thyrotoxicosis due to the fact that many symptoms of elevated thyroid hormone mimic those associated with sympathetic stimulation; They improve symptoms of hyperthyroid but do not typically alter thyroid levels

Propranolol is most commonly used. High doses of propranalol have been shown to reduce T3 levels by approx 20% by blocking the peripheral conversion of T4 to T3

Question 38

Important consideration when treating hypothyroidism in children vs. adults

Answer 38

Infants and children require more T4 per body weight than adults

Question 39

End state of untreated hypothyroidism associated with progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, water intoxication, shock, and death

Answer 39

Myxedema coma

Question 40

Tx of myxedema coma

Answer 40

All preparations for tx are typically given IV d/t poor absorption in pts in myxedema coma

Large loading dose T4 followed by smaller IV dosing

Question 41

Tx of myxedema in the setting of CAD

Answer 41

Correction of myxedema with T4 must be done cautiously to avoid provoking arrhythmia, angina, or acute MI (all symptoms of elevated T4 levels)

Question 42

Considerations when treating hypothyroidism in pregnancy

Answer 42

Women who are hypothyroid are typically infertile until restoration of normal thyroid levels

Maintenance of normal levels is crucial as fetal brain development depends on maternal T4

Question 43

Tx of Grave’s disease may involve anti-thyroid drug therapy, thyroidectomy, radioactive iodine, and adjuncts to anti-thyroid therapy

Describe tx of Grave’s with anti-thyroid drug therapy

Answer 43

Anti-thyroid drug therapy is most useful in young pts with small glands and mild disease

Methimazole or PTU is administered until remission (12-18 mos of tx and 50-68% incidence of relapse)

Methimazole is preferable to PTU (except in pregnancy) d/t once daily administration

Question 44

Tx of Grave’s disease may involve anti-thyroid drug therapy, thyroidectomy, radioactive iodine, and adjuncts to anti-thyroid therapy

Describe tx of Grave’s with thyroidectomy

Answer 44

Tx of choice for pts with very large glands or multinodular goiters

80-90% will require thyroid supplementation

Question 45

Tx of Grave’s disease may involve anti-thyroid drug therapy, thyroidectomy, radioactive iodine, and adjuncts to anti-thyroid therapy

Describe tx of Grave’s with radioactive iodine

Answer 45

Preferred tx for most pts over age 21

In pts with underlying heart disease or severe thyrotoxicosis and in elderly pts, treatment with anti-thyroid drugs until pt is euthyroid is preferable

80% will develop hypothyroidism and require replacement therapy

Question 46

Describe adjuncts to anti-thyroid therapy used in pts with Grave’s disease

Answer 46

Administration of beta blockers without sympathomimetic activity is beneficial

Beta blockers can control tachycardia, HTN, and atrial fibrillation

Diltiazam (calcium channel blocker) can be used to manage tachycardia in pts in whom beta blockers are contraindicated

Question 47

Describe tx of thyroid storm (thyrotoxic crisis)

Answer 47

Beta blockers to control arrythmia

Potassium iodide to prevent release of thyroid hormones from thyroid gland

PTU or methimazole to block hormone synthesis

IV hydrocortisone to protect against shock and to block peripheral conversion of T4 to T3

Supportive therapy to control any underlying issues

In rare situations where the above is inadequate, plasmapheresis or peritoneal dialysis may be used to lower the levels of circulating T4

Question 48

Which of the following is expected after TSH receptor activation? Activation of:

A. Adenylyl cyclase
B. Gene transcription
C. Jak/stat signaling pathway
D. MAP kinase pathway
E. Thyroid hormone receptor

Answer 48

A. Adenylyl cyclase

[TSH receptor is a GPCR]

Question 49

An agent is administered that blocks iodide organification. Hepatitis is of concern. Which of the following was most likely prescribed?

A. Bromocriptine
B. Isoniazid
C. Perchlorate
D. Propylthiouracil
E. Radioactive iodine

Answer 49

D. Propylthiouracil

Question 50

A pt is prescribed PTU q8h. After 4 weeks of therapy, she returns to the clinic with complaints of flu-like symptoms (chills, fever, sore throat), which have occurred over the past 2 days. She also reports a 2-day hx of a temperature of over 101 F. Which of the following lab results may be found in this patient at this time and could explain her presenting symptoms?

A. AST — 45 units/L (normal, 0-35)
B. Creatinine — 2.1 mg/dL (normal 0.6-1.2)
C. FT4 — 0.3 ng/dL (normal, 0.7-1.9)
D. Hct — 25% (normal female, 33-43)
E. Neutrophils — 450/mm (normal, 1500-5000)

Answer 50

E. Neutrophils — 450/mm (normal, 1500-5000)

Question 51

What course of action will most likely improve PTU-induced agranulocytosis? Discontinuation of PTU and:

A. Epoetin-alpha
B. Alprazolam
C. Filgrastim
D. Cyanocobalamin (Vit B12)
E. Pyridoxine (Vit B6)

Answer 51

C. Filgrastim — G-CSF — stimulates proliferation and differentation of progenitors already committed to neutrophil lineage

Question 52

A 24-year-old woman was found to have mild hyperthyroidism due to Graves’ disease. She appears to be in good health otherwise.

In Graves’ disease, the cause of the hyperthyroidism is the production of an antibody that does which of the following?

A. Activates the pituitary thyrotropin-releasing hormone (TRH) receptor and stimulates TSH release
B. Activates the thyroid gland TSH receptor and stimulates thyroid hormone synthesis and release
C. Activates thyroid hormone receptors in peripheral tissues
D. Binds to thyroid gland thyroglobulin and accelerates its proteolysis and the release of its supply
of T4 and T3
E. Binds to thyroid-binding globulin (TBG) and displaces bound T4 and T3

Answer 52

B. Activates the thyroid gland TSH receptor and stimulates thyroid hormone synthesis and release

The antibodies produced in Grave’s disease activate thyroid gland TSH receptors. Their effects mimic those of TSH.

Question 53

A 24-year-old woman was found to have mild hyperthyroidism due to Graves’ disease. She appears to be in good health otherwise.

The decision is made to begin treatment with methimazole. Methimazole reduces serum concentration of T3 primarily by which of the following mechanisms?

A. Accelerating the peripheral metabolism of T3
B. Inhibiting the proteolysis of thyroid-binding globulin
C. Inhibiting the secretion of TSH
D. Inhibiting the uptake of iodide by cells in the thyroid
E. Preventing the addition of iodine to tyrosine residues on thyroglobulin

Answer 53

E. Preventing the addition of iodine to tyrosine residues on thyroglobulin

The thioamides (methimazole and PTU) act in thyroid cells to prevent conversion of tyrosine residues in thyroglobulin to MIT or DIT

Question 54

Though rare, a serious toxicity associated with the thioamides is which of the following?

A. Agranulocytosis
B. Lupus erythematosus-like syndrome
C. Myopathy
D. Torsades de pointes arrhythmia
E. Thrombotic thrombocytic purpura (TTP)

Answer 54

A. Agranulocytosis

Rarely, the thioamides cause severe adverse reactions that include agranulocytosis, vasculitis, hepatic damage, and hypoprothrombinemia

Question 55

A 56-year-old woman presented to the emergency department with tachycardia, shortness of breath, and chest pain. She had had shortness of breath and diarrhea for the last 2 d and was sweating and anxious. A relative reported that the patient had run out of methimazole 2 wk earlier. A TSH measurement revealed a value of <0.01 mIU/L (normal 0.4–4.0 mIU/L). The diagnosis of thyroid storm was made. Which of the following is a drug that is a useful adjuvant in the treatment of thyroid storm?

A. Amiodarone
B. Betamethasone
C. Epinephrine
D. Propranolol
E. Radioactive iodine

Answer 55

D. Propranolol

In thyroid storm, beta blockers such as propranalol are useful in controlling the tachycardia and other cardiac abnormalities, and propranalol also inhibits peripheral conversion of T4 to T3

Question 56

A 65-year-old man with multinodular goiter is scheduled for a near-total thyroidectomy. Which of the following drugs will be administered for 10–14 d before surgery to reduce the vascularity of his thyroid gland?

A. Levothyroxine
B. Liothyronine
C. Lugol’s solution (mixture of potassium iodide and iodine)
D. Prednisone
E. Radioactive iodine

Answer 56

C. Lugol’s solution (mixture of potassium iodide and iodine)

Iodides inhibit the synthesis and release of thyroid hormone and decrease the size and vascularity of the hyperplastic gland. Lugol’s solution contains a mixture of potassium iodide and iodine

Question 57

Which of the following is a sign or symptom that would be expected to occur in the event of chronic overdose with exogenous T4?

A. Bradycardia
B. Dry, puffy skin
C. Large tongue and drooping of the eyelids 
D. Lethargy, sleepiness
E. Weight loss

Answer 57

E. Weight loss

In hyperthyroidism, the metabolic rate increases, and even though there is increased appetite, weight loss often occurs. The other choices are symptoms seen in hypothyroidism

Question 58

When initiating T4 therapy for an elderly patient with longstanding hypothyroidism, it is important to begin with small doses to avoid which of the following?

A. A flare-up of exophthalmos
B. Acute renal failure
C. Hemolysis
D. Overstimulation of the heart E. Seizures

Answer 58

D. Overstimulation of the heart

Pts with longstanding hypothyroidism, especially those who are elderly, are highly sensitive to the stimulatory effects of T4 on cardiac function. Administration of regular doses can cause overstimulation of the heart and cardiac collapse

Question 59

A 27-year-old woman underwent near total thyroidectomy. She was started on levothyroxine. What hormone is produced in the peripheral tissues when levothyroxine is administered?

A. Methimazole 
B. T3
C. T4
D. TSH
E. FSH

Answer 59

B. T3

Question 60

A 62-year-old woman presents with complaints of fatigue, sluggishness, and weight gain. She needs to nap several times a day, which is unusual for her. She has been taking T4 for the past 15 yr without significant problems regarding her energy level. Her recent history is significant for diagnosis of arrhythmia, and she is currently taking an antiarrhythmic drug. What is the most likely cause of her current condition?

A. Amiodarone 
B. Lidocaine
C. Procainamide 
D. Sotalol
E. Verapamil

Answer 60

A. Amiodarone

Amiodarone is an iodine-containing antiarrhythmic drug with complex effects on the thyroid gland and thyroid hormones. One of its actions is to inhibit peripheral conversion of T4 to T3. Note that propranalol also reduces conversion of T4 to T3. Procainamide (class 1A), lidocaine (class 1B), sotalol (class III), and verapamil (class IV) are antiarrhythmics and have no effect on T4 conversion

Question 61

A 25-year-old woman presents with insomnia and fears she may have “something wrong with her heart.” She describes “her heart jumping out of her chest.” She feels healthy otherwise and reports she has lots of energy. Lab tests confirm hyperthyroidism. Which of the following is a drug that produces a permanent reduction in thyroid activity?

A. 131-I
B. Methimazole
C. Propylthiouracil
D. Thiocyanate (SCN–) 
E. Thyroglobulin

Answer 61

A. 131-I

Radioactive iodine is the only medical therapy that produces a permanent reduction of thyroid activity. Anions such as thiocyanate (SCN-) and perchlorate (ClO4-) block the uptake of iodide by the thyroid gland through competitive inhibition of the iodide transporter. Their effectiveness is unpredictable and ClO4- can cause aplastic anemia, so these drugs are rarely used