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Flashcards in Drugs For Thyroid Disorders Deck (61)
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1
Q

List 4 pro-thyroid agents

A

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

2
Q

List 4 antithyroid agents

A

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

3
Q

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

A

Pendrin; thyroid peroxidase; tyrosine

T4

4
Q

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

A

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]

5
Q

Oral bioavailability of T3 vs T4

A

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.

6
Q

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)

A

Ileus

7
Q

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

A

Hyperthyroidism: clearance increased, half life decreased

Hypothyroidism: clearance decreased, half life increased

8
Q

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

What is the clinical purpose of these agents?

A

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

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

9
Q

Drugs that decrease T4 absorption

A
Antacids (aluminum hydroxide, calcium carbonate)
Ferrous sulfate
Cholestyramine
Colestipol
Ciprofloxacin
PPI’s
Bran
Soy
Coffee
10
Q

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

A

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

11
Q

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

A

5’-deiodinase

12
Q

Drugs that induce autoimmune thyroid disease with hypothyroidism or hyperthyroidism

A
IFN-a
IL-2
IFN-b
Lithium
Amiodarone
13
Q

General functions of thyroid hormones

A
Maturation and differentiation
Neurologic function
Growth
Metabolism
SNS function
Skeletal muscle
CV system
Reproduction
14
Q

Describe the thyroid hormone receptor

A

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

15
Q

Describe the MOA of thyroid hormone via interaction with its receptor

A

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

16
Q

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

A

False, it is roughly 10x lower

17
Q

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

A

Levothyroxine (T4)

18
Q

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

A

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

19
Q

Thioamids used as anti-thyroid agents

A

Methimazole

Propylthiouracil (PTU)

20
Q

Pharmacokinetics of PTU

A

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

21
Q

Pharmacokinetics of methimazole

A
Completely absorbed
Accumulates in thyroid gland
Slower renal excretion than PTU (65% dose recovered in 48 hrs)
Half life 6 hours
Once daily dosing
22
Q

T/F: Thioamides are relatively contraindicated in pregnancy

A

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

23
Q

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

A

PTU; methimazole

24
Q

MOA of thioamides (PTU and methimazole)

A

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

25
Q

Most serious complication of treatment with thioamides

A

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)

26
Q

AEs of thioamides

A

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

27
Q

Anion inhibitors used to tx hyperthyroid

A

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

28
Q

MOA of anion inhibitors

A

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

29
Q

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

A

True

30
Q

MOA of iodides used to tx hyperthyroidism

A

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

31
Q

Clinical use of iodides

A

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

32
Q

AEs of iodides

A

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

33
Q

Recommendations of iodides in pregnancy

A

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

34
Q

______ 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 _____

A

131-I; follicles

35
Q

Effects of radioiodine’s beta-ray radiation

A

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

36
Q

Advantages and contraindications associated with radioiodine

A

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

Contraindicated in women who are pregnant or breast feeding

37
Q

Clinical indications for beta blockers in thyroid conditions

A

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

38
Q

Important consideration when treating hypothyroidism in children vs. adults

A

Infants and children require more T4 per body weight than adults

39
Q

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

A

Myxedema coma

40
Q

Tx of myxedema coma

A

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

41
Q

Tx of myxedema in the setting of CAD

A

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

42
Q

Considerations when treating hypothyroidism in pregnancy

A

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

43
Q

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

A

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

44
Q

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

A

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

80-90% will require thyroid supplementation

45
Q

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

A

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

46
Q

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

A

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

47
Q

Describe tx of thyroid storm (thyrotoxic crisis)

A

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

48
Q

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
A

A. Adenylyl cyclase

[TSH receptor is a GPCR]

49
Q

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
A

D. Propylthiouracil

50
Q

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)

A

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

51
Q

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)
A

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

52
Q

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

A

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.

53
Q

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

A

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

54
Q

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)
A

A. Agranulocytosis

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

55
Q

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
A

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

56
Q

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
A

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

57
Q

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
A

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

58
Q

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

A

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

59
Q

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
A

B. T3

60
Q

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
A

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

61
Q

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
A

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