[PHARM] Thyroid and Anti-Thyroid Drugs

Question 1

What are the 4 thyroid drugs?

Answer 1

• Levothyroxine [T4]
• Liothyroxine [T3]
• Liotrix [a 4:1 ratio of T4:T3]
• Thyroid desiccated

Question 2

What are the 4 anti-thyroid agents?

Answer 2

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

Question 3

Which iodide transport enzyme controls the flow of iodide across the apical membrane of the thyroid follicular cell?

Answer 3

Pendrin

Question 4

Where is oral T₄ best absorbed within the GI tract?

Answer 4

Duodenum and ileum

Question 5

T4 and T3 absorption may be affected by what underlying condition?

Answer 5

Myxedema w/ ileus but NOT by mild hypothyroidism

Question 6

How does the half-life and clearance of T4 and T3 change in a hyperthyroid vs. hypothyroid state?

Answer 6

• Hyperthyroid = T4 and T3 clearance is ↑ and half-life ↓
• Hypothyroid = T4 and T3 clearance is ↓ and half-life ↑

Question 7

Which 6 agents inhibit 5’-deiodinase, blocking T4 to T3 conversion and increasing reverse T3 levels, and may be given in pt’s experiencing thyroid storm?

Answer 7

• Radiocontrast agents: iopanoic acid and ipodate
• Amiodarone
• β-blockers
• Corticosteroids
• PTU
• Flavanoids

Question 8

List 9 drugs/agents that decrease T4 absorption?

Answer 8

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

Question 9

List 7 drugs which induce hepatic CYP450s and increase the metabolism of T4 and T3?

Answer 9

• Rifampin
• Rifabutin
• Phenobarbital
• Phenytoin
• Protease inhibitors
• Carbamazepine
• Imatinib

Question 10

List 5 agents that are responsible for the induction of autoimmune thyroid diseas w/ hypo- or hyperthyroidism.

Answer 10

• Interferon-α
• Interferon-β
• Interleukin-2
• Lithium
• Amiodarone

Question 11

How long after administering thyroid hormone does it take to see the effects and why?

Answer 11

Lag time of hours or days due effects at the level of gene transcription

Question 12

After T3 enters the nucleus and binds the thyroid receptor (TR) what occurs?

Answer 12

• Corepressor is released and coactivator binds to the TR
• Homodimer separates, and TR binds to RXR (retinoid X receptor)
• Gene transcription ensues

Question 13

Even though T3 is 3-4x more potent than T4, why is it not recommended for routine replacement therapy?

Answer 13

• Short 1/2 life (requires multiple daily doses)
• Higher cost
• Difficulty w/ monitoring its adequacy of replacement

Question 14

What are preparations of T3 best used for clinically?

Answer 14

Short-term suppression of TSH

Question 15

What is the absorption, bioavailability, metabolism, half-life, and dosing like for the anti-thyroid drug, PTU?

Answer 15

• Rapidly absorbed, peak serum after 1 hour
• 50-80% bioavailability (incomplete absorption and/or large first-pass effect)
• Renal excretion (virtually all metabolites in 24 hrs)
• Half-life = 1.5 hours
• 3-4 doses/day (compared to 1x/day for Methimazole)

Question 16

What is the absorption, bioavailability, metabolism, half-life, and dosing like for the anti-thyroid drug, Methimazole?

Answer 16

• Completely absorbed
• Slower renal excretion than PTU (65% dose recovered - 48 hrs)
• Half-life = 6 hrs
• Once daily dosing

Question 17

Why are the anti-thyroid drugs, PTU and Methimazole, generally not recommended in pregnancy; which drug should be given if therapy is requied?

Answer 17

• Can cross the placenta and become concentrated in fetal thyroid
• PTU is recommended in first trimester
• Methimazole is drug of choice in second and third trimester

Question 18

What is the main MOA of both PTU and Methimazole?

Answer 18

• Inhibit thyroidal peroxidase-catalyzed rxns

- Blocks iodide organification

• Inhibits coupling of MIT and DIT to form T3 and T4

Question 19

How does the fall in T3 concentration with PTU + iodine differ from that of Methimazole + iodine?

Answer 19

PTU blocks peripheral conversion of T4 –> T3; significantly greater fall in [T3] and T3:T4 ratio

Question 20

What effect do PTU and Methimazole have on thyroid gland iodide uptake?

Answer 20

• Do NOT block thyroid gland iodide uptake
• Act to inhibit hormone synthesis, rather than release

Question 21

How long must therapy with PTU or Methimazole be given before stores of T4 and T3 are depleted?

Answer 21

3-4 weeks of therapy

Question 22

What are the most common AE’s associated with PTU or Methimazole?

Answer 22

• Maculopapular pruritic rash, at times accompanied by:
• Fever + nausea + GI distress

Question 23

What are some of the rare AE’s associated with PTU or Methimazole; which is more specific to each?

Answer 23

• Urticarial rash + Vasculitis + Lupus-like rxn
• LAD
• Hypoprothrombinemia
• Acute arthralgia
• Hepatitis (more common w/ PTU)
• Cholestatic jaundice (more common w/ methimazole)

Question 24

What is the most serious AE associated with PTU or Methimazole; who is most at risk and how is this condition reversed?

Answer 24

• Agranulocytosis (granulocyte count <500 cells/mm³)
• Risk ↑ in older pt’s and those receiving high-dose methimazole
• Reversed w/ drug discontinuation and CSF’s

Question 25

What is the MOA of the monovalent anions perchlorate, pertechnetate, and thiocyanate as anti-thyroid agents?

Answer 25

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

Question 26

What is the MOA of the anti-thyroid agent, Potassium Iodide?

Answer 26

- **Inhibit organification** and **hormone release** - ↓ the **size** and **vascularity** of **hyperplastic thyroid gland**

Question 27

What are the 3 clinical uses of the anti-thyroid agent, Potassium Iodide?

Answer 27

1) **Thyroid storm** - thyrotoxic sx's **improve rapidly** (within 2-7 days) 2) **Preoperative reduction** of **hyperplastic thyroid** 3) **Block** thyroidal uptake of **radioactive isotopes** of iodine in a **radiation emergency** or other exposure to **radioactive iodine**

Question 28

Although uncommon, what are some of the AE's which may be seen with the anti-thyroid agent, Potassium Iodide?

Answer 28

- Acneiform rash - Swollen salivary glands - Mucous membrane ulcerations - Conjunctivitis - Metallic taste

Question 29

Who should you avoid giving the anti-thyroid agent, Potassium Iodide?

Answer 29

**Pregnant women**, since iodides can cross the placenta and cause **fetal goiter**

Question 30

What effect does radioactive iodinde (¹³¹I) have on the thyroid?

Answer 30

**β-ray radiation** causes **destruction** of **thyroid parenchyma**, evidenced by **epithelial swelling, follicular disruption, edema**, and **leukocyte infiltration**

Question 31

What is radioactive iodinde (¹³¹I) used for and what are the advantages of using it?

Answer 31

- For tx of **thyrotoxicosis** - Advantages = **ease of administration**, **effectiveness**, **low expense**, and **absence of pain**

Question 32

Which β-blockers are effective adjunctive agents in the management of thyrotoxicosis and which is most commonly used?

Answer 32

- Those **w/o** sympathomimetic activity (i.e., **metoprolol**, **propranolol**, and **atenolol**) - **Propranolol** is **_most commonly_ used**

Question 33

What effect do β-blockers have on thyroid levels?

Answer 33

- Improve hyperthyroid sx's, but typically do **not** alter levels - **High doses** of **propranolol** have been shown to reduce **T3** through **blockade** of **peripheral** conversion of T4 --\> T3

Question 34

Radioactive iodine ¹³¹I is contraindicated in whom?

Answer 34

**Women** who are **pregnant** or **breast feeding**

Question 35

Which anti-thyroid drugs are considered safe in women who are breast feeding?

Answer 35

The **thiomides** ---\> **PTU** and **Methimazole**

Question 36

How do adults differ from infants/children in the amount of T4 needed per body weight?

Answer 36

**Infants**/**children** require **MORE** T4 per body weight than adults

Question 37

How should T4 be given and how long does it take to reach steady state levels?

Answer 37

- Given on **empty stomach** (due to interactions with foods and drugs) - Takes **6-8 weeks** to reach **steady-state levels**

Question 38

How is hypothyroidism managed in someone with myxedema coma as far as route of administration and dosing?

Answer 38

- Give **T4** via **IV** due to **poor absorption** in pt's w/ myxedema coma - **Large loading dose** of **T4** followed by **smaller IV dosing**

Question 39

How should a patient with myxedema and coronary artery disease be managed with T4?

Answer 39

Correction of myxedema with T4 must be done **cautiously** to **avoid** provoking **arrhythmia**, **angina**, or **acute MI** (sx's of elevated T4)

Question 40

Why is management of hypothyroidism in pt's trying to get pregnant and those currently pregnant so important?

Answer 40

- Hypothyroid women are typically **infertile** until restoration of normal thyroid levels - **Maintenance** of normal levels is **crucial** due to **fetal brain development** dependence of maternal T4

Question 41

When is anti-thyroid drug therapy most useful for Grave's disease and what are the preferred agents?

Answer 41

- Most useful in **young pt's** w/ **small glands** and **mild disease** - **Methimazole** or **PTU** administered until **remission** (12-18 mo. of tx) - **Methimazole** is **preferable** to **PTU** (**EXCEPT in pregnancy**) due to once-daily dosing

Question 42

When is a thyroidectomy the preferred tx for Grave's disease and what % of these pt's will require thyroid supplementation?

Answer 42

- Tx of choice for pt's w/ **very large glands** or **multinodular goiter** - **80-90%** will require thyroid supplementation

Question 43

When is radioactive iodine the preferred tx for Grave's disease; what about in pt's w/ underlying heart disease, severe toxicosis, and the elderly?

Answer 43

- Preferred tx for **most** pt's **\>21 years of age** - In pt's w/ underlying heart disease, severe thyrotoxicosis, or elderly tx w/ **anti-thyroids** until pt is **euthyroid** is **preferable** - **80%** will develop hypothyroidism and require replacement therapy

Question 44

What are the adjunct drugs which can be added to anti-thyroid therapy in pt with Graves?

Answer 44

- **β-blockers w/o intrinsic sympathomimetic activity** may be helpful in controlling tachycardia, HTN, and atrial fibrillation - If β-blocker is contraindicated can give the **CCB**, **diltiazem**, for management of **tachycardia**

Question 45

Which drugs are indicated for treating thyroid storm (thyrotoxic crisis) and why is each given?

Answer 45

- **β-blockers** to control the **arrhythmia** - **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 conversion of T4 to T3 in peripheral tissues/blood - **Supportive therapy** to control any underlying issues

Question 46

In the rare situation where anti-thyroid agents are inadequate in controlling thyroid storm, what can be done?

Answer 46

**Plasmapheresis** or **peritoneal dialysis** may be used to lower levels of circulating T4