Thyroid and Anti-Thyroid Drugs

Question 1

4 Thyroid Drugs

Answer 1

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

Question 2

Anti-Thyroid Drugs

Answer 2

1. Thioamides: Methimazole & PTU (propylthiouracil))
2. Iodides: Potassium Iodide
3. Radioactive Iodine (¹³¹I) sodium
4. B-blockers: Metoprolol, propranolol, atenolol

Question 3

Thioamides (Anti-thyroid agent)

Answer 3

1. Methimazole
2. Propylthiouracil (PTU)

Question 4

Iodides (Anti-thyroid agent)

Answer 4

• Potassium Iodide

Question 5

B-Blockers (Anti-thyroid drugs)

Answer 5

1. Metaprolol
2. Propanolol
3. Atenolol

Question 6

How are thyroid hormones made? (steps)

Answer 6

1. NIS (Na+/iodide symporter) moves [iodide] into the thyroid follicular cells from blood.
2. Pendrin, a iodide transporter enzyme, transports iodide from [across the apical membrane of follicular cell => colloid].
3. @ apical cell membrane:
   
   1. TPO (thyroid peroxidase): [iodide => iodine] via oxidation.
4. In thyroglobulin molecule (gylcoprotein w a shit ton of tyrosine):
   
   1. Iodide organification: iodine undergoes iodination of tyrosine resides => DIT and MIT
   2. [DIT + DIT] => T4 (thyroxine); [MIT + DIT] => T3 (triiodothyronine)
5. T3/T4, MIT and DIT go from colloid => apical membrane of the follicular cell via proteolysis and exocytosis,
6. Released into blood in 5:1 T4:T3 ratio, bound to TBG (thyroxine-binding globulin) in plasma.
7. T4 deiodinated to T3 (4x more portent than T4) or reverse T3 (metabollically inavtive)

Question 7

How is T4 inactivated?

Answer 7

1. Deamination
2. Decarboxylation
3. Conjugation

Question 9

Bioavailability and 1/2-life of thyroid hormones (T3/4)

Answer 9

• T4
  
  • Bioavailability = 80% (best in duodenum and ileum)
  • 1/2 life = 7 days
• T3
  
  • Bioavailability = 95%
  • 1/2 life = 1 day

Question 10

What thyroid drug is given for [thyroid replacement therapy] and why?

Answer 10

T4 (Levothyroxine)

1. Longer 1/2 half = once a day administration
2. More stable
3. Cheap
4. Lack of allergic foreign protein
5. Easy to measure

Question 11

Even though T3 is more potent (bioavailability of 95% vs 80%), why is it not recommended for replacement therapy?

Answer 11

1. Shorter 1/2 life = 3/4x/day
2. More expensive
3. Difficult to monitor

Question 12

Where is oral T4 best absorbed within the GI tract?

Answer 12

Duodenum and ileum

Question 13

Absorption of T4 and T3 may be affected by what underlying condition?

Answer 13

Myxedema w/ ileus but NOT by mild hypothyroidism

Question 14

1/2-life and clearance of T3/4 in a Hyperthyroid vs. Hypothyroid state

Answer 14

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

Question 15

Which 6 agents prevent peripheral conversion of T4 =>T3 by inhibiting 5’-deiodinase => [↑ reverse T3 levels and decrease in T3], and what is their purpose?

Answer 15

Agents that inhibit [T4 => T3 conversion] are given to patients with thyroid storm [thyrotoxic crisis] => reduce T3 levels.

1. Radiocontrast agents: iopanoic acid and ipodate
2. Amiodarone
3. β-blockers
4. Corticosteroids
5. PTU
6. Flavanoids

Question 16

List 9 drugs/agents that ↓ T4 absorption

Answer 16

1. Antacids (aluminum hydroxide, calcium carbonate)
2. Ferrous sulfate
3. Cholestyramine
4. Colestipol
5. Ciprofloxacin
6. PPI’s
7. Bran, Soy, and Coffee

Question 17

7 drugs that (+) liver CYP450s and ↑ the metabolism of T4 and T3?

Answer 17

1. Rifampin
2. Rifabutin
3. Phenobarbital
4. Phenytoin
5. Protease inhibitors
6. Carbamazepine
7. Imatinib

Question 18

5 drugs that cause AI thyroid disease w/ hypo- or hyperthyroidism.

Answer 18

1. • Interferon-α / Interferon-β
2. • IL-2
3. • Lithium
4. • Amiodarone

Question 19

How do drugs/conditions that change the clearance in patients with a NL thyroid react?

Answer 19

Thyroid starts to hyperfunction = maintain NL hormone concentration

Question 20

MOA of Thyroid Hormone

Answer 20

1. T3/T4 enter cell via active transport
2. T4 => converted to T3 via 5’-deiodinase
3. T3 enters nucleus => binds to TR (thyroid receptor)
4. Corepressor is released and coactivator binds
5. TR homodimer separtaes
6. TR binds to RXR (retanoid X receptor)
7. • transciption

Question 21

In the absence of hormone, what is the structure of the TR (thyroid receptor)?

Answer 21

1. TR (homodimer) bound to corepressor protein, which is bound to DNA on the TRE (thyroid hormone response element)

Question 22

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

Answer 22

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

Question 23

What are T3 preparations best used for clinically?

Answer 23

Short-term suppression of TSH

Question 24

How can we ↓ thyroid activity and hormones?

Answer 24

1. Block synthesis of TH
2. Modify the tissues response to TH
3. Destroy thyroid w/ radiation or surgery

Question 25

**_Thiomides_** * Drugs * MOA (general)

Answer 25

* **Methimazole** and **PTU** (propylthiouracil) * **Block synthesis** of thyroid hormone

Question 26

**_PTU_** Bioavailability, absorption,, metabolism, half-life, and dosing

Answer 26

* **BA of 50-80%** that is **rapidly** **absorbed**, **peaking** in our serum at **1 hour** =\> vitually all metabolites are **excreted in 24 hours** * BA is low d/t incomplete absorption and large 1st-pass effect. * 1/2 life = 1.5 hour * Dose = 3- 4x/ day

Question 27

**_Methimazole_** ## Footnote Bioavailability, absorption, metabolism, half-life, and dosing

Answer 27

* **BA is 100%** (completely absorbed) and **excreted slower** (65% in 48 hours) * 1/2 life = 6 hours * Dosing = **1x day**

Question 28

**Thiomides** in pregnancy and when breastfeeding

Answer 28

* **Pregnancy**: cross placental barrier and concentrates in thyroid = n_ot recommended_ * If must give = give PTU in 1st trimester and methimazole in 2nd/3rd trimerst * **Breastfeeding**: safe (secreted in milk at low concentrations)

Question 29

If you must give **thiomides** during **pregnancy**, what is recommended?

Answer 29

* 1st trimester = PTU * 2nd/3rd = Methimazole

Question 30

**MOA** of Thioamides (Methimazole and PTU)

Answer 30

**Block synthesis of TH =\> thus, takes 3-4 weeks before stores are depleted** 1. Inhibit thyroidal peroxidase (TPO) catalyzed rxns 2. Blocks iodide organification 3. Inhibits coupling of MIT and DIT to form T3 and T4 4. **\*\*\*\*\*PTU ALSO BLOCKS PERIPHERAL CONVERSION OF T4=\> T3, DROPPING T3 LEVELS EVN MORE** 5. Does NOT block thyroid gland uptake of iodide

Question 31

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

Answer 31

**FALL EVEN MORE** bc PTU blocks peripheral conversion of T4 --\> T3;

Question 32

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

Answer 32

- Do **NOT** block thyroid gland iodide uptake - **Inhibit hormone synthesi**s, rather than release

Question 33

**AE's** PTU or Methimazole? Which is most severe? \*\*\*

Answer 33

1. **Maculopapular pruritic rash**, at times accompanied by: _Fever_ + _nausea_ + _GI distress_ 2. **Agranulocytosis** (granulocyte count \< 500 cells/mm3) \*\*\*\* 1. Reverse by DQing drug or CSF

Question 34

Risk of **agranulocytosis** in ppl taking **Thiomides** is higher for who?

Answer 34

- Risk ↑ in **older pt's** and those receiving **high-dose methimazole**

Question 35

**Potassium Iodide (Anti-thyroid)** MOA

Answer 35

**Prevents** the **release** of TH. * Inhibits organification and hormone release * ↓ size and vascularity of hyperplastic thyroid gland

Question 36

3 clinical uses of **Potassium Iodide?**

Answer 36

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

Question 37

**AE's Potassium Iodide?**

Answer 37

**AE = uncommon** ## Footnote 1. - Acneiform rash 2. - Swollen salivary glands 3. - Mucous membrane ulcerations 4. - Conjunctivitis 5. - Metallic taste

Question 38

**Potassium Iodide** in Pregnancy

Answer 38

**Avoid**: crosses placental barrier and cause goiter in BB

Question 39

**Radioactive Iodione** * TX * MOA * Administartion * CI

Answer 39

* TX: thyrotoxicosis * Destroys thyroid parenchyma (epithlium swells and necrosis, follicle disrupts, edema and leukocyte infiltartaion) * Orally; rapidly absortbed =\> concentrated in thyroid and foollicles * DO NOT GIVE TO PG W or BREASTFEEDING

Question 40

**Radioactive Iodine** in PG and Breastfeeding

Answer 40

**_CI_** IN W WHO ARE PG OR BREASTFEEDING

Question 41

Advanages o**f Radioactive Iodine**

Answer 41

1. **Easy to adminiter (oral)** 2. **Effective** 3. **Cheap** 4. **No pain**

Question 42

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

Answer 42

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

Question 43

What effect do **β-blockers** have on thyroid levels?

Answer 43

**- 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 44

**Treatment** of Hypothyroidism

Answer 44

* **Levothyroxine (**T4) on **empty stomach**; effects seen in **6-8 weeks**

Question 45

What is a **myxedema coma?**

Answer 45

**End state of untreated hypothyroidism** = progressive weakness, stupor, hypothermia, hypoventillation, hypoglycemia, shock and death.

Question 46

Management of **hypothyroidism** in someone with **myxedema coma**

Answer 46

**- Large loading dose of IV T4** (bc poor absorption) followed by **smaller IV dosing**

Question 47

Management of **hypothyroidism** in someone with **myxedema + CAD**

Answer 47

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

Question 48

Why is tx of **hypothyroidism** in pt's _trying to get pregnan_t and those _currently pregnant_ so important?

Answer 48

* Trying to get pregnant & hypothyroidism = **infertile** * Pregnant = decelopment of **brain** depends on moms T4

Question 49

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

Answer 49

- 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 50

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

Answer 50

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

Question 51

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 51

* - 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 52

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

Answer 52

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

Question 53

Thyroid storm (Thyrotoxic crisis) treatment

Answer 53

* 1. B-blockers =\> control arrhythmia * 2. K+ iodide =\> prevent release of thyroid * 3. PTU/methimazole =\> prevent production of TH * 4. IV hydrocortisone =\> prevent shock and block conversion of T4=\> 3 in peripheral tissue * 5. Supportive therapy