Pharm - S2B2 - 02 Thyroid & Antithyroid Drugs

Front 1

The Thyroid gland maintains metabolic homeostasis by regulating these 3 things

Back 1

1. Growth & development

2. Body temperature

3. Energy levels

Front 2

What hormones are involved in accomplishing the functions of the thyroid gland?

Back 2

1. Triiodothyronine = T3

2. Tetraiodothyronine = T4 = Thyroxine

Front 3

What is the molecular composition of T3?

Back 3

one Monoiodotyrosine (MIT) + one Diiodotyrosine (DIT)

Front 4

What is the molecular composition of T4?

Back 4

2 Diiodotyrosine (DIT)

Front 5

What is the Thyroglobulin ratio of T3 and T4?

Back 5

1 T3 molecule for every 5 T4 molecules

or

T3:T4 = 1:5

Front 6

How much Iodide (I-) does the Thyroid gland remove from the extracellular pool each day?

Back 6

75 mg

Front 7

Thyroid hormone synthesis:
-Iodide is taken up by Thyroid follicular cells via a membrane __1__ transporter
-Iodide is coupled to __2__ residues on the __3__ molecule (=organification)
-formation of __4__ &__5__
-__6__ catalyzes coupling of 2 DIT molecules to form T4 or one molecule each of MIT and DIT to form T3
-Thyroglobulin is stored as __7__ in the lumen
-__8__ signals secretion to hydrolyze Thyroglobulin to free MIT, DIT, T3 & T4

Back 7

1. Na+/I-
2. tyrosine
3. thyroglobulin
4. MIT = monoiodotyrosine
5. DIT = diiodotyrosine
6. Thyroid peroxidase
7. colloid
8. TSH

Front 8

Plasma T3 and T4 are REVERSIBLY bound to __1__

Why is most of the thyroid hormone that is released T4?

Back 8

Thyroxine-binding globulin

T4:T3 ratio in Thyroglobulin is 5:1

Front 9

The peripheral metabolism of T4 is mainly by what mechanism?

What 2 things does it form?

Back 9

Deiodination

1. T3 = 3-4 times more potent than T4
2. rT3 = metabolically inactive

Front 10

Give 2 reasons why the total serum levels of T4 are higher than T3

Back 10

1. more of it is released (5:1 ratio)

2. metabolic clearance of T3 is much higher

Front 11

-

Back 11

Just know which one is higher and which one is lower

Front 12

Explain Hypothalamic-Pituitary-Thyroid Regulation

Back 12

1. Paraventricular nuclei in the Hypothalamus secrete TRH
2. TRH stimulates the Anterior Pituitary to release TSH
3. TSH acts on Thyroid to release T3 & T4
4. T3 & T4 act by negative feedback to inhibit formation of TRH & TSH

Front 13

Describe the Autoregulation within the Thyroid gland

Back 13

Modifies Thyroid hormone synthesis through blood iodine levels
-high iodine levels → inhibit iodide organification → reduced T3/T4 synthesis → hypothyroidism

**counterintuitive b/c the same substance, iodine, has opposite effects and
the effects depend on the concentration --> higher plasma Iodine = lower T3/T4

Front 14

Explain Grave's Disease

Back 14

Autoantibody to the TSH receptor in the Thyroid causes increased T3/T4 release

**TRH and TSH levels will be decreased due to negative feedback of T3/T4

Front 15

Explain Hashimoto's Disease

Back 15

Destructive Autoantibody causing decreased T3/T4 release

**TRH and TSH will be elevated b/c T3/T4 are not present for negative feedback

Front 16

Thyroid hormone receptors located in all cells are monomers that interact with ___1____ to form heterodimers

In the absence of T3 the heterodimer associates with a __2__ complex that binds to DNA to __3__

In the presence of T3 the __4__ dissociates, while __5__ form to stimulate __6__

Back 16

1. Retinoic Acid X Receptor (RXR)
2. co-repressor
3. inhibit gene expression
4. co-repressor
5. coactivators
6. Gene expression

** = T3 stimulates gene expression

Front 17

T3 receptors belong to a superfamily of __1__ receptors (c-erb which includes receptors for __2__ and __3__)

Back 17

1. nuclear

2. steroid hormones

3. Vitamins A & D

Front 18

Describe the Thyroid Hormone Mechanism of action (6 steps)

Back 18

1. T3/T4 are dissociated from thyroid-binding proteins
2. T3/T4 enter target cells by diffusion or transport
3. in cytoplasm 5'-deiodinase converts T4 to T3
4. T3 enters the nucleus to bind to T3 receptors
5. increased formation of RNA
6. increased protein synthesis

Front 19

Circulating iodine is 95% __1__ and 5% __2__

Back 19

1. organic iodine

2. iodide = I-

Front 20

Of the circulating iodine in the Organic form 95% is __1__ while the other 5% is __2__

Back 20

1. T4

2. T3

Front 21

What protects circulating T3 and T4?

Back 21

Thyroxin binding globulin (TGB)

*free or unbound hormones are minimal
*only the unbound hormones have metabolic activity

Front 22

In peripheral tissues what converts T4 to T3?

What are the 3 main organs that do this?

Back 22

Iodothyronine 5'-deiodinase

Liver, Thyroid, Kidneys

Front 23

What is the active hormone in most target tissues?

Back 23

T3

Front 24

List the 4 main effects of Thyroid Hormone

Back 24

1. Nervous, musculoskeletal, and reproductive issues

2. Calorigenic effect

3. Sympathetic hyperactivity

4. Metabolic effects

Front 25

List the Nervous, musculoskeletal, and reproductive effects Thyroid hormone has

Back 25

Nervousness
Emotional lability
Muscle weakness & fatigue
Osteoporosis
Menstrual irregularities

Front 26

Describe the Calorigenic effect thyroid hormone causes

Back 26

increased Oxygen consumption

Sweating

Front 27

Describe the Sympathetic hyperactivity effects Thyroid Hormone causes

Back 27

Up-regulates B1-adrenergic receptors in the heart
-tachycardia
-increased stroke volume & CO
-high-output heart failure
-arrythmia
-angina

**may want to use B-adrenergic blocking agent (propranolol) as an adjunct treatment for hyperthyroidism

Front 28

Describe the Metabolic effects Thyroid Hormone causes

Back 28

Decreased Cholesterol and TG's

Increased BMR

Hyperglycemia

Appetite

Front 29

Preparation of choice for Replacement and Suppression therapy for Hypothyroidism

Back 29

Synthetic Levothyroxine (T4)

Front 30

Why is Levothyroxine the preparation of choice for replacement therapy of Hypothyroidism?

Back 30

1. Stable
2. Uniform content
3. Low cost
4. Long half-life (7 days)
5. conversion to produce both T3 and T4

Front 31

Thyroid preparation though inexpensive, is not recommended for replacement therapy b/c of its antigenicity, instability, and variable hormone content

Back 31

Dessicated Thyroid

Front 32

Thyroid replacement that is 3-4 times more active than Levothyroxine but is not recommended for routine replacement therapy

Back 32

Liothyronine (T3)

Front 33

Why is Liothyronine not recommended for routine thyroid replacement therapy?

Back 33

1. High cost
2. Shorter half-life (24 hrs vs. 7 days)
3. **Cardiotoxicity** potential

Front 34

4:1 combination of synthetic T4 and T3, is also expensive with the same disadvantages as Liothyronine

Back 34

Liotrix

Front 35

List the 2 Thioamides (anti-thyroid drugs)

Back 35

Methimazole

Propylthiouracil

Front 36

Where do the 2 Thioamides accumulate readily?

Back 36

Thyroid gland for treatment of Thyrotoxicosis

Front 37

Thioamide that is 10X more active than the other

Back 37

Methim-azole

Front 38

What are the plasma half-lives for the 2 Thioamides?

Back 38

Methim-azole = 6 hrs

Propyl-thio-uracil = 1.5 hrs

Front 39

How long does it take for the Thioamides to have an effect?

Back 39

Slow onset!!! ➡ 3-4 weeks to deplete T4 stores

Front 40

What are the mechanisms of action of the Thioamides? (3)

Back 40

1. Inhibits peroxidase rxns = blocks Iodine Organification (conversion of I- to I2)
2. blocks Iodotyrosine coupling
3. Inhibit peripheral deiodination of T3 and T4

***Mechanism 1 is the major action

Front 41

What is the most common adverse effect of the Thioamides?

Back 41

Maculopapular pruritic rash

Front 42

What are the rare adverse effects of the Thioamides?

Back 42

Urticarial rash, vasculitis, arthralgia, lupus-like rxn, jaundice, hepatitis, hypothrombinemia

Front 43

What is the most dangerous adverse effect of the Thioamides?

Back 43

Agranulocytosis

Front 44

What 2 mechanisms of Potassium Iodides render them effective in Hyperthyroidism treatment?

Back 44

1. inhibition of hormone release by reducing Thyroglobulin proteolysis

2. decrease the size and vascularity of the Hyperplastic gland

Front 45

With Iodide treatment thyrotoxic symptoms improve within __1__, but should not be used alone b/c the gland "escapes" from iodide block after __2__

Back 45

1. 2-7 days

2. 2-8 weeks

Front 46

Why should chronic use of Iodides to treat Hyperthyroidism not be used in pregnancy?

Back 46

Iodide crosses the placenta and could cause Fetal Goiter

Front 47

What are 4 advantages of Iodide treatment for Hyperthyroidism?

Back 47

1. simplicity
2. inexpensive
3. relatively nontoxic
4. Absence of glandular destruction

Front 48

List the adverse rxns of Iodide treatment

Back 48

1. Acneiform rash
2. Swollen salivary glands
3. Mucous membrane ulceration
4. Conjunctivitis
5. Rhinorrhea
6. Metallic taste
7. Drug fever
8. Bleeding disorders
9. Anaphylaxis

Front 49

What are the disadvantages of Potassium Iodide treatment? (4)

Back 49

1. "escape"
2. Aggravation of Thyrotoxicosis
3. Allergic rxns
4. Increased intraglandular iodine which can delay the onset of Thioamide therapy or prevent use of radioactive iodine therapy for several weeks

Front 50

The only radioactive isotope used for treatment of Thyrotoxicosis

Back 50

Radioactive Iodine

Front 51

How is RAI administered?

Back 51

Oral solution
-RAI is rapidly absorbed and concentrated in the Thyroid gland

Front 52

What becomes evident within weeks after Radioactive Iodine treatment?

Back 52

Thyroid parenchymal destruction
-epithelial swelling
-necrosis
-follicular disruption
-edema
-Leukocyte infiltration

Front 53

What does the therapeutic effect of RAI depend on?

Back 53

Emission of Beta rays
-penetration range of 400-2000 micrometers
-effective half-life of 5 days

Front 54

What are 4 advantages of RAI?

Back 54

1. easy administration = oral solution
2. Effectiveness
3. Low expense
4. Absense of pain

Front 55

What is the major disadvantage of RAI?

Back 55

induction of Hypothyroidism

Front 56

What is the main contraindication of RAI?

Back 56

Pregnancy b/c RAI crosses the placenta and is also excreted in Breast Milk

Front 57

What is the mechanism of action of the Anion Inhibitors (Perchlorate, Pertechnetate, Thiocyanate)?

Back 57

competitively inhibit the iodide transport mechanism and therefore block Iodide uptake

*effectiveness is unpredictable

Front 58

List 3 Anion Inhibitors

Back 58

1. Thio-cyanate
2. Per-chlorate
3. Per-tech-netate

Front 59

Anion Inhibitor that is no longer used clinically because it causes Aplastic Anemia

Back 59

Potassium Perchlorate

Front 60

Though not FDA approved these act by inhibiting conversion of T4 to T3 in the liver, kidney, pituitary, and brain

Back 60

Iodinated Contrast media
-Ipodate = by mouth
-Dia-triz-oate = IV

Front 61

Since many symptoms of Thyrotoxicosis result from sympathetic hyperactivity, what have also been used for treatment?

Back 61

B-adrenergic blockers or Guan-ethi-dine