Thyroid & Anti-thyroid Drugs

Question 1

what are the thyroid hormones?

what hormones trigger their release?

Answer 1

T3 and T4

hypothalmic-pituitary-thyroid axis:

• TRH (hypothalamus) –> TSH (anterior pituitary) –> T3, T4 (follicular cells)

Question 2

discuss the regulators of the hypothalamic-pituitary-thyroid axis?

Answer 2

inhibition:

TRH & TSH both by T3,T4 (feedback)

TRH: by chronic stress

TSH: by

• somatostatin (also inhibits somatotrophes)
• dopamine (also inhibits lactotrophes)
• glucocorticoids

Question 3

whta inhibits release of TRH from hypothalamus?

Answer 3

• T3/T4 (negative feedback)
• chronic stress

Question 4

what are low, normal and high TSH levels

Answer 4

Question 5

define hyperthyroidism / thyrotoxicosis

what are the major causes of hyperthryoidism?

Answer 5

= hypermetabolic state due to excess circulating T3, T4

major causes

• primary
  
  • Grave’s (thyroid hyperplasia)
  • thyroiditis - inflammation/fibrosis damages thyroid & leads to excess TH release
    
    • granulomatous, subacute lympocytic
  • thyroid nodules / multdinodular goiter
• excess consumption of: 1. iodine or 2. TH supplements

Question 6

Graves is most common in what population?

Answer 6

women 20-40 yrs

Question 7

what are the major manifestations of hyperthyroidism / thyrotoxicity?

Answer 7

= hypermetabolic state

• too hot (heat intolerant)
• weight loss (increased metabolic rate)
• inc GI activity –> diarrhea
• rapid DTRs
• tachycardia / tachyarrythmias –>. HF

Question 8

hyperthyoidism is managed generally by what drug classes?

(list the drugs in each class)

Answer 8

1. antithyroid drugs:
   
   • thioamides: methimazol, propylthiouracil (PTU)
   • iodies (KI)
2. radioactive iodine (¹³¹I)
3. thyroidectomy

Question 9

thioamides

• incudes what drugs?
• have what MOA?
• have what clinical uses?
• what general AEs?

Answer 9

methimazole, propylthiouracil (PTU)

• MOA: both inhibit TH synthesis by inhibition of thyroperoxidase (no thyroglobulin iodination) _{^{PTU also inhibits T4–>T3}}
• clinical use: hyperthyroidism
• AEs: 1. hepatotoxicity, 2. dangerous in pregnancy

Question 10

methimazole

• what kind of drug?
• what MOA?
• clinical uses?
• PK - onset / potency / half life
• AEs/CIs?

Answer 10

• is a thioamide (antithyroid drug)
• MOA: inhibits TH synthesis by i_nhibiting thyroperoxidase_
• clinical uses: first line drug for hyperthyroidism
• PK:
  
  • onset - rapid
  • highly potent (> PTU)
  • t_1/2 = 6 hrs (> PTU)
• AE:
  
  • hepatoxic: hepatic failure / hepatitis / jaundice (< PTU)
  • teratogenic (> PTU)
  • agranulocytosis
  • common - GI/rash/fever
• CI: 1st trimester of pregnancy

Question 11

propylthiouracil (PTU)

• what kind of drug?
• what MOA?
• clinical uses?
• PK - onset / potency / half life

Answer 11

• thioamine (antithyroid drug)
• MOA:
  
  1. inhibits TH synthesis by inhibiting thyroperoxidase
  2. inhibits T4–>T3 synthesis by inhibiting D1 5’-diodinase
• clinical:
  
  • hyperthyroidism in 1st trimester of pregnancy
  • thyroid storm
  • if pt has AEs to methimazole
• PK
  
  • onset - slow
  • potency - low (< PTU)
  • t_1/2 = 1.5 ( < PTU)
• AEs:
  
  • hepatoxic: hepatic failure / hepatitis / jaundice (> methimazole)
  • teratogenic (< PTU)
  • agranulocytosis
  • common - GI/rash/fever

Question 12

when is PTU preferred over methimazole?

Answer 12

• for pt in 1st trimester of pregnancy
• for a “thyroid storm” - inhibits T3/T4 conversion

Question 13

how does propylthiouracil (PTU) differ from methiomazole pharmokinetically

Answer 13

PTU has

• < potency
• < half life
• slower onset of action (3-4 wks)
• more toxic - i.e., hepatotoxic

Question 14

potassium iodide (KI)

• what kind of drug?
• what MOA?
• what cinical uses?
• AEs?
• CIs?

Answer 14

• antithyroid drug
• MOA:
  
  • 150 mg (recommended dose): of proteolysis
  • > 6 mg: inhibits t_hyroperoxidase enzyme_
• clinical uses:
  
  • decrease size/vascularity of thyroid gland prior to surgery
  • inhibit uptake of radioactive iodine after exposure - likely following a nuclear accident
• AEs:
  
  • GI: unpleasant taste / salivary gland inflammation / gastritis
  • immune: anaphyolaxis / angioedema / thormbocytopenia
  • skin lesion
• C/I:
  
  • within 3 weeks prior to ¹³¹iodine radioation therapy

Question 15

in what form is KI given?

Answer 15

lugol’s solution

Question 16

anion inhibitors

• include what drugs?
• are what kind of drugs?
• have what MOA?
• have what clinical uses?

Answer 16

ate- perchlorate, pertechnetate, thiocynate

• antithyroid drugs
• MOA: competitive inhibition of I- uptake by Na/I symptorter on follicular cell
• clinical use: tx of hyperthyroidism due to excess iodine consumption
  
  • ​(ex - amiodarone-indued)
• AE:
  
  • aplastic anemia

Question 17

perchlorate

• what kind of drug
• MOA
• clinical uses
• AE

Answer 17

• antithyroid drugs
• MOA: competitive inhibition of I- uptake by Na/I symptorter (NIS) on follicular cell
• clinical use: tx of hyperthyroidism due to excess iodine consumption
  
  • ​(ex - amiodarone)
• AE:
  
  • aplastic anemia

Question 18

pertechenate

• what kind of drug
• MOA
• clinical uses
• AEs

Answer 18

• antithyroid drugs
• MOA: competitive inhibition of I- uptake by Na/I symptorter on follicular cell
• clinical use: tx of hyperthyroidism due to excess iodine consumption
  
  • ​(ex - amiodarone-indued)
• AE:
  
  • aplastic anemia

Question 19

thiocynate

• what type of drug
• MOA
• clinical uses
• AEs

Answer 19

• antithyroid drugs
• MOA: competitive inhibition of I- uptake by Na/I symptorter on follicular cell
• clinical use: tx of hyperthyroidism due to excess iodine consumption
  
  • ​(ex - amiodarone-indued)
• AE:
  
  • aplastic anemia

Question 20

I¹³¹

• what kind of drug?
• MOA?
• PK
• clinical uses?
• AEs?

Answer 20

• radioactive iodine
• MOA: taken up and concentrated in thyroid gland then –> destroys parenchymal cells
• PK - slow onset
• clinical uses: hyperplasia (Grave’s disease)
  
  • ​(untrolled hyperparathyoidism)
• AE:
  
  • permanent hyperthyroidism (almost inevitable)
  • radiation thyroiditis - tho not to the degree to cause cancer
  • sore throat
  • opthalmopathy exacerbation (presents in grave’s pts)

Question 21

which thyroid drug can cause permanent hypothyroidism?

what is the tx in this situation?

Answer 21

radioactive iodine (I¹³¹) - used to tx Grave’s

treatment: levothyroxine

Question 22

wat is the only “definitive” therpay for hyperthyroidism?

Answer 22

radioactive iodine (I¹³¹) - destroys parencymal cells

Question 23

what drug is given for exposure to a nuclear event?

Answer 23

KI (Lugol’s Solution)

Question 24

what drug can be given to decrease size and vascularity of thyroid gland pre-surgery?

Answer 24

KI (lugol’s solution)

Question 25

what cardiac manifestations are associated with thyrotoxicosis / hyperthyroidism? how are they managed?

Answer 25

**tachycardia / tachyarrythmia (a-fib) / heart faiure** can be treated with: * **beta blockers:** metoprolol, esmolol, propanolol - _rapid symptomatic relief_ * **CCBs:** diltiazem, verapamil - given if beta blockers C/I _(asthma_) * **corticosteroids**: given to _prevent shock_ from cardiac event

Question 26

what are the AEs of I¹³¹?

Answer 26

* **permanent hyperthyroidism** (almost inevitable) * **radiation thyroiditis** - tho not to the degree to cause cancer * _sore throat_ * opthalmopathy exacerbation (presents in grave's pts)

Question 27

what is the role of corticosteroids in the thyroid hormone metabolism?

Answer 27

* endogenous role: inhibits TSH secretion & T4-T3 conversion * tx role: given in hyperthyroidism / thyrotoxicosis: to manage _cardiac manifestations_ - tachy / arrythmias / HF * **protects patient from shock**

Question 28

amiodarone has what effects on thyroid metabolism?

Answer 28

* is **highly iodine rich** can cause hyperthyroidism or hypothyoirism * hyper: tx = perchlorate. pertechenate, thiocynate

Question 29

what is the role of lithium in thyroid hormone metabolism?

Answer 29

causes hypothyroidism

Question 30

hypothyroidism * defintion? * major causes?

Answer 30

hypo-metabolic state due to low cirulating T3 & T3 (\< 0.5 mlu/L) causes: * **hashiomoto's disease** * **congenital cretinism** * surgical removal of part/all of thyroid * thyroiditis\* *can also cause hyper*

Question 31

what is congenital cretinism & how does it present?

Answer 31

hypothyroidism present at birth presentation: dwarfism, mental retardation

Question 32

what are the manifestations of hypothyroidism?

Answer 32

hypometabolic state * _cold intolerance_ * _weight gain_ (decreased metabolic rate) * **bradycarda** * decreased drug metabolism * lethargy / faituge / weakness

Question 33

what are the classes of drugs used to treat hypothyroidism? list the drugs in each class?

Answer 33

hypothyoidism is treated by giving supplemental thyroid hormone - either synthetic or natural * synthetic TH * **levothyoxine (T4)** * **liothyronine (T3)** * **liotrix (T3 + T4)** * natural TH * dessicated thyroid (T3 + T4)

Question 34

biologically, what converts T4 into T3? where does this conversion occur?

Answer 34

T4 --\> T3 (more potent) * by **5'-deiodinases** in the _peripheral tissues_ * D1 5'-diodinases: in most of periphery * D2 5'-diodinases: in brain specifically

Question 35

contrast T4 and T3 in terms of * half life * potency * receptor binding affinity * what synthetic thyroid hormone drugs they're found in

Answer 35

* half life: T3 (1 day) **\<** T4 (7 days) * potency: T3 **\>** T4 (4x more) * receptor binding affinity: T3 **\>** T4 (10x more) * drugs: * T4 - levothyoxine * T3 - liothyronine

Question 36

thyroid hormones - MOA & physiological effects

Answer 36

* if drug if T4 (levothyroxine), its converted to T3 by **5'-dionidase** * T3 binds to **nuclear (Subclass II) receptors** *a*nd modulate gene transcription * two tissue specific receptor types: _THR-alpha_ and _THR-beta:_ * TRH alpha receptors regulate HR /body temp / skeleletal muscle function / bone development

Question 37

thyroid hormones PK (onset and half life)

Answer 37

* onset: **slow** (3-5 days) * half life: * T3 = 1 day * T4 = 7 days

Question 38

what are the physiologic effects of thyroid hormones?

Answer 38

* normal macromolecule developemnt * promotion of growth & development * **cardiovascular stimulation** * **feedback inhibition of TRH & TSH**

Question 39

thyroid hormone _clinical uses_? what is the goal of thyroid hornone therapy in each condidition?

Answer 39

hypothyroidism - goal to maintain _normal TSH_ cretinism - given in _newborns_ to prevent _irreversible mental retardation_ myxedoma coma (coma due to severe hypothyroidism) - give T3 + T4 prevention of tumor-growth nodule **following cancer surgery** goal to keep below _normal TSH (TSH suppression therapy)_

Question 40

thyroid hormone AE

Answer 40

* **sx of hyperthyroidism**: heat intolerance / weight loss / tachycardia / tachyarrythnias / * **osteoporosis** (if given long term, esp in post-menopausal women)

Question 41

thyroid hormones should be given in caution with patients with? which of these patient should be _started on a low dose_?

Answer 41

* adrenal insufficiency * diabetes * osteoporosis **start on a low dose:** * long standing hypothroidism * CV disease * age \> 60 yrs old

Question 42

what hypothyroid pts should be started on low-dose thyroid hormone?

Answer 42

pts * with long standing hypothyroidism * over age 60 * with CV disease

Question 43

what is TSH suppression therapy? when is it done and what drugs are used?

Answer 43

* done in pts * with thyroid nodules * that are post thyroid-cancer surgery * done with thyroid hormones (levothyroxine, liothyronine, liotrix)

Question 44

how do we treat a myxedema coma?

Answer 44

with thyroid hormones: levothyroxine (T4), liothyronine (T3), liotrix