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PHS 933 > Block 4 Lecture 2 -- Pharmacotherapy of Thyroid Diseases > Flashcards

Block 4 Lecture 2 -- Pharmacotherapy of Thyroid Diseases Flashcards

1
Q

What does lack of thyroid hormone produce in children?

A

cretinism

mental retardation, dwarfism, listlessness

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2
Q

What does lack of thyroid hormone produce in adults?

A

1) weight gain
2) fatigue
3) cold intolerance

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3
Q

Where and how is T3 produced?

A

deiodination of T4
80% from the periphery!
– especially liver

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4
Q

Compare the half-lives of T3 and T4.

A

T3: 1 day
T4: 6-8 days

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5
Q

Thyroxine-binding globulins (TBG) is upregulated by:

A

1) estrogens
2) clofibrate
3) tamoxifen
4) opiates
5) pregnancy
6) liver disease
7) HIV infection

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6
Q

Thyroxine-binding globulins are downregulated by:

A

1) glucocorticoids
2) androgens
3) anti-epileptics
4) furosemide

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7
Q

What proteins bind TH?

A

T3 and T4: TBG
– T4 with higher affinity; 1 molecule per TBG
T4: albumin, transthyretin

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8
Q

What proportion of bound TH is T4? What proportion of T4 is free?

A

90% of bound TH is T4

.03% of T4 is free

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9
Q

How are T3 and T4 eliminated?

A

conjugation in liver

    • glucuronidation
    • sulfation
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10
Q

Describe the TSH receptor and its effects

A

Gs

    • increase T4 release
    • increase I uptake
    • increase thyroglobulin synthesis and proteolysis
    • cause thyroid hyperplasia and hypertrophy
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11
Q

Describe the structure of TRH

A

tripeptide, released from the HT

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12
Q

What is the daily iodine requirement? Where is iodine found?

A 
150 ug (1-2 ug/kg)
-- fish, dairy, iodized salt
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13
Q

What happens in moderate iodine deficiency?

A

1) increased TSH
2) increased T3
3) decreased T4
4) hypertrophy to better extract I
- - simple “nontoxic” goiter

– hypothyroidism

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14
Q

What happens in severe iodine deficiency?

A

hypothyroidism

cretinism

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15
Q

What are the common causes of hypothyroidism?

A
    • iodine deficiency (most common)

- - if iodine sufficient, chronic autoimmune thyroiditis (Hashimoto’s disease)

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16
Q

What is Hashimoto’s disease?

A

chronic autoimmune thyroiditis

– circulating Abs to thyroid peroxidase or thyroglobulin

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17
Q

What are risk factors for hypothyroidism?

A

1) age
2) post-partum woman
3) pre-existing autoimmune disorder
4) f/h autoimmune disease

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18
Q

What is the most common thyroid disorder?

A

hypothyroidism

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19
Q

What are signs/symptoms of hypothyroidism?

A

1) +/- goiter
2) expressionless puffy face, cold dry skin, scaly scalp, brittle hair/fingernails, SQ thickening and edema
3) slow and low-pitched speech, impaired cognition
4) depression, weight gain, lethargy, fatigue, cold intolerance, muscle weakness
5) poor appetite, constipation

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20
Q

What are signs/symptoms of cretinism?

A

1) dwarfism
2) mental retardation
3) lethargy
4) puffy expressionless face
5) protruding tongue
6) dry yellow skin
7) poor appetite
8) umbilical hernia

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21
Q

How is hypothyroidism BEST diagnosed?

A

free T4 level

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22
Q

How is myxedema coma treated?

A

emergency. ..
1) synthetic T3
2) levothyroxine
4) corticosteroids

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23
Q

What are the forms of synthetic T3?

A

1) liothyronine
2) cytomel
3) triostat

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24
Q

What are signs/symptoms of myxedema coma?

A

1) profound hypothermia
2) respiratory depression
3) bradycardia
4) hyponatremia
5) dry skin
6) coma

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25
Q

How is myxedema coma precipitated?

A

infection or CVD in long-standing hypothyroidism

– usually in elderly during the winter

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26
Q

Describe the bioavailability of levothyroxine.

A

50-80%

– reduced by food, binding resins, Fe, Ca, AlOH

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27
Q

What is the t1/2 of levothyroxine? How long till steady state?

A

7 days

6 weeks to steady state; even after a dose change

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28
Q

What is the goal of therapy in hypothyroidism treated with levothyroxine?

A

achieve normal TSH

– titrate via TSH level

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29
Q

Describe dosing of levothyroxine.

A

start with 112ug

– lower in elderly and heart disease patients

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30
Q

How does pregnancy affect levothyroxine dose? Why?

A

need to increase dose

    • estrogens make more TBG
    • transplacental passage of thyroxine
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31
Q

Why is hypothyroidism in pregnancy bad? What is an important recommendation?

A

associated with fetal distress and impaired neuromotor development
– take an Iodine supplement (AAP) if pregnant or breastfeeding

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32
Q

How is congenital hypothyroidism treated?

A

levothyroxine, 10-15 ug/kg

– prompt treatment = no long term effects

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33
Q

Why is thyroxine important in infants?

A

thyroxine needed for proper myelination post-natally

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34
Q

What is the most common endocrinopathy?

A

nodular thyroid disease

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35
Q

How is nodular thyroid disease treated?

A

1) levothyroxine suppression therapy

+/- surgery

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36
Q

What is thyrotoxicosis?

A

elevated levels of T4 and T3

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37
Q

What is the most common cause of thyrotoxicosis?

A

Graves disease

– aka “toxic diffuse goiter”

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38
Q

What is Graves disease?

A

autoimmune disorder

– IgG activates TSH receptor

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39
Q

What are signs/symptoms of thyrotoxicosis?

A

1) exophthalmos
2) excessive heat generation/motor activity
- - warm/flushed/moist skin
- - weak/tremulous muscles
- - muscle wasting and osteoporosis
3) forceful tachycardia, angina, arrhythmia
4) appetite, weight loss, insomnia, anxiety

40
Q

What causes exophthalmos in thyrotoxicosis? How prevalent is it?

A

inflammation of periorbital tissues

– 50% of patients

41
Q

How is thyrotoxicosis treated?

A

thioureylenes

    • propylthiouracil (PTU)
    • methimazole (MMI)
42
Q

What is the MoA of thioureylenes?

A

1) inhibit thyroid peroxidase
- - generates thiocyanide, which inhibits I- uptake
2) block incorporation of iodine into Tyr’s of thyroglobulin
3) inhibits iodotyrosine coupline to iodothyronines

    • iodinated thyroglobulin stores slowly depleted
    • decreases immunosensitivity in Graves
43
Q

What is the most-sensitive step to anti-thyroid drugs in TH synthesis?

A

coupling of iodotyrosines into iodothyronines

44
Q

When is PTU preferred and why?

A

in severe disease
– addl MoA: inhibits peripheral conversion of T4 to T3
in nursing moms

45
Q

How is thyrotoxicosis in pregnancy treated?

A

minimal dose to minimize risk of hypothyroidism to fetus

PTU preferred in nursing moms

46
Q

What are adjuvant therapies to thioureylenes in thyrotoxicosis?

A

1) b-blocker: propranolol, atenolol
2) Ca-channel blockers: diltiazem
3) dexamethasone

47
Q

Why are b-blockers adjuvants to thioureylenes?

A

antagonize sympathetic/adrenergic effects

– tachycardia, palpitations, tremor, anxiety

48
Q

Compare propranolol to atenolol in thioureylene adjuvant therapy.

A
    • propranolol crosses BBB, atenolol does not
    • propranolol weakly inhibits peripheral T4 to T3 conversion
    • both given BID
49
Q

Why is diltiazem used as an adjuvant to thioureylenes in thyrotoxicosis? How often is it dosed?

A

decreases tachycardia and arrhythmias

QID

50
Q

Why is dexamethasone used as an adjuvant in thyrotoxicosis?

A
    • suppresses immunoreactivity

- - suppresses T4 to T3 conversion

51
Q

What remedies other than thioureylenes and adjuvants are used for thyrotoxicosis?

A

1) subtotal thyroidectomy
2) radioactive iodine
3) ionic inhibitors
4) iodide

52
Q

What ionic inhibitors are used in thyrotoxicosis?

A

1) thiocyanate (SCN-)
2) perchlorate (ClO4-)
3) fluoborate (BF4-)
4) lithium

53
Q

How do the ionic inhibitors work for thyrotoxicosis?

A
    • monovalent anions of similar size
    • interfere with iodide uptake

lithium:
– decreases thyroxine and T3 secretion

54
Q

Where is thiocyanate generated?

A

1) plant glycosides (cabbage)
2) cigarette smoke
- - smoking worsens hypothyroidism

55
Q

What are concerns for perchlorate?

A

1) dose over 2 g/day causes fatal aplastic anemia
2) water supply contamination
3) 10x more potent than thiocyanate

56
Q

When is iodide usually used for thyrotoxicosis?

A

prior to thyroid surgery after initial PTU/MMI

    • shrink the thyroid
    • avoid “thyroid escape”
57
Q

What are the effects of iodide therapy?

A

1) resolves non-toxic goiter
2) suppresses thyrotoxicosis
at high concentrations…
– decrease I- uptake
– inhibits synthesis of iodotyrosines and iodothyronine
– inhibits release of thyroxine

58
Q

At high concentrations, iodide suppresses all aspects of iodine metabolism. What is the Wolff-Chaikoff effect?

A

inhibiting the synthesis of iodotyrosines and iodothyronine

59
Q

Describe the response to iodide therapy.

A

24h: metabolic rate falls
– comparable to thyroidectomy
– rapid block to release and synthesis of TH
– vascularity, gland size decreases
10-15 days: max effect
15+ days: hyperthyroidism returns, more severe

60
Q

How is iodide supplied?

A
    • Lugol’s solution (strong iodide solution); 3-5 drops = 18-30mg
    • saturated solution of potassium iodide (SSKI); 1-3 drops
61
Q

How is iodide used to protect against radioactive fallout?

A

1) protect thyroid against radioactive iodine

2) diminish incidence of thyroid cancer

62
Q

How much iodide is needed to suppress thyroid function?

A

6 mg/day

63
Q

What are the ADRs of iodide?

A

1) hypersensitivity
- - angioedema, laryngeal edema
2) cutaneous hemorrhage, serum sickness, anemias
3) iodism
- - metallic taste, burning sensation in mouth/throat, head cold, cough, HA, salivation
4) skin lesions

64
Q

In what other drugs is iodine found?

A

1) amiodarone
2) topical antiseptics
3) radiology contrast agents

65
Q

What are the signs/symptoms of thyroid storm?

A

1) fever (101+)
2) severe tachycardia
3) n/v
4) agitation/confusion

coma/death in 20% of patients

66
Q

What causes thyroid storm?

A

precipitated by secondary illness in thyrotoxic patients

    • infection
    • stress
    • trauma
    • DKA
    • labor
    • heart disease
67
Q

How is thyroid storm treated?

A

treat the symptoms

1) IV fluid
2) antipyretics
3) sedatives
4) dexamethasone
5) beta-blocker

suppress thyroid

6) large-dose PTU
7) oral iodides after PTU

68
Q

What isotopes of oral radioactive iodide are used?

A

131 I- most common
– NaI (131) is the choice treatment for hypothyroidism

123 I
– used for thyroid scans

69
Q

Compare 131 I- to 123 I-

A

131 I-

    • t1/2 = 8 days
    • gamma rays and beta particles

123 I-

    • t1/2 = 13 h
    • gamma rays
70
Q

How do beta particles and gamma rays differ?

A

betas cause tissue damage
– pyknosis, necrosis of follicular cells
gammas pass thru tissues for quantification

71
Q

How do oral radioactive iodides work in hyperthyroidism?

A

taken up by thyroid, incorporated into thyroglobulin

    • damage tissue (beta)
    • uptake can be quantified (gamma)
72
Q

When is radioactive iodide therapy preferred in hyperthyroidism?

A

older patients
heart disease
toxic nodular goiter

73
Q

Why is radioactive iodide preferred in thyrotoxicosis?

A

1) no surgery
2) no parathyroid loss
3) no risk of death or cancer
4) easy to treat hypothyroidism

74
Q

Describe dosing of radioactive 131 NaI for thyrotoxicosis.

A

1) calculate dose to destroy thyroid; treat over 2-3 months
- - condition abates
2) further treatment possible for 6-12 months

75
Q

Describe outcomes of radioactive iodide therapy in thyrotoxicosis.

A
    • transient hyperthyroidism in 50% of patients during treatment
    • delayed hypothyroidism (intentional or due to overtreatment) in 80% of patients over 10 years
76
Q

How does hyperthyroidism present in pregnancy?

A
    • often improves as pregnancy progresses

- - often returns after birth

77
Q

What are ADRs of PTU/MMI?

A

1) agranulocytosis (1:500)
- - most serious
- - usually in first few months
2) urticarial reaction
- - most common
- - no cross-sensitivity

78
Q

What to look for in agranulocytosis reaction from PTU/MMI?

A

sore throat, fever, gingivitis

    • immediately report
    • reversible if caught early
79
Q

Compare PTU and MMI in PK/PD.

A 
PTU: 1-4 doses
-- t1/2 = 75min
MMI: 1-2 doses
-- t1/2 = 4-6h
-- 10x more potent

both equally cross placenta, are secreted in milk, and concentrate in thyroid

80
Q

Where are thioureylenes found?

A

cruciferous veggies (cabbage, brussel sprouts, broccoli)

81
Q

What do brassica plants contain?

A
    • thioureylenes

- - thiocyanate-generating compounds and goitrogens

82
Q

How is thyrotoxicosis diagnosed?

A

increased iodine uptake into thyroid
– 24h radioactive iodine uptake test (RAIU)

TSH usually low except in pituitary adenoma

83
Q

Describe epidemiology of nodular thyroid disease.

A
  • ) 50% by age 60
    • 4-7% incidence
    • risk increased by ionizing radiation
  • ) 4x more common in women
  • ) often undiagnosed, generally benign
  • ) 5% develop hypothyroidism
  • ) 10% develop thyroid cancer
84
Q

What tests are used to find TH levels to diagnose hypothyroidism?

A

1) total TH concentration
- - may not accurately reflect thyroid function (TBG amount or affinity)
2) TSH level
- - most common
- - sensitive indicator of free T4
- - elevated in primary, decreased in secondary

85
Q

How is response to TSH measured?

A 
recombinant TSH (Thyrogen)
-- measures the uptake of radiolabeled iodine
86
Q

When is cretinism usually recognized?

A

3-5 months of age

87
Q

What is primary hypothyroidism?

A

failure of thyroid to make thyroxine

88
Q

What is secondary hypothyroidism?

A

loss of pituitary function and TSH

89
Q

What is congenital hypothyroidism?

A

severe iodine deficiency or genetic thyroid/pituitary defects
– leads to cretinism

90
Q

Compare T4 and T3. Which is predominant, which is active?

A 
T4 predominant (100x more than T3)
T3 is active
91
Q

What is the function of TH?

A

essential for development and metabolic homeostasis

92
Q

In what patients is remission most likely in thyrotoxicosis after PTU/MMI treatment?

A

1) older patients
2) smaller goiters
3) prompt treatment
4) no history of relapse

93
Q

When is PTU/MMI treatment effective?

A

when goiter size is reduced

94
Q

How is thyrotoxicosis relapse treated?

A

RAI therapy

95
Q

Describe treatment timeline for thyrotoxicosis. What’s the remission rate?

A

once effective…

    • taper dose; update monthly;
    • maintenance dose (50-300mg/day) x 1-2 years
    • monitor yearly after ceasing therapy

remission rate = 40-50%

96
Q

Describe the epidemiology of Graves’ disease.

A
  1. 4% incidence in US
    - - 5-7x more common in women
    - - usually age 20-50
    - - usually associated with other autoimmune diseases

PHS 933 (14 decks)

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