Block 4 Lecture 2 -- Pharmacotherapy of Thyroid Diseases Flashcards Preview

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Flashcards in Block 4 Lecture 2 -- Pharmacotherapy of Thyroid Diseases Deck (96):
1

What does lack of thyroid hormone produce in children?

cretinism
(mental retardation, dwarfism, listlessness)

2

What does lack of thyroid hormone produce in adults?

1) weight gain
2) fatigue
3) cold intolerance

3

Where and how is T3 produced?

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

4

Compare the half-lives of T3 and T4.

T3: 1 day
T4: 6-8 days

5

Thyroxine-binding globulins (TBG) is upregulated by:

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

6

Thyroxine-binding globulins are downregulated by:

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

7

What proteins bind TH?

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

8

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

90% of bound TH is T4

.03% of T4 is free

9

How are T3 and T4 eliminated?

conjugation in liver
-- glucuronidation
-- sulfation

10

Describe the TSH receptor and its effects

Gs
-- increase T4 release
-- increase I uptake
-- increase thyroglobulin synthesis and proteolysis
-- cause thyroid hyperplasia and hypertrophy

11

Describe the structure of TRH

tripeptide, released from the HT

12

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

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

13

What happens in moderate iodine deficiency?

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

-- hypothyroidism

14

What happens in severe iodine deficiency?

hypothyroidism
cretinism

15

What are the common causes of hypothyroidism?

-- iodine deficiency (most common)
-- if iodine sufficient, chronic autoimmune thyroiditis (Hashimoto's disease)

16

What is Hashimoto's disease?

chronic autoimmune thyroiditis
-- circulating Abs to thyroid peroxidase or thyroglobulin

17

What are risk factors for hypothyroidism?

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

18

What is the most common thyroid disorder?

hypothyroidism

19

What are signs/symptoms of hypothyroidism?

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

20

What are signs/symptoms of cretinism?

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

21

How is hypothyroidism BEST diagnosed?

free T4 level

22

How is myxedema coma treated?

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

23

What are the forms of synthetic T3?

1) liothyronine
2) cytomel
3) triostat

24

What are signs/symptoms of myxedema coma?

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

25

How is myxedema coma precipitated?

infection or CVD in long-standing hypothyroidism
-- usually in elderly during the winter

26

Describe the bioavailability of levothyroxine.

50-80%
-- reduced by food, binding resins, Fe, Ca, AlOH

27

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

7 days
6 weeks to steady state; even after a dose change

28

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

achieve normal TSH
-- titrate via TSH level

29

Describe dosing of levothyroxine.

start with 112ug
-- lower in elderly and heart disease patients

30

How does pregnancy affect levothyroxine dose? Why?

need to increase dose
-- estrogens make more TBG
-- transplacental passage of thyroxine

31

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

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

32

How is congenital hypothyroidism treated?

levothyroxine, 10-15 ug/kg
-- prompt treatment = no long term effects

33

Why is thyroxine important in infants?

thyroxine needed for proper myelination post-natally

34

What is the most common endocrinopathy?

nodular thyroid disease

35

How is nodular thyroid disease treated?

1) levothyroxine suppression therapy
+/- surgery

36

What is thyrotoxicosis?

elevated levels of T4 and T3

37

What is the most common cause of thyrotoxicosis?

Graves disease
-- aka "toxic diffuse goiter"

38

What is Graves disease?

autoimmune disorder
-- IgG activates TSH receptor

39

What are signs/symptoms of thyrotoxicosis?

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

What causes exophthalmos in thyrotoxicosis? How prevalent is it?

inflammation of periorbital tissues
-- 50% of patients

41

How is thyrotoxicosis treated?

thioureylenes
-- propylthiouracil (PTU)
-- methimazole (MMI)

42

What is the MoA of thioureylenes?

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

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

coupling of iodotyrosines into iodothyronines

44

When is PTU preferred and why?

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

45

How is thyrotoxicosis in pregnancy treated?

minimal dose to minimize risk of hypothyroidism to fetus

PTU preferred in nursing moms

46

What are adjuvant therapies to thioureylenes in thyrotoxicosis?

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

47

Why are b-blockers adjuvants to thioureylenes?

antagonize sympathetic/adrenergic effects
-- tachycardia, palpitations, tremor, anxiety

48

Compare propranolol to atenolol in thioureylene adjuvant therapy.

-- propranolol crosses BBB, atenolol does not
-- propranolol weakly inhibits peripheral T4 to T3 conversion
-- both given BID

49

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

decreases tachycardia and arrhythmias

QID

50

Why is dexamethasone used as an adjuvant in thyrotoxicosis?

-- suppresses immunoreactivity
-- suppresses T4 to T3 conversion

51

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

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

52

What ionic inhibitors are used in thyrotoxicosis?

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

53

How do the ionic inhibitors work for thyrotoxicosis?

-- monovalent anions of similar size
-- interfere with iodide uptake

lithium:
-- decreases thyroxine and T3 secretion

54

Where is thiocyanate generated?

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

55

What are concerns for perchlorate?

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

56

When is iodide usually used for thyrotoxicosis?

prior to thyroid surgery after initial PTU/MMI
-- shrink the thyroid
-- avoid "thyroid escape"

57

What are the effects of iodide therapy?

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

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

inhibiting the synthesis of iodotyrosines and iodothyronine

59

Describe the response to iodide therapy.

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

How is iodide supplied?

-- Lugol's solution (strong iodide solution); 3-5 drops = 18-30mg
-- saturated solution of potassium iodide (SSKI); 1-3 drops

61

How is iodide used to protect against radioactive fallout?

1) protect thyroid against radioactive iodine
2) diminish incidence of thyroid cancer

62

How much iodide is needed to suppress thyroid function?

6 mg/day

63

What are the ADRs of iodide?

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

In what other drugs is iodine found?

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

65

What are the signs/symptoms of thyroid storm?

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

coma/death in 20% of patients

66

What causes thyroid storm?

precipitated by secondary illness in thyrotoxic patients
-- infection
-- stress
-- trauma
-- DKA
-- labor
-- heart disease

67

How is thyroid storm treated?

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

What isotopes of oral radioactive iodide are used?

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

123 I
-- used for thyroid scans

69

Compare 131 I- to 123 I-

131 I-
-- t1/2 = 8 days
-- gamma rays and beta particles

123 I-
-- t1/2 = 13 h
-- gamma rays

70

How do beta particles and gamma rays differ?

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

71

How do oral radioactive iodides work in hyperthyroidism?

taken up by thyroid, incorporated into thyroglobulin
-- damage tissue (beta)
-- uptake can be quantified (gamma)

72

When is radioactive iodide therapy preferred in hyperthyroidism?

older patients
heart disease
toxic nodular goiter

73

Why is radioactive iodide preferred in thyrotoxicosis?

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

74

Describe dosing of radioactive 131 NaI for thyrotoxicosis.

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

75

Describe outcomes of radioactive iodide therapy in thyrotoxicosis.

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

76

How does hyperthyroidism present in pregnancy?

-- often improves as pregnancy progresses
-- often returns after birth

77

What are ADRs of PTU/MMI?

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

78

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

sore throat, fever, gingivitis
-- immediately report
-- reversible if caught early

79

Compare PTU and MMI in PK/PD.

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

Where are thioureylenes found?

cruciferous veggies (cabbage, brussel sprouts, broccoli)

81

What do brassica plants contain?

-- thioureylenes
-- thiocyanate-generating compounds and goitrogens

82

How is thyrotoxicosis diagnosed?

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

TSH usually low except in pituitary adenoma

83

Describe epidemiology of nodular thyroid disease.

-) 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

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

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

How is response to TSH measured?

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

86

When is cretinism usually recognized?

3-5 months of age

87

What is primary hypothyroidism?

failure of thyroid to make thyroxine

88

What is secondary hypothyroidism?

loss of pituitary function and TSH

89

What is congenital hypothyroidism?

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

90

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

T4 predominant (100x more than T3)
T3 is active

91

What is the function of TH?

essential for development and metabolic homeostasis

92

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

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

93

When is PTU/MMI treatment effective?

when goiter size is reduced

94

How is thyrotoxicosis relapse treated?

RAI therapy

95

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

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

Describe the epidemiology of Graves' disease.

0.4% incidence in US
-- 5-7x more common in women
-- usually age 20-50
-- usually associated with other autoimmune diseases