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PHA223 > thyroid drugs > Flashcards

thyroid drugs Flashcards

1
Q

What glands regulate thyroid production?

A

hypothalamus, pituiraty, and thyroid gland

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2
Q

What is important for thyroid function?

A

dietary iodide

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3
Q

What joins the 2 parts of the thyroid gland?

A

isthmus

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4
Q

diseases that can affect the thyroid gland

A 
Grave's disease
multinodular disease
autoimmune disease
Hashimoto's
thyroiditis
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5
Q

What is the secretory unit of the thyroid gland?

A

thyroid follicle or acini

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6
Q

What surrounds the colloid?

A

epithelial cells

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7
Q

What is the colloid composed of?

A

thyroglobulin

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8
Q

What cells secrete calcitonin?

A

parafolicular cells (C cells)

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9
Q

What do follicular cells secrete?

A

thyroid hormones - T4 and T3

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10
Q

synthesis of thyroid hormones

A
  1. TRAPPING of iodide (Na/I pump) into the follicular cell
  2. SYNTHESIS of thyroglobulin (TG)
  3. OXIDATION of iodide (by the enzyme TPO)
  4. ORGANIFICATION of iodine at tyrosine site (TPO) (additionon iodine to tyrosine resudies)
  5. COUPLING (T1 - T2 - T3 - T4)
  6. PINOCYTOSIS of colloid (into follicular cell, lysosome degrades TG leaving the thyroid hormoned behind)
  7. SECRETION of thyroid hormones
  8. TRANSPORT of thyroid hormones into blood
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11
Q

What steps of thyroid hormone synthesis can be targeted in overproduction of thyroid hormone?

A

steps 3, 4 and 5

oxidation, organification and coupling

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12
Q

What is TPO?

A

thyroid peroxidase

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13
Q

What stages does TPO enzyme control?

A

stages 3, 4 and 5

oxidation, organification and coupling

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14
Q

What AA are thyroid hormones derived from?

A

tyrosine

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15
Q

structure of thyroid hormones

A

2 phenyl rings coupled through an X group

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16
Q

What must X be in thyroid hormone structure?

A

oxygen

-> forming a phenoxyphenyl pharmacophore

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17
Q

What must R1 be in thyroid hormone structure?

A

alanine

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18
Q

What must R3 and R5 be in thyroid hormone structure?

A

iodine

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19
Q

What must R3’ be in thyroid hormone structure?

A

iodine

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20
Q

What must R4’ be in thyroid hormone structure?

A

hydroxyl group

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21
Q

structural difference between T3 and T4

A

iodine at R5’ in T4
nothing in T3
(T4 - 4 iodines, T3 - 3 iodnies)

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22
Q

What happens to tyrosine in the organification process?

A

addition of iodine

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23
Q

What does organification require?

A

hydrogen peroxide

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24
Q

What forms when iodine is added to tyrosine in the organification process?

A

monoiodothyrosine (MIT)

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25
Q

What forms when 2 iodines are added to tyrosine?

A

diiodothyrosine (DIT)

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26
Q

What does peroxidase coupling form?

A

T3 and T4

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27
Q

Is T4 active?

A

no

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28
Q

What % of thyroid hormone is relrased as T4?

A

80% T4

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29
Q

How is T4 activated?

A

deiodinase enzyme removes an iodine from T4 which activates it to form T3

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30
Q

outer ring deiodination vs inner ring deiodination

A

outer ring deiodination forms active T3

inner ring deiodination forms reverse T3 (rT3), inactive (not recognised by the receptor)

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31
Q

What type of receptors do thyroid hormones act on?

A

nuclear hormone receptor (inside the cell, when activated move inside the nucleus)

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32
Q

thyroid hormone action

A
  1. T3/T4 into the cell
  2. T4 converted to T3
  3. T3 interacts with the thyroid hormone receptor
  4. T3+R dimerises with retinoid X receptor
  5. binds to DNA
  6. transcribes target genes
  7. has desired effect
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33
Q

tests that establish thyroid dysfunction

A

serum TSH

T3 and T4 measurements

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34
Q

tests that elcuidate cause

A

thyroid autoantibodies
serum thyroglobulin
thyroid enzymes
biopsy/ultrasound

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35
Q

What is measured when monitoring treatment?

A

serum thyroglobulin

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36
Q

What is tested when patient suspected of having thyroid disease?

A

TSH

T4

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37
Q

TSH levels

A

normal - euthyroid/healthy patients (excludes primary thyroid dysfunction)
increased - hypothyroidism
decreased - hyperthyroidism

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38
Q

How does thyroid scanning (radioactive iodine) work?

A

test for thyroid function

  • patient ingests radioactive iodine
  • return 24hrs later for scan with a gamma probe
  • short half life, low dose/risk
  • measures how much radioactive iodine is taken up by the thyroid gland in a time period
  • amount of iodine in the thyroid indicates status
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39
Q

symptoms of hyperthyroidism/thyrotoxicosis

A 
tremor
tachycardia/palpitations
weight loss
tiredness
warm/sweating
diarrhoea
anxiety/emotional
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40
Q

hyperthyroidism treatments (3)

A
  1. anti-thyroid drugs
  2. rado-active iodine
  3. surgery to remove the gland (thyroidectomy)
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41
Q

main drug used for hyperthyroidism

A

thionamides - carbimazole

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42
Q

What derivative is carbimazole from?

A

imidazole

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43
Q

What is carbimazole converted to in the body and how?

A

active metabolite - methimazole (MMI)

converted by the liver (1st pass metabolism)

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44
Q

What is carbimazole’s target?

A

thyroid peroxidase

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45
Q

What type of drug is carbimazole?

A

reversible inhibitor of thyroid peroxidase

46
Q

mechanisms of action of carbimazole

A
  • reduces oxidation of iodide to iodine
  • reduces organification of iodine to make iodotyrosine
  • inhibits coupling of iodotyrosine
47
Q

absorption of carbimazole

A

rapidly orally absorbed with 93% bioavailability

48
Q

excretion of carbimazole

A

renally excreted

49
Q

How to get maximum effect of carbimazole?

A

need to deplete thyroid horomone stores, can take weeks

50
Q

half life of carbimazole

A

6 hours

but accumulates in the thyroid gland and half life is 30-40hrs

51
Q

What does the thyroid gland do to carbimazole?

A

concentrates it

52
Q

What is propylthioruacil a derivative of?

A

uracil derivative

53
Q

mechanism of action of propylthiouracil

A
  • inhibits thyroid peroxidase
  • reduces oxidation of iodide to iodine
  • reduces organification of iodine to make iodotyrosine
  • inhibits coupling of iodothyrosine
54
Q

bioavailability of propylthiouracil

A

50-80%

55
Q

excretion of propylthiouracil

A

via kidneys

56
Q

additional effect of propylthiouracil

A

inhibits 5’ mono deiodinase enzymes which converts T4 to T3

  • prevents thyroid hormones becoming more active
57
Q

What group on PTU is essential for its activity (inhibiting deiodinase enzyme)?

A

C2 thioketo/enol and unsubstituted N1

58
Q

What groups enhance PTU inhibition of deiodinase enzyme?

A

C4 enol and alkyl groups at C5 and C6

59
Q

What group in methimazole prevents deiodinase inhibition?

A

methyl group at N1

60
Q

Is carbimazole or PTU more hepatotoxic?

A

propylthiouracil

61
Q

When is PTU used?

A

patients who have s/e to carbimazole

62
Q

When is PTU not recommended?

A

in children (because of its hepatotoxicity)

63
Q

PTU half life

A

2hrs

accumulates in thyroid and half life is 30-40hrs

64
Q

When can improvements be seen after starting propylthiouracil?

A

after 2-4 weeks

65
Q

When is patient euthyroid after starting PTU?

A

within 4-6 weeks

66
Q

serioud s/e with PTU in some patients

A
  • sudden onset of hepatotoxicity in some patients (0.1-0.2%)
  • marked increase in liver enzymes and liver necrosis observed
  • severe cases require liver transplant
67
Q

What is TPO?

A

a haemoprotein enzyme

68
Q

binding sites on TPO

A

2 binding sites for iodine and tyrosine

69
Q

What is oxidation of iodide dependent on?

A

presence of hydrogen peroxide

70
Q

What do carbimazole and PTU bind to for TPO inhibition?

A

they bind to the haem group
inactivating the enzyme
doesn’t allow the changing of Fe status from Fe3 to Fe4
H2O2 no longer required

71
Q

How does hyperthyroidism affect mother and baby during pregnancy?

A 
low birth weight
heart diseases
premature birth
thyroid storm
high BP during pregnancy
72
Q

thionamides and pregnancy

A

carbimazole has teratogenic effects (cannot use)

passes to foetus

73
Q

PTU during pregnancy

A

has less teratogenic effects
ued during pregnancy
has higher hepatotoxicity - caution needed
can cross BBB (lowest possible dose)
incorrect dose can elad to foetal goitre
may need monthly TFT testing
patients should be euthyroid before pregnancy

74
Q

carbimazole or PTU when breastfeeding

A

both safe

carbimazole preferred becaise it has less hepatotoxicity

75
Q

What enzyme does PTU and carbimazole block?

A

thyroid peroxidase

76
Q

What additional enzyme does PTU block?

A

deiodinase

77
Q

What effects does hyperthyroidism have on the heart?

A

ventricular dilation
persistent tachycardia
chronic heart failure

78
Q

What effects do thyroid hormones have on the heart?

A 
increases inotrophy
increases chronotrophy
- increases CO
- increases blood volume
- increases BP
79
Q

What is inotrophy?

A

event that changes muscle contraction/force

80
Q

What is chronotrophy?

A

event that changes heart rate

81
Q

What drug is given for treatment of tachycardia/tremours/palpitations/
anxiety in hyperthyriodism?

A

propranolol

- slows down the rapid heart beat

82
Q

How does propranolol work?

A

beta adrenoreceptor antagonist

blocks beta 1 and beta 2 receptors

83
Q

Treatment if drugs fail

A
  • remove the thyroid gland

- radioactive iodine (destroys the overactive tissue)

84
Q

causes of hypothyroidism

A 
autoimmine disease - Hashimoto's
surgery
radiotherapy
hypothalamus/pituitary disorder
iodine deficiency
85
Q

What is congenital hypothyroidism?

A

deficiency in thyroid hormones from birth

86
Q

If congenital hypothyroidism is not diagnosed what can it lead to?

A

cretinism

87
Q

How much iodine in amiodarone?

A

200mg of amiodarone contains 75mg of iodine

88
Q

How does amiodarone cause hypothyroidism? (AIH)

A

when amiodarone is metabolised, 6mg of iodine is released into the bloodstream
this inhibits 5’-deiodinase
T4 is not converted to T3

89
Q

What metabolises amiodarone?

A

cytochrome P450 in the liver

90
Q

What is amiodarone used for?

A

arrhythmias

91
Q

What can amiodarone also induce (apart from hypothyroidism)?

A

amiodarone induced thyrotoxicosis (AIT)

92
Q

How does amiodarone cause amiodarone induced thyrotoxicosis?

A

it causes destructive thyroditis that results in thyroid damage
thyroid glands enlargen and rupture
T3 and T4 are released into circulation uncontrollably

93
Q

What happens if amiodarone cannot be stopped and it is causing AIT?

A

thyroidectomy

94
Q

What is lithium taken for?

A

depression

95
Q

What can lithium cause?

A

it can cause goitre and hypothyroidism

96
Q

What must be monitored when taking lithium?

A

6 monthly TFTs

97
Q

hypothyroidism treatment

A

levothyroxine (T4)
liothyronine (T3)
liotrix (T4 and T3 mixture)

98
Q

How does levothyroxine work?

A

it’s a thyroxine substitute

it’s converted to its active metabolite triiodothyronine (T3)

99
Q

What is the most stable form of levothyroxine?

A

pentahydrate

100
Q

GI availability of levothyroxine

A

40-80%

101
Q

aim for hypothyroidism treatment

A

aim is to have TSH in the lower part of the reference range

102
Q

How long does it take for T4 to return to normal range?

A

weeks

103
Q

pKa of levothyroxine

A

6.7

104
Q

What decreases bioavailability of levothyroxine?

A

food

105
Q

protein binding of levothyroxine

A

99%

106
Q

duration of action of levothyroxine

A

several weeks

107
Q

half life of levothyroxine

A

3-4 days
50% faeces
50% urine

108
Q

What drug is given in hypothyroidism emergency?

A

liothyronine (T3)

109
Q

Why is liothyronine used in an emergency and what emergencies?

A

faster action
shorter duration

patients with heart disease
myxoedema coma

110
Q

What is thyroid function testing performed by?

A

immunoassay

PHA223 (43 decks)

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