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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
What forms when 2 iodines are added to tyrosine?
diiodothyrosine (DIT)
26
What does peroxidase coupling form?
T3 and T4
27
Is T4 active?
no
28
What % of thyroid hormone is relrased as T4?
80% T4
29
How is T4 activated?
deiodinase enzyme removes an iodine from T4 which activates it to form T3
30
outer ring deiodination vs inner ring deiodination
outer ring deiodination forms active T3 | inner ring deiodination forms reverse T3 (rT3), inactive (not recognised by the receptor)
31
What type of receptors do thyroid hormones act on?
nuclear hormone receptor (inside the cell, when activated move inside the nucleus)
32
thyroid hormone action
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
33
tests that establish thyroid dysfunction
serum TSH | T3 and T4 measurements
34
tests that elcuidate cause
thyroid autoantibodies serum thyroglobulin thyroid enzymes biopsy/ultrasound
35
What is measured when monitoring treatment?
serum thyroglobulin
36
What is tested when patient suspected of having thyroid disease?
TSH | T4
37
TSH levels
normal - euthyroid/healthy patients (excludes primary thyroid dysfunction) increased - hypothyroidism decreased - hyperthyroidism
38
How does thyroid scanning (radioactive iodine) work?
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
39
symptoms of hyperthyroidism/thyrotoxicosis
``` tremor tachycardia/palpitations weight loss tiredness warm/sweating diarrhoea anxiety/emotional ```
40
hyperthyroidism treatments (3)
1. anti-thyroid drugs 2. rado-active iodine 3. surgery to remove the gland (thyroidectomy)
41
main drug used for hyperthyroidism
thionamides - carbimazole
42
What derivative is carbimazole from?
imidazole
43
What is carbimazole converted to in the body and how?
active metabolite - methimazole (MMI) | converted by the liver (1st pass metabolism)
44
What is carbimazole's target?
thyroid peroxidase
45
What type of drug is carbimazole?
reversible inhibitor of thyroid peroxidase
46
mechanisms of action of carbimazole
- reduces oxidation of iodide to iodine - reduces organification of iodine to make iodotyrosine - inhibits coupling of iodotyrosine
47
absorption of carbimazole
rapidly orally absorbed with 93% bioavailability
48
excretion of carbimazole
renally excreted
49
How to get maximum effect of carbimazole?
need to deplete thyroid horomone stores, can take weeks
50
half life of carbimazole
6 hours | but accumulates in the thyroid gland and half life is 30-40hrs
51
What does the thyroid gland do to carbimazole?
concentrates it
52
What is propylthioruacil a derivative of?
uracil derivative
53
mechanism of action of propylthiouracil
- inhibits thyroid peroxidase - reduces oxidation of iodide to iodine - reduces organification of iodine to make iodotyrosine - inhibits coupling of iodothyrosine
54
bioavailability of propylthiouracil
50-80%
55
excretion of propylthiouracil
via kidneys
56
additional effect of propylthiouracil
inhibits 5' mono deiodinase enzymes which converts T4 to T3 - prevents thyroid hormones becoming more active
57
What group on PTU is essential for its activity (inhibiting deiodinase enzyme)?
C2 thioketo/enol and unsubstituted N1
58
What groups enhance PTU inhibition of deiodinase enzyme?
C4 enol and alkyl groups at C5 and C6
59
What group in methimazole prevents deiodinase inhibition?
methyl group at N1
60
Is carbimazole or PTU more hepatotoxic?
propylthiouracil
61
When is PTU used?
patients who have s/e to carbimazole
62
When is PTU not recommended?
in children (because of its hepatotoxicity)
63
PTU half life
2hrs | accumulates in thyroid and half life is 30-40hrs
64
When can improvements be seen after starting propylthiouracil?
after 2-4 weeks
65
When is patient euthyroid after starting PTU?
within 4-6 weeks
66
serioud s/e with PTU in some patients
- 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
What is TPO?
a haemoprotein enzyme
68
binding sites on TPO
2 binding sites for iodine and tyrosine
69
What is oxidation of iodide dependent on?
presence of hydrogen peroxide
70
What do carbimazole and PTU bind to for TPO inhibition?
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
How does hyperthyroidism affect mother and baby during pregnancy?
``` low birth weight heart diseases premature birth thyroid storm high BP during pregnancy ```
72
thionamides and pregnancy
carbimazole has teratogenic effects (cannot use) | passes to foetus
73
PTU during pregnancy
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
carbimazole or PTU when breastfeeding
both safe | carbimazole preferred becaise it has less hepatotoxicity
75
What enzyme does PTU and carbimazole block?
thyroid peroxidase
76
What additional enzyme does PTU block?
deiodinase
77
What effects does hyperthyroidism have on the heart?
ventricular dilation persistent tachycardia chronic heart failure
78
What effects do thyroid hormones have on the heart?
``` increases inotrophy increases chronotrophy - increases CO - increases blood volume - increases BP ```
79
What is inotrophy?
event that changes muscle contraction/force
80
What is chronotrophy?
event that changes heart rate
81
What drug is given for treatment of tachycardia/tremours/palpitations/ anxiety in hyperthyriodism?
propranolol | - slows down the rapid heart beat
82
How does propranolol work?
beta adrenoreceptor antagonist | blocks beta 1 and beta 2 receptors
83
Treatment if drugs fail
- remove the thyroid gland | - radioactive iodine (destroys the overactive tissue)
84
causes of hypothyroidism
``` autoimmine disease - Hashimoto's surgery radiotherapy hypothalamus/pituitary disorder iodine deficiency ```
85
What is congenital hypothyroidism?
deficiency in thyroid hormones from birth
86
If congenital hypothyroidism is not diagnosed what can it lead to?
cretinism
87
How much iodine in amiodarone?
200mg of amiodarone contains 75mg of iodine
88
How does amiodarone cause hypothyroidism? (AIH)
when amiodarone is metabolised, 6mg of iodine is released into the bloodstream this inhibits 5'-deiodinase T4 is not converted to T3
89
What metabolises amiodarone?
cytochrome P450 in the liver
90
What is amiodarone used for?
arrhythmias
91
What can amiodarone also induce (apart from hypothyroidism)?
amiodarone induced thyrotoxicosis (AIT)
92
How does amiodarone cause amiodarone induced thyrotoxicosis?
it causes destructive thyroditis that results in thyroid damage thyroid glands enlargen and rupture T3 and T4 are released into circulation uncontrollably
93
What happens if amiodarone cannot be stopped and it is causing AIT?
thyroidectomy
94
What is lithium taken for?
depression
95
What can lithium cause?
it can cause goitre and hypothyroidism
96
What must be monitored when taking lithium?
6 monthly TFTs
97
hypothyroidism treatment
levothyroxine (T4) liothyronine (T3) liotrix (T4 and T3 mixture)
98
How does levothyroxine work?
it's a thyroxine substitute | it's converted to its active metabolite triiodothyronine (T3)
99
What is the most stable form of levothyroxine?
pentahydrate
100
GI availability of levothyroxine
40-80%
101
aim for hypothyroidism treatment
aim is to have TSH in the lower part of the reference range
102
How long does it take for T4 to return to normal range?
weeks
103
pKa of levothyroxine
6.7
104
What decreases bioavailability of levothyroxine?
food
105
protein binding of levothyroxine
99%
106
duration of action of levothyroxine
several weeks
107
half life of levothyroxine
3-4 days 50% faeces 50% urine
108
What drug is given in hypothyroidism emergency?
liothyronine (T3)
109
Why is liothyronine used in an emergency and what emergencies?
faster action shorter duration patients with heart disease myxoedema coma
110
What is thyroid function testing performed by?
immunoassay

PHA223 (43 decks)

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