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thyroid drugs steve darby Flashcards

1
Q

what are the thyroid hormones essential for?

A

growth, development and metabolism

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2
Q

what is the thyroid gland regulated by?

A

-tightly regulated through the hypothalamus, pituitary and thyroid axis

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3
Q

what gland is capable of incorporating iodine into organic molecules?

A

iodine

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4
Q

who is thyroid disease common in?

A

very common in women and rises with age

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5
Q

what is an important dietary factor in thyroid function?

A

dietary iodine

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6
Q

what diseases can develop from the thyroid gland?

A 
graves
multinodular goitre
autoimmune
hashimoto's
thyroiditis
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7
Q

what is the secretory unit of the thyroid gland?

A

thyroid follicle or acini

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8
Q

how is the thyroid follicle or acini made up?

A

-• Secretory unit is the thyroid follicle
• Epithelial cells enclosing colloid
• Colloid is amorphous material mostly
composed of thyroglobulin
• Parafollicular cells / C-cells secrete Calcitonin
• Follicular cells secrete the thyroid hormones

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9
Q

what are the thyroid hormones secreted?

A
  • Thyroxin (T4)

* Tri-iodothyronine (T3)

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10
Q

how does the biosynthesis of thyroid hormones occur?

A
  1. Trapping of iodide
  2. Synthesis of thyroglobulin (TG)
  3. Oxidation of iodide (TPO)
  4. Organification of iodine at tyrosine
    site (TPO)
  5. Coupling
    - T1>T2>T3>T4 (TPO)
  6. Pinocytosis of colloid
  7. Secretion of thyroid hormones
  8. Transport of thyroid hormones into
    blood
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11
Q

what is the SAR of thyroid hormones?

A

– Derived from the amino acid tyrosine
– Two phenyl rings coupled through an X group.
– The phenyl rings must be appropriately substituted for hormone
action

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12
Q

are the derivatives of thyroid hormones more active?

A

Although many derivatives have been prepared it has been found that
none were more active than the natural hormones T4 and T3.

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13
Q

if R5’ is an iodine what is t4 considered?

A

a prohormone for t3

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14
Q

how do you decouple t4 to t3?

A

deeiodinase- take off iodine
from outer ring to give t3
from inner ring to give rT3 ( inactive)

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15
Q

what is the action of the thyroid hormone?

A 
• T3 (active form) interacts with
Thyroid hormone receptors
• Nuclear hormone receptors
• Dimerize with Retinoid X Receptor
• Bind to DNA
• Transcribe target genes
• Elicit desired effects
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16
Q

what tests establish thyroid function?

A

serum TSH

t3 and t4 measurements

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17
Q

what tests test that elucidate cause?

A 
Thyroid autoantibodies
– Serum thyroglobulin
– Thyroid enzymes
– Biopsy/ultrasound
– Scintiscan
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18
Q

what are the lab tests for monitoring treatment?

A

– Serum thyroglobulin

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19
Q

what happens in TFT clinical testing?

A 
96 well plates
• Each well = separate sample
• High throughput
• Colour change proportional to
protein level
• Entire plate read in 5 seconds in
plate reader
• Simply use different antibody for
different proteins - KITS
– TSH, T4, T3 et
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20
Q

when is TSH increased/ decreased?

A

– Increased in hypothyroidism
– Decreased in hyperthyroidism
– A normal [TSH] “usually” excludes primary
thyroid dysfunction.

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21
Q

what happens during thyroid scanning?

A

Patient ingests radioactive iodine
• Returns 24h later for scan with a gamma probe
• Radioactive Iodine123 uptake (RAIU) is a test of
thyroid function.
– Short half life, very low dose/risk
– Care with urine though… flush twice
– Care of use in pregnancy
• It measures how much radioactive iodine is taken
up by the thyroid gland in a given time period
• Amount of iodine in the thyroid is indicative of
status

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22
Q

what are the clinical manifestations of hyperthyroidism/ thyrotoxicosis?

A 
Tremor
– Tachycardia / Palpitations
– Weight loss
– Tiredness
– Feeling warm / Sweating
– Diarrhoea
– Anxiety and emotional symptoms

this is due to interactions with nervous system

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23
Q

what are the hyperthyroidism treatments?

A
  • Anti-thyroid drugs
  • Radioactive iodine (RAI)
  • Surgery to remove the gland (thyroidectomy)
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24
Q

what is carbimazole’s active form?

A

converted to methimazole- MMI in the liver

25
what is the MOA of carbimazole?
carbimazole is metabolized in the first pass to methimazole by the liver, which is responsible for the anti-thyroid activity
26
what is carbimazole's target?
thyroid peroxidase- tpo = acts as a thyroid peroxidase inhibitor
27
what is the MOA of carbimazole?
Reversible Inhibitor of thyroid peroxidase (production of thyroid hormones in thyroid gland) – Reduces oxidation of iodide to iodine – Reduces organification of Iodine to make iodotyrosine (organic form) – Inhibits coupling of iodotyrosine • T1>T2>T3>T4
28
is carbimazole rapidly absorbed?
yes with 93% bioavailability. it is renally excreted
29
what is the half life od carbimazole?
Carbimazole plasma 1/2 life = 6h… BUT……… | • Largely irrelevant as drug accumulates in the thyroid and half life is 30-40h
30
how does thiouracil work?
Inhibits thyroid peroxidase (production of thyroid hormones in thyroid gland) – Reduces oxidation of iodide to iodine – Reduces organification of Iodine to make iodotyrosine (organic form) – Inhibits coupling of iodotyrosine • T1>T2>T3>T4
31
how is thiouracil excreted?
primarily via the kidney
32
how does PTU convert t4 to t3?
PTU ALSO inhibits 5’ mono-deiodinase enzyme which converts T4 to T3
33
how does the SAR of thiouracils affect deiodionation?
The C2 thioketo/enol and an unsubstituted N1 are essential for activity. • Activity is enhanced by a C4 enol and alkyl groups at C5 and C6. • The methyl group at N1 in Methimazole prevents deiodinase inhibition • PTU MORE HEPATOTOXIC than carbimazole
34
when is PTU used?
* PTU used is patients who develop side effects to carbimazole * PTU NOT recommended in children - due to associated hepatoxicty
35
which drug for hyperthyroidism is more potent?
carbimazole- more doses of PTU required for the same effect
36
how does thyroid peroxidase inhibition work?
TPO is a haemoprotein enzyme with 2 binding sites for Iodine and Tyrosine • To serve as an iodinating agent, iodide must be oxidized - dependent on the presence of H2O • Carbimazole/MMI and PTU bind to heme groups preventing this key stage and inactivate the enzyme
37
how does hyperthyroidism affect the baby and mother?
-low birth weight -high blood pressure during pregnancy heart diseases -premature birth thyroid storm
38
what is the go to drug for hyperthyroidism in pregnancy and why?
carbimazole is suspected to have teratogenic effects PTU less so- favored anti-thyroid treatment in pregnancy but PTU has a higher hepatoxicity so care is needed
39
how should PTU be managed in pregnancy?
PTU can cross the blood brain barrier – use lowest possible dose • Incorrect dose can lead to foetal goitre • May involve monthly TFT screening • Pre-existing patients should “ideally” be euthyroid prior to pregnancy • When breast feeding – PTU and carbimazole are considered safe BUT carbimazole has less hepatotoxicity so is therefore preferred
40
what are the t3/t4positively regulated genes?
``` a-myosin heavy chain sarcoplasmic reticulum ca2+ ATPase na+/k+ ATPase b1-adrenergic receptor voltage gated k+ channel ```
41
what are the t3/t4 negatively regulated genes?
``` b-myosin heavy chain phospholamban adenylyl cyclase catylitic sub-units na+/ca+ exchange thyroid hormone receptor a1 ```
42
why are bb used in thyroid disease?
``` Hyperthyroidism causes tachycardia and tremors • Propranolol used in the treatment of thyrotoxicosis • β-adrenoreceptor antagonist – blocks β1 and β2 receptors • Alleviates hyperthyroidism symptoms ```
43
what happens if thyroid drugs fail?
iodine accumulates in thyroid gland destroying the overactive tissue this leads to hypothyroidism
44
what are the general causes of hypothyroidism?
* Autoimmune disease – Hashimoto’s * Surgery * Radiotherapy * Hypothalamus/Pituitary disorder * Iodine Deficiency
45
what is congenital hypothyroidism?
deficiency in the thyroid from birth | lacking thyroid or even ectopic thyroid gland
46
how is congenital hypothyroidism lowered?
``` • Neonatal screening program detects this, pin prick of blood from the foot • Prevents symptoms developing • Life long hormone replacement • If undiagnosed may lead to cretinism • ALL NEWBORNS IN THE UK ARE SCREENED FOR CONGENTIAL HYPOTHYROIDISM ```
47
how does amiodarone induced hypothyroidism occur?
Amiodarone metabolism (Cytochrome P450 in the liver) leads to liberation of 6mg of free iodine (40x daily intake • Direct cytotoxic effect on follicular cells leading to thyroiditis
48
how does amiodarone induced thyrotoxicosis occur?
• Destructive thyroiditis that results in thyroid damage • Excess release of preformed T4 and T3 into the circulation
49
what needs to be monitored in AIT?
TFT every 6 months
50
what happens if amiodarone treatment cannot be stopped in AIT?
thyroid removal is an option
51
what should be tested in li induced hypothyroidism?
Routine 6 monthly TFT
52
what can li cause? how does it do this?
Lithium can cause goitre and hypothyroidism • The inhibitory effect of lithium occurs mainly at the level of hormone secretion
53
what are the 4 basic treatments for hypothyroidism?
``` • Desiccated Thyroid USP (United States Pharmacopoeia) desiccated thyroid extract from pig/cow • Release T4, T3, T2, T1 – Unacceptable variability – Hypersensitivity – Ethical issues • Levothyroxine (T4) • Liothyronine (T3) • Liotrix – a mixture of T4 and T3 (4:1), no advantage and costs more ```
54
what is the MOA of levothyroxine?
• Thyroxine substitute >converted to its active metabolite | triiodothyronine (T3)
55
what should happen to TSH and T4?
should return to clinical reference range ( euthyroid) Aim to have TSH to lower part of reference (no over stimulation) – T4 to normal range within weeks
56
what is the pka of levothyroxine?
6.7
57
what is the elimination half life for levothyroxine?
3-4 days : 50% faeces, 50% urine
58
what is the emergency treatment for hypothyroidism?
``` liothyronine Synthetic form of T3 • Used when a rapid onset and cessation of action is required – patients with heart disease – myxoedema coma • Faster action, shorter duration ```

PHA 332 (42 decks)

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