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PHA 332 > thyroid drugs steve darby > Flashcards

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
Q

what is the MOA of carbimazole?

A

carbimazole is metabolized in the first pass to methimazole by the liver, which is responsible for the anti-thyroid activity

26
Q

what is carbimazole’s target?

A

thyroid peroxidase- tpo = acts as a thyroid peroxidase inhibitor

27
Q

what is the MOA of carbimazole?

A

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
Q

is carbimazole rapidly absorbed?

A

yes with 93% bioavailability. it is renally excreted

29
Q

what is the half life od carbimazole?

A

Carbimazole plasma 1/2 life = 6h… BUT………

• Largely irrelevant as drug accumulates in the thyroid and half life is 30-40h

30
Q

how does thiouracil work?

A

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
Q

how is thiouracil excreted?

A

primarily via the kidney

32
Q

how does PTU convert t4 to t3?

A

PTU ALSO inhibits 5’ mono-deiodinase enzyme which converts T4 to T3

33
Q

how does the SAR of thiouracils affect deiodionation?

A

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
Q

when is PTU used?

A
  • PTU used is patients who develop side effects to carbimazole
  • PTU NOT recommended in children - due to associated hepatoxicty
35
Q

which drug for hyperthyroidism is more potent?

A

carbimazole- more doses of PTU required for the same effect

36
Q

how does thyroid peroxidase inhibition work?

A

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
Q

how does hyperthyroidism affect the baby and mother?

A

-low birth weight
-high blood pressure during pregnancy
heart diseases
-premature birth
thyroid storm

38
Q

what is the go to drug for hyperthyroidism in pregnancy and why?

A

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
Q

how should PTU be managed in pregnancy?

A

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
Q

what are the t3/t4positively regulated genes?

A 
a-myosin heavy chain
sarcoplasmic reticulum ca2+ ATPase
na+/k+ ATPase
b1-adrenergic receptor
voltage gated k+ channel
41
Q

what are the t3/t4 negatively regulated genes?

A 
b-myosin heavy chain
phospholamban
adenylyl cyclase catylitic sub-units
na+/ca+ exchange
thyroid hormone receptor a1
42
Q

why are bb used in thyroid disease?

A 
Hyperthyroidism causes
tachycardia and tremors
• Propranolol used in the treatment
of thyrotoxicosis
• β-adrenoreceptor antagonist –
blocks β1 and β2 receptors
• Alleviates hyperthyroidism
symptoms
43
Q

what happens if thyroid drugs fail?

A

iodine accumulates in thyroid gland destroying the overactive tissue
this leads to hypothyroidism

44
Q

what are the general causes of hypothyroidism?

A
  • Autoimmune disease – Hashimoto’s
  • Surgery
  • Radiotherapy
  • Hypothalamus/Pituitary disorder
  • Iodine Deficiency
45
Q

what is congenital hypothyroidism?

A

deficiency in the thyroid from birth

lacking thyroid or even ectopic thyroid gland

46
Q

how is congenital hypothyroidism lowered?

A 
• 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
Q

how does amiodarone induced hypothyroidism occur?

A

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
Q

how does amiodarone induced thyrotoxicosis occur?

A

• Destructive thyroiditis that results in thyroid damage
• Excess release of preformed T4 and T3 into the
circulation

49
Q

what needs to be monitored in AIT?

A

TFT every 6 months

50
Q

what happens if amiodarone treatment cannot be stopped in AIT?

A

thyroid removal is an option

51
Q

what should be tested in li induced hypothyroidism?

A

Routine 6 monthly TFT

52
Q

what can li cause? how does it do this?

A

Lithium can cause goitre and hypothyroidism
• The inhibitory effect of lithium occurs mainly at the
level of hormone secretion

53
Q

what are the 4 basic treatments for hypothyroidism?

A 
• 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
Q

what is the MOA of levothyroxine?

A

• Thyroxine substitute >converted to its active metabolite

triiodothyronine (T3)

55
Q

what should happen to TSH and T4?

A

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
Q

what is the pka of levothyroxine?

A

6.7

57
Q

what is the elimination half life for levothyroxine?

A

3-4 days : 50% faeces, 50% urine

58
Q

what is the emergency treatment for hypothyroidism?

A 
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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