thyroid drugs Flashcards
What glands regulate thyroid production?
hypothalamus, pituiraty, and thyroid gland
What is important for thyroid function?
dietary iodide
What joins the 2 parts of the thyroid gland?
isthmus
diseases that can affect the thyroid gland
Grave's disease multinodular disease autoimmune disease Hashimoto's thyroiditis
What is the secretory unit of the thyroid gland?
thyroid follicle or acini
What surrounds the colloid?
epithelial cells
What is the colloid composed of?
thyroglobulin
What cells secrete calcitonin?
parafolicular cells (C cells)
What do follicular cells secrete?
thyroid hormones - T4 and T3
synthesis of thyroid hormones
- TRAPPING of iodide (Na/I pump) into the follicular cell
- SYNTHESIS of thyroglobulin (TG)
- OXIDATION of iodide (by the enzyme TPO)
- ORGANIFICATION of iodine at tyrosine site (TPO) (additionon iodine to tyrosine resudies)
- COUPLING (T1 - T2 - T3 - T4)
- PINOCYTOSIS of colloid (into follicular cell, lysosome degrades TG leaving the thyroid hormoned behind)
- SECRETION of thyroid hormones
- TRANSPORT of thyroid hormones into blood
What steps of thyroid hormone synthesis can be targeted in overproduction of thyroid hormone?
steps 3, 4 and 5
oxidation, organification and coupling
What is TPO?
thyroid peroxidase
What stages does TPO enzyme control?
stages 3, 4 and 5
oxidation, organification and coupling
What AA are thyroid hormones derived from?
tyrosine
structure of thyroid hormones
2 phenyl rings coupled through an X group
What must X be in thyroid hormone structure?
oxygen
-> forming a phenoxyphenyl pharmacophore
What must R1 be in thyroid hormone structure?
alanine
What must R3 and R5 be in thyroid hormone structure?
iodine
What must R3’ be in thyroid hormone structure?
iodine
What must R4’ be in thyroid hormone structure?
hydroxyl group
structural difference between T3 and T4
iodine at R5’ in T4
nothing in T3
(T4 - 4 iodines, T3 - 3 iodnies)
What happens to tyrosine in the organification process?
addition of iodine
What does organification require?
hydrogen peroxide
What forms when iodine is added to tyrosine in the organification process?
monoiodothyrosine (MIT)
What forms when 2 iodines are added to tyrosine?
diiodothyrosine (DIT)
What does peroxidase coupling form?
T3 and T4
Is T4 active?
no
What % of thyroid hormone is relrased as T4?
80% T4
How is T4 activated?
deiodinase enzyme removes an iodine from T4 which activates it to form T3
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)
What type of receptors do thyroid hormones act on?
nuclear hormone receptor (inside the cell, when activated move inside the nucleus)
thyroid hormone action
- T3/T4 into the cell
- T4 converted to T3
- T3 interacts with the thyroid hormone receptor
- T3+R dimerises with retinoid X receptor
- binds to DNA
- transcribes target genes
- has desired effect
tests that establish thyroid dysfunction
serum TSH
T3 and T4 measurements
tests that elcuidate cause
thyroid autoantibodies
serum thyroglobulin
thyroid enzymes
biopsy/ultrasound
What is measured when monitoring treatment?
serum thyroglobulin
What is tested when patient suspected of having thyroid disease?
TSH
T4
TSH levels
normal - euthyroid/healthy patients (excludes primary thyroid dysfunction)
increased - hypothyroidism
decreased - hyperthyroidism
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
symptoms of hyperthyroidism/thyrotoxicosis
tremor tachycardia/palpitations weight loss tiredness warm/sweating diarrhoea anxiety/emotional
hyperthyroidism treatments (3)
- anti-thyroid drugs
- rado-active iodine
- surgery to remove the gland (thyroidectomy)
main drug used for hyperthyroidism
thionamides - carbimazole
What derivative is carbimazole from?
imidazole
What is carbimazole converted to in the body and how?
active metabolite - methimazole (MMI)
converted by the liver (1st pass metabolism)
What is carbimazole’s target?
thyroid peroxidase
What type of drug is carbimazole?
reversible inhibitor of thyroid peroxidase
mechanisms of action of carbimazole
- reduces oxidation of iodide to iodine
- reduces organification of iodine to make iodotyrosine
- inhibits coupling of iodotyrosine
absorption of carbimazole
rapidly orally absorbed with 93% bioavailability
excretion of carbimazole
renally excreted
How to get maximum effect of carbimazole?
need to deplete thyroid horomone stores, can take weeks
half life of carbimazole
6 hours
but accumulates in the thyroid gland and half life is 30-40hrs
What does the thyroid gland do to carbimazole?
concentrates it
What is propylthioruacil a derivative of?
uracil derivative
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
bioavailability of propylthiouracil
50-80%
excretion of propylthiouracil
via kidneys
additional effect of propylthiouracil
inhibits 5’ mono deiodinase enzymes which converts T4 to T3
- prevents thyroid hormones becoming more active
What group on PTU is essential for its activity (inhibiting deiodinase enzyme)?
C2 thioketo/enol and unsubstituted N1
What groups enhance PTU inhibition of deiodinase enzyme?
C4 enol and alkyl groups at C5 and C6
What group in methimazole prevents deiodinase inhibition?
methyl group at N1
Is carbimazole or PTU more hepatotoxic?
propylthiouracil
When is PTU used?
patients who have s/e to carbimazole
When is PTU not recommended?
in children (because of its hepatotoxicity)
PTU half life
2hrs
accumulates in thyroid and half life is 30-40hrs
When can improvements be seen after starting propylthiouracil?
after 2-4 weeks
When is patient euthyroid after starting PTU?
within 4-6 weeks
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
What is TPO?
a haemoprotein enzyme
binding sites on TPO
2 binding sites for iodine and tyrosine
What is oxidation of iodide dependent on?
presence of hydrogen peroxide
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
How does hyperthyroidism affect mother and baby during pregnancy?
low birth weight heart diseases premature birth thyroid storm high BP during pregnancy
thionamides and pregnancy
carbimazole has teratogenic effects (cannot use)
passes to foetus
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
carbimazole or PTU when breastfeeding
both safe
carbimazole preferred becaise it has less hepatotoxicity
What enzyme does PTU and carbimazole block?
thyroid peroxidase
What additional enzyme does PTU block?
deiodinase
What effects does hyperthyroidism have on the heart?
ventricular dilation
persistent tachycardia
chronic heart failure
What effects do thyroid hormones have on the heart?
increases inotrophy increases chronotrophy - increases CO - increases blood volume - increases BP
What is inotrophy?
event that changes muscle contraction/force
What is chronotrophy?
event that changes heart rate
What drug is given for treatment of tachycardia/tremours/palpitations/
anxiety in hyperthyriodism?
propranolol
- slows down the rapid heart beat
How does propranolol work?
beta adrenoreceptor antagonist
blocks beta 1 and beta 2 receptors
Treatment if drugs fail
- remove the thyroid gland
- radioactive iodine (destroys the overactive tissue)
causes of hypothyroidism
autoimmine disease - Hashimoto's surgery radiotherapy hypothalamus/pituitary disorder iodine deficiency
What is congenital hypothyroidism?
deficiency in thyroid hormones from birth
If congenital hypothyroidism is not diagnosed what can it lead to?
cretinism
How much iodine in amiodarone?
200mg of amiodarone contains 75mg of iodine
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
What metabolises amiodarone?
cytochrome P450 in the liver
What is amiodarone used for?
arrhythmias
What can amiodarone also induce (apart from hypothyroidism)?
amiodarone induced thyrotoxicosis (AIT)
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
What happens if amiodarone cannot be stopped and it is causing AIT?
thyroidectomy
What is lithium taken for?
depression
What can lithium cause?
it can cause goitre and hypothyroidism
What must be monitored when taking lithium?
6 monthly TFTs
hypothyroidism treatment
levothyroxine (T4)
liothyronine (T3)
liotrix (T4 and T3 mixture)
How does levothyroxine work?
it’s a thyroxine substitute
it’s converted to its active metabolite triiodothyronine (T3)
What is the most stable form of levothyroxine?
pentahydrate
GI availability of levothyroxine
40-80%
aim for hypothyroidism treatment
aim is to have TSH in the lower part of the reference range
How long does it take for T4 to return to normal range?
weeks
pKa of levothyroxine
6.7
What decreases bioavailability of levothyroxine?
food
protein binding of levothyroxine
99%
duration of action of levothyroxine
several weeks
half life of levothyroxine
3-4 days
50% faeces
50% urine
What drug is given in hypothyroidism emergency?
liothyronine (T3)
Why is liothyronine used in an emergency and what emergencies?
faster action
shorter duration
patients with heart disease
myxoedema coma
What is thyroid function testing performed by?
immunoassay
