thyroid drugs steve darby Flashcards
what are the thyroid hormones essential for?
growth, development and metabolism
what is the thyroid gland regulated by?
-tightly regulated through the hypothalamus, pituitary and thyroid axis
what gland is capable of incorporating iodine into organic molecules?
iodine
who is thyroid disease common in?
very common in women and rises with age
what is an important dietary factor in thyroid function?
dietary iodine
what diseases can develop from the thyroid gland?
graves multinodular goitre autoimmune hashimoto's thyroiditis
what is the secretory unit of the thyroid gland?
thyroid follicle or acini
how is the thyroid follicle or acini made up?
-• 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
what are the thyroid hormones secreted?
- Thyroxin (T4)
* Tri-iodothyronine (T3)
how does the biosynthesis of thyroid hormones occur?
- Trapping of iodide
- Synthesis of thyroglobulin (TG)
- Oxidation of iodide (TPO)
- Organification of iodine at tyrosine
site (TPO) - Coupling
- T1>T2>T3>T4 (TPO) - Pinocytosis of colloid
- Secretion of thyroid hormones
- Transport of thyroid hormones into
blood
what is the SAR of thyroid hormones?
– Derived from the amino acid tyrosine
– Two phenyl rings coupled through an X group.
– The phenyl rings must be appropriately substituted for hormone
action
are the derivatives of thyroid hormones more active?
Although many derivatives have been prepared it has been found that
none were more active than the natural hormones T4 and T3.
if R5’ is an iodine what is t4 considered?
a prohormone for t3
how do you decouple t4 to t3?
deeiodinase- take off iodine
from outer ring to give t3
from inner ring to give rT3 ( inactive)
what is the action of the thyroid hormone?
• 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
what tests establish thyroid function?
serum TSH
t3 and t4 measurements
what tests test that elucidate cause?
Thyroid autoantibodies – Serum thyroglobulin – Thyroid enzymes – Biopsy/ultrasound – Scintiscan
what are the lab tests for monitoring treatment?
– Serum thyroglobulin
what happens in TFT clinical testing?
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
when is TSH increased/ decreased?
– Increased in hypothyroidism
– Decreased in hyperthyroidism
– A normal [TSH] “usually” excludes primary
thyroid dysfunction.
what happens during thyroid scanning?
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
what are the clinical manifestations of hyperthyroidism/ thyrotoxicosis?
Tremor – Tachycardia / Palpitations – Weight loss – Tiredness – Feeling warm / Sweating – Diarrhoea – Anxiety and emotional symptoms
this is due to interactions with nervous system
what are the hyperthyroidism treatments?
- Anti-thyroid drugs
- Radioactive iodine (RAI)
- Surgery to remove the gland (thyroidectomy)
what is carbimazole’s active form?
converted to methimazole- MMI in the liver
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
what is carbimazole’s target?
thyroid peroxidase- tpo = acts as a thyroid peroxidase inhibitor
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
is carbimazole rapidly absorbed?
yes with 93% bioavailability. it is renally excreted
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
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
how is thiouracil excreted?
primarily via the kidney
how does PTU convert t4 to t3?
PTU ALSO inhibits 5’ mono-deiodinase enzyme which converts T4 to T3
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
when is PTU used?
- PTU used is patients who develop side effects to carbimazole
- PTU NOT recommended in children - due to associated hepatoxicty
which drug for hyperthyroidism is more potent?
carbimazole- more doses of PTU required for the same effect
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
how does hyperthyroidism affect the baby and mother?
-low birth weight
-high blood pressure during pregnancy
heart diseases
-premature birth
thyroid storm
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
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
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
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
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
what happens if thyroid drugs fail?
iodine accumulates in thyroid gland destroying the overactive tissue
this leads to hypothyroidism
what are the general causes of hypothyroidism?
- Autoimmune disease – Hashimoto’s
- Surgery
- Radiotherapy
- Hypothalamus/Pituitary disorder
- Iodine Deficiency
what is congenital hypothyroidism?
deficiency in the thyroid from birth
lacking thyroid or even ectopic thyroid gland
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
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
how does amiodarone induced thyrotoxicosis occur?
• Destructive thyroiditis that results in thyroid damage
• Excess release of preformed T4 and T3 into the
circulation
what needs to be monitored in AIT?
TFT every 6 months
what happens if amiodarone treatment cannot be stopped in AIT?
thyroid removal is an option
what should be tested in li induced hypothyroidism?
Routine 6 monthly TFT
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
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
what is the MOA of levothyroxine?
• Thyroxine substitute >converted to its active metabolite
triiodothyronine (T3)
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
what is the pka of levothyroxine?
6.7
what is the elimination half life for levothyroxine?
3-4 days : 50% faeces, 50% urine
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
