1
Q
Explain T3 and T4 hormone synthesis.
A
- RER in follicular cells produce thyroglobulins and secrete them into the colloid space via exocytosis
- thyroid peroxidase enzyme oxidises iodine from the blood and also iodinates tyrosyl residues on thyroglobulin in the colloid to form mono/di-iodotyrosyl
- theses iodotyrosyls couple with one another to form T3 and T4
- the iodinated thryoglobulin is now endocytosed into the follicular cell
- lysosomes and endopeptidases in the follicular cells result in the release of T3 and T4 into the bloodstream
- this last step can be influenced by TSH levels
2
Q
What is the metabolism of T3 and T4 hormones?
A
- T4 has a long half life of 6-8 days because this is the inactive form that is bound to proteins
- T3 has a short half life of 1 day
- 80% of peripheral T3 is produced from deiodination of T4 in various different organs
- liver is the major site of non-deiodinative degradation of T3 and T4 hormones by conjugation with glucuronic acid and sulfuric acid before excretion in bile
3
Q
What is the Wolf-Chaikoff effect?
A
- an autoregulatory phenomenon
- excess iodine transport into the thyroid gland can lead to transient inhibition of thyroid peroxidase enzyme so there is decreased thyroid hormone synthesis
*used as a treatment method by infusion of large amounts of iodine in hyperthyroid patients. this autoregulation explains the hypothyroid side effects experienced by patients on iodine containing drugs like amiodarone. potassium iodide can also be administered during nuclear emergencies
4
Q
What are the drugs used to treat hypothyroidism?
A
- Levothyroxine
- Liothyronine
5
Q
What are the features of levothyroxine (T4)?
A
- commonly used to treat chronic hypothyroid patients because has a long half life of 6-8 days but liothyronine only has a half life of 0.75 days and is expensive
- oral/IV formulation
- poor and eratic oral absorption
- excreted in the urine
6
Q
What are the features of liothyronine (T3)?
A
- used in emergency cases like myxedema coma because has a rapid onset of action of 3 hours compared to 3-5 days (oral)/ 6-8 hours (IV) onset of levothyroxine
- well absorbed
- binds well to plasma proteins like levothyroxine also
- Short half life of 0.75 days and is expensive so not used for chronic hypothyroidism
7
Q
What are the adverse effects of liothyronine and levothyroxine?
A
- in adults, overdosing can cause cardiac arrest, hypertension, palpitations, tachycardia, anxiety, heat intolerance, hyperactivity, insomnia, irritability and weight loss
- in children, overdosing can cause insomnia, restlessness, accelerated growth and bone maturation
- Long term use of high dose L-T4 has been associated with increased bone resorption and reduced bone mineral density, especially in post-menopausal women whom have decreased levels of estrogen which promotes osteoblast activity
8
Q
How is levothyroxine therapy monitored in chronic hypothyroid patients?
A
- serum TSH should be measured 6-8 weeks after to check that there is adequate replacement
- Persistently elevated TSH levels may be due to inadequate dosing, poor compliance, malabsorption, drug or food interaction
*Levothyroxine should be taken 30-45 minutes before food on empty stomach. Levothyroxine has many DDI. Increase estrogen increases the amount of thyroxine-binding globulin so an increase in levothyroxine dose is required as more levothyroxine will be bound and there will be reduced plasma levothyroxine
9
Q
What is myxedema coma?
A
- combination of abnormal thyroid function, physical exam findings of severe hypothyroidism and altered mental status
- bradycardia and hypothermia present as well usually
- Treatment is often administered intravenously, since there may be edema of the gut wall that limits oral absorption (usually liothyronine)
10
Q
What are some special considerations when prescribing Levothryoxine replacement?
A
- subclinical hypothyroidism : pt with raised TSH but normal thyroid hormone levels. don’t usually treat these patients because there is not much benefit. UNLESS THEY ARE PREGNANT/HAVE VERY HIGH TSH
- elderly patients : gradual dose decrease needed because of age related decrease in thyroxine degradation and in lean body mass. levothyroxine may also precipitate severe angina or myocardial infarction in elderly with asymptomatic ischemic heart disease so should start at small dose and titrate up initially. Excess levothyroxine in elderly is associated with reduced bone mineral density and increased risk of fractures
- pregnant patients : thyroid hormone insufficiency can cause impaired neuropsychological development of the fetus. Maternal hypothyroidism is associated with miscarriage, premature birth, and low birth weight. women with known hypothyroidism need a 30%–50% increase in levothyroxine during pregnancy (reduced after birth). subclinical hypothyroidism in pregnant women should also be treated with levothyroxine.
- ischemic heart disease patients : untreated hypothyroidism can lead to persistent bradycardia, an adverse atherogenic lipid profile, and deterioration in myocardial function. but levothyroxine is inotropic on heart so full dose can lead to acute coronary syndrome in patients with silent heart disease. so heart disease patients should be started on small dose then titrated up
11
Q
What drugs can be used to treat hyperthyroidism?
A
- thioamides (anti thyroid drugs)
- high concentrations of iodine
- radioactive iodine
12
Q
What are some thioamides?
A
- carbimazole (active metabolite is thiamazole)
- propylthiouracil
13
Q
What is the mechanism of action of thioamides?
A
- inhibit thyroid peroxidase enzyme and interfere with thyroglobulin iodination
- also inhibit coupling of iodotyrosyl residues
- additionally propylthiouracil inhibits deiodination of T4 to T3 so tend to use this during thyrotoxicosis
14
Q
What are the features of propylthiouracil?
A
- short half life of 75 minutes so need frequent dosing of 1-4 times a day
- well absorbed orally so can take tgt with food
- hepatic metabolism and excreted in urine
- crosses the placenta and low levels may be present in breast milk
15
Q
What are the features of carbimazole?
A
- long half life of 6-13 hours so only need once or twice a day dosing
- orally well absorbed, hepatic metabolism and urine excretion like propylthiouracil
- also crosses the placenta and small levels detected in breast milk
16
Q
What are the adverse effects of thioamides?
A
- agranulocytosis normally develops within first 3 months of use. If patient gets any signs of infection, they should stop and have a complete blood count. Agranulocytosis is reversible upon discontinuation.
- commonly there is a purpuric, urticarial papular rash
- cholestatic jaundice may also occur
- propylthiouracil has been reported to cause fatal liver injury and live failure. so need to monitor liver function during administration and cannot give children.
17
Q
How are thioamides given during pregnancy?
A
- thiamazole associated with development of fetal abnormalities such as aplasia cutis and choanal atresia so propylthiouracil given during 1st trimester in organogenesis. But because of potential maternal adverse effects of propylthiouracil switch to thiamazole for the 2nd trimester onwards
18
Q
What is the mechanism of action of iodide for hyperthyroidism?
A
- high conc of iodine inhibit thyroid peroxidase so there is Suppressed idination of thyroglobulin and coupling of iodotyrosyls so there is less hormone synthesis
- also decrease thyroid gland size and vascularity when given 1-2 weeks so can use this pre-surgery to decrease vascularity of thyroid
- also decrease T4 to T3 conversion in peripheries
- during thyrotoxicosis give one hour after giving thioamides to prevent worsening of thyrotoxicity initially
- used to also treat goitre caused by iodine deficiency
19
Q
What are iodide’s adverse effects?
A
- cause allergic reactions like angioedema, laryngeal edema so rashes and suffocation
- iodide intoxication can also lead to metallic taste, gastrointestinal intolerance, soreness of the teeth and gums, increased salivation, irritation of the eyes, lacrimation, rhinorrhoea and headache
- cannot give during pregnancy because can cross over and cause fetal goitre
20
Q
What is the mechanism of action of radioactive iodine?
A
- enters follicular cells
- Destructive β particles destroy follicular cells with little damage to surrounding tissue
- γ radiation passes through the tissue and can be quantified by external detection for diagnostics
- possible to destroy the thyroid gland completely without detectable injury to adjacent tissues
- I 131 has β and γ but I 123 only has γ rays
- used in grave’s (but may worsen the orbiotopathy) and toxic nodular goitre
- good alternative to surgery and is low cost
21
Q
What are the adverse effects of radtioactive iodine?
A
- delayed hypothyroidism
- Small increase in risk of stomach, kidney and breast cancer because they also express the sodium iodine transporter
- worsens Graves’ ophthalmopathy
- cannot give to pregnant women because can crossover and expose fetus to the radiation
22
Q
How is thyrotoxic storm treated?
A
- give antithyroid drugs and then iodine 1 hr later to prevent more thyroid hormone synthesis with initial iodine absorption
- bile acid sequestratent bind to free T3 hormones in the intestine and cause increased clearance of it
- beta blockers control peripheral effects of excess thyroid hormones
- glucocorticoids reduced T4 to T3 conversion and treat risk of adrenal insufficiency from severe thyrotoxicosis
