Thyroid drugs Flashcards
Thyroid hormone synthesis
Peripheral metabolism of thyroid hormones
Thyroid hormone synthesis
- dietary iodine –> active uptake to the thyroid gland
- I- + Tyroside –> MIT or DIT (organification)
- MIT + DIT combine in the thyroid gland –> forms T3 + rT3
- DIT + DIT = T4
- Proteolysis and exocytosis release T3 and T4
- T3 and T4 are bound to and circulate with thyroid binding globulin
Peripheral metabolism of thyroid hormones
- deiodination of T4 produces T3 or rT3 depending on which iodine is removed
- T3 is more potent than T4
- drugs, severe illness and starvation can inhibit 5’ deiodinase –> results in low T3 and increased rT3
Mechanisms of action of thyroid hormones
- site of action is the nucleus where gene expression for metabolism is controlled
- T4 and T3 dissociate from TBG and enter cell –> T4 is converted to T3 –> binds to receptor
- receptor for T3 exists in 2 forms = alpha and beta monomers –> can form alpha-alpha, alpha-beta, and beta-beta dimers
- dimers bind to DNA response elements and control RNA synthesis
- more receptors on responsive tissues –> pituitary, kidneys, heart, skeletal muscles, lungs, intestine
- yield different proteins upon activation –> Na/K ATPase, cardiac and smooth muscle contractile proteins, enzymes for lipid metabolism
- increase NA/K ATPase = increase in ATP turnover and oxygen consumption
- lag of hours/days to see the effects
Regulation of thyroid function
- thyroid pituitary axis
- thyroid autoregulation –> thyroid regulates uptake of iodide and hormone synthesis in non-TSH dependent manner –> large doses of iodine inhibit iodide organification
- abnormal thyroid stimulators –> e.g. graves disease
Treatment of hypothyroidism
Hypothyroidism is treated with T4 supplementation –> although T3 is more potent than T4…
- it has a shorter half life, requiring multiple daily doses = expensive/inconvenient
- due to higher potency, risk for cardiac toxicity is greater –> should be avoided in patients with cardiac disease
- T4 gets converted to T3 intracellularly
- T3 is only used for a short term suppression of TSH
Thyroid preparations
- Levothyroxine = T4 (synthroid)
- Liothyronine = T3
- Liotrix = 4:1 ratio of T4:T3
T4 supplements should be taken on empty stomach, preferably at least 30 min before breakfast
Hypothyroidism in pregnancy
Hypothyroid women frequently have anovulatory cycles
- relatively infertile until restoration of euthryoid state
- previous widespread use of thyroid hormone for infertility - now know there is no use in euthyroid women
Pregnant hypothyroid women need close monitoring
- early development of fetal brain depends on maternal thyroxine
- modest increase in dose (20-30%) is required to normalize serum TSH –> thyroid binding globulin levels are increased during pregnancy, resulting in lower levels of free T3
Myxedema coma
Untreated hypothyroid state
- medical emergency
- progressive weakness, stupor, hypothermia, hypoventilation, hypoglycemia, hyponatremia, water intoxication, shock and death
- IV therapy –> aboid excessive water intake
- loading dose of T4 to fill empty thyroid binding globulin
- –> 300 to 400 microgram T4 followed by 50 microgram daily
- –> IV T3 can be used but it is difficult to monitor and cardiotoxic
Toxicity
- monitor TSH levels
- older patients hearts are very sensitive to circulating T4 levels –> can cause angina pectoris or arrhythmia
- chronic over treatment can increase the risk of atrial fibrillation and accelerated osteoporosis
- in children –> restlessness, insomnia, accelerated bone maturation and growth are signs of toxicity
- in adults –> increased nervousness, heat intolerance, episodes of palpitations and tachycardia or unexplained weight loss may present
Management of Grave’s disease
- anti-thyroid drug therapy –> small glands and mild disease
- thyroidectomy –> near total thyroidectomy is a treatment of choice for patients with large glands or multinodular goiters
- radioactive iodine –> preferred treatment for most patients over 21 years
Anti-thyroid drugs - Thioamides
Thiocarmamide group is essential for anti-thyroid activity
Methimazole
- T1/2 = 6 hours
- 65-70% dose is recovered in the urine in 48 hours
Propylthiouracil
- T1/2 = 1.5 hours
- most of it is excreted by kidneys as inactive glucuronide within 24 hours
Short half life does not influence duration of action, since these agents accumulate in the thyroid gland
- dose every 6-8 hours for PTU
- daily for methimazole
Cross placenta –> PTU is more protein bound so less readily
Most dangerous side effect = agranulocytosis
Anti-thyroid durgs - Thioamides
- mechanism of action
Prevent hormone synthesis by:
- –> inhibiting thyroid peroxidase catalyzed reactions
- –> blocking iodine organification
- –> block coupling of iodotyrosines
- do not block the uptake of iodine
- PTU (methimazole to lesser extent) inhibit the peripheral deiodination of T3 and T4
- since they affect synthesis rather than release of hormones, onset of action is slow –> often requires 3-4 weeks before the stores of T4 are depleted
Anti-thyroid drugs - Anion inhibitors
Monovalent anions = perchlorate (CLO4-) + thiocyanate (SCN-)
- block uptake of iodide through competitive inhibition of iodide transport mechanism
- effects can be overcome by large doses of iodide
Anti-thyroid drugs - Iodides
Mechanism
- inhibit organification
- inhibit hormone release through inhibition of thyroglobulin proteolysis
- decrease size and vascularity of the hyperplastic gland –> preferred for pre op preparation before surgery
Rapid improvement in thyrotoxicosis symptoms in 2-7 days –> valuable in thyroid storm
Disadvantage = increase in intraglandular iodine stores
- delay onset of thioamide therapy
- prevent use of radioactive iodine for weeks
Should not be used alone –> gland escapes the block and withdrawal can produce severe thyrotoxicosis
Should be avoided in pregnancy –> can cross placenta and produce fetal goiter
Antithyroid drugs - radioactive iodine (I-131)
Given orally, concentrated by thyroid
- therapeutic effect depends on emission of beta rays
- effective half life = 5 days
- destruction of thyroid parenchyma within a few weeks
- should not be given to pregnant or nursing women –> cross placenta and secreted in breast milk
Anti-thyroid drugs - beta blockers
Used for symptomatic relief
- beta blockers without intrinsic sympathomimetic activity is treatment of choice –> propanolol
Thyroid storm
Life threatening thyrotoxicosis crisis
- excessive adrenergic activity
Symptoms
- fever with flushing and sweating
- tachycardia
- afib
- high pulse pressure
- occasionally heart failure
- restlessness, agitation, delirium, coma
- nausea, vomiting, diarrhea
- death due to heart failure or shock
Treatment
- control cardiac symptoms
- supportive therapy to control fever and heart failure
- underlying condition that may have precipitated the attack
- propanolol
- KI solution - blocks release of T3/T4 from TBG
- PTU/methimazole - stop hormone synthesis
- hydrocortisone - for shock to stop conversion of T4 to T3
