Thyroid Drugs Flashcards
L-Triiodothyronine (T3)
- Iodine containing hormones that control the body’s metabolic rate
- Synthesized from Diiodotyrosine (DIT) and Iodotyrosine (MIT)
- Synthesized in follicles of the thyroid; most T3 formed in target tissues via peripheral metabolism of T4
4B’s of T3 function:
- Brain maturation
- Bone growth (synergism with GH)
- Beta-adrenergic effects (B1 receptors: CO, HR, SV, contractility)
- Basal metabolic rate (increase): via increase Na/KATPase activity
Use: Best used for short term suppression of
TSH
Adverse properties/side effects:
- shorter t1/2 than T4, so must be given multiple times per day.
- Also more expensive, harder to monitor
- greater risk of cardiotoxicity; Avoid in patients with heart disease
L-Thryoxine (T4)
- Iodine containing hormones that control the body’s metabolic rate
- Synthesized from two Diiodotyrosines (DITs)
- Synthesized at a T4:T3 ratio of 5:1
Use: Drug of choice for replacement
therapy for hypothyroidism
• Can give once a day
Adverse effects:
- Cardiac symptoms: angina and palpitations
- Use with care, particularly in elderly
Biosynthesis of Thyroid hormones
- Follicular cells of thyroid make Thyroglobulin, which is a capsule that holds hormone products
- Iodide anions are absorbed from blood via Na/I- symporter, and oxidized to I2 via THYROIDAL PEROXIDASE (TPO)
- TG encapsules I2 to form MIT and DIT, T3 and T4
- TG complex is endocytosed from luminal/apical side of follicular cell
- TSH enhanced endocytosis and release of hormones: T3 and T4 released into blood, while MIT and DIT are recycled
Conversion of T4
- Deiodinase enzymes
D1 & D2: Deiodinizes T4 into T3
D1: Liver, Kidney, Thyroid
D2: Brain, Pituitary, BAT, Heart, Muscle
D3: Deiodinizes T4 into rT3 (deactivated form)
- Placenta, Skin, Brain
Thyroxine-Binding Globulin (TBG)
- binds 95% of T3/T4 in the blood
- only free T3/T4 hormone is active
- PITUITARY responds to and regulates levels of free hormone
Any condition that alters binding results in dramatic changes in free hormone levels:
- Hepatic failure: decreases TBG
- Pregnancy or OCP use (Estrogen): increases TBG
Autoregulation of Thyroid Hormones
Thyroid Releasing Hormone: Made in hypothalamus, stimulates TSH
Thyroid Stimulating Hormone: made in anterior pituitary, stimulates follicular cells
T3: provides negative feedback to anterior pituitary to decrease sensitivity to TRH
System can respond to amount of iodide available:
- low dose iodide: increase TG synthesis & release to keep up with intake
- marked elevation –> Wolff-Chaikoff effect: suppresses TG synthesis & release; get involution of gland after several weeks
- Escape: Release mechanisms return to normal
Iodide Goiter
- Suppression (excess iodine induced Wolff-Chaikoff effect) without escape (cannot release T3/T4)
- results in enlarged thyroid gland
Mechanism of Action of T3 and T4
- Free forms of T3 and T4 dissociate from
proteins and enter the cell (behaves like a hydrophobic hormone)
• Inside the cell, T4 is converted to T3 by D1
• T3 enters the nucleus, binds to receptors
• Receptor binds to DNA TRE (Thyroid response element)
• Transcription of certain mRNAs are
influenced
• Proteins are synthesized
Thioamides
- used to treat Hyperthyroidism, e.g., Graves Disease
METHIMAZOLE (MMI) and PROPYLTIOURACIL (PTU)
Use: major drugs for treatment of
thyrotoxicosis
Mechanism: Drug binds to and inactivates TPO - Blocks iodide organification - Blocks coupling of iodotyrosines - PTU also blocks peripheral conversion of T4 to T3
Pharmacokinetics:
- slow onset of action: takes 3-4 weeks to deplete hormones
- both concentrate in thyroid and excrete via urine
Adverse effects:
- skin rash, joint pain, agranulocytosis in 0.2 % patients
• Hepatotoxicity with both, worse w/PTU
- - There is 60-70% relapse; will require surgery or radioactive iodine treatment
• PTU still preferred in pregnancy – Less crosses placenta – PTU recommended for nursing mothers – Also in thyroid storm b/c of secondary mech (block peripheral conversion of T4 to T3) – MMI can cause congenital scalp defects
Iodide, e.g., KI
Use: in combo with PTU and a Beta-blocker in thyroid storm (acute thyroid crisis).
Mechanism of action: Use in excessive amounts to induce Wolff-Chaikoff Effect (down-regulation of symporter)
- results in inhibition of organification and hormone release, and decrease of size of hyperplastic gland
- Effect reverses with time (escape) if used alone
Adverse effects: uncommon and usually reversible when discontinued. - acniform rash - swollen salivary glands - mucous membrane ulcerations • Don’t use in pregnancy-can cause fetal goiter
Preoperative treatment for subtotal
thyroidectomy
- Thioamide drug till euthyroid (~ 6 wk)
• KI 10 days prior to surgery to reduce size
and vascularity (aim is to reduce surgical risk)
• give Beta-blocker to antagonize
catecholamines for symptomatic relief of
thyrotoxicosis that mimics manifestations
of Beta receptor stimulation
Radioactive iodide (I131)
Use: Treatment of thyrotoxicosis
Mechanism:
- taken orally
- rapidly concentrated in thyroid follicle cells, where Beta particles selectively destroy gland w/o injury to adjacent cells
- Patient becomes euthyroid in 6-8 wks
Adverse reactions: eventually causes
hypothyroidism in 50% of patients, but this
is likely part of natural progression of
disease.
- Contraindicated in children and pregnancy
- No evidence of cancer risk increase with
treatment
Beta adrenergic blocking agents
Block adrenergic symptoms of thyrotoxicosis
Glucocorticoids
Block peripheral T4 to T3 conversion
