Thyroid and Antithyroid Drugs Flashcards
Thyroid
- endocrine gland that makes thyroid hormones (TH) & calcitonin
Thyroid Hormone (TH) increases:
- metabolic rates
- O2 consumption
- heat production
- cardiac rate and output
TH is responsible for
- growth
- development
- function
- maintenance of all tissues
rT3
reverse T3
INACTIVE
NIS
Sodium/Iodide Symporter
- target for treating thyroid disorder
- halt = decrease I in cell
T4
major hormone released
- can become T3 in target tissues
- very tightly bound to TBG
Thyroxide
T4 (4 I)
Triiodothyronine
T3 (3 I)
T3 potentcy
- 3-4x more potent/active than T4
Deiodination
T4 -> T3 or rT3
Metabolism of TH
- CYP3A stimulates T4->T3 conversion in liver
5-deiodinase inhibition
- inhibits activation of T4->T3 => decreased T3 (most active version)
inhibited by:
- amiodarone
- iodinated contrast media
- B-blockers
- corticosteroids
- severe illness
- starvation
Low T4 levels stimulate
T4 production to maintain homeostasis
Deiodination/Deamination
metabolizes T3 & T4, removed in urine and bile
T4 vs T3
t1/2
T4: 7 days
T3: 1 day
What stimulates creation of TH
TSH
Hypothalamic-Pituitary-Thyroid Axis
activation
pyschosis or prolonged cold
TSH
release/inhibition
- TRH stimulates TSH released
- somatostatin and dopamine inhibit TSH release
TSH stimulates
T4 and T3 synthesis and release
- increases TPO expression and vascularity
T4 & T3 inhibit
- TSH synthesis and release
NEGATIVE feedback
High intrathyroidal iodide levels blcok
thyroid activity (autoregulation)
TRH/TSH/T4/T3 pathway
increased TRH -> increased TSH -> stimulates thyroid gland -> increased T4&T3 AND increased TPO
TPO
thyroid peroxidase
- very reactive
Thyroid Hormone Action
- T4&T3 dissociate from TBP (thyroid binding protein)
- FT4 & FT3 (free) enter cells
- when directed T4 -> T3 by 5-deiodinase
- T3 enters and binds T3R a or b
- T3R-RXR activates gene transcription
5-deiodinase
converts T4->T3
T3 active because
I at T3 & T5: prevents ring rotation
Hyperthryoidism
- EXCESS thyroid hormones
- high metabolic rate (skinny)
- Suppressed TSH
- – too much TH => decrease in TSH (- feedback)
- thyroid storm => excessive adrenergic activity, fever, flushing, and sweating
Hypothroidism
- NOT ENOUGH thyroid hormones
- more common in women
- affect almost all metabolic processes
- primary hypothyroidism (issue at thyroid glands)
Prolonged hypothyroidism can lead to
- myxedema: skin lesions
Subclinical Hypothyroidism
- no symptoms
- high TSH, normal T4
- ** TSH overcompensates for issues of decreased TH ***
Hashimoto’s Thyroiditis
Chronic Lymphocytic Thyroiditis
- autoimmune disorder
- most common cause of hypothyroidism (most frequent in women)
- caused by autoantibodies against Tg, TPO, or TSH receptor on thyroid glands
- inflammation, swelling (goiter) and destruction of thyroid glands => lower T3 and T4; higher TSH
Other Causes of Hypothyroidism
- diet
- drugs (amiodarone)
- genetic
- radiation
- thyroidectomy
- congenital
- secondary or tertiary disorder
- pregnancy
- age & gender
Management of Hypothyroidism
- if caused by drugs, removed the drug
- other causes: thyroid replacement therapy
Levothyroxine
T4
- synthetic natural hormone, long t1/2 (T4!)
- used as thyroid replacement therapy
BEST
Liothyronine
T3
- synthetic natural hormone, shorter t1/2
- faster onset but greater risk of cardiotoxicity
- used as thyroid replacement therapy
Monitor increased risk of cardiotoxicity; faster; immediate stimulation
Liotrix
T4 & T3
not in US
Desiccated Thyroid
- higher risk of toxicity; never justified
Levothyroxine Side Effects
- cardiotoxicity (but less than liothyronine (T3))
- osteoporosis
- hyperthyroidism
- allergic reactions
Myxedema with Coronary Artery Disease
- do coronary artery surgery first
Myxedema Coma
- medical emergency; death can occur
- large loading dose to saturate TBG
- liothyronine for faster action
Pregnancy
- relatively infertile
- daily dose of T4
Hyperthyroidism/Thyrotoxicosis
- excess thyroid hormones
- high metabolic rate
- suppressed TSH
- Thyroid storm
Thyroid Storm
- avoid
- acute thyrotoxicosis resulting in excessive adrenergic activity, fever, flushing, and sweating
- life threatening; fatal if untreated
- avoid aspirin
- propranolol, PTU, then Iodide; dexamethasone
- figure out what’s causing the issue and remove it
Graves Disease
- most common cause of hyperthyroidism; defect in suppressor Tcells & Bcells
- genetic
- diffuse toxic goiter (swelling)
TSH-R Ab
- Graves disease
- autoantibodies activate TSH-receptor on thyroids
- T4 &T3 elevated
- TSH suppressed
Exophthalmos
Graves
- caused by TSI stimulation of TSH-R on eye
- bulging eyes
Pretibial Myxexedema
Graves
- waxy, discolored induration of the skin
Other causes of Hyperthyroidism
- toxic nodular goiter
- thyroid adenoma
- amiodarone
Management of Hyperthyroidism
- anti-thyroid drug therapy
- destruction of thyroid gland: radioiodine
- surgical thyroidectomy
- block iodide uptake: anionic inhibitors
- modify tissue responses: B blockers (propanolol)
Anti-thyroid drug therapy
- inhibit thyroid gland from making too much TH
- thioamides: PTU and MMI
Propylthiouracil
PTU; thioamide
- 6-n-propylthiouracil
- binds and inhibits TPO, blocking iodide oxidation
- inhibits 5-deiodinse peripherally
- 2-4 months to take effect (more rapid than MMI)
- non-pregnant adults
PTU Adverse Effects
- agranulocytosis
- thrombocytopenia
- hepatoxicity
Thioamides
PTU & MMI
- both inhibit TPO (PTU also inhibits 5-deiodinase)
- effects take time (PTU more rapid)
- not recommended for pregnancy (category D)
- Adverse effects: agranulocytosis & hepatotoxicity
Pregnant PTU vs MMI
not used unless benefits outweigh risks
- PTU during 1st trimester
- MMI preferred later
Methimazole
MMI; thioamide
- indicated for hyperthyroidism, adjunct to surgery
- inhibits TPO (DOES NOT BLOCK T4->T3 like PTU)
- LONGER t1/2 (5-6 hrs)
- first line in nonpregnant because lower risk of hepatotoxicity
MMI Adverse Events
- agranulocytosis, liver failure, vaculitis
Difference between PTU and MMI
- PTU additional mechanism (inhibits 5-deiodinase: T4->T3 in peripheral tissues)
- MMI longer t1/2
- PTU more rapid
Radioiodine
RAI; destruction of thyroid gland
- antithyroid drugs fist
- single oral dose
- no use in pregnant or nursing mothers; low cancer isk
- 131 Iodide; no other iodides used during treatment
Adjuncts to Anti-thyroid
- Propranolol: used for tachycardia, hypertension, and atrial fibrillation
- Dexamethasone
Propanolol; PTU, Iodide; Dexamethasone
Propranolol
Thyroid Storm
- block end-organ effects
Dexamethasome
Thyroid Storm
- block all peripheral activation of T4
Iodide
- block TPO and proteolysis of Tg
- QUICK (1-2 days)
- reduce size and vascularity of thyroid gland prior to surgery
- body adapts: can cause severe withdrawal symptoms
- leaves thyroid LOADED w IODIDE: problematic for RAI and thiamide therapy
Anionic Inhibitors
- monovalent anions
- block uptake of iodide by competing w/ NIS
- major use in iodide-induced hyperthryoidism
Surgical Thyroidectomy
- for large goiters
- antithyroid drugs->KI->thyroid replacement
