Kruse DSA: Drugs for Thyroid Disorders Flashcards
The Thyroid Agents?
- levothyroxine (T4)
- Liothyronine (T3)
- Liotrix (a 4:1 ratio of T4:T3
- Thyroid desiccated
Antithyroid agents
- Radioactive iodine (131 I) sodium
- Methimazole
- Potassium iodide
- propylthiouracil (PTU)
Whta is an essential element in the making of thyroid hormone?
- Iodine
- unabsorbed iodide is excreted in the urine
What transports iodide into the thyroid gland?
NIS
-sodium/iodide symporter
What is Pendrin
- an apical cell iodide transport enzyme
- controls the flow of iodide across the membrane
- also in cochlea…. if we don’t have it, deafness and goiter= Pendred syndrome
What is Iodide oxidized by at the apical cell membrane?
thyroidal peroxidase
What is is called when iodine rapidly iodinates tyr residues within the thyroglobulin molecule to form MIT and DIT?
iodide organification
What is Thyroglobulin
-a large glycoprotein that contains about 70 tyr aa’s, which are the major substrates that combine with iodine to form the thyroid hormones
what do 2 DIT molecules combine to make?
thyroxine T4
What is made when one DIT and one MIT combine?
triiodothyronine (T3)
What is the T4:3 ratio withing the thyroid gland?
5:1
What are some things that will block the conversion of T4 to T3?
- radiocontratst media
- B-blockers
- corticosteroids
- amiodarone
Thyroid hormone transport
- T4 and 3 bine to TBG in plasma
- free levels of thyroid hormone is low
Peripheral metabolism of thyroid hormones
T4 gets turned to T3 (2 kinds)
Which T3 is the metabolically inactive one?
3,3,5-triiodothyronine (reverse T3
-3,5,3-“ “ is the one that does stuff
How is T4 inactivated?
- deamination
- decarboxylation
- conjugation
When is the half life of T4 and 3 decreased and the clearance increase?
in hyperthyroidism patients
What are some agents that inhibit the conversion of T4 to T3 and increase reverse T3 levels?
- radiocontrast agents: iopanoic acid, ipodate
- amiodarone
- B-blockers
- corticosteroids
When would we use the things that inhibit T4 to T3 conversion?
-to reduce T3 levels in pts who are experiencing a thyroid storm
What are drugs that decrease T4 absorption
- antacids
- ferrous sulfate
- cholestyramine
- colestipol
- ciprofloxacin
- proton pump inhibitors
- bran
- soy
- coffee
What is the significance of drugs that induce hepatic CYP450s?
-increase the metabolism of T4 and T3
What drug conditions will give us an alteration of T4 and T3 metabolism with modified serum T3 and T4 levels, but not free T4 or TSH?
- induction of increased hepatic enzyme activity
- inhibition of 5’-deiodinase with decreased T3 and increased reverse T3
What drugs are involved with induction of increased hepatic enzyme activity?
- Nicardipine
- imantinib
- protease inhibitors
- phenytoin
- carbamazepine
- phenobarbital
- rifampin
- rifabutin
What drugs are involved witih the inhibition of 5”-deiodinase with decreased T3 and increased reverse T3
- Ipopanoic acid
- Ipodate
- Amiodarone
- B-blockers
- Corticosteroids
- PTU
- flavonoids
What drugs cause induction of autoimmune thyroid disease with hypothyroidism or hyperthyroidism?
- Interferon-alpha
- IL-2
- IFN-B
- lithium
- amiodarone
MOA for the thyroid hormone
- thyroid receptor is bound to DNA at the TRE
- no hormone, it’s a homodimer bound to corepressor ptns and is inactive
- T4 and T3 enter cell by active transport and T4 is converted to T3 by 5’-deiodinase
- T3 enters nucleus, binds TR, corepressor releases, coactivator binds, homodimer separates, TR bind to RXR (retinoid X receptor), and gene transcription occurs
What is the preparation of choice for thyroid hormone?
levothyroxine (T4)
What are the Thioamides again?
- antithyroid agents
- Methimazole
- PTU
PK of PTU
- renal excretion a lot
- accumulates in thyroid gland
- shorter half life than methimazole
- 3-4 doses/day
PK of Methimazole
- completely aborbed
- accumulates in thyroid galnd
- slower renal excretion than PTU
- half life 6 hrs
- once-daily dosing
Why is methimazole agents not recommended in preggo?
-cross placental barrier and concentrated by fetal thyroid
How do we treat a preggo women then who have hyperthyroidism?
- PTU in the first trimester
- Methimazole in 2nd and 3rd trimesters
- secreted in breast milk at low concentrations and considered safe
MOA of antithyroidal agents
- inhibits the thyroidal peroxidase-catalyzed rxns and blocks iodide organification
- also inhibits couple of MIT and DIT
What does PTU do?
blocks peripheral conversion of T4 to T3
-significantly greater fall in T3 concentration and T3:T4 ratio may occur with PTU and iodine compared to methimazole and iodine
Do thioamides block thyroid gland iodide uptake?
no
since the hormone synthesis, rather than release, is inhibites, how long will it take before the stores of T4 and T3 are depleted?
3-4 weeks
Toxicity of Thioamides?
- most common are maculopapular pruritic rash, at times accompanied by systemic signs such as fever, nausea, and GI distress
- most serious complication is agranulocytosis, can be reversed with drug discontinuation and CSFs
Anion inhibitors
-monovalent anions: perchloratem, pertechnetate, and thiocyanate
MOA of anion inhibitors
block thyroid gland uptake of iodide by competitively inhibiting the iodide transport mechanism
- effects can be overcome by large doses of iodides
- effects are unpredictable and clinical usefulness is limites
Iodides MOA
-inhibit organification and hormone release; decrease the size and vacularity of the hyperplastic thyroid gland
clinical use of iodide
- ) thyroid storm- thyrotoxic symptoms improve rapidly (within 2-7 days)
- ) preoperative reduction of a hyperplastic thyroid gland
- ) block thyroidal uptake of radioactive isotopes of iodine in a radiation emergency or other exposure to radioactive iodine
Toxicity of Iodides
-Adverse rxns are uncommon, but include acneiform rash, swollen salivary glands, mucous membrane ulcerations, conjunctivitis, metallic taste
When should Iodides be avoided?
- during preggo
- iodides can cross the placenta and cause fetal goiter
Radioactive Iodine
- 131 I
- orally
- destruction of thyroid parenchyma: epithelial swelling and necrosis, follicular disruption, edema, and leukocyte infiltration
- contraindicated in women who are preggo or breast feeding
B-blockers
- good for managing thyrotoxicosis because a lot of the thyroid hormone effects are in line with sympathetic effects
- “olol”s, propanolo is commonly used
- do not alter thyroid levels
- high doses can reduce T3 levels by blocking the peripheral conversion of T4 to T3
What is the drug of choice for replacement thyroid replacement therapy?
levothyroxine
- child need more than adults
- should be given on an EMPTY STOMACH
- 6-8 weeks to reach stead-state levels
What do we do for pts who are in a mysedema coma?
- give it IV
- large loading dose of T4 followed by smaller IV dosing
What about for mysedema and cornary artery disease
-correction of myxedema with T4 must be done cautiously to avoid provoking arrhythmia, angina, or acute MI (those are all related to high T4 levels)
What sucks about women who are hypthyroid?
they are typically infertile until restoration of normal thyroid levels
-maintenance of normal levels is crucial due to fetal brain development dependence on maternal T4*
What do we give someone who has Grave’s disease?
-methimazole or PTU until remission (12-18 months)
Which one is preferred, methimazole or PTU?
methimazole due to once-daily administration
What is the tx of choice for pts with very large glands or multinodular goiters
thyroidectomy
-will probably require thyroid supplementation
What is radioactive iodine the preffered treatment in?
- for most patients over 21
- in pts with underlying heart disease or severe thyrotoxicosis and in elderly patients, tx with antithyroid drugs until the patients is euthyroid is preferable
- 80% will develop hypothyroidism and require replacement therapy
What are some adjuncts to antithyroid therapy?
- administration of B-blockers without intrinsic sympathomimetic activity is beneficial
- B-blockers can control tachycardia, htn, and atrial fibrillation
- Diltiazem (calcium-channel blocker) can be used to manage tachycardia in patients in whom B-blockers are contraindicated
What do we do if someone is having a thyroid storm (thyrotoxic crisis)?
- B-blockers to control the arrhythmia
- potassium iodide to prevent release of thyroid hormones from the thyroid gland
- PTU or methimazole to block hormone synthesis
- IV hydrocortisone to protect against shock and to block the conversion of T4 to T3 in peripheral tissues/blood
- Supportive therapy to control any underlying issues
What do we do for thyroid storm if everything else is inadequate?
-plasmapheresis or peritoneal dialysis may be used to lower the levels of circulating T4
