Thyroid and Antithyroid Drugs Flashcards
general functions of thyroid hormones:
- growth
- development
- body temperature
- energy metabolism
Thyroid hormone synthesis process:
1) iodine uptade into thyroid gland (Na/I symport - NIS)
2) Peroxidase mediated oxidation of iodide to iodine (IN COLLOID)
3) iodination of tyrosine residues within thyroglobulin molecule (iodide organification) =Monoiodotyrosine(MIT)+Diiodotyrosine(DIT) (IN COLLOID)
4) MIT and DIT combined to form either T3 and T4
Thyroid hormone secretion and transport:
1) Secretion
- Thyroglobulin (Tgb) taken up by thyroid cell via phagocytosis or pinocytosis
- degredation of Tgb (via lysosomes) =release of thyroid hormone-most is T4
2) Transport-small amount is free –> most is bound to thyroxine binding globulin (TBG) in blood
Thyroid hormone - Absence of thyroid hormone MOA?
-Thyroid T3 receptors (TR) bound to thyroid response element (TRE) already in nucleus–>homo dimer
==> suppression of that gene-
**TRANSCRIPTION REPRESSION
Thyroid hormone - Presence of thyroid hormone MOA?
- T3 transported into cell
- T3 directly binds to monomer of TR in the nucleus (while T4 needs to be converted to T3 by 5’-deiodinase (5’DI))
- Co-repressor and TR monomer dissociates.
- TR and Retinoid X Receptor (RXR) form hetero-dimer ==> increased gene transcription
- *TRANSCRIPTIONAL REGULATION
How does hypothalamus work with thyroid hormones?
-secretes TRH -thyrotropin-releasing hormone in response to stress, cold, acute psychosis, circadian and pulsatile rhythms
What secretes TRH? What does TRH do?
- hypothalamus secretes thyrotropin releasing hormone
- TRH promotes release of TSH (thyroid stimulating hormone) by anterior pituitary
What secretes TSH? What does TSH do?
- anterior pit secretes
- TSH promotes synthesis of T4 and T3
How does feedback regulation work with thyroid function?
- T3 and T4 negative feedback regulate to hypothalamus and pituitary
- high concentrations of iodide in the blood inhibit - regulation at THYROID GLAND
- low concentration of iodide in blood stimulate thyroid hormone synthesis -REGULATION AT THYROID GLAND
Thyroid hormone effect on: sympathetic nervous system
1) inc Beta receptors
2) dec alpha receptors
Thyroid hormone effect on: growth and development
1) brain development, neurogenesis
2) bone growth and skeletal maturation –> activation of osteoblasts and clasts
Thyroid hormone effect on: thermogenic body factors
increase cellular energy consumption resulting in heat production
Thyroid hormone effect on: respiratory system
- inc O2 consumption
- inc CO2 formation
- RR increase
Thyroid hormone effect on: CNS
- inc rapidity of thinking/reasoning (cerebration)
- effect spinal cord synapses that control muscle tone
Thyroid hormone effect on: GI
-increase secretions and motility
Thyroid hormone effect on: skin and hair
- trophic (growth promoting) actions maintain and promote normal skin, nail and hair growth
- prevent accumulations of glycosaminoglycans in interstitial space
Thyroid hormone effect on: Cardiovascular
- inc HR (+chronotropic)
- inc force of of contarction (+ inotropic)
- inc CO
- inc Blood volume
- dec vascular resistance
(VIA INC BETA-RECEPTOR EXPRESSION)
Thyroid hormone effect on: metabolism
1) fat
- dec circulating cholesterol via inc LDL receptors
- inc lipolysis
2) carbs
- inc intestinal absorption of carbs
- inc glycolysis
- inc gluconeogen
- inc insulin secretion
3) protein-inc protein synthesis and catabolism
4) vitamins-inc need and usage of viatmins as cofactors –> inc inc enzyme expression
5) inc metabolic rate
Primary (TYPE 1) hypotyroidism causes:
1) congenital defect
- lack of thyroid development
- lack of TSH receptor response
- lack of thyroid hromone synth
2) autoimmune thyroiditis (HASHIMOTOS)
- inflitration of lymphocytes in thyroid gland = enlarged gland, fibrosis, decrease function
- HIGH TSH LEVELS
3) Iodide deficiency
- dietary lack = large amounts of Tgb produced in response to HIGH TSH levels
- enlargement of thyroid gland (GOITER)
4) Other: surgical, radiation, radioiodine tx of hyperthyroidism, meds (lithium)
Secondary (TYPE 2) hypothyroidism causes:
Impaired TSH production
- head trauma
- cranial neoplasm
- brain infection
- cranial irradiation
- neurosurgery
Thyroid hormone drugs:
MOA?
- levothyroxine (T4)
- liothyronine (T3)
- liotrix (mix T3 and T4)
activation T3 receptors = transcriptional regulation
Goal of thyroid hromone drugs in treating hypothyroidism?
-inc blood T4, normalize TSH, alleviate symptoms
Which thyroid hormone drug is drug of choice? Why?
- Levothyroxine -
- more stable
- low cost
- easy lab measurement
- 7-day t1/2
- more physiologically available bc yields T3 and T4
What consideration should be taken when giving thyroid hormone drugs?
- old people with coronary artery disease (CAD)
- low thyroid hormone is protective –> be careful with dosing to not provote arrhythmias, angina or MI
Which thyroid hormone drug is most potent and has more oral bioavailability? Why is it not the drug of choice?
-Liothyroine but shorter t1/2
Thyroid hormone drugs- AE
- child
- adult
- geriatric
Basically causes hyperthyroidism
1) child = restlessness, insomnia, accelerated bone maturation
2) adult = nervousness ,heat intolerance, palpitations, tachycardia, WL
3) old= artrial fib, osteoporosis
Primary hyperthyroidism or thyrotoxicosis - causes:
1) graves disease - autoantibodies stimulate TSH receptors –> inc production of T3 and T4. LOW TSH LEVELS
2) Thyroid adenoma/carcinoma - hyperfunction of a single adenoma or multiple toxic nodules
3) autoimmune thyroiditis (Hashimotos disease) - release of preformed T3 and T4 during follicular cell destruction
4) Thyroid storm -acute thyroid activity due to stress (surgery, infection…) in a patient with undiagnosed or untreated hyperthyroidism (FATAL)
5) Excess iodide - too much iodide –> contributes to graves
secondary hyperthyroidism - causes:
-Dysfunction of hypothalamus or pituitary - auto-secretion of thyroid releasing hormone (TRH) or thyroid stimulating hormone (TSH)
Hashimotos is what kind of thyroid disease?
HYPOthyroid
BUT during initial destruction of follicular cells you get a lot of previously synthesized T3 and T4 release = hyperthyroid. THen when depleted and function gone (could take months) you get the HYPOthyroid disease
Anti-thyroid (thioamides) drugs:
-MOA?
- methimazole
- propylthiouracil
-inh peroxidase reaction, iodine organification, and coupling of the iodotyrosines
Methimazole vs propylthiouracil
- dosing?
- oral absorption?
- potency?
- protein binding?
- Methimazole 1x/day vs propylthiouracil - every 6-8hrs
- Methimazole variable abs vs Propylthiouracil very fast absor
- Methimazole IS WAY MORE potent
- Propylthiuracil binds a lot while methimazole doesnt bind proteins at all
Issues with antithyroid agents?
-crosses placenta = fetal risk of hypothyroidism -propylthiouracil would be preferred if pregnant female in 1st trimester must take bc it binds proteins more strongly
Benefit to propylthiouracil?
rapid absorption= good for thyroid storm
antithyroid agents - AE?
-rash
nausea
-agranulocytosis (can be fatal)
Methimazole specific AE?
altered taste and smell
propylthiouracil specific AE?
severe/fatal hepatitis
Drug of choice for hyperthyroidism?
methimazole
Pregnant patient with hyperthyroidism give which drug?
propylthiouracil - but in general we try to not give even if female is pregnant
Effects of anti-thyroid drugs seen how soon?
takes a while - need to deplete T3 and T4 already made
Iodides agents:
- type?
- MOA?
- important thing with use?
antithyroid drug
- potassium iodide
- lugols solution (5% iodine + 10% potassium iodide)
- inh homrone release by inh proteolysis of Tgb
- high doses inh the organification step
-will only inh for 2-8 days and after will get withdrawl storm =thyrotoxicosis
Which drugs decrease the size of the thyroid gland? Why is this helpful?
- old antithyroid agents - Iodides
- potassium iodide
- lugols solution
-good for preop prep for surgery!
Onset of iodides? Feature is useful for what condition?
Rapid onset: 2-7 days with first effects noticeable within 24 hours
great for thyroid storm
- potassium iodide
- lugols solution
iodides
-AEs?
-RARE but: metallic taste sore gums/teeth feels like you have a cold(headache, sneezing, cough) skin lesions hypersensitivity angioedema laryngeal edema
fetal goiter if taken during pregnancy
What drug do you not want to give with iodides (antithyroid drugs)?
-dont want to give thioamides (other anti-thyroid drugs)
-iodide stop break down but still making so youd be delaying effect of thioamides which stops production and effects arent seen until all stores of already made T3 and T4 are gone
(INCREASE INTRAGLANDULAR STORES OF IODIDE THUS DELAYING ONSET OF THIOAMIDE THERAPY)
Radioacive iodine
- type?
- drug name?
- MOA?
- anti-thyroid - for hyperthyroid
- Radioactive iodine is the name durp
- concentrated in thyroid –> emission of gamma and beta rays –> beta destroy parenchymal cells and gamma pass through tissue and used in detecting concentration of RAI remaining in the thyroid glands
Radioactive iodine
AEs?
- -hypothyroidism durp– TOO MUCH DESTRUCTION*
- leukemia and neoplasia
- NOT DURING PREGNANCY - crosses placenta and concentrates in fetal thyroid
Radioactive iodine
- cure rate?
- after treatment?
- 80% cured after single dose – resolves 2-3 months
- give beta-blockers, iodide, or antithyroid drug to control hyperthyroidism (thyroid storm bc destroying thyroid cells) while waiting for effect
Perchlorate
- type?
- AE?
- antithyroid drug - anion inh
- aplastic anemia
Pertechnetate
-type?
-antithyroid drug - anion inh
Thiocyanate
-type?
-antithyroid drug - anion inh
Anion inh drugs:
- name them
- MOA?
- overcome drug effects by?
- perchlorate
- pertechnetate
- thiocyanate
- Inh the energy-dependent uptake of iodide into the thyroid cell (mediated by Na/Iodide symporter
- must give a lot of iodide to overcome drugs
Anion inh drugs:
-uses?
tx iodide-induced hyperthyroidism such as amiodarone-iodine induced thyrotoxicosis
Important antithyroid adjunct: Beta blocker
- which drug?
- MOA?
- major use?
- why use these?
1) propranolol
2) B1 and B2 antagonist
- inh conversion of T4 to T3 via 5’-deiodinase (5’DI)
3) controls tachycardia, HTN and atrial fib thats common with hyperthyroidism
4) rapid onset - can help with thyroid storm
Important antithyroid adjunct- diltiazem - used for?
CALCIUM CHANNEL BLOCKER- used to control tachycardia in asthmatic since Beta blockers are a no go
Important antithyroid adjunct: barbiturates - used for?
increased T4 metabolism
Important antithyroid adjunct: bile acid sequestrants - used for?
increase biliary T4 excretion
Beta blocker - AE?s
- asthma
- AV blockade
- hypotension
- bradycardia
