Rose: Thyroid Physiology and Pharmacology Flashcards by Sarah Carlson

Describe the hierarchy of control that regulates the secretion of thyroid hormone.

TRH>
TSH>
T3/T4

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What inhibits TSH release?

Somatostatin, DA and high glucocorticoids (adrenal cortex)

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Describe the structure of TRH.

TRH is synthesized as a PREprohormone>

processed to mature protein= TRIPEPTIDE

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What is the function of TRH?

STIMULATES the release of TSH from THYROTROPHS from the anterior pituitary

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What does TSH regulate?

energy homeostasis
feeding behavior
thermogenesis
autonomic regulation

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How does TRH signaling lead to the release of TSH?

TRH binds to transmembrane TRH on thyrotrophs>
TRH coupled to PLC>
IP3>
increased Ca>
release of TSH containing secretory vesicles/synthesis of TSH

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Describe the structure of TSH. What part of the structure of TSH gives it it’s specificity?

Glycoprotein consisting of alpha and beta chains

alpha chains= same found in other pituitary hormones

beta chains= confer specificity of hormonal action of TSH

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Where are the receptors for TSH located?

thyroid follicular cells

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How does TSH signaling lead to the release of TH?

TSH binds TSHR (GPCR)>
activates adenylate cyclase>
increases cAMP>
stimulates TH release and synthesis

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How does the production of new thyroid hormone affect the regulation of the components needed to make thyroid hormone?

upregulates thyroid peroxidase synthesis
thyroglobulin transcription
Na/I transport activity

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What are the 7 steps required to synthesize thyroid hormone?

Iodine is transferred into the follicular cell>
iodine is oxidized to iodide
Iodination of tyrosines attached to thyroglobulin protein backbone> MonoIT, DiioIT
Conjugation of MIT and DIT> T3/T4
Endocytosis of T3 and T4
Proteolysis of conjugates into mature T3 and T4
Secretion of T3 and T4 out of cell

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What are the two steps in thyroid hormone synthesis that require thyroid peroxidase?

Oxidation iof iodide to iodine

4. Conjugation of MIT and DIT to form T3 and T4

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What is a common drug target to inhibit TH synthesis?

Thyroid peroxidase

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What is the diff between T3 and T4?

T2 is more active and has a shorter half life (1 day compared to 6 days)

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The majority of T3/T4 is bound to…

Thyroxin binding protein

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How does Free T3/T4 enter the cell?

diffusion/carrier mediated transport

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What happens once T3/T4 enter the cell?

T3/T4 bind TRH>
homodimerize w/ another T3: TRH>
Homodimers bind TREs>
initiates transcription of thyroid responsive genes

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What happen to thyroid carrier proteins during pregnancy (or an estrogen/androgen treatment)?

INCREASE

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How do hyperthyroidism, malnutrition and nephritic syndrome affect thyroid carrier proteins?

All of these diseases cause PROTEIN LOSS>

and therefore lead to a DECREASE in carrier proteins

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Bindings sites of TBG?

1 binding stie for 1 TH

binds 75% T4
Binds 75% T3

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Binding sites of Transthyretin?

2 binding sites for TH

binds 20% T4
binds 5% T3

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Binding sites for albumin?

SEVERAL binding sites for TH

binds 5% of T4
binds 20% of T3

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What is important for the activation and deactivation of TH?

Deiodinases

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DI and II activate?

T4 to T3

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DI and DIII deactivate?

T4 to rT3

Where is DI prevalent?

liver and kideny

What is the role of DI?

Can convert T4 to active OR inactive form T4 > T3 (increases T3 in circulation) T4> rT3 (disposal)

What is the drug target for Prophylthiouracil?

Where is DII found?

brain pituitary skeletal and cardiac muscles

What is the role of DII?

convert T4 to supply INTRACELLULAR T3

Where is DIII found?

brain skin placenta

What is the role of DIII?

DEACTIVATES hormones

What is TH necessary for and what does it promote?

Necessary: normal metabolism, growth, development Promotes: O2 consumption, heat production, free radical formation

What are the main functions of TH?

regulation of BMR increased heat production increased glucose utilization permissive sympathetic effects (increase HR and contractility)

How does congential lack of TH or maternal hypothyroidism affect infants?

``` mental retardation short statue delayed motor development coarse hair protuberant abdomen ```

What causes hypothyroidism in infants?

1. Lack of iodine in maternal diet (rare) 2. Mother w/ Hashimoto's thyroiditis> blocks anti-TSH receptor Ab 3. Exposure to radioactive iodine/antithyroid drugs in pregnancy

A newborn presents w/ resp. difficulty, cyanosis, jaundice, poor feeding, retarded bone maturation and shorter than expected lengths of the proximal tibial epiphysis. Dx?

Hypothyroidism

How do you dx hypothyroidism in an infant?

TSH/T4 screening is mandated in most states *if hormone replacement is started w/in a few days birth growth/development will be normal, if not mental development will not progress but physical can

What sxs are associated w/ hypothyroidism in adults?

``` Insidious onset: lethargy slowed intellectual funciton stiff/aching muscles cold intolerance delayed deep tendon reflex anovulation/amenorrhea ```

What causes primary hypothyroidism?

Problems w/ the THYROID GLAND 1. congential defects 2. gland destruction (surgical, radioactive, external radiation) 3. Iodine def 4. Autoimmune- Hashimotos

What is Hashimoto thyroiditis?

Chronic lymphocytic thyroiditis > | immune mediated gland destruction

What are causes of HYPERthyroidism?

1. Graves disease 2. thyrotoxicosis 3. thyroid storm

What is Grave's disease?

Excess TSH that you can't shut off

What causes Grave's disease?

T cells become sensitive to thyroid Ag> stimulate B cells> B cells produce Abs that mimic TSH> hyperstimulate TH production (TSI= thyroid stimulating IGs)

How does Grave's disease affect a fetus?

``` High TSI (IgG) can cross the placental membrane> neonatal hyperthyroidism ```

What is thyrotoxicosis?

any cause of EXCESSIVE TH concentration and its effect on organ systems

What is a thyroid storm?

EXTREME CASE of thyrotoxicosis= medical emergency

How do you tx a thyroid storm?

B adrenergic blockers Thioamides (antithyroid) corticosteroids

What are some of the physiological effects of HYPERthyroidism?

HYPERcatabolic Increased protein turnover> loss in skeletal muscle w/ myopathy Muscle weakness muscle degeneration muscle fatigue heat intolerance

What is a goiter?

enlarged thyroid gland

How does hypothyroidism cause a goiter?

``` Decreased IODINE in diet> low T3/T4 synthesis> signals Hypothal to make more TRH> more TSH> stimulates thyroid gland to produce thyroperoxidase, thyroglobulin, increase iodine uptake, increased growth of follicular cells> BUT no T3/T4 available w/ out iodine> NOT negative feedback> GOITER ```

How can hyperthyroidism cause a goiter?

lots of circulating T3/T4> NFB shuts down hormone axis > BUT increased stimulation of thyroid form Igs in circulation

What's the FIRST test that is ultra sensitive to test for thyroid disorder?

TSH= most accurate measure of thyroid activity ``` Low= HYPER High= HYPO ```

What do high T3/T4 levels indicate?

HYPERthyroidism

What is a TSI test?

Measures TSI in blood **ppl w/ Grave's disease will have this

Low TSH | High T4

Hyperthyroidism

High TSH | Low T4

Primary hypothyroidism

Low TSH | Low T4

Secondary hypothyroidism

What drugs are used to tx hypothyroidism?

Levothyroxine (T4) | Liothyroinine (T3)

Which drug used to treat HYPOthyroidism has a great potency and quicker onset?

What drugs are used to tx HYPERthyroidism and prep the thyroid for surgery?

1. Methimazole/Carbimazole 2. Proprylthiouracil 3. K Iodine

What is hte MOA of Methimazole/Carbimzole and Proprylthiouracil?

Inhibit thyroid peroxidase> affects: oxidation of iodide conjugation rxns producing T3/T4 Proprylthiouracil also inhibits DI> inhibits conversion of T4 to T3

What is hte MOA of K Iodine?

High drug concentration INHIBITS iodine metabolism

What is the first line treatment for Graves?

Methimazoles and Carbimazole *lasts 24hrs, takes 2 wks to have effect

What is a second line treatment for Graves and a first line tx for hyperthyroidism seen in pregnant women?

Proprylthiouracil

Hepatoxicity is assoc with what tx for hyperthyroidism?

Proprylthiouracil *this is why it's second line for Graves

Allergic rxns, sore teeth, gums, and excess salivation are all associated with what tx for hyperthyroidism?

K Iodine

What is the TU of K Iodine?

Prep for thyroid surgery tx thyroid storm protect from radioactive Iodine

What is I-123 used for?

scan thyroid (imaging)

What is I-131 used for? What is the main disadvantage of using I-131?

``` destroy thyroid (ablation) too much destruction ```