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Endo/Eye/Derm - Women/Men > EXAM 3 Thyroid and Antithyroid drugs Dr. Pond > Flashcards

EXAM 3 Thyroid and Antithyroid drugs Dr. Pond Flashcards

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1
Q

What are the cells of thyroid glands called?

A

Follicle cells
-> secrete thyroid hormones

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2
Q

What is the lumen of follicle cells of thyroid glands filled with?

A

Colloid

Thyroglobulin -> precursor for thyroid hormones

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3
Q

What is a function of Colloids?

A

Precursor for thyroid hormones

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4
Q

What are the cells that lie in between follicle cells?

A

Parafollicle cells or extra-follicle cells

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5
Q

What is the function of Parafollicle cells?

A

Calcitonin secretion

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6
Q

What is the function of Calcitonin?

A

it inhibits osteoclastic bone resorption
-> decrease in Ca2+ and phosphate

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7
Q

What are the thyroid hormones?

A

Thyroxine = T4 (4 iodines)

Triiodothyronine = T3 (3 iodines)

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8
Q

Which protein binds to thyroid hormones in the blood?

A

Thyroxine binding globulin (TBG)

Thyroid hormones are lipophilic and dont like to stay in the blood unbound

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9
Q

Thyroid hormones are derived from which amino acid?

A

Tyrosine

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10
Q

How is iodide from the bloodstream taken up by follicular cells?

A

Iodide trap

Na+-iodide co-transporter: Na+ comes in towards its gradient and iodide comes with it against its gradient (so Na+ carries iodide along)

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11
Q

What happens to iodide after uptake into follicular cells?

A

Oxidation
-> it loses an electron: from iodide (-I) to iodine (I)

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12
Q

What happens to iodine in the Colloid?

A

it will bind to tyrosine residues if Thyrosine globulines

IODINATION

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13
Q

How do iodide levels affect thyroid hormone levels?

A

low level of iodide -> decrease in T3 and T4 (since iodide is needed for synthesis)

high level of iodide -> may inhibit the synthesis and release of thyroid hormones (negative feedback)

-> we don’t want too level or too high levels od iodide

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14
Q

Which stages of thyroid hormone synthesis are affected by high concentrations of iodide?

A

Iodination of Thyroid globulins (tyrosine residues)

Proteolysis of thyrosinglobulins in lysosomes

-> inhibition due to negative feedback

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15
Q

What happens after iodine binds to thyroid globulins?

A

tyrosine residues of the thyroids couple in thyrosind globulins and are stored that way -> until the signal (TSH) for the need for thyroid hormones occur

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16
Q

What is the signal that causes Pinocytosis (uptake of thyroid globulin cells into follicular cells)?

A

TSH binding to receptor cells on the thyroid glands
-> the need for thyroid hormone synthesis

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17
Q

What happens when the signal for the need for thyroid hormones occurs?

A

Thyroid globulins are taken up follicular cells and fused with lysosomes (contain proteases) to phagolysosomes

-> proteases cut all the other amino acids within the thyroid globulins -> and the thyroid hormones with the coupled tyrosine bonds stay intact
-> release into the bloodstream

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18
Q

Hypothalamus-Pituitary-Thyroid-Axis

A

Hypothalamus -> releases TRH (thyroid releasing hormone)

TRH binds to the anteroir pituitary gland -> leading to release of TSH (thyroid stimulating hormone)

TSH binds to thyroid glands -> release in thyroid hormones (T4 and T3)

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19
Q

What are factors that increase thyroid hormone release?

A

-acute psychosis
-cold
-circadian and pulsatile rhytms

-high TRH, high TSH

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20
Q

What are factors that decrease thyroid hormone release?

A

-severe stress
-corticoids (like cortisol) or dopamine

-high levels of T3 and T4 (negative feedback)

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21
Q

What is the ultimate function of thyroid hormones?
MOA

A

regulation of gene transcription
-> by binding to nuclear receptors (thyroid receptor) on the DNA

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22
Q

What happens to T4 once it enters the cell?

A

Deiodination of the outer ring (thyroxin T4 to Triiodothyronine T3)

by 5´DI: 5´deiodinase !!!

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23
Q

What is the state of the thyroid receptor before T3 binds?

A

bound to another thyroid hormone receptor (homodimer) and a corepressor
-> INACTIVATED

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24
Q

What is the state of the thyroid receptor after T3 binds?

A

the second thyroid hormone receptor leaves -> the corepressor leaves

the retinoid X receptor binds to the first thyroid hormone receptor (heterodimer) -> Coactivator binds to the first thyroid hormone receptor

-> ACTIVATION

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25
Q

Which region of the DNA are thyroid receptors bound to?

A

TRE
thyroid response elements (regulatory sequences)

when T3 binds to the receptor, the receptor changes its conformation -> Co-activator binds

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26
Q

What is the recommended daily uptake of iodide?

A

150 μg

75 μg is used daily for hormone synthesis, the rest is excreted

27
Q

What is considered the reverse T3?

A

during deiodination, the iodide is removed from the wrong ring (inner ring) -> this compound is inactive

28
Q

Which of the thyroid hormones is produced in higher amounts?

A

T4 with 75 mcg

VS

T3 with 25 mcg

29
Q

Which of the thyroids is preferred in therapy?

A

T4
-> due to its longer half-life (7 days; 1 day for T3)
-> it is the natural way of metabolism when using T4 and let the boy convert it to T3

30
Q

Which drugs may affect the metabolism of T4 and T3?

A

-CYP 3A4 inhibitors like phenobarbital, phenytoin -> increase their metabolism -> decreases level

-> not an an issue in euthyroid patients bc healthy thyroid can compensate for the defecit

31
Q

How do thyroid hormones affect anticoagualtion therapy?

A

in hyperthyroidism -> lower dose of warfarin

in hypothyroidism -> higher dose of warfarin

32
Q

What are the 2 forms of T3 receptors?

A

alpha and beta
-depending on the expression pattern and the tissue and can have different responses to thyroid hormones

33
Q

What is the overall effect of thyroid hormones in the body?

A

many different metabolic effects
-> overall an increase in basometabolic rate (BMR)
-> stimulates calorigenes, increased breakdown of energy
-> stimulates growth hormones -> growth in children (children with hypothyroidism don’t grow well)
-> regulates the effects of the nervous system and the heart to catecholamines (NE, epinephrine, dopamine) increasing the number of adrenergic receptors on the heart

-> development of the nervous system -> hypothyroidism in children may lead to learning defects and mental retardation

34
Q

What is the permissive effect of thyroid hormones?

A

Hormone A is required for hormone B to have its maximum effect

the thyroid hormones will increase the effect of adrenergic receptors in the heart and in the nervous system -> mimicking sympathetic effects of the NS (sympathomimetic)

35
Q

What is the BBW for thyroid hormones?

A

they should not be used solely or with other agents for weight loss

36
Q

Patient presentation in Hypothyroidism

A

-Myxedema (puffiness)
-cold (due to low heat predection)
-dry skin/hair
-weight gain (metabolic rate is low)
-lethargy

-slowed mental processes - in adults
-mental retardation - in children
-cretinism in children (severe physical and mental retardation)

-infertility, impotence
-arrhythmias, bradycardia, decreased SV and CO
-> due to decreased number of adrenergic receptors in the heart

37
Q

What is the most common cause of Hypothyroidism?

A

Hashimito’s disease
-> autoimmune destruction of thyroids
5x more come in women

38
Q

When might Hashimoto’s disease present in women?

A

occasionally occurs during or after pregnancy

39
Q

What is a Goiter and when does it present in patients?

A

-enlargement of the thyroids

-seen early in Hashimoto’s disease bc of the inflammation that is going on during the autoimmune destruction

-absent later, as the thyroid is destroyed

-degree of hypothyroidism might be mild to severe

40
Q

Treatment of Hypothyroidism

A

supplementation

-Levothyroxine (Synthroid): I-isomer of thyroxine T4
-> long half-life (7days), converted to T3 intracellular

-Liothyronine (T3): 3-4x more potent, but short hafl-life (24h)
-> more expensive
-> greater risk fo cardiotoxicity
-> more difficult to monitor in lab

41
Q

Which drug contains T4 and T3?

A

Liotrix (thyroxine T4 and liothyronine T3)
-> expensive

42
Q

Which thyroid hormone drug is of animal origin?

A

Desiccated thyroid
->more unstable
-> variable hormone concentration
-> may be seen in older patients who had been using it for a long time and didn’t switch

43
Q

Not enough VS too much thyroids

A

Not enough:
-constipation
-cold intolerance
-weight gain
-fatigue, lethargy
-impaired intellectual performance or other mental
status changes (e.g., depression)
-bradycardia

Too much:
diarrhea
heat intolerance/sweating
weight loss
hyperactivity, tremor, insomnia
emotional lability, irritability &
anxiety
tachycardi

44
Q

Patient presentation of Hyperthyroidism

A

-Exophthalmos: increased pressure behind the eyes, bulding eyes
-tachycardia (sympathomimetic effect)
-Hot (high metabolism)
-lose weight
-decreased fertility
-menstrual irregularities

45
Q

What is the most common cause of Hyperthyroidism?

A

Graves disease

-autoimmune disorder
-more often in women
-occasionally during or after pregnancy

46
Q

What are the symptoms of Grave’s disease?

A

-bulding eyes
-Goiter (diffuse toxic goiter - historically bc patients had enlarged thyroid and were feverish)
-> Grave’s disease is also called thyrotoxicosis
-10x more in women

47
Q

How is Grave’s disease different from Hashimoto’s disease?

A

in Graves’s disease the body produces TSI (thyroid stimualting immunoglobulin) -> that binds to TSH receptors but stiumlates the thyroid longer and stronger than TSH -> overproduction of thyroid

-> in Hashimoto’s disease the thyroid gets destroyed immune cells

48
Q

How would the levels of T4, T3 and TSH look like in Grave’s disease?

A

-high T4 and T3 -> overproduction stimulated by TSI

-low TSH -> negative feedback

49
Q

How are the symptoms of Exophthalmos (bulging eyes) explained?

A

TSI binds to TSH receptors in tissue behind the eyes and causes inflammation and swelling

50
Q

Which drug is used to treat Exophthalmos?
(don’t need to know)

A

teprotumumab-trbw (Tepezza)
-blocks IGF-1 receptor on the tissue behind the eye

51
Q

Treatment approaches for Hyperthyroidism

A

-agents that interfere with the production of thyroid hormones
-agents that interfere with the release of thyroid hormones

-Glandular destruction with radiation or surgery

52
Q

Which drug is used for Hyperthyroidsim?

A

Thioamides

-Propylthiouracil (PPT)
-methimazole
-most useful in young patients with mild disease

-> remission of 12-18 months
-> 70-80% incidence of relapse

53
Q

MOA of Propylthiouracil (PPT) and methimazole

A

-inhibit oxidation (catalyzed by peroxidase) of iodide to iodine
-inhibit Iodination of tyrosine residues of thyroid gloublins

-slow onset, since the synthesis is targeted -> so it will still release what is there until it works

54
Q

Why is there a slow onset when using thioamides?

A

because the colloids have thyroid globulins stored
-> the actual effect is seen after the the remaining thyroid is depleted
-> onset of 3-4 weeks

55
Q

Toxicites of Thioamides

A

-GI and nausea
-Rash (maybe with fever)
-Agranulocytosis: rare, but potentially fatal (higher risk with high doses in elderly)

for Methimazole:
-altered sense of taste/smell
-cholestatic jaundice (can be fatal)

for propylthiouracil PPT:
-Hepatitis

56
Q

Kinectics of Thioamides

A

-not predictable in regards to half-life since they accumulate in the thyroid

-PPT has a half-life of 1.5 hr but is given q6-8h

-methimazole has a half-life of 6hr and can be given once daily

-it may cross the placenta and concentrate in the fetal thyroid -> CAUTION in pregnant (since they occasionally suffer from hyperthyroidism during or after pregnancy)

57
Q

Which molecule may be used as a drug for hyperthyroidism?

A

Iodide
-it inhibtis iodination of thyroid globulins
-it inhibits proteolysis of thyroid globulins -> no release of thyroid hormones

58
Q

What is the time of onset when using Iodides?

A

2-7 days (faster than with thioamides)
-> because the release is inhibited

-but it is only a temporary effect

59
Q

What is the role of Iodide in therapy?

A

-used acutely and temporarily, maybe in the meantime of scheduling surgery

-has a disadvantage: it increases iodine storage which delays the therapy with thioamide, also prevents the use of radioactive iodine therapy for several weeks

-cross the placenta and cause fetal goiter

60
Q

Iodide ADE

A

ADEs are uncommon
-rash
-swollen salivary glands, mucous membrane ulcerations
-conjunctivitis
-runny nose
-bleeding disorder

61
Q

Which isoform of radioactive iodine is used for treatment?

A

I-131
-other ones are only used for imaging

62
Q

How does radioactive iodine work in hyperthyroidism?

A

-Emits β rays
-range: 400-2000 μm
-half-life of 5 days

-Destroys thyroid: epithelial swelling and necrosis,
follicular disruption, edema, leukocyte infiltration

63
Q

Advantages and disadvantages of I-131

A

advantage: easy, effective, cheap, relatively pain-free

disadavatnage:
-the parathyroid may be affected
-patients have a fear of radioactive agents
-it crosses the placenta and is excreted in breast milk -> affects fetal thyroid

64
Q

What must be done after surgery or radioactive-induced thyroid destruction?

A

thyroid supplementation
-Levothyroxine (Synthroid) - T4
-Liothyronine T3

Endo/Eye/Derm - Women/Men (30 decks)

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