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PHCY 310 > L 44 Pharmacology of Thyroid Disorder > Flashcards

L 44 Pharmacology of Thyroid Disorder Flashcards

1
Q

Purpose of thyroid hormones x4

Therefore, thyroid disorders can have … and … consequences

A

Regulation of metabolism, heat production, protein synthesis, and many other body functions.
Therefore, thyroid disorders can have severe and widespread consequences.

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2
Q

The thyroid is the … endocrine gland in the body and is located ….
It is … below the … and in front of the …
The thyroid is a … vascular gland and it secretes … main hormones: … … and …

A

The thyroid is the largest endocrine gland in the body and is located anterior in the neck.
It is immediately below the larynx and in front of the trachea.
The thyroid is a highly vascular gland and it secretes 3 main hormones: Thyroxine, Tri-iodothyronine and calcitonin

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3
Q

Out of the 3 main hormones that the thyroid secretes, which 2 are known as ‘the thyroid hormones’?

A

Thyroxine (T4)

Try-iodothyronine (T3)

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4
Q

What is the functional unit of the thyroid? What is its other name?

A

The follicle or the acinus.

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5
Q

Describe the functional unit of the thyroid

A

The follicle is surrounded by follicle cells.

The follicle is filled with sticky colloid, which is thyroglobulin (a precursor for thyroid hormones)

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6
Q

What are the 3 steps in which thyroid hormones (T3, T4) are produced?

A
  1. Uptake of plasma iodide by follicular cells
  2. Oxidation of iodide and iodination of tyrosine residues of thyroglobulin
  3. Secretion of thyroid hormone into blood
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7
Q

Explain the first step of thyroid hormone production

A

The uptake of iodide by follicular cells is a very rapid process that occurs by active transport (energy dependent and against a conc grad)

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8
Q

Explain the second step of thyroid hormone production

A

a) Iodide is oxidised to iodine (I2) by thyroperoxidase, and using hydrogen peroxide
b) Tyrosine residues of the thyroglobulin are iodinated into hormone precursors.
c) The iodinated thyroglobulin forms a store of thyroid hormones precursors in the thyroid gland

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9
Q

What would the chemical word equation be for the conversion of iodide to iodine?

A

e.g Iodide + hydrogen peroxide —(thyroperoxidase)–> iodine

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10
Q

Where is thyroperoxidase found?

A

They thyroperoxidase enzyme is located on the interface of the follicle cell and the colloid.

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11
Q

What is the amino acid involved in thyroid hormone creation? What protein does it come from?

A

Amino acid: tyrosine and it comes from thyroglobulin.

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12
Q

If tyrosine is iodinated with 1 iodine molecule, it forms…
If tyrosine is iodinated with 2 iodine molecules, it forms…
What combinations are required to make the 2 thyroid hormones?

A

If tyrosine is iodinated with 1 iodine molecule, it forms MIT (mono-iodotyrosine).
If tyrosine is iodinated with 2 iodine molecules, it forms DIT (di-iodotyrosine)

To make T3: MIT + DIT (= 3 iodine residues)
To make T4: DIT + DIT (= 4x iodine residues)

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13
Q

Explain the 3rd step of thyroid hormone production?

A

Secretion:
Iodinated thyroglobulins endocytosed into the follicular cell.
Endocytotic vesicles fuse with lysosomes.
Proteolytic enzymes act on the iodinate thyroglobulin precursors to produce thyroid hormones T3 and T4 which are then secreted into the blood.

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14
Q

What happens to the leftover MIT and DIT when thyroid hormones are being secreted?

A

Leftover MIT and DIT are scavenged by the follicle cells and iodide is removed and reused.

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15
Q

Where does the iodide come from?

A

Diet

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16
Q

What mechanism is used to control the release of thyroid hormones?

A

Homeostatic mechanisms

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17
Q

When thyroid hormones are required, what hormone is released from the hypothalamus in response to stimuli?

A

Thyrotropin-releasing hormone (TRH) is released from the hypothalamus in response to stimuli.

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18
Q

What does the thyroid releasing hormone (TRH) act upon?

A

The anterior pituitary

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19
Q

What does stimulation of the ant pit via TRH cause?

A

Release of TSH (thyroid stimulating hormone) aka thyrotropin.

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20
Q

What is the other action of TSH?

A

It inhibits the hypothalamus via negative feedback to turn off thyroid hormone release cascade.

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21
Q

What does TSH stimulate?

A

The thyroid gland

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22
Q

What does the thyroid gland secrete in response to TSH stimulation

A

Thyroid hormones are secreted into the blood to go to the target cells.

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23
Q

What do thyroid hormones inhibit?

A

The ant pit and hypothalamus in a negative feedback loop.

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24
Q

… is released from the hypothalamus in response to stimuli.
… is then released from the anterior pituitary
… acts on the receptors in the membrane of thyroid follicle cells and also controls the steps in thyroid hormone synthesis.

A

TRH is released from the hypothalamus in response to stimuli.
TSH is then released from the anterior pituitary
TSH acts on the receptors in the membrane of thyroid follicle cells and also controls the steps in thyroid hormone synthesis.

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25
Q

TRH is released from the … in response to stimuli.
TSH is then released from the …
TSH acts on the receptors in the membrane of … … … and also controls the steps in thyroid hormone ….

A

TRH is released from the hypothalamus in response to stimuli.
TSH is then released from the anterior pituitary
TSH acts on the receptors in the membrane of thyroid follicle cells and also controls the steps in thyroid hormone synthesis.

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26
Q

High levels of … suppress TRH and TSH
Low levels of … stimulate TRH and TSH
… has a negative feedback on .. release

A

High levels of T3/T4 suppress TRH and TSH
Low levels of T3/T4 stimulate TRH and TSH
TSH has a negative feedback on TRH release

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27
Q

High levels of T3/T4 … TRH and TSH
Low levels of T3/T4 … TRH and TSH
TSH has a … feedback on TRH release

A

High levels of T3/T4 suppress TRH and TSH
Low levels of T3/T4 stimulate TRH and TSH
TSH has a negative feedback on TRH release

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28
Q

The actions of thyroid hormones can be split into 2 classes:

A

Metabolic effects

Growth/development effects

29
Q

What are the metabolic actions of thyroid hormones?

A

Increase carbohydrate, fat and protein metabolism.

Increased oxygen consumption and heat production by increasing basal metabolic rate.

30
Q

What organs are affected by thyroid hormones increasing the metabolic rate?

A

Heart, kidney, liver and muscle

31
Q

In terms of carb, fat and protein metabolism, which thyroid hormone has a better activity?

A

T3 has 5x the activity of T4

32
Q

What are the growth and developmental actions of the thyroid hormones? Direct + indirect

A

Direct effects on cell growth, CNS maturation, sexual development and reproductive function
Indirect effects: stimulates growth hormone production and increases GH effect on cells.

33
Q

How are thyroid hormones transported in the blood?
Which thyroid hormone is at a higher concentration?
Which hormone is metabolically cleared faster? How much faster?

A

Bound to thyroxine-binding protein in the blood.
T4 is at a higher plasma concentration.
T3 is metabolically cleared 20x faster than T4

34
Q

How are T3 and T4 metabolised? 3x steps

A
  1. Metabolised by de-iodination, deamination and decarboxylation
  2. Conjugated with glucuronic acid and sulfate
  3. Both conjugated and free forms are partly eliminated in bile
35
Q

Many thyroid disorders are … disorders.
They are more common in .. than …
Disorders are usually associated with an …. of the thyroid gland (…)

A

Many thyroid disorders are autoimmune disorders.
They are more common in women than men.
Disorders are usually associated with an enlargement of the thyroid gland (goitre)

36
Q

What is hyperthyroidism?

What are the 2 main types?

A

Excessive activity of thyroid hormones.

2 types: Diffuse toxic goitre/Graves disease (same) and toxic nodular goitre.

37
Q

What are the symptoms associated with Hyperthyroidism? x8

A

High metabolic rate (sweating, increased skin temperature)

Nervousness, tremor, tachycardia, increased appetite but with weight loss, sensitivity to heat

38
Q

What is the cause of diffuse toxic goitre?

A

Antibodies activate the TSH receptor, or a mutation forms of the TSH receptor to increase signal transduction, therefore increasing thyroid hormone production.

39
Q

Why doesn’t negative feedback stop diffuse toxic goitre?

A

You do get a little bit of negative feedback to reduce TSH production, however the stimulation is on the thyroid gland (TSH receptor), you don’t actually need TSH to be present (antibodies are activating the thyroid gland without TSH), therefore it continues.

40
Q

How does goiter form?
What is goitre?
What else occurs during goitre?

A
  • The thyroid gland grows and continues to produce thyroid hormone.
  • This forms an enlarged thyroid gland (bulge in neck) = goitre.
  • Immunologically mediated inflammatory reaction occurs in the extrinsic muscles and fat of the eye, causing swelling and exophthalmos
41
Q

What is exophthalmos

A

Bulging eyes

42
Q

What is the characteristic of goitre?

A

Bulging eyes (exophthalmos) and bulge in neck.

43
Q

What causes exophthalmos

A

Immunologically mediated inflammatory reaction occurs in the extrinsic muscles and fat of the eye, causing swelling and exophthalmos

44
Q

Drugs for hyperthyroidism x3 classes.

Which classes are antithyroid drugs? Why?

A

Thionamides: carbimazole, propylthiouracil
Radioactive iodine
B blockers to decrease hyperthyroidism symptoms.

Radioactive iodine and thionamides are antithyroid drugs as they act directly on the thyroid gland to prevent thyroid hormone being made.

45
Q

What drugs are used to treat the symptoms of hyperthyroidism?
Which drugs treat exophthalmos?

A

B blockers (to decrease symptoms)
Guanethidine eye drops
Glucocorticoids (e.g prednisolone or hydrocortisone)
Eye drops and glucocorticoids treat exophthalmos.

46
Q

MoA of thionamides

A

Competitively inhibits thyroperoxidase to decrease iodine binding and oxidation, therefore decrease T3/T4 synthesis

47
Q

Are thionamides immunosuppressive?

How quickly do thionamides work? Why?

A

Yes, they have immunosuppressant effects.

Max effects until all the currently circulating T4 has been degraded, so 4-6 weeks to decrease levels.

48
Q

Does T3 or T4 have the longer half life?

A 
T4 = 4-6 weeks
T3 = 6 days
49
Q

What are the PK points of thionamides?

A
  • Route of admin
  • Metabolism and elimination
  • Oral administration
  • Metabolism via liver and elimination via kidney
50
Q

Which thionamide is converted to an active metabolite? What is it called?
What is it’s t0.5? Does the active metabolite or precursor have a longer half life?

A

Carbimazole is converted to the active metabolite methimazole.
T0.5 = 6-15 hours (active metabolite (methimazole) has a longer t0.5)

51
Q

Is carbimazole a prodrug?

A

No because it has activity on its own. The active metabolite of carbimazole (methimazole) has more activity though.

52
Q

Methimazole produces … inhibition of thyroid incorporation of … within … hours. However the clinical effect takes …. due to the long T0.5 of … and stores of hormones that need to be depleted

A

Methimazole produces 90% inhibition of thyroid incorporation of iodine within 12 hours. However the clinical effect takes several weeks due to the long t0.5 of T4 and stores of hormones that need to be depleted.

53
Q

Propylthiouracil appears to work more rapidly than carbimazole because it …

A

Because it also reduces the de-iodination of T4 and T3 in the periphery/systemic circulation.

54
Q

Radioactive iodine administration?
How is reactive iodine taken up?
MoA of reactive iodine? Whihch type of radiation is effective here?

A

Radioactive iodine is administered as sodium salt in a single dose.
It is taken up by the thyroid as it is processed in the same way as iodide - incorporated into thyroglobulin.
MoA: Emits B and y radiation. B particles have a short-range and are therefore only absorbed locally for a cytotoxic effect in the thyroid only.

55
Q

Radioactive iodine has a t0.5 of 8 days, so the radiation effectively disappears by …

A

2 months

56
Q

Iodine administration is used to … thyroid hormone production but only for a … …
Administration:
High doses can reduce symptoms in … days and max effect at …

A

Iodine administration is used to suppress thyroid hormone production but only for a short time.
Administration: oral KI solution
High doses can reduce symptoms in 1-2 days and max effect at 10-15 days.

57
Q

MoA of iodine

A

Excess iodine causes inhibitory mechanisms so the thyroid hormone production is reduced for a period of time.

58
Q

What is hypothyroidism?

A

Insufficient activity of thyroid hormones

59
Q

Symptoms of hypothyroidism x7

A
  • Low metabolic rate
  • Slow speech
  • Deep hoarse voice
  • Lethargy
  • Bradycardia
  • Sensitivity to cold
  • Mental impairment
60
Q

Types of hypothyroidism x4

A
  1. Hashimoto’s thyroiditis
  2. Iodine deficiency
  3. Thyroidectomy
  4. Radioiodine ablation (removal)
61
Q

Drugs for hypothyroidism x3

A

Iodine (if deficient)
Thyroxine
Tri-iodothyronine

62
Q

Which of the hypothyroid drugs are synthetic analogues of thyroid hormones?

A

Thyroxine

Tri-iodothyronine

63
Q

What is the synthetic analog of thyroxine and tri-iodothyronine

A 
Thyroxine = levothyroxine
Tri-iodothyronine = liothyoxine
64
Q

What is the MoA of synthetic analogs of thyroid hormoned?

A

They simply replace the natural thyroid hormone in the body.

65
Q

What is the synthetic analogue of thyroxine?

A

Levothyroxine

66
Q

Liothyoxine is a synthetic analogue of …

A

Tri-iodothyronine

67
Q

Levothyroxine is a synthetic analogue of …

A

Thyroxine

68
Q

… has a faster onset of action, but a shorter duration of action than ….

A

Tri-iodothyronine has a faster onset of action, but a shorter duration of action than thyroxine.

69
Q

How would you pick what drug was required for hypothyroidism?

A

If you don’t have enough iodine, you give more iodine

If you don’t have enough hormone, you give more hormone.

PHCY 310 (65 decks)

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