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Pharmacology > Pharmacology of the thyroid hormones > Flashcards

Pharmacology of the thyroid hormones Flashcards

1
Q

Blood brain barrier

A
  • the brain is the central control unit
  • the brain has to be protected against peripheral influences
  • for this reason a barrier is formed →the blood-brain barrier (BBB)
    The BBB is built by endothelial cells, pericytes, and astrocytes.
    The endothelial cells are tightly connected via tight junctions.
    However, in some areas the BBB is not formed by vessels/endothelial cells.
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2
Q

Circumventricular organs

A
  1. choroid plexus: CSF production and filtration
  2. pineal gland: Melatonin release
  3. median eminence: release of CRH, TRH, GnRH
  4. area postrema: trigger of vomiting
  5. subfornical organ: fluid balance
  6. vascular organ of lamina terminals (fever regulation)
  7. posterior pituitary: Oxytocin and ADH release
  • The circumventricular organs are characterized by extensive vasculature and fenestrated capillaries which lead to a ‘leaky’ BBB.
  • sensory organs: area postrema (AP), subfornical organ (SFO) and vascular organ of lamina terminalis
  • secretory organs: posterior pituitary, pineal gland, choroid plexus and median eminence
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3
Q

Hypothalamus pituitary axis

A

Neuroendocrine cells of the hypothalamus release hormones into the hypothalamic-pituitary portal system or release hormones directly into the posterior pituitary (PP, “HHL”)
The release of hormones from the endocrine cells of the anterior pituitary is regulate via releasing hormones transported in blood of the portal vein system.

releasing hormones:
GnRH = Gondatropin-releasing hormone
GHRH = Growth hormone-releasing hormone
TRH = Thyrotropin releasing hormone
CRH = Corticotropin releasing hormone

hormones of the anterior pituitary
LH = Luteinizing hormone
FSH = Follicle stimulating hormone
TSH = Thyrotrpin stimulating hormone
ACTH = Adrencorticotropic hormone
GH = Growth hormone
PL = Prolactin

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4
Q

Thyrotropin releasing hormone

A
  • molecular weight: 359.5 Da
  • short half-life
  • stimulates TSH and prolactin secretion from the anterior pituitary
    Only 15 % of the TRH positive cells were located in the para ventricular nucleus (PVN) and project into the portal vein system.
    →TRH is also a neurotransmitter
    → Application increases arousal and energy expenditure and antagonizes the effect of barbitals.
    → Analogues with a long half-life (e.g. Taltirelin) are used in Asia for treatment of special forms of ataxia.

Structure: (pyro)Glu-His-Pro-NH2

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5
Q

TRH system

A

hypophysiotropic TRHergic neurons→Paraventricular Nucleus
nonhypophysiotropic TRHergic neurons→DMH, Raphe palidus, MPA

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6
Q

Thyrotropin releasing hormone receptor

A

TRH-R is a seven transmembrane receptor which is Gαq/11 coupled. After activation the receptor is internalized by beta-arestine.

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7
Q

Thyroid stimulating hormone

A

TSH is a glycoprotein and consists of two subunits, the alpha and the beta subunit.
* α subunit (92-amino acids): nearly identical to that of human chorionic gonadotropin (hCG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH)
* The α-subunit is thought to be the effector region responsible for stimulation of adenylate cyclase.
* β-subunit (118-amino acids): unique to TSH
* The β-subunit determines the receptor specificity
The TSH receptor is found mainly on thyroid follicular cells; is Gαs coupled.
Long time stimulation increase the vascularisation and a hypertrophy of thyreocytes in the thyroid gain.
Mutations in the TSH-receptor can lead to a constitutive active receptor and to a TSH independent thyroid hormone release. This somatic mutation takes place in the within a lifetime.

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8
Q

Histology of the thyroid gain

A

The Thyroid contains follicles which are surrounded by follicle epithelial cells. Follicle epithelial cells secrete colloid in to the follicle lumen. Microvilli project into the follicular lumen where the colloid is secreted. Calcitonin producing C-cells (parafollicular cells) are located next to the follicle epithelial.

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9
Q

Iodine

A

→ daily supply > 150 μg in adults
→ CAVE in some arias in the world the daily Iodine concentration is not reachable
→ In Germany salt with and without iodine is available

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10
Q

Iodide transporter (Na+/I- Symport, NIS)

A

→ basolateral active transport mechanism
→ driven by a sodium gradient
→ increases the iodide ion concentration in the thyroid (more then 20- to 50-fold higher then the plasma concentrations
→ NIS can be antagonized competitively by perchlorate

Iodide transporter Pendrin (SLC26A4)
→ transport of iodide into the colloidal lumen

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11
Q

Thyroid Oxidase (ThOx)

A

→ heterodimeric protein at the apical plasma membrane produces H2O2

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12
Q

Thyroid Peroxidase (TPO)

A

→ Protein in the apical membrane
→ oxidates iodine to iodide and IOH
→ catalyzes the reaction with the oxidized iodine and thyrosin of the thyreogloboline. And form monoiodotyrosine (MIT-) and diiodotyrosine-(DIT-)
→ catalyzes the coupling of mono- or diiodophenol with DIT to T3 and T4

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13
Q

Thyreoglobulin (TG)

A

→ Protein which is secreted and stored in the follicle lumen
→ TG is taken up by pinocytotic transport into the follicle epithelial cells. One TG molecule forms ~5 T4 molecules

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14
Q

Thyroid stimulating hormone receptor activation

A
  • Up-regulation in the activity of the sodium-iodide symporter (NIS) on the basolateral membrane of follicular cells,
    →Iodide is moved across the apical membrane into the colloid of the follicle by pendrin .
    Thyroperoxidase oxidizes two Iodide to form Iodine.
  • Stimulates iodination of thyroglobulin within the follicular lumen
  • Stimulates the conjugation of iodinated tyrosine residues.
    →formation of thyroxine (T4) and triiodothyronine (T3) that remain attached to the thyroglobulin protein.
  • Increased endocytosis of the iodinated thyroglobulin protein across the membrane back into the follicular cell.
  • Proteolysis of the iodinated thyroglobulin is stimulated to form free thyroxine (T4) and triiodothyronine (T3).
  • Secretion of thyroxine (T4) and triiodothyronine (T3) across the basolateral membrane of follicular cells to enter the circulation.
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15
Q

Synthesis of the thyroid hormones

A

Tyrosine
-> 3-Monoiodotyrosine
-> 3, 5 Diiodotyrosine
via conjugation

3, 3’, 5, 5’ tetra iodothyronin (Thyroxin T4)
- synthesized only in the thyroid
- 90 % of the released hormone
- T4 is deiodinate in the periphery in to T3

3, 5, 3’ tri iodothyronin (T3)
- synthesized in the thyroid and periphery
- 9 % of the released hormones
- T3 bioactivity is 4-8 fold higher then T4

3, 3’, 5’ tri iodothyronin (rT3)
- 1 % of the released hormones
- biological inactive
- increase concentration in an ill status

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16
Q

Thyroid hormone receptor

A
  • two thyroid hormone receptors THRα and THRβ exist, which are located on 2 different genes
  • Isoforms are generated by alternative splicing
  • THR have two “zinkfinger” domains to bind on the DNA
  • THR bind mainly T3 at the hormone binding site
  • After T3 binding the THR binds the DNA and increase or reduce expression of target gens
  • THRs are located in the nucleus as dimers with the 9-cis-13,14-dihydro-retinoic acid responsive RXR (retinoid X receptor ) and the complex binds to the hormone responsive element in the promoter region.
  • After T3 binding of corepressors and coactivators are change.
17
Q

Thyroid hormone metabolism

A

T4 is activated by deiodination to T3 via deiodinases
T3 is inactivated by deiodination to inactive 3,3 ́-T2 via deiodinases

T4 -> Typ-I-Deiodinase, Typ-3-Deiodinase -> rT3 -> Typ-I-Deiodinase, Typ-II-Deiodinase -> 3.3’ T2

T4 -> Typ-I-Deiodinase, Typ-II-Deiodinase -> T3 -> Typ-I-Deiodinase, Typ-III-Deiodinase -> 3,3’ T2

18
Q

Typ-I-Deiodinase (5’ Deiodinase)

A

-> converts T4 to T3
→ expressed in liver, kidney, thyroid, skeleton muscle, and heart.
→ Function: supply T3 to the periphery
→ increased activity in hyperthyroidism
→ Propylthiouracil (PTU)is an DIO1 inhibitor: reduction in T3 plasma concentration

19
Q

Typ-II-Deiodinase (5’-Deiodinase)

A

-> converts T4 to T3
→ expressed in brain and pituitary
→ Function: stabilizes intracellular T3 levels in the CNS
→ low T4-levels: activation of enzyme activity
high T4-level: inhibition of enzyme activity

20
Q

Typ-III-Deiodinase (5-Deiodinase)

A

→ deiododination of T4 to rT3 and T3 to 3,3’-T2
→ expressed in placenta, fetal liver, and CNS
→ Function: inactivation of T4 and T3
→ Inactivation of maternal T4

21
Q

Thyroid hormone transporter

A

The primary TH transporter is the monocarboxylate transporter 8 (MCT8)
→MCT8 is currently known to be highly specific for thyroid hormones

secondary thyroid transporters are
- the monocarboxylate transporter 10 (MCT10)
- the organic anion transporting polypeptide transporters (OATP1C1, OATP1A2, OPTP1A4)
- the large neutral amino acid transporters (LAT1 and LAT2)
→These transporters are also able to transport different kinds of amino acids

22
Q

Iodine deficience

A
  • Over 90% of goitre cases are caused by iodine deficiency
  • A goiter, is a swelling of the neck or larynx resulting from an enlargement of the thyroid gland, associated with a thyroid gland that is not functioning properly.
  • Hyperplasia of the thyroid to compensate for the decreased efficacy
  • Iodine deficiency in children can disturb normal growth as well as mental and cognitive development
23
Q

Morbus Basedow (Hyperthyroidism)

A

Pathogenesis and Symptoms TSH↓, fT3↑ und fT4↑
- Hyperthyroidism and growth of the thyroid
- Stimulation of auto-antibodys against the TSH- receptor of the thyroid gland
→ stimulation of the thyriod
→ stimulation of: fT3 und fT4 → stimulates growth → Goitre
- Inactive antibodies and antibodies with an inhibitory function may also be involved. The combination of the different types of antibodies affect the clinical outcome.
- The histopathology is described with:
→ Graves’ ophthalmopathy (endokrine Ophthalmopathie , Exophthalmus)
→ Dermopathie (prätibiales Myxödem, Akropachie, Onycholyse)

24
Q

Graves ophthalmopathy

A

Graves’ ophthalmopathy
Expression of an antibody against the extracellular part of the TSH receptor in orbital fibroblasts preadipocytes and thyroid cells
Active lymphocytes infiltrate retro orbital tissue and eye muscles. This leads to an inflammatory process via released cytokines.
Storage of mucopolysaccharides lead to edema and growing of the eye muscle.
- Visualization of the growing of the eye muscles and the thickened retroorbilal tissue

25
Q

Antithyroid agent

A

Mechanisms:
Inhibition of thyroid peroxidase
Inhibition of the oxidation of I- to I2
* Inhibition of the incorporation of I2
* Inhibition of the coupling of the iodotyrosyl rest

Bsp: Thioharnstoff, Propylthiouracil, Thiamazol (Methimazol), Carbimazol

26
Q

Hashimoto Thyreoiditis (Hypothyroidism)

A

Pathogenesis and Symptoms TSH↑, fT3↓ und fT4↓
- Most common causes for a hypothyroidism
- Young patients often develop goitre, however it can also exist in an atypical form without a goitre.
- Antibodies against the thyroid gland
→ TPO-AK (Auto antibodies against the thyroid peroxidase)
→ TG-AK (Auto antibodies against the thyroglobulin)
- histology: lymphocytic infiltration in the thyroid
→Destruction of the thyroid tissue

27
Q

Blood-brain barrier

A
  • the brain is the central control unit
  • the brain has to be protected against peripheral influences
  • for this reason a barrier is formed →the blood-brain barrier (BBB)
    The BBB is built by endothelial cells, pericytes, and astrocytes.
    The endothelial cells are tightly connected via tight junctions.
28
Q

Allan Herndon Dudley Syndrome

A

X-linked syndrome with psychomotor deficits
-> Mental retardation, dysarthria, ataxia, muscle hypoplasia
-> Hypomyelination in the brain
-> High T3, low T4 serum levels
-> Caused by mutations in monocarboxylate transporter 8 (MCT8)

MCT8
->12 hydrophobic transmembrane domains
-> Highly specific T3↑ and T4↓ transporter
-> Expression: brain, lung, liver, thyroid gland, gonads and muscle1

Peripheral hyperthyroidism but hypothyroidism in the brain
-> Due to expression of MCT8 and other TH transporters

29
Q

Therapy of the Allan Herndon Dudley Syndrome

A
  • Tiratricol (also known as TRIAC or triiodothyroacetic acid) is a thyroid hormone analogue.
  • Triiodothyroacetic acid is also a physiologic thyroid hormone that is present in the normal organism at low concentrations.
  • TRIAC enters the brain without using the MCT 8 transporter and reduces the central symptoms of AHDS.
30
Q

Gene therapy of the Allan Herndon Dudley Syndrome

A

T4 and T3 can not penetrate the blood brain barrier (BBB)
→ Expression of the MCT 8 transporter in the components of the BBB
→ Regeneration of the T4 and T3 transport

o Recombinant AAVs can be used for gene therapy in the brain
o They can be injected Intraparenchymal →Problem: risk of hemorrhage (3%), limited distribution of the vector
o High doses of AAV9 injected into the blood can cross the blood-brain barrier →Problem: off-target effects
Example:
Omasemnogene abeparvovec (Zolgensma®) scAAV9 vector with CAG promoter driving ubiquitous SMN1 expression
Dose: 1.1 x 1014 vg/kg
Approval: May 2020 by EMA

AAV-BR1-CAG-Mct8 treatment of Mct8/Oatp1c1 DKO mice elevates T3 levels in the brain.
AAV-BR1-CAG-Mct8 treatment of Mct8/Oatp1c1 DKO mice improves peripheral TH levels.

No improvements in Trh and Tshb gene expression in Mct8/Oatp1c1 DKO mice brain with AAV- BR1-CAG-Mct8 treatment.

31
Q

Changes in motofunction in P120 mice

A

120 days after injection of AAV-BR1-Mct8 motoric functions are rescued in tendency

Pharmacology (22 decks)

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