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Pharmacology III > Exam 1 thyroid > Flashcards

Exam 1 thyroid Flashcards

1
Q

Thyroid (what it do)

A
  • largest organ for endocrine hormone production
  • secrete T4 and T3
  • promote normal fetal/childhood growth and devel
  • regulate hr and myocardial contractility
  • affect GI motility and renal water clearance
  • modulate body’s energy expenditure, heat generation, and weight
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2
Q

Thyroid gland gross anatomy

A
  • richly vascularized
  • 15-20g in N American adults
  • can weigh many hundreds of grams in a goiter
  • 2 lobes connected by band of tissue (isthmus)
  • attached to trachea
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3
Q

Thyroid Gland Structure

A
  • composed of follicles
  • follicular epithelium makes up outside of follicle
  • follicle center is filled with colloid
  • 20-40 follicles in a lobule
  • connective tissue separates lobules
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4
Q

Follicular Epithelium function

A
  • produce and secrete T4 and T3
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5
Q

Colloid function

A
  • produces and stores thyroglobulin (prohormone)
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6
Q

Cell types in Thyroid gland (2)

A
  • Follicular epithelium (colloid, T3, T4)
  • cells have extensive ER, many lysosomes and mitochondria
  • Parafollicular cells (calcitonin): calcitonin controls Calcium levels in body
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7
Q

Overall function of thyroid follicular epithellium

A
  • generate the amt of thyroid hormone necessary for homeostasis or fetal devel
  • 80ug T4/T3 per day
  • 3 major roles:
  • capture and transport sufficient iodide
  • synthesize sufficient thryoglobulin
  • recapture of the thyroglobulin and removal and secretion of thyroid hormones
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8
Q

3 thyroid hormones

A
  • T4: most abundant
  • T3: most potent activator of the thyroid hormone receptor
  • rT3: isomer of T3 that binds the thyroid hormone receptor but does not activate it
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9
Q

Iodine Requirements

A
  • need iodine from diet
  • converted to iodide
  • absorbed in GI
  • most iodide excreted by kidneys
  • dietary iodine deficiency affects ~100 million people in world
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10
Q

Iodine dietary deficiency

A
  • less than 50ug/day
  • thyroid cannot sustain adequate hormone production
  • results in gland enlargement (goiter) and HYPOthyroidism
  • results in neurological and growth deficits in children
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11
Q

Transport and concentration of iodide

A
  • Sodium-Iodide symporter (NIS)
  • energy from Na-K ATPase
  • maintains a [ ] for free iodide in the thyroid gland 30-40x higher than in plasma (8-10mg) (buffers variation in dietary intake)
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12
Q

Sodium Iodide Symporter (NIS)

A
  • iodide atom moved AGAINST electrochem gradient
  • also transports TcO4, ClO4, and SCN
  • controlled by TSH (increased transcription of NIS gene, target NIS to cell membrane, prolongs NIS half life)
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13
Q

radioactive TcO4 used for

A
  • imaging thyroid
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14
Q

KClO4 does what?

A
  • block iodide uptake by NIS
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15
Q

Which disease pathologically stimulates NIS?

A
  • Graves’ Disease (autoimmune hyperthyroidism)
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16
Q

Wolff-Chaikoff Effect

A
  • large amts of iodine in system (15-20 fold above normal) suppresses both NIS transporter activity AND NIS gene expression
  • this causes temporary hypothyroidism
  • effect lasts few days and is followed by the “escape phenomenon”: recover ability to produce and secrete hormone
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17
Q

Iodotyrosine dehalogenase (Dhal) enzymes

A
  • Dhal1 transcription is stimulated by cAMP (induced by TSH)
  • membrane protein concentrated at the apical cell surface which faces the colloid
  • catalyzes NADPH-dependent deiodination of monoiodotyrosine (MIT) and diiodotyrosine (DIT)
  • iodide released is reconjugated to newly synthed thryoglobulin
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18
Q

Pendrin

A
  • located on apical membrane
  • transports iodide to membrane-colloid interface
  • key in binding iodide to thyroglobulin
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19
Q

Thyroglobulin Synth

A
  • three to four T4 molecs in each molec of human Tg dimer under normal conditions
  • one in five molecs of human Tg contains a T3 residue
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20
Q

Organification of Iodide

A
  • oxidation of iodide
  • incorporation of oxidated iodide into MIT and DIT (MIT and DIT are hormonally inactive)
  • ? of page 8
  • mediated by TPO (thyroid peroxidase)
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21
Q

TPO

A
  • located in apical membrane of thyroid cell

- requires H2O2 generated by calcium dependent Duox1 and 2 enzymes (AKA THOX1 and THOX2)

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22
Q

Thiourea Drugs

A
  • inhibit TPO
  • can cause intrathyroidal deficiency in patients receiving these agents
  • Methimazole (MMI)
  • Carbimazole (CBZ)
  • Propylthiouracil (PTU)
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23
Q

Rate of organic iodinations is dependent on _____

A
  • the degree of thyroid stim by TSH
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24
Q

Iodide excess does what in iodide oxidation and organification?

A
  • inhibits DUOX2 glycosylation

- may be additional mech for Wolff-Chaikoff effect

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25
Q

Iodothyronine Synth: what are they and how made?

A
  • MIT and DIT precursors of active iodothyronines T4 and T3
  • to make T4 you need 2 DIT molecs
  • to make T3 you need 1 DIT and 1 MIT
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26
Q

What drugs inhibit binding and coupling of DITs and MITs for iodothyronine synth?

A
  • Thiourea drugs
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27
Q

T4 has highest concentration where?

A
  • the colloid
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28
Q

Thyroglobulin is stored where and contains what?

A
  • stored in the colloid

- contains MIT, DIT, T3, and T4

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29
Q

How much T4 in a 20g thyroid gland? and how long can that much maintain normal thyroid funct?

A
  • 5000 ug of T4
  • enough to maintain a euthyroid state (normal) for at least 50 days
  • low rate of hormone turnover (1% per day)
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30
Q

Thyroid hormone release steps

A
  • ENDOcytosis of colloid from follicular lumen
  • does this by macropinocytosis (non-selective uptake) by small coated vesicles that form at the apical surface (dominant process)
  • or by macropinocytosis by pseudopods formed at the apical membrane
  • both processes stimed by TSH
  • then the vesicles fuse with lysosomes which cleave off T3s and T4s from thryoglobulin and MCT8 moves them to the cytosol, and then is transported out by transporters
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31
Q

T4 is accessible to thyroidal type 1 and 2 _______ which does what?

A
  • deiodonases
  • this does basal and TSH stimulated conversion of T4 to T3
  • most T3 produced by peripheral 5’ deiodination of T4
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32
Q

Conversion of T4 to T3 is inhibited by ____

A

propylthiouracil (PTU)

33
Q

What can inhibit thyroid hormone release from a transporter?

A
  • iodide by inhibiting stim of thyroid adenylate cyclase by TSH and by stim immunoglobulins of Graves’ Disease
  • why you see rapid improvement that iodine causes in hyperthyroid patients
  • lithum also inhibits thyroid hormone release (less commonly used)
34
Q

Circulation of Thyroid hormone (makeup)

A
  • T4= 90%
  • T3 = 9%
  • rT3 = 1%
  • most bound to plasma proteins
  • very very little T4 and T3 are unbound or free (0.04% and 0.4%
35
Q

Three major thyroid hormone transport proteins

A
  • Thyroxine-binding globulin (TBG)
  • Transthyretin
  • Albumin
36
Q

How long is half life of thyroid hormone in the plasma/

A
  • stable 7 day half life
37
Q

Thyroxine-binding globulin (TBG): drugs that decrease plasma TBG (4)

A
  • Androgenic steroids
  • glucocorticoids
  • danazol
  • L-asparaginase
38
Q

Thyroxine-binding globulin (TBG): drugs that can increase plasma TBG (2)

A
  • estrogens

- 5-fluorouracil

39
Q

Thyroxine-binding globulin (TBG): drugs that can displace T4 and T3 binding to TBG (4)

A
  • salicylates
  • high-dose phenytoin
  • phenylbutazone
  • IV furosemide
40
Q

Thyroxine-binding globulin (TBG): heparin stimulation of lipoprotein lipase

A
  • release FFA that displace thyroid hormones from TBG
41
Q

What happens when TBG levels are altered/ there is displacement of thyroid hormones from TBG?

A
  • initiates feedback loops due to high free hormone levels
  • hypothalamic-pituitary-thyroid axis preserves normal free hormone concentrations by lowering serum total thyroid hormone levels
42
Q

Type 1 5’-deiodinase

A
  • activity increased in hyperthyroidism (greater conversion of T4 to T3)
  • activity decreased in hypothyroidism
  • inhibited by propylthiouracil and amiodarone
  • also inhibited by iodinated radiocontrast dyes
  • dietary selenium deficiency can also impair T4-T3 converison
43
Q

Type 2 5’- deiodinase

A
  • predominantly expressed in brain and pituitary
  • maintains a constant level of intracellular T3 in the CNS
  • very sensitive to circulating T4
  • lower circulating T4 rapidly increases [enzyme] to maintain level of intracellular T3
44
Q

Type 3 5’-deiodinase

A
  • found in placental chorionic membranes and glial cells in CNS
  • inactivated T4 by converting to rT3
  • inactivates T3 by converting it ot 3,3-diiodothyronine (3,3-T2)
  • may protect fetus and brain from excess T4 or deficiency
45
Q

Type 3 5-deiodinase is what in hyperthyroidism and what in hypo?

A
  • hyper: elevated

- hypo: decreased

46
Q

Other forms of T4 metabolism

A
  • ~80% of T4 is metabolized by deiodination
  • remainder is inactivated by glucuronidation in the liver and billiary secretion!!
  • lesser extent sulfination, deamination or decarboxylation
47
Q

Plasma half lives of T4, T3, and rT3

A
  • T4: 7 days (10% of extrathyroidal T4 cleared/day)
  • T3: 1 day (lower binding affinity for plasma proteins)
  • rT3: 0.2 days
48
Q

Thyroid hormone receptors overview

A
  • present in most cells of the body
  • contrain thyroid hormone-binding, DNA-binding, and dimerization domains
  • Two classes of thyroid hormone receptors (TRalpha and TRbeta)
49
Q

TRalpha and beta

A
  • can be expressed as multiple isoforms
  • TR monomers can interact in a dimerization rxn to form homodimers
  • TR monomers can interact with RXR to form heterodimers
  • TR dimers bind to gene promoter regions!
  • activated by binding of thyroid hormone
  • mulitiple different combos of TRs and tissue distribution create tissue specificity
50
Q

affect of the absence of thyroid hormone on receptors

A
  • alters their conformation
  • associate with compressor molecs
  • bind to and inactivate thyroid hormone stimulated genes
51
Q

What is the effect of thyroid hormone binding to TR:RXR or TR:TR dimers

A
  • promotes dissociation of the corepressors

- recruits coactivators to the DNA and activates gene transcription

52
Q

Effects of hormone at target tissues

A
  • is able to down-regulate TSH gene expression
  • causes neg feedback of thyroid hormone on hypothalamic-pituitary-thyroid axis
  • also nongenomic effects on mitochondrial metabolism
  • plasma membrane receptors that stim intracellular signal transduction
  • thyroid hormone present, T3 interacts with coactivator and corepressor dissociates
53
Q

General Phys effects of the thyroid hormones: infancy

A

important for growth and devel of the nervous system

- congentical deficiency in thyroid hormone rsults in cretinsim (severly stunted physical and mental growth)

54
Q

General Phys effects of the thyroid hormones: adulthood

A
  • regulate general body metabolism and energy expenditure

- regulates Na+/K+ ATPase and many enzymes of intermediary metabolism

55
Q

High levels of thyroid hormone: Adults

A
  • can result in futile cycling and an increase in body temp
  • many effects resemble sympathetic neural stim
  • increase contractility and hr
  • excitability, nervousness, and sweating
56
Q

Low levels of thyroid hormone: Adults

A
  • mxyedema (swelling of skin, waxy appearance)
  • lethargy
  • dry skin
  • coarse voice
  • cold intolerance
57
Q

Calorgenic actions of thyroid hormone

A
  • T4 and T3 increase the O2 consumption of almost all metabolically active tissues
  • some exceptions, T4 of the anterior pituitary INHIBITS TSH secretion
  • single does of T4 has measurable effects after several hours and lasts 6+ days
  • some calorgenic action due to metabolism of FA
  • increases activity of Na/K ATPase in many tissues
58
Q

Effects secondary to calorigenesis

A
  • nitrogen excretion increased

- if food intake is not increased, endogenous protein and fat stores are catabolized - weight loss

59
Q

Calorigenesis: hypothyroid children

A
  • small does of thyroid hormone causes positive nitrogen balance due to growth
  • large doses cause protein catabolism similar to that in adults
  • potassium liberated during protein catabolism excreted in urine
  • increase in urinary hexosamine and uric acid excretion
60
Q

hypothyroidism and vitamins

A
  • vitamin deficiency syndromes may be precipitated
  • need for all vitamins is increased
  • thyroid hormones are necessary for hepatic conversion of carotene to Vit A
  • carotene accumulation in blood gives yellow tint to skin
61
Q

hypothyroidism and skin

A
  • ECM complex parts (proteins w/ polysaccharides, hyaluronic acid, and chondriotin sulfate) accumulate
  • promote water retention
  • get myxedema
62
Q

hypothyroidism and women repro

A
  • milk secretion decreased in hyop

- thyroid hormone essential for normal menstrual cycles and fertility

63
Q

hyper and CV system

A
  • raise body temp
  • vasodilation
  • renal Na increased and water absorption increases which expands blood volume
  • so cardiac output is increased
  • pulse pressure and hr increased, increased contractility too
64
Q

hyper and hypo effects on nervous system

A
  • hypo: mentation slow, cerebrospinal fluid protein level elevated
  • hyper: rapid mentation, irritability, and restlessness
  • thyroid hormones enter brain as adults
  • astrocytes in brain convert T4 to T3
  • hyper: some effects probably secondary to increased responsiveness to catecholamines
65
Q

brain devel and thyroid hormone

A
  • deficiency during devel: cause mental retardation, motor rigidity, and def-mutism
  • effects on brain devel, esp cerebral cortex, basal ganglia, and cochlea
  • rxn time of stretch reflexes prolonged in hypo, shortened in hyper
66
Q

Thyroid hormones and rxn to catecholamines

A
  • increased metabolic rates, stim nervous sys, produce CV effects
  • tremlousness, sweating
  • can be reduced by b-blockers such as propanolol
67
Q

b-blockers used extensively in what? (& ex of b-blocker)

A
  • propanolol
  • treatment of thyrotoxicosis, thyroid storms
  • little effect on other actions of thyroid hormones
68
Q

thyroid effects on skeletal muscle

A
  • muscle weakness in HYPERthyroidism (may b/c increased protein catabolism
  • HYPO also associated w/ muscle weakness, cramps, and stiffness (less clear)
69
Q

thyroid effects on carb metabolism

A
  • thyroid hormone increases rate of absorption from GI
  • independent of calorigenic action
  • plasma glc levels rise rapidly after a meal
  • lowers circulating cholesterol levels
  • action independent of stim of O2 consumption
  • due to increased formation of LDL receptors in liver which takes up cholesterol
70
Q

Thyroid effects on growth

A
  • essential for normal growth and skeletal maturation
  • hypothyroid children:
  • bone growth slowed and epiphysial closure delayed
  • growth hormone secretion depressed
  • thyroid hormones potentiate effect of growth hormone on tissue
71
Q

Hypothalamic- Pituitary- Thyroid Axis

A
  • Hypo: secrets TRH (thyrotropin releasing hormone)
  • Pituitary: secretes TSH in response to TRH
  • Thyroid Gland: TSH stims every aspect of thyroid hormone production, also promotes increased vascularization and growth of thyroid gland
72
Q

Pathology in HPT axis-

A
  • TSH or TSH mimic secreted at high levels: thyroid gland enlarged to several times its size (goiter)
  • neg feedback to hypothalamus/pituitary inhibits TRH and TSH gene transcription (thyroid hormone effects both the hyp and pituitary
73
Q

Graves disease

A
  • IgG for TSH receptor that activates it
  • stimulates synthesis and release thyroid hormone
  • does not respond to neg feedback, get hyperthyroidsim
  • high plasma thyroid hormone levels, low or undetectable TSH, High Tslg
74
Q

Hashimoto’s

A
  • antibodies specific for many thyroid gland proteins found in patients
  • selectively destroy thyroid function, gradual, inflammatory (analogous to type I diabetes)
  • results in hypothyroidism, early may be transient increase in thyroid hormone levels, eventually gland is almost completely destroyed
  • clinical symptoms lethargy and decreased metabolic rate
  • need pharmacological replacement with oral synthetic thyroid hormone
75
Q

Thyroid function can alter which categories of drugs? (4)

A
  • anticoagulation
  • glc control
  • cardiac
  • sedatives, analgesics
76
Q

Treatment of hypo

A
  • replace with regular administered exogenous thyroid hormone
  • generally T4, can make a reservoir of prodrug to be an effective buffer
  • also normalizes metabolic rates
  • longer half life, only need 1 pill/day
77
Q

Synthetic T4 used to treat hypo? (and adverse)

A
  • Levothryoxine
  • adverse: hyperthyroidism, osteopenia (bone loss), pseudotumor cerebri (increased intracranial pressure), seizure, myocardial infarction
78
Q

What to take when in myxedema coma?

A
  • Liothyronine
  • synthetic T3
  • faster onset, enhances recovery from life-threatening hypo
79
Q

Thyroid Storm overview

A

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Pharmacology III (18 decks)

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