Transcript Synthesis, storage and release of thyroid hormones

Thyroid hormones
and
antithyroid drugs
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normal amount of thyroid hormones
are essential for normal growth and
development by maintaining the level
of energy metabolism in the tissue.
Either too little or too much thyroid
hormones will bring disorders to the
body.
Part 1 Thyroid hormones
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Two major thyroid hormones are:
triiodothyronine（T3, the most active form）
thyroxin（T4）
The characteristic of their chemical structure is
that they all contain iodine as an essential part
of the molecule.
Structure
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inadequate secretion of thyroid
hormone (hypothyroidism) can bring
many disorders to the body (eg.
bradycardia, poor resistance to cold,
both mental and physical slowing.)
[Synthesis, storage and
release of thyroid hormones]
Synthesis
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Iodine is the raw material of the thyroid
biosynthesis. Once taken up by the
thyroid gland, iodine undergoes a series
of enzymatic reactions before it
converts into active thyroid hormones.
Synthesis; four steps
1. iodine trapping :uptake of iodine by the thyroid
gland
2. oxidation of iodine: (to its active form)
thyroid peroxidase (key enzyme of the synthesis)
3. iodide organification :the iodination of tyrosyl
groups of thyroglobulin
productions: MIT and DIT
4. formation of T4 and T3 from MIT and DIT :
thyroid peroxidase
storage
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store in the colloid droplets of
thyroglobulin
release
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The hormones are released by
proteolysis of thyroglobulin .
Enzyme: thyroglobulin hydrolase
The ratio of T4 to T3 within
thyroglobulin is about 5:1
Differences between T3 and T4
the effect of T3 is much faster,
stronger and shorter than that
of T4.
conversion
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T4 can converse
to T3 through
deniodonite in
peripheral tissues
as well as in the
thyroid.
(catalyzed by
deiodinase)
Regulation:
TRH
Hypothalamus
TSH
pituitary
T3,T4
thyroid
Controled by HPT(hypothalamic-pituitary-thyroid) axis
Regulation
TRH (thyrotropin releasing hormone)
TSH (thyroid stimulating hormone or thyrotropin)
[Pharmacokinetics]
Pharmacological actions
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Effects on growth and development
Calorigenic effects :
Hypersensitivity to catecholamine :
Pharmacological actions
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1.Effects on growth and
development :
responsible for normal growth and
maturation of human being , especially
for nervous and skeletal tissues.
so the absence of thyroid hormones
before birth leads to both mental and
physical retardation（cretinism）
Pharmacological actions
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2.Calorigenic effects:
T3 /T4 can increase oxygen
consumption, promote metabolism and
BMR（basal metabolic rate） ,↓utility.
 So hyperthyroidism will result in excess
heat production and body wasting.
Pharmacological actions
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3. hypersensitivity to
catecholamine
Cardiovascular effects:
Tachycardia, hypertension
nervous Effects: anxiety, nervous.
mechanism
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TR
CBP
NUCLEAR R
Clinical uses
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the major indications for the
therapeutic use of thyroid
hormones are for hormone
replacement therapy in patients
with hypothyroidism .
Clinical uses
1.Cretinism :congenital hypothyroidism
often happens in newborn babies, mainly caused by
iodine deficiency before birth .
Success in the treatment of cretinism depends on the
age at which therapy is started.
The earlier, the better.
Cretinism
Symptoms:
1.Physical slow:
dwarf, with short extremities ,
2.mentally retarded: inactive, uncomplaining and
listless.
incidence :about 1 per 400 births
Prevention and therapy:
Prevention: Iodine replacement is the best method
prior to pregnancy.
Therapy: thyroid hormones replacement(T4 is more
often used than T3)
Clinical uses
2.Myxedema: adult hypothyroidism
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Happens after individual development
Slow in mentality
With special edema
Mortality :60%
Clinical uses
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3.Simple goiter:
A kind of prevalent disease
caused by insufficient dietary
iodine
TSH can promote hyperplasy
and hypertrophy of thyroid
gland.
4. Differential diagnosis of
simple goiter and
hyperthyroidism
Simple goiter
adverse reactions
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hyperthyroidism
Part 2
Antithyroid drugs
Grave’s syndrome
Treatment of hyperthyroidism
The goal of therapy is to decrease the
additional hormone and attend to
normal levels.
Can be accomplished by
 removing part of the gland
 Inhibiting synthesis
 Blocking releasing
four categories of anti-thyroid drugs
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Ⅰ Thioureas : (硫脲类)
interfere directly with the synthesis of thyroid
hormones
Ⅱ High concentrations of iodine :
decrease the release of thyroid hormones
Ⅲ Radioactive iodine :
damage the gland with ionizing radiation
Ⅳ β- receptor antagonists:
control the manifestations
Ⅰ Thioureas(硫脲类)
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Thiouracils:
methythiouracil , propylthiouracil
Imidazoles:
methimazole , carbimazole.
Ⅰ Thioureas
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Pharmacological action :
Decrease the level of thyroid hormones
Mechanism
 1.inhibit the thyroid peroxidase :
(key enzyme of synthesis)
interfere the oxidation of iodine and
the coupling of MIT and DIT to
form T3/T4
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2. inhibit conversion from T4 to T3
3.immunosupressive effect: TSI
Pharmacokinetics:
 Absorption
 Distribution
 Excretion
 Pass through placenta, milk
Therapeutic uses
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1.As definitive treatment to control
hyperthyroidism
2.Preoperative preparations for subtotal
thyroidectomy: to control the disorder in
preparation for surgical treatment.
(thioureas plus large dose of iodine)
3. Thyroid crisis Propylthiouracil is the first
choice.
Adverse reactions
1.allergic response
2.GI reaction
3.granulocytopenia (0.3%-0.6%)
4.Longterm use:
goiter and hypothyroidism
Drug interactions
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↑
Li，sulfasulfonamide，PAS，
paraminan（对氨苯甲酸），
phenylbutazone，barbital，
phentolamine，sulfonyl urea，vitB12
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↓
iodine
Ⅱ Iodine and iodide
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Oldest agent
have completely different effects
due to different doses
Pharmacological effects
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in small dose:
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↑ synthesis of
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thyroid hormones
in large dose : antithyroid
1) ↓the release of thyroid hormones into the
circulation: strong
Mechanism: Inhibit thyroglobulin hydrolase
2)↓synthesis of thyroid hormones: weak
Mechanism: Inhibit thyroid peroxidase
Therapeutic uses
1.Simple goiter : in small dose
2.In preparation for thyroidectomy :
used after the hyperthyroidism has been
controlled by thioureas, given for 7 to 10 days
immediately preceding the operation. (The
changes after a fairly long term of administration
include: the vascularity of the thyroid gland is
reduced, the gland becomes much firmer and
smaller.)
3.Thryotoxic crisis
Adverse reactions
1. Chronic iodism
2.Acute allergic action :
angioneurotic edema and larynx edema
3. Thyroid dysfunction
Ⅲ Radioactive iodine
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131I
: most often used isotope of
iodine
γ rays（1%）:
β particles（99%): destructive
Effects on the thyroid gland
131I
is rapidly and efficiently trapped by the
thyroid gland and slowly emitsβparticles and γrays.
The destructive βparticles can destroy the
thyroid cells with little damage to surrounding
tissues (the penetration range is only 0.4-2.0mm).
Theγrays can pass through the tissue and be
quantified by external detection
Clinical uses
1.hyperthyroidism: administrated
orally and the effective dose differs
for individual patients.
2.diagnosis of thyroid functions
Adverse reactions:
hypothyroidism
contraindications
pregnancy and milk mothers
IV β-adrenergic receptor antagonists
------ adjuvant therapy
many of the symptoms of hyperthyroidism are
associated with sympathetic stimulation, so β-R
blockers are effective in antagonizing the
catecholaminegic symptoms such as tachycardia,
palpitations ,anxiety and tension.
Action:
(1)block 1-R of heart
(2)block -R of CNS
(3) block -R of presynaptic
membrane of peripheral nerve.
(4) Inhibit T4 converted into T3
Uses:
1.Control the symptoms of
hyperthyroidism before
confirmed diagnosis
2.Thyroid crisis
3.Preoperation of hyperthyroidism
4.Hyperthyroidism
Section 3
TSH and TRH
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