Download 甲状腺激素和抗甲状腺药

甲状腺激素和抗甲状腺药
Thyroid hormones and antithyroid drugs
北京协和医学院基础医学院药理学系
叶菜英
Summary
Thyroid hormones
Necessary to maintain normal metabolism, growth and
development.
Hypothyroidism
Cause Cretinism if it happens in embryo or neonatal period.
Cause myxedema if it happens in adults when the thyroid
hormone could be used in replacement therapy.
Hyperthyroidism
A syndrom characterized by thyroid oversecretion and
metabolic disorder caused by multiple reasons.
It can be treated with radioactive iodine (131I) irradation,
antithyroid drugs and operation.
Thyroid hormones
Thyroxine, T4
Triiodothyreninum natricum, T3
Synthesized and secreted by thyroid
抗甲状腺药
分为4类：
硫脲类 Thiourea
碘和碘化物
（复方碘溶液，
lugol’s solution） ）
放射性碘（131I）
β受体阻断药（心得安等从略）
硫脲类
•
•
•
•
硫氧嘧啶类（thiouracil）：
甲基硫氧嘧啶（methykthiouracil）
丙基硫氧嘧啶（propylthiouracil）
咪唑类（imidazoles）
他巴唑（Tapazole，甲巯咪唑methimazole）
甲亢平（卡比马唑Carbimazole）
Thyroid hormones
Thyroid hormones are iodic amino acids
Active components
Thyroxine, T4
Triiodothyreninum natricum, T3
Chemical constitution
甲状腺激素的化学结构
Physiological disposition of thyroid hormones
 Absorbed rapidly when take orally , activity T3>T4，
maintaining time T4>T3.
T1/2 of T4 and T3 are 6－7 days and 1－2 days,
respectively.
 Deiodination in mitochondria of liver and kidney,
eliminated by kidney affer conjugated with glucuronic
acid and sulfuric acid.
 T3, T4 can also pass the placenta and enter milk.
 Figure: the amount of normal adults’ thyroid hormones
produced and metabolized daily.
Synthesis, storage and regulation of thyroid
hormones
Iodine uptake
Iodine activation and tyrosine iodation
Condensation and storage
Disintegration and release
Regulation
Steps of thyroid hormones synthesis, release and
regulation (Ⅰ)
Iodine uptake: I－ in blood can be uptaken into
cells by iodine pump in the adenocyte membrane .
The amino acids can be used to synthesize thyroid
globulin in cells.
Iodine activation and tyrosine iodation:
I － uptaken into cells can be oxydized to active
iodine by peroxydase. Active iodine binds to
tyrosine of TG and forms monoiodotyrosine (MIT)
and diiodotyrosine (DTT).
Steps of thyroid hormones synthesis, release and
regulation (Ⅱ)
Condensation and storage: In the thyroid globulin
molecule , two DTTs are condensed to T4 , one DTT and one
MIT are condensed to T3，which are all stored in gland
alveolus colloid .
Disintegration and release: T3 and T4 are released into
blood after hydrolyzed by proteases .At the same time , some
of them can be turned back to tyrosine and I－ by deiodinase
in cells and reused.
Regulation: By the positive and negative feedback
regulation of hypothalamus-anterior lobe-thyroid axis.
Hypothalamus secrets TRH ,anterior lobe secrets TSH and
thyroid synthesize T3 , T4.
Synthesis, storage and release of thyroid hormone
Gastrointestinal IMIT+DIT
Blood I-
I-
Peroxidase
Iodation
Io
MIT Con-
denDIT sation
T3
Protease
TG
DIT+DIT
Tyr TG
MIT 一碘酪氨酸
T4
T4
blood
DIT 二碘酪氨酸
TG 甲状腺球蛋白
T3
Acinar
lumina
Activation
Synthesis
Storage Release
Thyroid hormones
Mechanism of action
The binding of T3 and R increases the uptake of aa
and glucose, resulting in the entrance to cytoplasm of
T3 .
After reacting with CBP, T3 is educed. The free T3 can
bind R in the mitochondria and make ADP to ATP.
Besides, it can enter the nuclear and bind R there,
which can increase the transcription of DNA and
the content of mRNA. Then the new proteins can
be synthesized and play roles.
Thyroid hormones
Mechanism of action（figure)
It is believed now that the thermogenic
action of T3 and T4 is due to the increase
of sodium pumps activity on the cell
membrane . Na+,K+—ATPase activity
ATP utilization
ADP concentration
mitochondria respiration oxide
consumption and heat production
Physiological and pharmacological actions
Keep normal growth and development
Promote synthesis of proteins as well as growth and
development of skeleton and CNS. T3, T4 deficient
secretion: causes cretinism in infants and young
children and mucous edema in adults.
Promote metabolism and increase heat production
Promote oxidation, increase oxygen consumption, basal
metabolic rate and heat production.
Elevate sensitivity of sympathetic - adrenal system
Nervousness, trembling, heartbeat speed up, blood
pressure increase
Thyroid clinical application
Replacement therapy mainly
Therapy and diagnosis
Application
Cretinism
Treating the infants and children
as soon as possible could cure them to
normal . If treating too late,
they need to be treated a lifetime.
Mucous edema
Increase the dosage of thyroid pallet gradually .
Too large dosage may aggravate heart diseases .
Patients in coma should be given a fist aid,
which is infusion of T3 （40-120μg）intravenoiusly ,
reinjection 5－15μg every 6h and oral administration
when awake. Hypopituitarism patients should be given
cortical hormone first and followed by thyroid hormone.
Simple goiter
Replacement therapy can inhibit TSH oversecretion and
contract the glandular organ, 3-6 months.
T3 inhibition test
Differential diagnosis for Patients with iodine high uptake.
Adverse effects
Overdose
hyperthyreosis
thyroid crisis: anxiety,
fear, restlessness, high
body
temperature,
increase and irregular
heart rate, increase pulse
pressure, congestive heart
failure
with
vomit,
diarrhea and dehydration
which lead to coma and
death
Adverse effect
Combination
old people
heart disease bishydroxycoumarin
dantina or aspirin
Angina or
heart infarction
Increase
toxicity of
thyroid
hormone
Contraindication
diabetes
hypertension
Coronary heart
disease
pyknocardia
Antithyroid Drugs
Therapies of hyperthyrosis include 131I
radiotherapy, exairesis or medication.
Thiourea homologues are mainly used clinically.
Iodine and iodide are used just in preparation
for operations and thyroid crisis therapy. β
receptor blockers can be used as adjunctive
therapy for thyroid crisis.
硫脲类
硫氧嘧啶类：
• 甲基硫氧嘧啶
• 丙基硫氧嘧啶
咪唑类
• 他巴唑（又称甲巯咪唑）
• 甲亢平（又称卡比马唑）
Thiourea
Physiological process
Absorption: Easy to be absorbed when taken orally.
Thiouracil is the most fast to be absorbed. The bioavailability
is 80％ and the plasma protein binding rate is 75%. 20－30
min after administration , the drug turns to become effective
with T1/2 of 2h. Imidazole is absorbed slowly. T1/2 of
tapazole is 6h.
Distribution: Organs generally all over the body and can pass
the placenta . The concentration in lacto is about 3 times as in
blood .
Metabolism: Mainly in liver, fast . 60％ are destroyed in vivo,
the rest are eliminated by urine in a conjugative form.
Carbimazole functions after turning into tapazole in vivo.
Thiourea
Pharmacological actions
Inhibit peroxydase in adenocytes , which results in the inhibited
oxydation of I－ to I0 . Then , the iodation and couple of tyrosines can be
stopped . So the biosynthesis of T3 and T4 is inhibited. But the effect
occurs slowly as the iodine uptake and the hormone already synthesized
are not effected.
Long time medication can lead to decrease of T3 and T4, which feedback
increases the secretion of TSH and makes thyroid hyperplasy and
hyperemic compensatorily.
Propylthiouracil can inhibit T4 turning to T3 and control T3 level in
blood . So it is the first choice in hyperthyroidism crisis, severe
hyperthyroidism and pregnant hyperthyroidism.
Inhibit immuno-system (as hyperthyroidism is related with abnormal
immunoreactions).
Pathogenesis of Exophthalmos hyperthyroidism
and function link of thiourea homologues
This disease is caused by an autoimmune IgG antibody
LATS (long acting thyroid stimulator), which can bind to
the receptors on thyroid adenocytes and stimulate
oversecretion of thyroid hormones.
Thiourea homologues can not only inhibit synthesis of
thyroid hormones, but also LATS in patients, which is a
kind of immuno inhibition.
Thiourea
Clinical application
Hyperthyroidism
For who has mild symptoms and is not suitable to have
operations and 131I radiotherapy. Give Larger dose at the
beginning. After 1~3 months, symtoms decreased and basal
metabolic rate returns to almost normal . Reduce to maintaining
dose with a peroid of 1~2 years. Also can be used as adjunctive
therapy of 131I radiotherapy.
Preparation before operation
Medication before operation is good to decrease bleeding in
operation and prevent thyroid crisis after operation.
Adjunctive medication of thyroid crisis
Besides integrate measures, large dose of Thiourea homologues
can be used as adjunctive therapy, So is Propranolol.
Comparison among common thiourea
homologues drugs
drug potency
therapeutic dose
maintenance adverse effects agranulemia
(mg/d)
mild
dose
moderate severe (mg/d)
Methyl 1
200-300
400-600
thiouracil
300-400
50-100
Propyl 0.75
thiouracil
Tapazole 10
20-30
40-60
Carbimazole10
30-40
5-10
incidence(%) incidence(%)
13.8
0.5
3.3
0.4
7.1
1.9
0.1
0.8
Thiourea
Adverse effects
Although there are lots of adverse effects of thiourea
homologues, incidences of propylthiouracil and tapazole
are lower, 3％ and 7％respectively.
Common adverse effects：
Skin rash, headache, dinus, gastrointestinal uncomfortable ,
fatigue and so on.
Severe adverse effects：
Bone marrow depression, agranulocytosis and so on.
Note: Periodic inspection of hemogram. The medication
shoule be stopped if the symptoms as pharyngalgia, fever,
cathaeresis occur. Thyroid cancer patients are forbidden to
take.
Iodine and iodide
Actions and applications
Low dose of iodine (physiological dose) could prevent and
cure simple (endemicity) goiter. Add 1/10000~1/100000
potassium iodide or sodium iodide to salt could prevent the
desease.
Large dose of iodine could inhibit the release of T3 and T4
(due to the inhibition of TG hydratase).
Used as adjunctive therapy for hyperthyroidism:
①preparation before operation: administration of aqueous
iodine solution two weeks before operation degenerates the
glandular tissue, decreases vessels and bleeding;
②adjunctive therapy for thyroid crisis: could be used
combined with thiourea homologues.
Iodine and iodide
Adverse effects and application notes
Acute effects: acute circumscribed edema ， laryngeal
edema and apnoea.
Chronic toxicity: mouth and throat burning sensation,
increase secretion of salivary, eye irritation and so on.
Induce dysthyroid and hyperthyroidism after long
medication.
Iodine could pass into the milk and through placenta,
leading to neonat goiter. Pregnant and lactant women
shoule take the drug with causious.
Allergic and active tuberculosis patients are forbidden to
take.
Radioactive iodine（131I）
Actions
131I
T1/2 is 8.04 days
could be uptaken by throid , participate in the
synthesis of T3, T4 and is stored in follecular colloid.
131I mainly generatesβray （99％）with average and
maximum path of 0.5mm and 2mm respectively. So the
irradiation function is limited in the thyroid.It can
destroy the glandular organ but can seldom destroy the
surrounding tissues.
Γray generated by 131I accounts for 1％ and can be
detected in vitro. It is usually used in the examination
of thyroid iodine uptaking function.
Radioactive iodine（131I）
Clinical application
 Thyroid iodine uptake function examination:
iodine uptake rate high when hyperthyroid, time of iodine
uptake peak antelocation
iodine uptake rate low when hypothyroid , time of iodine
uptake peak retroposition
 Hyperthyroidism
Trace amount could be used in diagnosis of
thyroid functional status and thyroid adenoma .
Radioactive iodine
Adverse effects and application notes
Hypothyroidism is the predominant complication. The
adverse effects can be reduced by strict dose control
and resisted by thyrine.
Patients with Total white blood cells less than
3000/mm3 are not suitable to take it. So are pragnant
and lactant women, patients younger than 20 years old
or with severe liver or kidney deseases.
 receptor blockers
Valuable adjunctive therapy drugs for hyperthyroidism
and thyroid crisis . They could improve symptoms caused
by augmented sympathetic activity such as speed up heart
rate and increase heart contraction force . They can also
reduce the thyroid hormone secretion and T3 synthesis by
inhibiting 5`-deiodinase .
Control hyperthyroidism symptoms and can be used in
preparation before operation .
 receptor blockers
Clinical application

Adjunctive therapy for hyperthyroidism and hyperthyroidism
crisis.
Mechanism of pharmacological actions

Excited sympathetic-adrenergic system
β1 receptor blockage — heart rate drop

Central β receptor blockage — to reduce anxiety
β2 receptor on NA energinic peripheral nerve
endings presynaptic membrane blockage reduces
the release of NA.
Appropriately reduce T3, T4 secretion.
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