???????????Thyroid hormones and antithyroid drugs

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???????????Thyroid hormones and antithyroid drugs

• Pharmacology department , School of basic
  medicine , Peking union medical college
• ???

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Thyroid hormones and antithyroid drugs

• 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.

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Thyroid hormones

• Include
• Thyroxine,T4
• Triiodothyreninum natricum,T3
• Synthesized and secreted by thyroid

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Antithyroid drugs

• Four categories
• ???(Thiourea)
• ?????
• (?????,lugols solution)
• ????(131I)
• ß?????(??????)

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???(Thiourea)

• ?????(thiouracil)
• ??????(methykthiouracil)
• ??????(propylthiouracil)
• ???(imidazoles)
• ???
• (Tapazole,????methimazole)
• ???(????Carbimazole)

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Thyroidhormones

• Thyroid hormones are iodic amino acids
• Active components
• Thyroxine,T4
• Triiodothyreninum natricum,T3
• Chemical constitution

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Chemical constitution of thyriod hormones
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Thyroid hormones

• physiological disposition
• Absorbed rapidly when take orally , activity
  T3gtT4,maintaining time T4gtT3?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.
• Figurethe amount of normal adults thyroid
  hormones produced and metabolized daily.

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Synthesis , storage and regulation of thyroid
hormones

• Iodine uptake
• Iodine activation and tyrosine iodation
• Condensation and storage
• Disintegration and release
• Regulation

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Steps of thyroid hormones synthesis , release and
regulation

• Iodine uptakeI- 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 iodationI-
  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).

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Steps of thyroid hormones synthesis , release and
regulation

• Condensation and storageIn 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 releaseT3 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 .
• RegulationBy the positive and negative feedback
  regulation of hypothalamus-anterior lobe-thyroid
  axis. Hypothalamus secrets TRH ,anterior lobe
  secrets TSH and thyroid synthesize T3 ,T4.

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synthesis , storage and release of thyroid hormone
Gastrointestinal I-
T3
Acinar lumina
T3
MITDIT
MIT
Con-den-sation
Protease
Peroxid-ase
Iodat-ion
Blood I-
I-
Io
TG
DIT
T4
T4
DITDIT
TG
Tyr
MIT ????? DIT ????? TG ??????
??
Storage
Synthesis
Release
Activation
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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.

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Thyroid hormones

• ????(??)
• 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,KATPase
  activity ATP utilization ADP
  concentration
• mitochondria respiration oxide consumption and
  heat production

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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 secretioncauses 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

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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.

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Adverse effects
adverse effect
overdose
contraindication
combination
old people heart disease
diabetes hypertension Coronary heart
disease pyknocardia
hyperthyreosis
bishydroxycoumarin dantina or aspirin
thyroid crisisanxiety , 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
Angina or heart infarction
Increase toxicity of thyroid hormone
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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 .ß
  receptor blockers can be used as adjunctive
  therapy for thyroid crisis .

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???(Thiourea)

• ?????(thiouracil)
• ??????(methykthiouracil)
• ??????(propylthiouracil)
• ???(imidazoles)
• ???(Tapazole),
• ????(methimazole)
• ???(????Carbimazole)

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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 .
• Distributionorgans generally all over the body
  and can pass the placenta . The concentration in
  lacto is about 3 times as in blood .
• MetabolismMainly 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 .

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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) .

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Etiopathogenesis 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 .

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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 13 months ,
  symtoms decreased and basal metabolic rate
  returns to almost normal . Reduce to maintaining
  dose with a peroid of 12 years . Also can be
  used as adjunctive therapy of 131I radiotherapy .
  
• Preparation before operationMedication before
  operation is good to decrease bleeding in
  operation and prevent thyroid crisis after
  operation .
• Adjunctive medication of thyroid crisisBesides
  integrate measures , large dose of Thiourea
  homologues can be used as adjunctive therapy , So
  is Propranolol .

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Comparison among common thiourea homologues drugs

• drug potency therapeutic dose
  maintenance adverse effects agranulemia
• (mg/d) dose
  incidence() incidence()
• mild moderate severe (mg/d)
• Methyl 1 200-300 400-600 13.8 0.5
• thiouracil 300-400 50-100
• Propyl 0.75 3.3 0.4
• thiouracil
• Tapazole 10 20-30 40-60 7.1 0.1
• Carbimazole10 30-40 5-10 1.9 0.8

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Thiourea

• Adverse effects
• Although there are lots of adverse effects
  of thiourea homologues , incidences of
  propylthiouracil and tapazole are lower , 3 and
  7respectively.
• Common adverse effects
• skin rash , headache , dinus ,
  gastrointestinal uncomfortable , fatigue and so
  on .
• Severe adverse effects
• bone marrow depression , agranulocytosis and
  so on .
• Noteperiodic inspection of hemogram . The
  medication shoule be stopped if the symptoms as
  pharyngalgia , fever , cathaeresis occur .Thyroid
  cancer patients are forbidden to take .

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Iodine and iodide

• Actions and applications
• Low dose of iodine (physiological dose) could
  prevent and cure simple (endemicity) goiter . Add
  1/100001/100000 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
  ?preparation before operationadministration of
  aqueous iodine solution two weeks before
  operation degenerates the glandular tissue ,
  decreases vessels and bleeding ?adjunctive
  therapy for thyroid crisis could be used
  combined with thiourea homologues .

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Iodine and iodide

• Adverse effects and application notes
• Acute effectsacute circumscribed edema,laryngeal
  edema and apnoea
• Chronic toxicitymouth 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 .

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Radioactive iodine(131I) T1/2 is 8.04 days

• Actions
• 131I could be uptaken by throid , participate in
  the synthesis of T3,T4 and is stored in
  follecular colloid .
• 131I mainly generatesßray (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 .
• Gray generated by 131I accounts for 1 and can
  be detected in vitro . It is usually used in the
  examination of thyroid iodine uptaking function .

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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 .

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????(131I)

• 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 .

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? 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 .

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? receptor blockers

• Clinical application
• Adjunctive therapy for hyperthyroidism and
  hyperthyroidism crisis .
• Mechanism of pharmacological actions
• Control symptoms caused by excited sympathetic -
  adrenergic system
• ß1 receptor blockage - heart rate drop
• Central ß receptor blockage - to reduce
  anxiety
• ß2 receptor on NA energinic peripheral nerve
  endings presynaptic membrane blockage reduces the
  release of NA.
• Appropriately reduce T3, T4 secretion .

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Thanks!