Thyroid hormones and antithyroid drugs

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Thyroid hormones and antithyroid drugs
Huifang Tang Email tanghuifang_at_zju.edu.cn
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Metabolism of thyroid hormones
1. Uptake of iodide 2. Oxidation of iodide
(peroxidase) and iodination and coupling of
tyrosine 3. Formation of thyroxine (T4) and
triiodothyronine (T3) from iodotyrosine 4.
Secretion of thyroid hormones (proteolytic
enzymes) 5. Regulation by thyroid stimulating
hormone (TSH), T4, T3
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Formation of thyroxine (T4) and triiodothyronine
(T3) from iodotyrosine
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Different forms of thyroid hormones
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Action of thyroid hormones interaction with
their receptors in the nuclei
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• Regulation of Thyroid hormone

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Pharmacology of thyroid hormones

• 1. Normalizing growth and development
• 2. Promoting body metabolism
• Body temperature energy levels, ect.
• 3. Enhancing sympathetic activity
• 4. Cardiovascular Effects

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Therapeutic drugs on thyroid function

• Hyperthyroidism
• antithyroid drugs thiourea derivatives
• iodine and
  iodides
• ? receptor
  antagonists
• surgery
• radioiodines 131I, 125I
• Hypothyroidism
• thyroid hormones
• iodine and iodides

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A. thyroid hormones

• 1. Treatment of hypothyroidism

Hypothyroidism
Cretinism(???)
Myxedema(?????)
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A. thyroid hormones

• Common signs and symptoms
• Cretinism a situation induced by a insufficiency
  of thyroid hormone at birth and during minority,
• execute growth, twined facial features, increased
  tongue and mental detainment
• Adult
• Fatigue, weakness, weight gain or increased
  difficulty, losing weight, cold intolerance
• Coarse, dry hair, dry and rough pale skin, hair
  loss
• Muscle cramps and frequent muscle aches
• Constipation(??)
• Depression, irritability
• Memory loss
• Abnormal menstrual cycles, decreased libido

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A.thyroid hormones

• Myxedema
• describes a specific form of cutaneous and
  dermal edema secondary to increased deposition of
  connective tissues, as seen in various forms of
  hypothyroidism

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Etiology
A. thyroid hormones

• PRIMARY HYPOTHYROIDISM
• Hoshimotos thyroiditis-most common
• Irradiation of thyroid
• Surgical removal
• Late stage invasive fibrous thyroiditis
• Iodine deficiency
• Drug therapy (Lithium)
• Infiltrative Diseases
• Sarcoidosis, Amyloidosis
• Scleroderma, Hemochromatosis

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A. thyroid hormones

• SECONDARY HYPOTHYROIDISM
• 5 of cases.
• Pituitary or hypothalamic neoplasm.
• Congenital hypopituitarism.
• Pituitary necrosis (Sheehans syndrome)

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Diagnosis
A. thyroid hormones

• In Primary Hypothyroidism
• TSH is high.
• Free thyroid hormone are depressed.
• In Secondary Hypothyroidism
• Both TSH and free thyroid hormones are low.

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Thyroid Hormone Replacement
A. thyroid hormones

• Levothyroxine(?????) can cause increases in
  resting heart rate and blood pressure
• So replacement should start at low doses in older
  and patients at risk for cardiovascular
  compromise
• Myxedema Coma
• Below normal temperature, decreased breathing,
  low blood pressure, low blood sugar,
  unresponsiveness
• Hydrocortisone, T3

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A.thyroid hormones

• 2. Simple goiter (???????)
• Supply iodide--iodide deficiency
• Thyroid hormones
• Surgry--nodule

simple goiter
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B. Antithyroid drugs
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Hyperthyroidism
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Thyroid crisis clinical features

• Exacerbation of features of hyperthyroidism-
  hyperpyrexia. May be extreme (gt39oC) and is
  generally considered essential to diagnosis.
• - confusion, fits, coma, muscle weakness.
  Very common.
• - arrhythmias, cardiac failure. Decreasing
  pulse rate and BP with the development of shock
  are associated with poor prognosis- vomiting,
  diarrhoea. Occasionally jaundice associated with
  poor prognosis- hyperkalaemia relatively common
  (15) but rarely a problem in itself- rarely
  apathetic hyperthyroidism (usually elderly
  patients) may present in crisis with features of
  profound exhaustion, hyporeflexia, severe
  myopathy, marked weight loss and hypotension

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How To Diagnose Hyperthyroidism

• TSH expect this to be low
• Free T4 expect to be high
• Nuclear thyroid scintigraphy I131 uptake and scan
  expect iodine uptake to increased
• TSH-receptor stimulating autoantibody levels (TSI
  levels, ???????????)

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Therapeutic drugs for Hyperthyroidism

• antithyroid drugs thiourea derivatives
• iodine and
  iodides
• ? receptor
  antagonists
• radioiodines 131I, 125I
• surgery

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B. Antithyroid drugs

• Thiourea derivatives
• Propylthiouracil ?????
• Methimazole (tapazole) ????
• Carbimazole ????
• Iodine and iodides
• ? Receptor antagonists
• Radioiodide (131I)

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B. Antithyroid drugs

• Thiourea derivatives

????Thiamazole
?????(PTU)
????
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thyroid peroxidase (TPO)
Mechanism of inhibition of thyroid hormone
synthesis by thiaureas
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B. Antithyroid drugs

• Thiourea derivatives
• 1. Pharmacological effects
• (1) Inhibiting the formation of thyroid hormones
  by interfering with iodination inhibiting
  peroxidation, then the iodination and coupling
• Symptom relieving 2-3 weeks
• Basic metabolic rate returning 12 months
• (2) Inibiting peripheral deiodination of T4 T4 ?
  T3 ? (propylthiouracil)
• (3) Decrease the carbohydrate metabolism mediated
  by ß-receptor
• (4) Immunosuppress action, decrease TSI

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B. Antithyroid drugs

• Physiological process
• Absorption easy to be absorbed when taken
  orally.
• Thiouracil is the most fast to be absorbed.
  Imidazole is absorbed slowly.
• The bioavailability is 80
• The plasma protein binding rate is 75.
• T1/2 2h. T1/2 of tapazole is 4.7h.
• 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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B. Antithyroid drugs

• 3. Clinical uses
• (1) Non-operative therapy of hyperthyroidism
  latent period
• (2) Preoperative therapy of hyperthyroidism
  combined with iodide
• (3) Thyrotoxic crisis combined with larger dose
  of iodide, propylthiouracil

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B. Antithyroid drugs

• 4. Adverse effects
• (1) agranulocytosis (0.3-0.6)
• (2) Hypersensitivity
• (3) GI reactions
• (4) Goiter
• Caution
• periodic inspection of hemogram. The medication
  shoule be stopped if the symptoms as
  pharyngalgia, fever occur.
• Female during lactation period, thyroid cancer
  patients and nodular goiter with hyperthyroidism
  are forbidden to take.

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B. Antithyroid drugs

• Iodine and iodides
• 1. Pharmacological effects
• (1) Small doses simple goiter
• (2) Larger doses inhibiting the release of
  thyroid hormones (proteolysis ?) and synthesis
• After iodide use, the thyroid vascularity is
  reduced, and the gland becomes much firmer, the
  cells become smaller( (inhibiting TSH release).
• After two week use, I uptake is inhibited,
  hyperthyroidism. So not treat hyperthyroidism
  along.

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Wolff-Chaikoff??
Mechanism of iodides
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B. Antithyroid drugs

• 2. Clinical uses
• (1) Small doses simple goiter
• Add 1/100001/100000 potassium iodide or sodium
  iodide to salt could prevent the desease.
• Early stage potassium iodide (10mg) or Lugols
  solution (0.1ml or 0.5 ml/d)
• Lugols solution 5 iodine and 10 potaasium
  iodide
• (2) Larger doses
• Preoperative therapy of hyperthyroidism Lugols
  solution combined with thiourea derivatives (for
  2 weeks)
• Thyrotoxic crisis combined with thiourea
  derivatives (propylthiouracil)

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B. Antithyroid drugs

• 3. Adverse effects
• (1) Acute effects hypersensitivity, angioedema,
  swelling of the larynx
• (2) Chronic intoxication (iodism)
• (3) Thyroid dysfunction exacerbation of
  hyperthyroidism, goiter

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B. Antithyroid drugs

• ? Receptor antagonists
• 1. Pharmacological effects
• (1) Heart ?1 block
• (2) CNS relieving anxiety
• (3) Presynaptic ?2 receptor NE release ?
• (4) Inhibiting the conversion of T4 to T3
• 2. Clinical uses
• Adjuvant therapeutic drug

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B. Antithyroid drugs

• Radioiodedes
• 131I,
  125I, 123I
• 1. Pharmacological effects
• 131I is rapidly absorbed, concentrated by the
  thyroid, and into storage follicles.
• Its effects depends on emission of ß-rays and a
  penetration range of 500-2000µm, the thyroid was
  destructed within a few weeks after
  administration.

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B. Antithyroid drugs

• Radioiodine 131I, 125I, 123I
• 2. Clinical uses
• Hyperthyroidism in long course, and other drugs
  can not control the symptom.
• Diagnosis. (? ray generated by 131I accounts for
  1 and can be detected in vitro . It is usually
  used in the examination of thyroid iodine
  uptaking function )
• iodine uptake rate high when hyperthyroid , time
  of iodine uptake peak antelocation
• iodine uptake rate low when hypothyroid , time of
  iodine uptake peak retroposition

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B. Antithyroid drugs

• Radioiodine 131I, 125I, 123I
• 3. Adverse effects
• Hypothyroidism.
• Radioactive iodine should not be administered to
  pregnant women or nursing mothers, since it cross
  the placenta and is excreted in breast milk.

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Summary

• Therapeutic drugs on thyroid function
• Hyperthyroidism
• antithyroid drugs
• thiourea derivatives (
  Propylthiouracil ????? Methimazole (tapazole)
  ???? Carbimazole ????)
• iodine and iodides
• ? receptor antagonists
• surgery
• radioiodines 131I, 125I
• Hypothyroidism
• thyroid hormones
• iodine and iodides

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(conti.)
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