Thyroid Drugs

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Thyroid Drugs

• Kaukab Azim, MBBS, PhD

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Learning Outcomes

• By the end of the course the students should be
  able to discuss in detail
• Physiology, synthesis and feed back control of
  thyroid hormone synthesis
• Thyroid disorders
• Hypothyroidism
• Cretinism, Myxedema coma
• Hyperthyroidism
• Thyroid storm
• Drugs for the treatment of hypothyroidism and
  hyperthyroidism

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Thyroid Hormones

• Thyroid hormones
• Thyroxine T4 (90)
• Triiodothyronine T3
• Thyroid gland also secretes Calcitonin serum
  calcium lowering hormone

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Thyroid Hormones - Facts

• Thyroid hormones are required for the growth and
  development of all tissues.
• Thyroid hormone is critical for nervous,
  reproductive and skeletal growth.
• Thyroid deprivation in early life results in
  irreversible mental retardation.
• Thyroid hormones also augment sympathetic system
  function primarily by increasing the number of
  adrenergic receptors.

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Hypothalamus-pituitary-thyroid axis

• TSH secretion by anterior pituitary is stimulated
  by hypothalamic TRH
• Feedback inhibition of TSH and TRH occurs with
  high levels of circulating thyroid hormones (T3
  T4)
• Dopamine, Glucocorticoids and somatostatin can
  suppress TSH secretion

(High dose)
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Thyroid hormone synthesis

• Uptake of iodide by thyroid gland
• Oxidation of iodide
• Organification
• Iodination of tyrosine residues on thyroglobulin
• MITs and DITs
• Coupling formation of T4 and T3
• Proteolysis of thyroglubulin and secretion of
  thyroid hormones
• Conversion of T4 to T3 in peripheral tissues

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Thyroid hormone synthesis
T4
TBP
T3
Free T4 T3
(Iodide Organification)
4. Coupling
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Metabolism of thyroid hormones
Outer ring
Inner ring
(T4)
5-deiodinase
(4X potent than T4)
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Metabolism of Thyroid hormones

• Drugs that inhibit deiodination
• Beta blockers
• High dose propylthiouracil
• Corticosteroids
• They inhibit the 5-deiodinase activity necessary
  for conversion of T4 to T3 resulting in low T3
  and high reverse T3 (rT3)

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Thyroid hormones Mechanism of action

• T4 and T3 must dissociate from thyroxine binding
  globulin (TBG) in plasma before entering into the
  cells.
• In the cells, T4 is deiodinated to T3 that enters
  nucleus and attaches to specific receptors which
  promotes mRNA and protein synthesis.

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Hypothyroidism

• Clinical manifestations
• Lethargy
• Wt. gain
• Bradycardia
• Constipation
• Cold intolerance
• Menstrual irregularities
• Cretinism (congenital hypothyroidism)
• Myxedema coma most extreme manifestations of
  untreated hypothyroidism

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Drugs for Hypothyroidism

• Levothyroxine (T4)
• It is the treatment of choice for replacement
  therapy in hypothyroid patients
• It has a long half life 7 days once a day dose.

• Triiodothyronine (T3)
• Short half life (1 day)

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Drugs for Hypothyroidism

• T4 and T3 given orally.
• T4 is better for long term replacement therapy
• I.V. administration in myxedema coma
• During pregnancy, hypothyroid woman require
  higher doses

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Hyperthyroidism

• Clinical manifestation
• Weight loss and with increase in appetite.
• Nervousness and irritability.
• Palpitations.
• Heat intolerance and increased sweating.
• Tremors.
• Thyroid enlargement
• Menstrual irregularities

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Hyperthyroidism

• Treatment options
• Surgical
• Antithyroid drugs
• By inhibiting uptake of iodine
• By inhibiting synthesis
• By inhibiting release of hormones from thyroid
• Medical destruction of thyroid tissue
• Radioiodine (I131)

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Drugs for hyperthyroidism
Thioamides Propylthiouracil, Methimazole Inhibit hormone synthesis
Iodide salts KI, Lugols solution Blocks hormone release
Iodinated contrast media Ipodate Inhibition of peripheral T4 to T3 conversion inhibits hormone release
Anion inhibitors Perchlorate, thiocyanate block uptake of iodide by thyroid
Radioactive iodine (131I) destruction of thyroid tissue
Beta-blocker Propranolol, esmolol Controls heart rate
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(-)
Anion Inhibitors
T4 T3
5-deiodinase
(-)
Propylthiouracil, Ipodate, beta blockers,
cortocosteroids
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1. Thioamides

• Propylthiouracil, Methimazole
• Inhibit hormone synthesis
• Acts by inhibiting thyroid peroxidase to block
  iodine organification and coupling reactions
• These are the major drugs for treatment of mild
  thyrotoxicosis and in preparation of patients for
  subtotal thyroidectomy

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Thioamides

• Slow onset of action ( 4 weeks)
• Propylthiouracil is relatively safe and preferred
  in pregnancy
• Methimazole is more potent and longer acting than
  Propylthiouracil
• Propylthiouracil also inhibits peripheral
  deiodination of T4 and T3

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Thioamides Adverse drug reactions

• Common Maculopapular Rash, Arthralgia,
  vasculitis
• Serious side effect Agranulocytosis

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2. IodidesPotassium iodide, Lugols solution

• Mechanism of action
• Inhibit hormone release
• Inhibit organification
• Decrease size and vascularity of the hyperplastic
  gland.
• Effect is reversible and transient not for long
  term as thyroid gland escapes from its effect
  after 14 days
• Contraindicated in pregnancy fetal goiter

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3. Iodinated contrast media

• Ipodate and Iopanoic acid
• They inhibit the peripheral conversion of T4 into
  T3 in the liver, kidney and brain
• Inhibition of hormone release is an additional
  mechanism
• Adjunctive therapy in the treatment of thyroid
  storm

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4. Anion Inhibitors

• Perchlorate (ClO4-), Pertechnetate (Tco4-),
  Thiocyanate (SCN-)
• competitively block the uptake of iodide
• Adverse effect Aplastic anemia

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5. Radioactive Iodine

• 131I is the only isotope used in treatment of
  thyrotoxicosis while others are used in
  diagnosis.
• Emission of beta particles destroys the thyroid
  gland.
• Patients can become hypothyroid managed with
  thyroxine (T4)
• Contraindications
• Pregnancy lactation
• Age lt25 yrs

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Thyroid storm

• Clinical manifestation
• High fever often above 40C
• Fast and often irregular heart beat
• Vomiting, diarrhea and agitation. 
• Heart failure and myocardial infarction may
  occur.
• Death may occur despite treatment.
• Causes
• Patients with known hyperthyroidism whose
  treatment has been stopped or become ineffective,
• Untreated mild hyperthyroidism who have developed
  an intercurrent illness (such as an infection).

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Thyroid storm

• Treatment
• Propranolol /Esmolol / Diltiazem
• Iodide/ipodate ipodate also block the T4 to T3
  conversion
• Propylthiouracil
• Hydrocortisone blocks the T4 to T3 conversion

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• Qs