Transcript Thyroid gland hormones

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
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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
5’-deiodinase
Inner ring
(T4)
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(4X potent than T4)
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:
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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
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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:
Inhibit hormone synthesis
Iodide salts:
Blocks hormone release
Propylthiouracil, Methimazole
KI, Lugol’s solution
Iodinated contrast
media: Ipodate
Anion inhibitors:
Inhibition of peripheral T4 to T3
conversion; inhibits hormone release
block uptake of iodide by thyroid
Perchlorate, thiocyanate
Radioactive iodine
(131I)
Beta-blocker:
Propranolol, esmolol
destruction of thyroid tissue
Controls heart rate
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(-)
Anion Inhibitors
5’-deiodinase
T4
T3
(-)
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. Iodides:
Potassium iodide, Lugol’s 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 <25 yrs
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Thyroid storm
• Clinical manifestation
– High fever often above 40°C
– 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
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infection).
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
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