Thyroid and antithyroid drugs

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Thyroid and antithyroid drugs (Abstract)
Assoc. Prof. Iv. Lambev E-mail
itlambev_at_mail.bg www.medpharm-sofia.eu
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THYROID DRUGS
Thyroxine (T4) and tri-iodothyronine (T3)
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T3 and T4 are synthesized in the thyroid gland.
Inorganic iodine is trapped with great avidity by
the gland, oxidized and attached to tyro- sine.
Combination of mono- and/or- di-iodinated
tyrosine forms T3 and T4. The thyroxine
peroxidase is im- portant both in the initial
oxidation and the final combination steps.
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Tyrosine
Inorganic iodine
Thyroxine peroxidase
Mono-iodotyrosine (MIT)
Inorganic iodine
Thyroxine peroxidase
Di-iodtyrosine (DIT)
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T3
Thyreoglobulin
MIT DIT
T4
Thyreoglobulin
DIT DIT
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Tyrosine
Di-iodotyrosine
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T4 L-Thyroxine
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Synthesis and release of T3 and T4 are controlled
by the anterior pitu- itary hormone, thyrotrophin
(TSH - thyroid-stimulating hormone).
Its secretion is controlled by the hypo- thalamic
thyrotrophin-releasing hormone (TRH) and
somatostatin. Circulating T3 and T4 exert a
nega- tive feedback on the TSH and TRH.
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Hypothalamus
TRH
Somatostatin
()
(-)
Adenohypophysis
TSH
()
(-)
(-)
Glandula Thyreoidea
()
(-)
p l a s m a
T3
lt I
gt I
T4
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Regulation of thyroid hormone synthesis
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Worldwide iodine nutrition
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24 hrs
80 mcg T4 40 mcg T3 200 mcg I
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Circulating thyroid hormones are highly
protein-bound to TBG (thyroxine-binding
globulin). Less than 0.1 from T4 is free. Only
the free fraction can bind to specific cell
receptors.
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Plasma
T4 95
T3 5
99.9199.97
Thyroxine-binding globulin
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AGENTS INLFUENCING PROTEIN- BINDING OF
L-THYROXINE (T4)

• INCREASE
• estrogens
• methadone
• heroin
• clofibrate
• tamoxifen

• DECREASE
• glucocorticoids
• aspirin
• phenytoin
• carbamazepine
• furosemide

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T3 is much more biologically active than T4. The
plasma half-life of T3 is 36 h. T4 has t1/2 168
h.
After entering into cells T4 converts into T3
which binds to receptor protein and inte- racts
with DNA in the cell nucleus, causing the
synthesis of new messen- ger RNA and hence of new
proteins.
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The main effects of T3 and T4

• Stimulating of metabolism (which
• results in a raised basal metabolic
• rate).
• Promotion of normal growth and
• maturation, particularly of the
• CNS, and skeleton.
• Sensitization to the effects of
• catecholamines (DA, NA, Adrenaline).

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Intracellular (nuclear) steroid/thyroid receptors
Effector Coupling Time scale Examples
gene transcription via DNA hours steroid
receptors thyroid receptors vitamin D receptors
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Directly at nuclear receptors Thyroid
hormones (T3, T4)
T3 or T4 penetrates the nucleus Combines with
their receptors Alters DNA-RNA mediated protein
synthesis
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• T3T4 indications
• hypothyroidism
• T3 is reserved for
• patients with
• myxoedemic coma.

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Hypothyroidism
Hyperthyroidism

• Lack of energy
• Weight gain
• Feeling cold
• Dry skin and hair
• Constipation
• Haevy menstrual periods

• Fatigue, weight loss
• Feeling hot
• Palpitations, irritability
• More bowel movements
• Schorter or lighter
• menstrual periods

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Facial appearance in hypothyroidism
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Jodthyrox? (T4 lt I)
Levothyroxine? (T4) - tabl. 25 mcg
Liothyronin? (T3)
Thyreoidea siccata?
Thyrotrophin (TSH)
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ANTITHYROID DRUGS

• Thioureas agents
• Beta-blockers
• Radioactive iodine (131I)

They are used to treat hyperthyroidism.
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Thiourea agents inhibit thyroxine peroxidase, and
therefore the synthesis of T3 and T4. Because of
the long half-life of T4, changes in the rate
synthesis takes several weeks to lower
circu- lating concentrations to normal.
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• Carbimazole (prodrug)
• Thiamazole
• (Methimazole USAN)

• Propylthiouracil
• Thiamazole
• tabl. 5 mg

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• Thioureas adverse effects
• Agranulocytosis
• Nausea, taste disturbance
• Placental transfer and secretion
• in breast milk can produce neo-
• natal hypothyroidism (small
• doses are probably safe).

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Beta-blockers have imme- diate symptomatic effect
on palpitation and tremor but do not alter the
rate of T3 T4 synthesis. 131I (t1/2 8 days) is
used to treat multinodular toxic goiters. It
is taken up by the abnormal tissue.