Transcript Document

Medical University of Sofia, Faculty of Medicine
Department of Pharmacology and Toxicology
Thyroid and antithyroid drugs
© Assoc. Prof. Iv. Lambev, PhD
E-mail: [email protected]
THYROID
DRUGS
Thyroxine (T4) and
tri-iodthyronine (T3)
T3 and T4 are synthesized in the
thyroid gland. Inorganic iodine is
trapped with great avidity by the
gland, oxidized and attached to tyrosine. Combination of mono- and/ordi-iodinated tyrosine forms T3 and
T4. The thyroxine peroxidase is important both in the initial oxidation
and the final combination steps.
Tyrosine
Inorganic iodine
Thyroxine peroxidase
Mono-iodtyrosine (MIT)
Inorganic iodine
Thyroxine peroxidase
Di-iodtyrosine (DIT)
MIT + DIT
Thyreoglobulin
T3
DIT + DIT
Thyreoglobulin
T4
NH 2
CH 2 -CH
HO
COOH
Tyrosine
I
NH 2
CH 2 -CH
HO
COOH
I
Di-iodtyrosine
I
I
CH 2 -CH
O
HO
I
NH 2
I
T4 = L-Thyroxine
COOH
Synthesis and release of T3 and T4
are controlled by the anterior pituitary hormone, thyrotrophin (TSH thyroid-stimulating hormone). Its
secretion is controlled by the hypothalamic thyrotrophin-releasing
hormone (TRH) and somatostatin.
Circulating T3 and T4 exert a negative feedback on the TSH and TRH.
Hypothalamus
TRH
Somatostatin
(+)
(-)
Adenohypophysis
TSH
(+)
(-)
(-)
Glandula Thyreoidea
(+)
T3
<I plasma
(-)
>I
T4
Regulation
of
thyroid
hormone
synthesis
Worldwide iodine nutrition
24 hrs:
80 mcg T4
40 mcg T3
200 mcg I
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.
Plasma
T4: 95%
T3: 5%
99.91–99.97%
Thyroxine-binding
globulin
AGENTS INLFUENCING PROTEINBOUND OF L-THYROXINE (T4)
INCREASE
•estrogens
•methadone
•heroin
•clofibrate
•tamoxifen
DECREASE
•glucocorticoids
•aspirin
•phenytoin
•carbamazepine
•furosemide
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 interacts with DNA in the cell nucleus,
causing the synthesis of new messenger RNA and hence of new proteins.
The main effects of T3 and T4:
•Stimulating of metabolism (which
resulting 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).
Intracellular (nuclear)
steroid/thyroid receptors
Effector
Coupling
Time scale
Examples
gene transcription
via DNA
hours
steroid receptors
thyroid receptors
vitamin D receptors
T3&T4 – indications:
•hypothyroidism
•T3 is reserved for
patients with
myxoedemic coma.
Facial
appearance
in
hypothyroidism

Jodthyrox
(T4 + < I)

Levothyroxine (T4)
- tabl. 25 mcg

Liothyronin (T3)

Thyreoidea siccata
Thyrotrophin (TSH)
ANTITHYROID
DRUGS
•Thioureas agents
•Beta-blockers
131
•Radioactive iodnie ( I)
They are used to treat
hyperthyroidism.
Thioureas agents
inhibit thyroxine peroxidase,
and therefore synthesis of T3
and T4. Because of long half-life
of T4, changes in rate synthesis
takes several weeks to low circulating concentrations to normal.
•Carbimazole (prodrug)
Thiamazole
(Methimazole – USAN)
•Propylthiouracil
•Thiamazole
- tabl. 5 mg
Thioureas – adverse effects
•Nausea, taste disturbance
•Agranulocytosis
•Placental transfer and secretion
in breast milk can produce neonatal hypothyroidism (small
doses are probably safe).
Beta-blockers have immediate symptomatic effect on
palpitation and tremor but do
not alter the rate of T3 & T4
synthesis.
131I (t
8 days) is used to treat
multinodular toxic goiters. It is
taken up by the abnormal tissue.
1/2
www.drugsupport.data.bg
www.pharmsupport.data.bg
www.pharmsupport1.data.bg
www.pharmsupporttwo.data.bg