medical university of sofia, faculty of medicine department of pharmacology and toxicology thyroid...
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Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology
Thyroid and antithyroid drugs
© Assoc. Prof. Iv. Lambev, PhDE-mail: [email protected]
Thyroxine (T4) andtri-iodthyronine (T3)
THYROIDDRUGS
THYROIDDRUGS
T3 and T4 are synthesized in thethyroid gland. Inorganic iodine istrapped with great avidity by thegland, oxidized and attached to tyro-sine. Combination of mono- and/or-di-iodinated tyrosine forms T3 andT4. The thyroxine peroxidase is im-portant both in the initial oxidationand the final combination steps.
Mono-iodtyrosine (MIT)Mono-iodtyrosine (MIT)
TyrosineTyrosine
Di-iodtyrosine (DIT)Di-iodtyrosine (DIT)
Inorganic iodine Thyroxine peroxidase
Thyroxine peroxidaseInorganic iodine
MIT + DIT
DIT + DIT
T3
T4
Thyreoglobulin
Thyreoglobulin
Tyrosine
Di-iodtyrosine
CH2-CHHO
NH2I
I
COOH
CH2-CHHO
NH2
COOH
T4 = L-Thyroxine
CH2-CH
NH2I
I
O
I
I
HOCOOH
Synthesis and release of T3 and T4are controlled by the anterior pitu-itary hormone, thyrotrophin (TSH -thyroid-stimulating hormone). Itssecretion is controlled by the hypo-thalamic thyrotrophin-releasinghormone (TRH) and somatostatin.Circulating T3 and T4 exert a nega-tive feedback on the TSH and TRH.
AdenohypophysisAdenohypophysis
Glandula ThyreoideaGlandula Thyreoidea
TSH
HypothalamusTRH Somatostatin
(+)
(+)
(+)
p l a s m aT3 < I > I T4
Regulationof
thyroid hormonesynthesis
Worldwide iodine nutrition
80 mcg T440 mcg T3200 mcg I
24 hrs:24 hrs:
Circulating thyroid hormones arehighly protein-bound to TBG(thyroxine-binding globulin).
Less than 0.1% from T4 is free.Only the free fraction canbind to specific cell receptors.
PlasmaT4: 95% T3: 5%
Thyroxine-bindingglobulin
99.91–99.97%
AGENTS INLFUENCING PROTEIN-BOUND OF L-THYROXINE (T4)AGENTS INLFUENCING PROTEIN-BOUND OF L-THYROXINE (T4)
INCREASE•estrogens•methadone•heroin•clofibrate•tamoxifen
DECREASE•glucocorticoids•aspirin•phenytoin•carbamazepine•furosemide
T3 is much more biologically activethan 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.
The main effects of T3 and T4:•Stimulating of metabolism (which resulting in a raised basal meta- bolic rate).•Promotion of normal growth and maturation, particularly of the CNS and skeleton.•Sensitization to the effects of cate- cholamines (DA, NA, Adrenaline).
Intracellular (nuclear)steroid/thyroid receptors
EffectorCouplingTime scaleExamples
gene transcriptionvia DNAhourssteroid receptorsthyroid receptorsvitamin D receptors
T3&T4 – indications:•hypothyroidism•T3 is reserved for patients with myxoedemic coma.
Facial appearancein hypothyroidism
Jodthyrox (T4 + < I)Levothyroxine (T4) - tabl. 25 mcgLiothyronin (T3)Thyreoidea siccata
Thyrotrophin (TSH)
They are used to treathyperthyroidism.
•Thioureas agents•Beta-blockers•Radioactive iodnie (131I)
ANTITHYROIDDRUGS
ANTITHYROIDDRUGS
Thioureas agentsinhibit thyroxine peroxidase,and therefore synthesis of T3and T4. Because of long half-life of T4, changes in rate synthesistakes several weeks to low circu-lating 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 neo- natal hypothyroidism (small doses are probably safe).
Beta-blockers have imme-diate symptomatic effect on palpitation and tremor but donot alter the rate of T3 & T4 synthesis.131I (t1/2 8 days) is used to treatmultinodular toxic goiters. It istaken up by the abnormal tissue.
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