Transcript T 3

Pharmacology of
endocrine disorders
- hormones of thyroid gland,
thyreostatics
Jan Bultas, P. Potměšil
[email protected]
2013
Thyroid and anti-thyroid drugs
A/ THYROID THERAPEUTICS B / anti-THYROID THERAPEUTICS
I. hormones
I. derivatives of thiourea
1/ levothyroxin,
1/ carbimazol
2/ thiamazol (= methimazol)
3/ propylthiouracil
or combination:
levothyroxin+liothyronin
II. drugs with iodine
(2/ liothyronin)
II. drugs with iodine
1/ kalii iodidum
= kalium iodatum
1/ kalium iodatum thyreostatic eff.
if applied >6000 microgr/d
2/ radioactive iodine 131I
(III. kalii perchloras)
(inh. of iodine pump, protection of thyroid
gl. during radionuclide examination)
Treatment of diseases of thyroid
gland – hormones from thyroid gl.
T4 (tyroxin)
T3 (trijodthyronin,
liothyronin)
calcitonin
(parafollicular cells)
Thyroid hormones
thyroxin (T4)
trijodthyronin (T3)
hypothalamus
TRF
hypophysis
TSH
thyroid
gl.
T4 a T3
Molecular effects of T3 and T4
• genomic effects:
- stimulation of nuclear transcription factors (↑ activity DNAdependent RNA-polymerase) and increase of synthesis of new
RNA
• non-genomic effects
- stimulation of many ion channels and enzymes –
influencing of nerv. synapt., metabolism of calcium,
cell proliferation (e.g. neurons and glial cells in CNS)
- influencing of production of ATP (by phosphorylation
of ADP) or heat by oxidative phosphorylation on
mitochondrial membrane
Function of thyroid hormones
I. primarily:
• regulation of metabolism (oxidative phosphorylation)
• regulation of developement of foetal nervous system
II. secondary:
• potentiation of effect of catecholamines
• increase of contractility of myocardium and
acceleration of heart rate
• increase of gut motility
• acceleration of muscle contraction
• stimulation of synthesis of bile acids → increase of
catabolism of cholesterol with  LDL-cholesterol
Synthesis of thyroid hormones
• uptake of iodine by gl. thyreoidea (Na/I symporter, stimul. by TSH)
• binding of iodine to thyreoglobulin
• storage of tyreoglob. with mono- a di-iodtyrosine residues
(MIT / DIT) in follicles
• synthesis of T4 and T3 from MIT / DIT (very low turnover, huge stock)
• release of T4 and T3 to plasma (proteolysis of thyreoglobulin)
• conversion of T4 to T3 in tissues
• degradation of T3
Synthesis of thyroid hormons
Iodization of
tyreoglobuline
reabsorption tyreoglob.
Oxidation of
iodine
Synthesis of
tyreoglob.
Release of
T4 and T3
Uptake of iodine
Release of
T4 and T3
Synthesis of thyroid hormons
Secretion of T4 and T3
• stimulation of hypothalamus (cold, stress) 
 TRH (tyrotropin releasing hormone)  TSH
• TSH - iodine uptake
- synthesis and secretion of thyroglobulin
- synthesis of T3, T4
- hydrolysis tyreoglob.  secretion of T3 and T4
• inhibition of TSH by negative feedback T3 > T4
• secretion of T3 and T4 is inhibited by lithium
Transport of T4 and T3
type
%
Binding to thyroxine-binding globulin (TBG)
70%
Binding to transthyretin (pre-albumin) and para-albumin
30%
Non bound T4 (fT4)
0,03%
Non bound T3 (fT3)
0,3%
risk of displacement from binding to plasm. proteins
free T4 is present in much lower concentr. – main eff. is mediated by T3
Thyroxin and trijodtyronin
T4 - main circulating hormon (98.5% T4, 1.5% T3)
- bound to proteins (TBG, albumin),  free fraction
- only free fraction of T4 and T3 is effective
- conversion of T4 to T3 in tissues
- long half-life of effect - one week approximately
T3 - main effective hormone (about one order more
effective)
- shorter half life ( day)
-  binding to proteins,  free fraction
Thyroxin (levothyroxin - T4)
• synthetic - conversion to T3
• the most frequently used dosis during treatment
of hypothyreosis 1,6 ug/kg ( of dosis in
cardiologic patients and if patient is > 60 yrs)
• normalization of TSH is leading info about
succesful therapy, control after dosis adjustment
after 4-6 wks, high persistence of effect
• biochemically all patients are eutyroid,
not all patients are eutyroid from the clinical point
of view
• medicinal products with brand names:
Eltroxin, Letrox
Trijodtyronin (liotyronin - T3)
• shorter duration of effect (1-2x daily)
• 10x stronger and faster effect -  Adv. eff.: palpitation
• applied in combination with thyroxine in pat. with
subj. insuff. compensation of hypothyreosis
• in majority of patients thyroxine is more
advantageous
• brand name of medicin. prod.: Thyreotom
Information about clinical effect of
treatment - laboratory tests
•
•
•
•
level of TSH in serum [plasma]
free (event. total) T4
free T3
…
Hypothyreosis - treatment
substitution:
- thyroxin (levotyroxin) – in majority of patients we can achieve
optimal eff.,
- alternative is to use comb. of thyroxine and triiodtyronine
(e.g. 1:4), used for improvement of subj. condition when lab.
finding indicate euthyroid function and subj. symptoms of
hypothyreosis are present
- titration of dosis according to lab. and also biochem. results
- most frequently used dose 1.6 g/kg
-  dose in cardiacs and persons > 60 yrs
- brand names of MP are: Eltroxin, Euthyrox, Letrox,
Thyreotom,…
Treatment of
thyreotoxicosis
• pharmacotherapy
- thionamides (carbimazol,
methimazol, propylthiouracyl)
- high doses of iodine, -blockers
• ablation by radioactive iodine
• surgical ablation (subtot. STE)
THIONAMIDES - carbimazol,
methimazol, propylthiouracyl
• derivatives of thiourea
• inhibit peroxidase reaction and iodization of tyrosine
residues in thyreoglobuline - decrease of synthesis of T4
and T3
• carbimazol conversion to effect. methimazol
• propylthiouracyl inhibits in addition conversion of T4 to T3
• proper pharmacodynam. effect is rapid, because of long
half-life of T4 clin. effect is apparent after 2-3 wks
SE: granulocytopenia, exantema
Effect of thyreostatic drugs
Iodization of tyreoglob.
Reabsorption of tyreoglob.
carbimazol
propylthiouracyl
iod (high doses)
oxidation
Of iodine
tyreoglob. synth.
Release of
T4 a T3
Uptáke of
iodine
Conversion of
release
T4 to T3
of T4 and T3
propylthiouracyl
glucocorticoids
Strategy of therapy with thyreostatic
medicin. products
• titrating regimen– we decrease initial dosis of
thyreostatic drug according to clin. state and
accrding to values of free
T3 and T4 - more practical approach
• block regime – application of combination of
thyreostatic drug (for suppresion of function) and
thyroxine for substitution
• long-term comparison without clinical difference
CAVE: inducers of CYP (rifampicin, phenobarbital,
phenytoin) significantly accelerate degradation of T3 and T4
Effect of -blockers during
thyreotoxicosis
T4 - increases expression of cardial rec. 1
- increases activity of catecholamines
 palpitation, tachycardia
 -blockers are advantageous during thyreotoxicosis
Radioiodine (isotop
131I)
• + emitter (importance only  radiation)
• cytotoxic effect approximately after 2
months
• incorporation to thyreoglobulin
• treatment of Graves Basedow disease
• do not prescribe to children and gravid
women
Iodine for treatment of
thyreopathy
(Lugol solution)
• substitutive treatment - low doses
• tyreostatic treatment - high doses of iodine
suppress release of T4 and T3 by inhibition of
iodidation of tyrosine in tyreoglobuline – rapid
effect
• treatment of tyreotoxic crisis (effect after 24 hrs)
• preparement before strumectomia
Surgical treatment –
subtotální strumektomie
before operation:
• tyreostatic treatment (avoid release of T4 and
T3 and development of tyreotox. crisis)
• iodine (decreases vascularization)
• risk of hypoparathyreosis and cut of n. phrenicus
Treatment of thyreotoxic crisis
stabilization of circulation
- blockade of rec. 1
reduction of tachycardia
and risk of arytmias
(bisoprolol, metoprolol,…)
- blockade of rec. 2
calming down of tremor
(metipranol –Trimepranol)
decrease of thyroid function
-carbimazol, event.
propylthiouracyl
- iodine (Lugol), lithium
- high doses of
glucocorticoids
Mortality of crisis reduced from 100% to 20%
Strategy of treatment of tyreotoxicosis
ablation with radioiodine: GB disease, tox. adenoma
- 80-90% eutyroid till 2 months
- worsening of oftalmopathy (need to comb. with
glucocorticoids)
tyroidectomia: GB disease, tox. adenoma, Carc.
- 90% eutyroid, does not worsen opthalmopathy
- risk of compl. (hypoparathyreosis, n. phrenicus)
tyreostatic drugs: GB disease (if adenoma only preparement for STE)
- 60% eutyroid after 12-18 months of treatment, does not
worsen opthalmopathy, less effective during tox. adenoma