Pharmacology of endocrine disorders - hormones of thyroid gland, thyreostatics Jan Bultas, P....
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![Page 1: Pharmacology of endocrine disorders - hormones of thyroid gland, thyreostatics Jan Bultas, P. Potměšil jbult@lf3.cuni.cz 2013.](https://reader033.fdocuments.net/reader033/viewer/2022061420/56649f225503460f94c3b47d/html5/thumbnails/1.jpg)
Pharmacology of
endocrine disorders
- hormones of thyroid gland,
thyreostatics
Jan Bultas, P. Potměš[email protected]
2013
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Thyroid and anti-thyroid drugs
A/ THYROID THERAPEUTICS
I. hormones
1/ levothyroxin,
or combination:levothyroxin+liothyronin
(2/ liothyronin)
II. drugs with iodine
1/ kalii iodidum= kalium iodatum
B / anti-THYROID THERAPEUTICS
I. derivatives of thiourea
1/ carbimazol2/ thiamazol (= methimazol)3/ propylthiouracil
II. drugs with iodine
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)
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Treatment of diseases of thyroid gland – hormones from thyroid gl.
T4 (tyroxin)
T3 (trijodthyronin, liothyronin)
calcitonin (parafollicular cells)
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Thyroid hormones
thyroxin (T4) trijodthyronin (T3)
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hypothalamus
hypophysis
thyroid gl.
TRF
TSH
T4 a T3
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Molecular effects of T3 and T4
• genomic effects:
- stimulation of nuclear transcription factors (↑ activity DNA-
dependent 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
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Function of thyroid hormonesI. primarily:• regulation of metabolism (oxidative phosphorylation)• regulation of developement of foetal nervous systemII. 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
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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
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Synthesis of thyroid hormons
Synthesis oftyreoglob.
Uptake of iodine
Iodization of tyreoglobuline
Oxidation ofiodine
reabsorption tyreoglob.
Release ofT4 and T3
Release ofT4 and T3
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Synthesis of thyroid hormons
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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
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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. proteinsfree T4 is present in much lower concentr. – main eff. is mediated by T3
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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
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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
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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
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Information about clinical effect of treatment - laboratory tests
• level of TSH in serum [plasma]
• free (event. total) T4
• free T3
• …
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Hypothyreosis - treatmentsubstitution: - 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,
…
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Treatment of thyreotoxicosis
• pharmacotherapy
- thionamides (carbimazol,
methimazol, propylthiouracyl)
- high doses of iodine, -blockers
• ablation by radioactive iodine
• surgical ablation (subtot. STE)
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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
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Effect of thyreostatic drugs
tyreoglob. synth.
Uptáke ofiodine
Iodization of tyreoglob.
oxidationOf iodine
Reabsorption of tyreoglob.
Release ofT4 a T3
releaseof T4 and T3
carbimazolpropylthiouracyliod (high doses)
propylthiouracylglucocorticoids
Conversion ofT4 to T3
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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
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Effect of -blockers during thyreotoxicosis
T4 - increases expression of cardial rec. 1
- increases activity of catecholamines
palpitation, tachycardia
-blockers are advantageous during thyreotoxicosis
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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
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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
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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
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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%
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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