Pharmacology of

endocrine disorders

- hormones of thyroid gland,

thyreostatics

Jan Bultas, P. Potměšiljbult@lf3.cuni.cz

2013

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)

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

hypophysis

thyroid gl.

TRF

TSH

T4 a T3

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

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

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

Synthesis oftyreoglob.

Uptake of iodine

Iodization of tyreoglobuline

Oxidation ofiodine

reabsorption tyreoglob.

Release ofT4 and T3

Release ofT4 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. proteinsfree 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 - 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,

…

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

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

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