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10/28/2014
PHARMACOLOGICAL TREATMENT OF
THYROID DISEASES
1.
2.
3.
4.
Synthesis, chemistry and physiology of thyroid
hormones
Regulation and disorders of hormone synthesis
Therapy of hypothyroidism: Hormone replacement
Therapy of hyperthyroidism : Anti-thyroid drugs
–T3: triiodothyronine (lyothyronine)
-T4: thyroxine
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1915: isolation (Kendall)
1926: discovery of the chemical structure
1927: synthesis (Harington és Barger)
1952: synthetic production of T3
1.1. Synthesis of thyroid hormones I.
-Iodine uptake: TSH-dependent
20-50
times higher iodine
concentration in the thyroid
gland than in the plasma (100
times in stimulated conditions!)
-Iodine incorporation: TSHdependent
(increased
production of H2O2)
Hormones are produced during the
synthesis of a special glycoprotein,
thyroglobulin. Elementary iodine
is
oxydased
(due
to
thyroperoxidase) and binds to
the thyrosyl side chanes of
TG⇒ mono- and diiodotyrosine
(MIT and DIT)⇒ T3 and T4
(normally 1:4, but in iodine
deficiency might be more T3)
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1.1. Synthesis of thyroid hormones II.
Endocytosis:
TSHdependent
(increases
lysosomal
endopeptidase
activity); TG is degradaded
in the lysosomes of the
follicular cells ⇒ T3 and T4
outflow into the bloodstream
- Peripheral metabolism: T4→
T3 metabolism by the 5’deiodinase enzyme (in the
peripheral tissues in 30-35%)
1.2. Chemistry of the thyroid hormones
- Dehalogenation at the C3 and C5 positions is essential for the
biological effects (eg. rT3 is inactive)
-T3 is 4-times more effective than T4
- Only the L-stereoisomeric form is biologically active
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1.3. Physiological effects of T3/ T4
- Growth, development (neural systems, skeletal
-
-
muscle, reproductive tissues)⇒ thyreoid gland:
kretenism (mental and growth retardation)
Increased basal metabolism, oxydative processes,
regulation of the body temperature
Increased cholesterol→ bile acid transformation
Increased lipolytic/ glycolytic effects of
catecholamines, increased glucose absorption ⇒
increased blood glucose and fatty acid levels
Increased catehcolamine-sensitivity of the heart⇒
tachycardia
Mechanism: high affinity T3
receptor is present in the
nucleus and the
cytoplasm (α and β forms,
quantity is tissuespecific)⇒
the HR complex binds to
specific regions of the
DNS (THRE)⇒ regulation
of DNA transcription and
protein synthesis
(derepression or
activation of gene
transcription)
There is a binding site in
the mitochondrial
memrane too.
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2.1. Regulation of hormone
synthesis
-Daily production: 70-90µg T4
and 15-30 µg T3 get into the
circulation
Synthesis is increased by
- HTH: TRH
- Pituitary: TSH
2.2. Kinetics of T3/T4
-Transport in the circulation: T3 and bind to thyroxinebinding globulin (TBG; higher affinity to T4), T4 also
binds to thyroxine-binding prealbumine
-Free fraction: T4 0.03-0.04%, T3 0.2-0.5%
-T1/2: 6-7 days
- Amount and hormone-binding of TBG increases in eg.
pregnancy, decreases in eg. liver diseases
- Metabolism: deiodination⇒ glucuronidation,
sulphatation (conjugation), enterohepatic recirculation
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2.3. Disorders of the thyroid function
Normal serum hormone levels
free T3: 2.5-6 pmol/l
free T4: 9-24 pmol/l
TSH: 0.5-4.5 mU/l
Hypothyreoidism
Hyperthyreoidism
Symptoms:
Symptoms:
-Weight loss despite good appetite
-Increased body weight
- Diarrhea
-Constipation
- Nervousness, excitedness
-Slow thinking, decreased physical-Tremor, sleeping disorders,
activity, sleepiness, tiredness
anxiety
- Mixoedema
- Increased sweating
- Laboratory parameters:
-Atrial arrhytmias
increased serum cholesterol
- Laboratory parameters: decreased
Congenital: kretenism
serum cholesterol
Special type: Graves-Basedow
disease
3. Pharmacological therapy of hypothyroidism
3.1. HORMONE-SUBSTITUTION TH.
(Long ago: dried thyroid gland powder)
Synthetic L-thyroxine (levothyroxine) or Ltriiodothyronine/ (liothyronine;
levotriiodothyronine)
L-thyroxine: more balanced effect, longer
action, safer administration
Clinical use:
- Kretenism
- Mixoedema
- Hypothyroid condition after thyroid gland
operation
- Usually long-lasting therapy is needed
-Well-balanced dosing might be neccessary
to be altered due to drug interactions
- TSH control is needed every 6 months
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Kinetics:
-Good oral absorption from the small intestine, but
influenced by lots of alimentary factors and drugs (iron, Al,
calcium) and the normal bacterial flora, motility
-Oral bioavailability: 75-95%
-Strong plasma protein binding
-T4⇒ T3 metabolism in the periphery
-Levothyroxine t1/2: 7 days; liothyronine t1/2: 1 day
-Small ratio is excreted into the milk
Dosing:
Oral (except mixoedema coma
when i.v.)
Should be taken before meals
(better and safer absorption),
The daily required amount
should be divided into 3 doses!
Small starting dose and gradual
increase to 0.05-0.15 mg/day
Drug interactions:
- Increased effect with tricyclic antidepressants
- Increased oral antidiabetic drug and insuline
requirements
- Cholestyramine decrease the absorption
- Enzyme inducers (e.g. phenitoin, carbamazepine,
ethanol) increase the metabolism
- Protein binding
Increase
Oestrogens, tamoxifen,
methadone, clofibrate,
5-FU, heroine
Decrease
GCC, salycilates, androgens,
antiepileptic drugs,
furosemide
Liver diseases, acute
infections
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Side effects:
- Cardiovascular complaints (tachycardia, atrial
arrhytmia/fibrillation, angina)
- Sweating, weight loss, anxiety
- Osteoporosis (especially in elderly women)
3.2. Iodine supplementation
Iodine deficiency might be the reason of insufficient
thyroid gland function.
Daily requirement: 0.1 mg (food, drinking water, salt)
For profilaxis or for the therapy of thyroid nodules
with hypo- or normofunction: 0.05-0.15 mg
iodine/day p.o.
Good absorption, good distribution, concentration in
the thyroid gland, elimination through the kidneys
4. Therapy of hyperthyroidism
4.1. INHIBITION OF HORMONE SYNTHESIS
4.1.1. EXCESSIVE IODINE INTAKE
Effect:
- High amount of iodine decreases all steps of T3/T4
synthesis (but particularly proteolysis)
- Decreased thyroid gland size, vascularization and
the symptoms of hyperthyroidism
- Effect can be observed within maximum 10-15 days
- Contraindicated in pregnancy! (can cause nodules in
the foetus)
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Clinical application: daily D 300-600 mg
-Thyrotoxic crisis: daily 1-2 g isopropanol-diiodate
- Preoperative treatment before thyroid gland
operations for the prevention of thyrotoxic crisis:
Lugol solution (5% elementary iodine + 10% potassium
iodine)
Side effects:
- acute allergic reactions
-„iodism”: fever, skin raches, swollen salivary glands,
mucosal irritations
Iodine-containing contrast materials (ipodate,
iopanoate): decrease hormone synthesis and also
peripheral T4→T3 metabolism (daily 1g)
3.1.2. THIOAMIDES
(metimazol)
Chemistry:
- Common structural feature is the thiocarbamide
group, which is essential for the anti-thyroid activity
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Mechanism of action:
- Decrease the incorporation of
the uptaken iodine into the
tyrosil side-chaine of TG by
inhibiting the peroxydase enzyme
- The peripheral hormone levels
decrease after 3-4 weeks (there
is a stored TG pool)
-Propylthiouracil also inhibits
peripheral T4⇒T3 metabolism and
enhances T4⇒ rT3 metabolism
(might
be
more
effective
acutely)
- Exert immunosupressive effect:
in Basedow disease decrease the
level of the stimulating antibody
and the lymphocyte number
- increase the thyroid gland size
by increasing TSH production
(compensatory)
Kinetics:
-Oral bioavailability:
-metimazole: 100%
propylthiouracil: 50-70%
(partial absorption, first
pass effect)
- Plasma protein binding:
metimazole: negligible
propylthiouracil: 75%
-Plasma t1/2:
metimazole: 4-6 h
propylthiouracil: 75 min
-Elimination:
As inactive glucuronide through the kidneys
Propylthiouracil less penetrates through the placenta
(it should be chosen in pragnancy)
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Clinical use:
- Oral administration, exc. thyrotoxic crisis when i.v.
- Higher initial D, then gradual decrease
- First usually metimazole, then in case of side effects or
ineffectivity propylthiouracil
Side effects:
- Increased thyroid gland size (even nodules) due to the
compensatory TSH production increase
- Allergic symptoms (predominantly skin)
- Bone marrow damage (leukopenia, thrombocytopenia,
agranulocytosis, aplastic anaemia)
- Headache, painful swelling of the salivary gland,
paresthesia, hear loss, liver toxicity
3.1.3. LITHIUM-CARBONATE
- Decreases the outflow of thyroid hormones
- Decreases peripheral T4→T3 metabolism
- Rarely given before operations or 131J-treatment
3.1.4. PERCHLORATE
-Inhibits the Na+/J- symporter, and therefore
decreases iodine uptake by the thyroid gland
- Very rarely used due to the rare side effect of
agranulocytosis
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3.2. RADIODESTRUCTION OF THE THYROID
GLAND: 131I
Mechanism of action:
- It is taken up and accumulated in the thyroid gland,
produces β irradiation, which is very short
penetrating(0.5 mm), so only destroys tissues locally
- Usually p.o. 4-10 mCi
- Premedication: propylthiouracil to achieve
euthyroid condition
- Effect starts after 1-2 weeks and reaches its
maximum 3 months later
Clinical use:
Basedow disease, thyroid nodules, inoperable cancers
or metastatic cancers in the thyroid gland
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