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THYROID HORMONES AND


HORMONE
ANTAGONISTS
Pr Nermine Bouchi
4ème année S 2 durée : 1h30
Acquis
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 Connaitre les principales étapes de la synthèse des


hormones thyroidiennes
 Connaitre le mécanisme de régulation de la synthèse et
de la libération des hormones thyroidiennes
 Connaitre le mécanisme d’action des hormones
thyroidiennes
 Connaitre les effets pharmacologiques des hormones
thyroidiennes
 Connaitre les médicaments actifs dans l’hypothyroidie
 Connaitre les médicaments actifs dans l’hyperthyroidie
et leur mécanisme d’action
THYROID
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La thyroïde est une glande


située à la base du cou

Elle recouvre la trachée et


est située en dessous du
larynx, sous la pomme
d’Adam.

Elle a la forme d'un


papillon avec deux
lobes.
Thyroid Gland: Hormones
"shield shaped"

Source of 2 different types


of hormones synthesizes
by :
 Thyroid follicular cells

 Iodothyronine hormones
: thyroxine =T4
 Triodothyronine = T3
 stored as amino acids
residues of
thyroglobulin
 Parfollicular cells

 Calcitonin

The thyroid gland


Thyroid hormones
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 Iodine-containing amino acid derivatives of thyronine


 Amino-acid precursor = tyrosine
 T4 = thyroxine = 3,5,3’,5’-Tetraiodothyronine
 T3 = 3,5,3’-triiodothyronine

Les HT se différencient entre elles par le nombre et la place


variables des atomes d'iode.
Thyroid hormones synthesis : regulation
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 HPT axis
 Hypothalamic hormone called
thyrotropin-releasing hormone (TRH) SST
increases secretion of an anterior
pituitary hormone called Glucocorticoids
thyroidstimulating hormone (TSH, or Dopamine
thyrotropin). Retinoids
 TSH is the prime regulator of iodide
uptake and thyroid hormone
formation by the thyroid gland.
 The secretion of TRH and TSH is
regulated, in turn, by feedback
inhibition of their secretion by T4 and
T3

 Somatostatin (SST) can inhibit TRH


action, as can dopamine and high
concentrations of glucocorticoids
 Thyroid hormone synthesis and
secretion is regulated by two main
mechanisms:
 an “autoregulation”
mechanism, which reflects the
available levels of iodine
 regulation by the
hypothalamus and anterior
pituitary

 Autoregulation
 low iodide levels in the
gland →↑ iodine
transport into follicular
cells
 high iodide levels→ ↓
iodine transport into
follicular cells

Thus, there is negative


feedback regulation of iodide
transport by iodide
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 UPTAKE OF IODIDE:
 Iodide is transport via a transporter Metabolic step
NIS : sodium iodide symporter .
 OXIDATION AND IODINATION
 Thyroid peroxydase transforms
iodide to its active form hypoiodite
 Hypoiodite reacts with the tyrosyl
group of thyroglobulin 
monoiodotyrosyl MT and
diiodotyrosyl DIT
 FORMATION OF T4 AND T3
 Coupling of two DIT  T4
 Coupling of MIT and DIT  T3
 SECRETION OF THYROID HORMONES
 T3 & T4 are stored within
thyroglobulin
 They are secreted by proteolysis :
endocytosis of thyroglobulin drops
which fuse with lysosomes
containing the proteolytic enzymes
 release of T4 and T3 and of MT
&DIT
 Some T4 is converted to T3 at this
point
 Exit of the hormones at the basal
membrane
8  MT and DIT are metabolised and
iodine is reused
Thyroid hormones synthesis
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These hormones are secreted at steady rates and maintain the status quo.
Thyroid hormones are formed in follicles lined by a single layer of follicular cells. They are stored
within the colloid contained within the follicles in the form of a protein called thyroglobulin. Also,
contained within the colloid are enzymes needed for thyroid hormone synthesis, and iodide
(ionized form of iodine).
THYROID HORMONES
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Tg, thyroglobulin;
DIT, diiodotyrosine;
NIS, sodium-iodide symporter;
MIT, monoiodotyrosine;
TPO, thyroid peroxidase;
HOI, hypoiodous acid;
EOI, enzyme-linked species;
D1 and D2, deiodinases;
PTU, propylthiouracil;
MMI, methimazole
SCN thiocyanate & ClO4- perchlorate
Conversion of T4 to T3 in peripheral tisues
 Daily production :
 T4 is 80-100g
 T3 is 30-40g
 T3 has much greater biological activity
than T4.
 T4 →T3
 A large amount of T4 (25%) is
converted to T3 in peripheral
tissues.
 This conversion takes place mainly
in the liver and kidneys.
 The T3 formed is then released to
the blood stream.
 T4→rT3
 In addition to T3, an equal amount
of “reverse T3” =rT3 may also be
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formed.
 rT3 has no biological activity.
Conversion of T4 to T3 in Peripheral Tissues
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 40% of T4 is converted to each of T3 and rT3,


 20% is metabolized via other pathways, such as glucuronidation in the liver and
excretion in the bile
Transport of Thyroid Hormones
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 Thyroid hormones are not very soluble in water (but are


lipid-soluble).
 Thus, they are found in the circulation associated with
binding proteins:
- Thyroid Hormone-Binding Globulin (TBG) (~70% of
hormone)high affinity for T4 less for T3
- Pre-albumin (transthyretin), (~15%) binds only T4
- Albumin (~15%) binds thyroxine when the other carriers
are saturated
 Less than 1% of thyroid hormone is found free in the
circulation.
 Only free thyroid hormone is biologically available to
tissues.
THYROID HORMONES : Pharmacokinetics
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 T4
 Slowly excreted
 Euthyroidism t½= 6-8days
 Hyperthy. t½= 3-4days
 Hypothy. t½= 9-10 days

 T3:
 T1/2 = 1 day(less avidly
bound to protein)
 Metabolism :
 Liver the major site
 the major route is
deiodination of T4 to either
T3 or reverse T3
Mechanism of Action of T3
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 T3/T4 acts through the thyroid hormone receptor


 Steroid nuclear receptor superfamily
 Intracellular
 Found in many tissues of the body, but not in
adult brain, spleen, testes, uterus, and thyroid
gland itself.
 Acts as a transcription factor:
 When not bound to hormone, the thyroid
hormone receptor binds to target DNA (TRE
on 5’ flanking region). It is associated with
corepressor proteins that cause DNA to be
tightly wound and inhibit transcription.
 Binding of hormone causes a conformational
change, resulting in loss of corepressor
binding and association with coactivator
proteins, which loosen DNA structure and
stimulate transcription.
 www.youtube.com/watch?v=c6s6SZ9Vnbk
Thyroid hormones recceptor
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1) TH entry into the cell,


2) its intracellular metabolism
and distribution,
3) cytosolic (non genomic)
effects,
4) translocation into the
nucleus,
5) association with the
receptor
6) modifications in co-
regulators or other post
receptor effects are
required for the proper
mediation of TH action Non-genomic effects ??
NO production by endothelial cells
Thyroid Hormones : physiological effects
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 Thyroid hormones are essential for normal growth of tissues


 Brain
  abscence of TH during the period of active neurogenesis (up to 6
months postpartum)  irreversible mental retardation : cretinism
 prevented by administration of TH during the first 2 weeks of
postnatal life
 Cretinism is Endemic or Sporadic
 Endemic Cretinism : Iodine is extremly deficiencyiodine
replacement must be instituted before pregnancy
 Sporadic Cretinism : failure of the thyroid to develop normally or
a defect in the synthesis of TH in that case goiter is present
 TH is critical for normal development of the skeletal system and
musculature
 Thermogenesis : ↑ O2 consumption of most organs except for brain
Thyroid Hormones : PD
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 Cardiovascular effects:
 Increased sensitivity to catecholamine with proliferation
of beta receptor
 hyperthyroidism →↑ heart rate , cardiac hypertrophy,
decreased vascular resistance,
 Hyperthyroidism is a common cause of artrial fibrillation
 hypothyroidism→bradycardia, increased peripheral
vascular resistance, increased mean arterial pressure

 Reproductive system:
 Normal reproductive behavior and physiology is
dependent on having essentially normal levels of thyroid
hormone.
 Hypothyroidism in particular is commonly associated with
infertility.
Thyroid Hormone :Metabolic effects
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 Protein synthesis and degradation:


 low thyroid hormone levels: ↑ protein synthesis (low metabolic rate;
growth)
 high thyroid hormone levels : ↑ protein degradation (high metabolic rate;
energy)
 Carbohydrates metabolism
 low doses of thyroid hormone : ↑ glycogen synthesis (low metabolic rate;
storage of energy)
 high doses: ↑ glycogen breakdown (high metabolic rate; glucose
production)
 Lipids metabolism :
 ↑ thyroid hormone levels :
 stimulate fat mobilization, → ↑ concentrations of fatty acids in plasma.
 enhance oxidation of fatty acids in many tissues.
 ↑ expression of hepatic LDL receptors and  metabolism of
cholesterol to bile acids
 plasma concentrations of cholesterol and triglycerides are inversely
correlated with TH levels.
Hypothyroidism
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 low T4 levels  impaired growth and development and  metabolic activity


 Severe hypothyroidism  myxedema

• Iodine deficiency
• Chronic autoimmune thyroiditis
(Hashimoto's thyroiditis)
•↑ TSH

 Sometimes associated to
 Pendred syndrome (genetic disorder that causes early hearing loss in children)
 Turner syndrome (genetic condition in which a female does not have the usual pair
of two X)
Hypothyroidism signs and symptoms
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Hypothyroidism pharmacotherapy
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 Thyroid hormone replacement therapy :


 Thyroxine (levothyroxine sodium) is the hormone of choice due to its
 Consistent potency
 Prolonged duration of action

 T3 drawbacks
 Requirement for more frequent dosing
 Higher cost
 Transient elevations of serum T3 concentrations above the normal range
 Less “physiological” intracellular T3 levels in tissues expressing D2

 Goal of therapy
 Normalize: serum TSH (in primary hypothyroidism) OR free T4 (in
secondary or tertiary hypothyroidism)
 Relieve symptoms of hypothyroidism
Hypothyroidism pharmacotherapy
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 Preparations
 Levothyroxine sodium (L-T4) EUTHYROX (synthetic T4)
 T1/2 = 7 days
 Taken on empty
stomach
 Overdosage  hyperthyroidism symptoms

 Liothyronine (L-T3) (synthetic T3)


 t1/2 = 0.75 days
 Not suitable for replacement therapy
 Used
 when a more rapid onset of action is desired such as in the rare
presentation of myxedema coma
 if rapid termination of action is desired such as when preparing a
thyroid cancer patient for 131I therapy.

 Liotrix : mixture of thyroxine and triiodothyronine 4:1


Hyperthyroidism
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 Thyrotoxicosis =
 Excess of circulating thyroid hormone.(La thyrotoxicose est le syndrome
clinique qui traduit l’élévation de la concentration des hormones thyroïdiennes libres)
 High T4 levels  hyperactivity of organ systems (particularly the nervous and
cardiovascular systems) and  metabolic rate.
 Causes:
 Basedow - Grave’s disease, an autoimmune disorder in which antibodies
serve as agonists to the TSH receptors on the thyroid’s surface, causing
thyroid growth and activation of hormone synthesis and secretion
 Thyroid tumors which cause the uncontrolled synthesis and secretion of
thyroid hormones.
 Thyroiditis, inflammation of the thyroid typically caused by
infection.(destruction vésiculaire avec libération d’hormones thyroidiennes
préformées due à une infection virale (thyroïdite subaiguë), ou à un
phénomène auto-immun (thyroïdites sub-aiguës, thyroïdites silencieuses,
thyroïdites induites par l’interféron)
 Thyroid storm
incresed sweating & thirst
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Hyperthyroidism
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 Three treatment modalities are used in


hyperthyroidism:
 antithyroid agents,

 surgery, and

 radioactive iodine (RAI) treatment.

 The goals of therapy are to


 Eliminate excessive thyroid hormone production

 Control the symptoms of hyperthyroidism.


Hyperthyroidism pharmacotherapy
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 Thioamides = antithyroid agents
 Propylthiouracil , methimazole
 Interfere directly with the synthesis of thyroid hormones

 Anion inhibitors
 Perchlorate (ClO4 –), pertechnetate (TcO4–), and thiocyanate (SCN–)
 Block the iodide transport mechanism
 Uncommon use because of aplastic anemia

 Iodides
  release of thyroid hormones from the gland and may  hormone synthesis

 Radioactive iodine 131 = 131I


 Damages the thyroid gland with ionizing radiation.

 -blockers : propranolol
 Control the cardiovascular symptoms of hyperthyroidism until definitive
treatment becomes effective
 Inhibit the peripheral conversion of T4 to T3.
Hyperthyroidism pharmacotherapy
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 interfere directly
 block the with the synthesis   release of
iodide of TH thyroid
transport hormones
mechanism from the
gland and
may 
hormone
synthesis
Anti-thyroid drugs
29

Mechanism of action :
 Inhibition of thyroperoxydase enzyme catalyzing reactions:

 iodine organification:
 inhibit incorporation of iodine into tyrosyl residues of thyroglobulin → ↓
↓ synthesis of MIT, DIT
 Iodotyrosines coupling → ↓ production of T4 and T3

 Propyl thiouracil (PTU) inhibits peripheral deiodination of T4 to T3


 Used in the treatment of severe hyperthyroid states or of thyroid storm
where a decreased rate of T4→T3 conversion would be beneficial
 All decrease thyroid stimulating Ig in Graves ‘ disease:
 Decrease the antithyrotropin antibodies
 Soluble IL-2 and IL-6 receptors decrease with time :immunosupppressants
Anti-thyroid drugs
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 Delay in therapeutic effect


 Preformed iodinated thyroglobulin is hydrolyzed and the hormones are released
into the circulation
 Over time : inhibition of new hormone synthesis  depletion of stores of
iodinated thyroglobulin
 Only when the preformed hormone is depleted and the concentrations of
circulating thyroid hormones begin to decline do clinical effects become
noticeable.
 Thyrotoxic state usually improves within 3-6 weeks after the initiation of anti-
thyroid drugs
 Maximal effect should appear after 6-8 weeks of therapy
 Patients should be examined and thyroid function tests (serum FT4 and total or
free triiodothyronine concentrations) measured every 2-4 months then every 4-6
months when euthyroidism is established
 Methimazole TAPAZOLE
 Potency : Methimazole = 10x propylthiouracil
 Carbimazole (prodrug converted to methimazole)
 Long-term use leads to thyroid hyperplasia
Anti-thyroid drugs : PK
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PROPYLTHIOURACIL METHIMAZOLE
Plasma protein binding 75% Nil
Plasma t1/2 75 minutes 4-6 hours
Concentrated in thyroid Yes Yes
Metabolism of drug during illness
Severe liver disease Normal Decreased
Severe kidney disease Normal Normal
Dosing frequency 1-4 times daily Once or twice daily
Transplacental passage Low Low
Levels in breast milk Low Low
ANTI THYROID DRUGS : Adverse Effects
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 Most common : Pruritis, maculopapular rash


 Typical side effects : headache, nausea, vomiting, itchy skin and
rash, muscle aches and pains.
 Rare but serious : Agranulocytosis: if noted treatment should be
discontinue , as well as decreased platelet production
 Usually occurs during the first few weeks or months of therapy
 Caution and frequent leukocyte(NFS) counts are required
 Patients should be instructed to immediately report the development of
sore throat or fever, which are often signs of the presence of
leukopenia.
 Reversible upon D/C of the drug
 Propylthiouracil: Serious liver failure  PTU reserved for patients allergic
or intolerant to methimazole
 Administration of high dosage of anti-thyroid drugs can cause
hypothyroidism →↓ of dosage
Anti-thyroid drugs : therapeutic uses
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 Three main uses


 As definitive treatment, to control the disorder in anticipation
of a spontaneous remission in Graves' disease
 Methimazole : agent of choice in Graves’ disease
 In conjunction with radioactive iodine, to hasten recovery while
awaiting the effects of radiation
 To control the disorder in preparation for surgical treatment

 Propylthiouracil is used in
 Pregnant women & children
 In thyroid storm
 life-threatening complication of thyrotoxicosis
 Fever, tachycardia, agitation, confusion, nausea, vomiting, diarrhea 
coma & death
 Supportive measures : IV fluids, antipyretics, cooling blankets, and
sedation
Inorganic Iodide: Potassium iodide
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 Mechanism of action: Iode stable (Lugol) inhibe transitoirement la synthèse hormonale par
effet Wolff Chaikoff.
 block of organification : A 2 days transient acute inhibition of the synthesis of
iodotyrosines and iodothyronines : « Wolf Chaikoff effect »
 The Wolff–Chaikoff effect is an autoregulatory phenomenon: the elevated levels of
circulating iodide inhibits organification in the thyroid gland, the formation of thyroid
hormones inside the thyroid follicle, and the release of thyroid hormones into the
bloodstream
 Response is rapid : within 24 h and basal metabolic rate may fall at a rate
comparable to that following thyroidectomy :
 inhibition release of hormones: ↓ hormone synthesis , ↓ size and vascularity (Attenuate
the effect of TSH on the thyroid gland)
 Maximal therapy effect after 10-15 days of continuous therapy
 Escape phenomenon" which is described by resumption of normal organification of
iodine and normal thyroid peroxidase function. : Anti thyroid effect is not for long term as
gland escapes from its effect in 2-8 weeks:
  in NIS mRNA and protein   iodide transport   intracellular iodide
concentration
Inorganic Iodide
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 Therapeutic uses:
 Lugol’s solution , potassium iodide

 used prior to thyroid gland surgery to decrease the


vascularity of the thyroid gland
 hyperthyroidism and thyroid storm: Graves’disease,
thyroiditis
 rarely used as sole therapy for hyperthyroidism
 Inhibit the release of thyroid hormones after RAI treatment.

 Contraindications :
 pregnancy : iodide can cross the placenta
Iodide : adverse effects
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 Hypersensitivity reactions :
 Angioedema , laryngeal edema
 Serum-sickness : fever, arthralgia, lymph node enlargement,
and eosinophilia

 Iodism (iodide intoxication)


 Metallic taste, burning in the mouth and throat as well as
soreness of the teeth and gums, Increased salivation ,
salivary glands swelling,
 GI discomfort : diarrhea (may be bloody)
 Productive cough, running eyes and nose
 Skin lesions
Radioactive iodine
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 Several radioactive isotopes:


 123I  -emitter : t½=13 hours
 131I  emits both  and  particles : t½= 8 days

 Disposition of 131I : per os


 Rapidly absorbed by the gut  fast accumulation in thyroid 
incorporated into the iodoamino acids  deposited in the
colloid of the follicles, from which it is slowly liberated

 Therapeutic uses:
 Thyroid destruction of an overactive thyroid or in thyroid cancer
 Clearest indication : hyperthyroidism in older patients and in those
with heart disease
 Diagnosis of disorders of thyroid function
β-Adrenoceptor antagonists
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 β-blockers decrease the supersensitivity of the tissues to


catecholamines in hyperthyroidism.

 Effective in antagonizing the sympathetic/adrenergic effects of


thyrotoxicosis   tachycardia, tremor, and stare, and relieving
palpitations, anxiety, and tension

 β-blockers don’t block all the metabolic effects of the hormone 


not used alone except in mild thyrotoxicosis in preparation for
radioiodine therapy.

 The chosen β-blockers should be non-selective and without intrinsic


sympathetic activity e.g. propranolol & timolol

 Usually only short-term treatment is required, 2-6 weeks, and it


should be discontinued once the patient is euthyroid.
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 The Wolff–Chaikoff effect (pronounced "woolf' cha'kof"),[1] discovered by Drs. Jan Wolff
and Israel Lyon Chaikoff at the University of California, is a reduction in thyroid hormone
levels caused by ingestion of a large amount of iodine.[2] 4] Patients with Graves' disease
are more sensitive than euthyroid patients,[5] and iodine has been used to manage Graves'
disease.
 The Wolff–Chaikoff effect is an autoregulatory phenomenon that inhibits organification in the
thyroid gland, the formation of thyroid hormones inside the thyroid follicle, and the release of
thyroid hormones into the bloodstream.[6] This becomes evident secondary to elevated levels
of circulating iodide. The Wolff–Chaikoff effect lasts several days (around 10 days), after
which it is followed by an "escape phenomenon",[7] which is described by resumption of normal
organification of iodine and normal thyroid peroxidase function. "Escape phenomenon" is
believed to occur because of decreased inorganic iodine concentration secondary to down-
regulation of sodium-iodide symporter (NIS) on the basolateral membrane of the thyroid
follicular cell.
 The Wolff–Chaikoff effect can be used as a treatment principle against hyperthyroidism
(especially thyroid storm) by infusion of a large amount of iodine to suppress the thyroid
gland. Iodide was used to treat hyperthyroidism before antithyroid drugs such as
propylthiouracil and methimazole were developed. Hyperthyroid subjects given iodide may
experience a decrease in basal metabolic rate that is comparable to that seen after
thyroidectomy.[6] The Wolff–Chaikoff effect also explains the hypothyroidism produced in
some patients by several iodine-containing drugs, including amiodarone. The Wolff–Chaikoff
effect is also part of the mechanism for the use of potassium iodide in nuclear emergencies.[8][9