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Iodothyronine hormones
: thyroxine =T4
Triodothyronine = T3
stored as amino acids
residues of
thyroglobulin
Parfollicular cells
Calcitonin
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
Autoregulation
low iodide levels in the
gland →↑ iodine
transport into follicular
cells
high iodide levels→ ↓
iodine transport into
follicular cells
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
10
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 80-100g
T3 is 30-40g
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
11
formed.
rT3 has no biological activity.
Conversion of T4 to T3 in Peripheral Tissues
12
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
15
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
19
• 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
21
Hypothyroidism pharmacotherapy
22
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
23
Preparations
Levothyroxine sodium (L-T4) EUTHYROX (synthetic T4)
T1/2 = 7 days
Taken on empty
stomach
Overdosage hyperthyroidism symptoms
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
25
Hyperthyroidism
26
surgery, and
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
-blockers : propranolol
Control the cardiovascular symptoms of hyperthyroidism until definitive
treatment becomes effective
Inhibit the peripheral conversion of T4 to T3.
Hyperthyroidism pharmacotherapy
28
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
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
32
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
34
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
35
Therapeutic uses:
Lugol’s solution , potassium iodide
Contraindications :
pregnancy : iodide can cross the placenta
Iodide : adverse effects
36
Hypersensitivity reactions :
Angioedema , laryngeal edema
Serum-sickness : fever, arthralgia, lymph node enlargement,
and eosinophilia
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
38
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