Transcript Thyroid pharmacology

Thyroid pharmacology
THYROID GLAND
Location
• 12 to 20 g in size
• In neck, anterior to trachea
• Between cricoid cartilage and suprasternal notch
• Highly vascular and soft in consistency.
THYROID GLAND
Consists of two lobes
• Connected by an isthmus
• 4 parathyroid glands
– Posterior region of each pole
• Laryngeal nerves traverse lateral borders of gland
Secretions
Produces two related hormones
• Thyroxine (T4)
• Triiodothyronine (T3)
Action
Play a critical role in
• Cell differentiation during development
• Help to maintain thermogenic and metabolic
homeostasis in adult.
• Act through nuclear hormone receptors to modulate
gene expression
Regulation of thyroid hormone synthesis
T4 and T3 feed back to inhibit
• Hypothalamic production of thyrotropin-releasing
hormone (TRH)
• Pituitary production of thyroid-stimulating hormone
(TSH)
TSH-R, thyroid-stimulating hormone receptor, Tg- thyroglobulin
NIS - sodium-iodide symporter; TPO- thyroid peroxidase
DIT - di-iodotyrosine; MIT - monoiodotyrosine
Thyroid Hormone Synthesis
Thyroid hormones are derived from thyroglobulin
• Large iodinated glycoprotein
After secretion into the thyroid follicle
• Tg is iodinated on selected tyrosine residues that are
subsequently coupled via an ether linkage
• Reuptake of Tg into thyroid follicular cell allows
proteolysis and the release of T4 and T3.
Iodine Metabolism and Transport
• Iodide uptake is a critical first step in thyroid
hormone synthesis
• Ingested iodine is bound to serum proteins
(particularly albumin)
• Unbound iodine is excreted in urine
• Iodine extracts from circulation in a highly efficient
manner
– 10 to 25% of radioactive tracer (e.g., 123I) is taken up by
the normal thyroid gland over 24 h; this value can rise to
70 to 90% in Graves' disease.
Na+/I- symporter (NIS)
• Mediate Iodide uptake
• Expressed at basolateral membrane of thyroid
follicular cells.
• Expressed
– Most highly in thyroid gland
– Low levels in salivary glands, lactating breast, placenta
• Low I2 levels increase amount of NIS & stimulate
uptake
• High I2 levels suppress NIS expression & uptake
Selective expression of NIS in thyroid allows
– Treatment of hyperthyroidism
– Isotopic scanning
– Abolition of thyroid cancer with radioisotopes of iodine
Without significant effects on other organs
Mutation of the NIS gene is a rare cause of congenital
hypothyroidism
Oranification
• Iodide enters thyroid 
• Trapped and transported to apical membrane of
thyroid follicular cells 
• Oxidized in an organification reaction (Tyroid
PerOxidase & H2O2 )
Coupling
Reactive iodine atom is added to selected tyrosyl
residues within Tyroglobulin
Iodotyrosines in Tg are then coupled via an ether
linkage in a reaction Catalyzed by TPO
Either T4 or T3 can be produced by this reaction
• Depending on number of iodine atoms present in
iodotyrosines.
Storage, Release
• After coupling, Tg is taken back into thyroid cell
• It is processed in lysosomes to release T4 and T3
• Uncoupled mono- and diiodotyrosines (MIT, DIT) are
deiodinated by enzyme dehalogenase
• Recycling any iodide that is not converted into
thyroid hormones
Factors Influence Synthesis and Release
TSH is the dominant hormonal regulator of thyroid
gland growth and function
Variety of growth factors, most produced locally in
thyroid gland, also influence synthesis
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Insulin-like growth factor I (IGF-I
Epidermal growth factor
Transforming growth factor β (TGF- β)
Endothelins
Various cytokines.
• Disorders of thyroid hormone synthesis
– Rare causes of congenital hypothyroidism
• Majority of disorders due to recessive mutations in
TPO or Tg
• Defects also identified in
– TSH-R
– NIS
– Pendrin anion transporter
• Transports I2 from cytoplasm to follicle lumen
– H2O2 generation
– Dehalogenase
• Biosynthetic defect of thyroid hormone 
• Inadequate amounts of hormone 
• Increased TSH synthesis 
• Goiter
Transport And Metabolism
• T4 is secreted from the thyroid gland in at least 20fold excess over T3
Both circulate bound to plasma proteins
• Thyroxine-binding globulin (TBG)
• Transthyretin (TTR), formerly known as thyroxinebinding prealbumin (TBPA)
• Albumin
Functions of serum-binding proteins
• Increase pool of circulating hormone
• Delay hormone clearance
• Modulate hormone delivery to selected tissue sites
Con. of TBG is relatively low (1 to 2 mg/dL)
• High affinity for thyroid hormones (T4 > T3), it carries
about 80% of bound hormones
Albumin has relatively low affinity for thyroid hormones
(high plasma con ~3.5 g/dL)
• It binds up to 10% of T4 and 30% of T3.
TTR carries about 10% of T4 but little T3.
• ≈ 99.98% of T4 and 99.7% of T3 are protein-bound
• T3 is less tightly bound than T4
• Amount of free T3 > free T4
Unbound (free) cons
• T4 ~2  10-11 M
• T3 ~6  10-12 M
Deiodinases
• In many respects, T4 may be thought of as a
precursor for more potent T3
• T4 is converted to T3 by the deiodinase enzymes
Type I deiodinase
• Located primarily in thyroid, liver, kidney
• Has a relatively low affinity for T4
Type II deiodinase
• Higher affinity for T4
• Found primarily in pituitary gland, brain, brown fat,
thyroid gland
T4 - T3 conversion may be impaired by
• Fasting
• Acute trauma
• Oral contraseptive agents
• Propylthiouracil
• Propranolol
• Amiodarone
• Glucocorticoids
THYROID HORMONE ACTION
• Act by binding to nuclear receptors, termed thyroid
hormone receptors (TRs) ά and β
• Both ά and β are expressed in most tissues
• Both receptors are variably spliced to form unique
isoforms
Thyroid hormone receptors ά
Highly expressed in
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Brain
Kidney
Gonads
Muscle
Heart
• TR ά 2 isoform contains a unique carboxy terminus
that prevents thyroid hormone binding
• It may function to block actions of other TR isoforms
Thyroid hormone receptors β
Highly expressed in
– Pituitary
– Liver
TR β 2 isoform
• Has a unique amino terminus
• Selectively expressed in hypothalamus & pituitary
• Play a role in feedback control of thyroid axis
(1) T4 or T3 enters the nucleus
(2) T3 binding dissociates CoR from TR
(3) Coactivators (CoA) are recruited to the T3-bound receptor
(4) gene expression is altered
Thyroid Hormone Resistance (RTH)
An autosomal dominant disorder characterized by
• Elevated free thyroid hormone levels
• Inappropriately normal or elevated TSH
• Individuals with RTH (in general) do not exhibit signs
and symptoms that are typical of hypothyroidism
• Apparently hormone resistance is compensated by
increased levels of thyroid hormone
HYPOTHYROIDISM
• Worldwide most common cause of
hypothyroidism - Iodine deficiency
Other causes
• Autoimmune disease (Hashimoto's thyroiditis)
• Iatrogenic causes (treatment of
hyperthyroidism)
Treatment
• T4 - 10 to 15 ug/kg/ day
• Dose adjusted by close monitoring of TSH
levels
• T4 requirements- relatively great during first
year of life
• High circulating T4 level is usually needed to
normalize TSH
• Early treatment with T4 results in normal IQ
levels
Hyperthyroidism
• Excessive thyroid function
Thyrotoxicosis
• State of thyroid hormone excess
Major etiologies of thyrotoxicosis
• Hyperthyroidism caused by Graves' disease
• Toxic multinodular goiter
• Toxic adenomas
Treatment
Hyperthyroidism of Graves' disease is treated by reducing thyroid
hormone synthesis
• Antithyroid drugs
• Reducing the amount of thyroid tissue with radioiodine (131I)
• Subtotal thyroidectomy
No single approach is optimal and that patients may require
multiple treatments to achieve remission.
Antithyroid drugs are the predominant therapy in many centers
in Europe and Japan
Radioiodine is more often the first line of treatment in North
America
ANTITHYROID DRUGS
(Drugs used in hyperthyroidism)
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Thioamides (reduce the synthesis of thyroid hoemones)
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Carbimazole
Methimazole
Propylthiouraciliodide
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Radioactive iodine (I131)
Iodide ( high doses)
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Ionic inhibitors (inhibit iodide uptake) - use is obsolete due to toxicity
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Thiocyanates
Perchlorates
Nitrates
Propranolol - Adjunct therapy in thyrotoxicosis
• Mechanism
Thioamides
– reduce the synthesis of thyroid hormones by inhibiting iodination
of tyrosine and coupling of iodotyrosine to form T3 and T4
• Clinical use
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– Carbimazole
• Graves disease-till remission of symptoms (30-60mg)
maintenance dose(5-15mg)
– Propylthiouracil (300-450 mg/d orally) maintenance dose (50-150
mg/d)
• Nodular toxic goiter
• Prior to surgery for hyperthyroidism
• With radioactive iodine to decrease symptoms before
radiation effects are manifested
Adverse effects
– Hypothyroidism
– Vasculitis, agranulocytosis, Hypoprothrombinaemia
– Cholestatic jaundice
– Hair pigmentation
Iodides
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Mechanism
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Selectively trapped by the thyroid gland (uptake being
increased in hyperthyroidism and reduced in hypothyroidism).
Large doses inhibit secretion of thyroid hormones by inhibition
of thyroglobulin proteolysis
Induce involution and decrease vascularity of the gland.
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Clinical use
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Preoperative use in thyroid surgery(Potassium iodide, 60
mg orally thrice daily)
Thyroid crisis
Accidental over dosage of radioactive iodine (to protect
the thyroid follicles)
Prophylactic use in endemic goiter. Added to salt (1 in
100,000 parts )as iodized salts.
As an expectorant, antiseptic for topical use
Adverse effects- Thioamides
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maculpapular pruritic rash
murticarial rash
Arthralgia
Lymphadenopathy
lupus-like syndrome
Polyserositis
• Adverse reactions
– Acute hypersensitivity reactions (angioneurotic oedema, skin
haemorrage, drug fever)
– salivation, lacrimation, soreness of throat, conjunctivitis, coryza-like
symptoms, skin rashes
– Foetal or neonatal goiter
Radiioactive iodine
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Mechanism of action
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Trapped by the thyroid follicles and incorporated into
thyroglobulin
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Emits both beta and gamma rays(half-life 8 days)
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Beta rays - short range and act on thyroid tissue only
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The gamma rays are more penetrative and can be
detected by Gieger counter for diagnostic use.
Clinical Use
• Radioactive sodium iodide (5-8 m curie) orally.
• Grave’s disease, including relapse after subtotal
thyroidectomy.
• Toxic nodular goiter
• Thyroid carcinoma
• Diagnosis of thyroid function . 50-100 micro curie is
administered.
• best in patients over 35 years and in the presence of cardiac disease
• Clinical response is slow and may take 6-12 weeks for suppression of
hyperthyroid symdrome
Effects of drugs on thyroid functions
Drugs.
Effect
Dopamine, l-dopa, corticosteroids,
somatostatin
Inhibition of TRH and TSH
secretion.
Iodides, lithium.
Inhibition of thyroxine synthesis, and
hypothyroidism
Cholestyramine, colestipol,
sucralfate, aluminium salts
Inhibit thyroxine absorption from gut
Phenytoin, carbamazepine,
rifampicin, phenobarbitone
Enzyme induction. May enhance T3
and T4 metabolism
Propylthiouracil, amiodarone
Inhibit conversion of T4 to T3
corticosteroids, beta-blockers
Androgens, glucocorticoids,
Decrease thyroxine-binding globulin
Oestrogens, tamoxifen, mitotane
Increase thyroxine-binding globulin
Salicylates, mefenamic acid,
furosemide
Displace T3 and T4 from thyroxine
–binding globulin.