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- thyroglobulinNIS - sodium-iodide symporter; TPO- thyroid peroxidaseDIT - 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

• 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 20-fold excess over T3

Both circulate bound to plasma proteins

• Thyroxine-binding globulin (TBG)

• Transthyretin (TTR), formerly known as thyroxine-binding 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 1011 M

• T3 ~6 1012 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– 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

TreatmentHyperthyroidism 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)

• Thioamides (reduce the synthesis of thyroid hoemones)

– Carbimazole– Methimazole– Propylthiouraciliodide

• Radioactive iodine (I131)• Iodide ( high doses) • Ionic inhibitors (inhibit iodide uptake) - use is obsolete due to toxicity

– Thiocyanates– Perchlorates– Nitrates

• Propranolol - Adjunct therapy in thyrotoxicosis

Thioamides• Mechanism

– reduce the synthesis of thyroid hormones by inhibiting iodination of tyrosine and coupling of iodotyrosine to form T3 and T4

• Clinical use– 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

• Mechanism – 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.

• Clinical use• 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

• 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

• Mechanism of action

– Trapped by the thyroid follicles and incorporated into thyroglobulin

– Emits both beta and gamma rays(half-life 8 days)

– Beta rays - short range and act on thyroid tissue only

– 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.