2.antithyroidal and thyroid drugs

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THYROID HORMONES AND ANTI THYROID DRUGS

Prepared by: Mirza Anwar Baig M.Pharm (Pharmacology)

Anjuman I Islam's Kalsekar Technical Campus,School of Pharmacy.

New Panvel,Navi Mumbai

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CONTENTS:1. Introduction to thyroid gland,thyroid

hormones2.Process of production and storage of

thyroid hormones3.Effects of thyoid hormones4.Diseases related to thyroid hormones5.Therapeutic uses of thyroidal drugs6.Anti thyroidal drugs

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What are thyroid hormones?• The thyroid gland secretes 3 hormones-

thyroxine (T4), triiodothyronine (T3) and calcitonin.

• The former two are produced by thyroid follicles, have similar biological activity.

• Calcitonin produced by interfollicular 'C' cells is chemically and biologically entirely different. It is considered regulates calcium metabolism.

1.Introduction to thyroid gland, thyroid hormones.

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Bried histroy of invention:The physiological significance of thyroid gland wasrecognized only after Graves and Basedow (1835, 1840)associated the clinical features of the 'Graves' disease'with swelling of thyroid gland and Gull (1874) correlatedmyxoedema with its atrophy.

Kendall (1915) obtained crystalline thyroxine and suggested its chemical formula which was confirmed in 1926.

Thyroxine was the first hormone to be synthesized in the laboratory.

Later, as T4 could not account for all the biological activity of thyroid extract, search was made and more potent T3 wasdiscovered in 1952

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THE THYROID GLAND

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FEEDBACK REGULATIONTHE HYPOTHALAMIC-PITUITARY-THYROID AXIS

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THYROID GLAND HISTOLOGY

Compiled by: Prof.Anwar Baig (AIKTC.SOP)

2. Process of production and storage of thyroid hormones

11Compiled by: Prof.Anwar Baig (AIKTC.SOP)

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THYROID HORMONES


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T4 and T3 hormones


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PITUITARY-THYROID AXIS

– –

+


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3.Effects of thyoid hormones

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• TSH binds to specific cell surface receptors that stimulate adenylate cyclase to produce cAMP.

• TSH increases metabolic activity that is required to synthesize Thyroglobulin (Tg) and generate peroxide.

• TSH stimulates both I- uptake and iodination of tyrosine resides on Tg.

4. Mechanism of actions of thyroidal hormones:


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THYROID HORMONES IN THE BLOOD

• Approximately 99.98% of T4 is bound to 3 serum proteins: Thyroid binding globulin (TBG) ~75%; Thyroid binding prealbumin (TBPA or transthyretin) 15-20%; albumin ~5-10%

• Only ~0.02% of the total T4 in blood is unbound or free.

• Only ~0.4% of total T3 in blood is free.


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THYROID HORMONE DEIODINASES

• Three deiodinases (D1, D2 & D3) catalyze the generation and/disposal of bioactive thyroid hormone.

• D1 & D2 “bioactivate” thyroid hormone by removing a single “outer-ring” iodine atom.

• D3 “inactivates” thyroid hormone by removing a single “inner-ring”iodine atom.

• All family members contain the novel amino acid selenocysteine (SeC) in their catalytic center.


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BASICS OF THYROID HORMONE ACTION IN THE CELL


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Hypothyroidism and Hyperthyroidism

5. Diseases related to thyroid hormones


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EXAMPLES OF THYROID DISEASES

1° Hypothyroidism Hyperthyroidism


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EXAMPLES OF THYROID DISEASES

Congenital HypothyroidismJuvenile Hypothyroidism


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●● RepresentativeRepresentative drugs drugs levothyroxine (L-T4, levoxyl, synthroid) liothyronine (T3, cytomel, triostat) liotrix (T4 plus T3) (euthyroid, thyrolar)

Thyroid drugs

●● PharmacokineticsPharmacokineticseasily absorbed; the bioavailablity of T4 is 80%, and T3 is 95%.Drugs that induce hepatic microsomal enzymes (e.g., rifampin, phenbarbital, phenytoin, and etc) improve their metabolism.

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5.Therapeutic uses of thyroidal drugs The most important uses are as replacement therapy in deficiency states:

1 . Cretinism:

It is due to failure of thyroid development or a defect in hormone synthesis (sporadic cretinism) or due to extreme iodine deficiency (endemic cretinism).

It is usually detected during infancy or childhood.

Treatment with thyroxine (8-12 pg/kg) daily should be started as early as possible, because mental retardation that has already ensued is only partially reversible.

Response is dramatic:physical growth and development are restored and further mental retardation is prevented.

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2. Adult hypothyroidism • Develops as a consequence of thyroiditis,

thyroidectomy; or may be idiopathic.• Important drugs that can cause

hypothyroidism are 131 I, iodides, lithium and amiodarone.

• Treatment with T4 is most gratifying. • Individualization of proper dose is critical,

aiming at normalization of serum TSH levels. Increase in dose is mostly needed during pregnancy.

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3. Myxoedema coma • It is an emergency; characterized by progressive mental

deterioration due to acute hypothyroidism.• Rapid thyroid replacement is crucial,Though liothyronine

(T3) acts faster, its use is attended by higher risk of cardiac arrhyethemia,angina, etc.

• Drug of choice is thyroxine • Corticosteroids to cover attendant adrenal insufficiency,

ventilatory and cardiovascula support.4.Nontoxic goiter:

It may be endemic or sporadic. Endemic is due to iodine deficiency may be accentuated by factors present in food or milk. A defect in hormone synthesis may be responsible for sporadic cases.In both the cases deficient production of thyroid hormone leads to excess TSH secretion and thyroid enlarges, more effective trapping of iodide occurs and probably greater prproportion of T 3 is synthesized.Thus, treatment with T4 is in fact replacement therapy in this condition works.

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HYPERTHYROIDISM• Elevated levels of T3 and T4 in the blood.

• Causes :1. Carcinomas

2.Thyroiditis

3.Autoimmune


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GRAVES' DISEASE

• Most common cause of hyperthyroidism 60-80%.

• Autoimmune disorder associated with circulating immunoglobulins that bind to and stimulate the thyrotropin ( TSH) receptor , resulting in sustained thyroid over activity & it can be familial.


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Manifestations of Hyperthyroidism • Nervousness , irritability.• Tremors• palpitation• Weight loss• sweating• Heat intolerance• Diarrhea• short breath• Itching• Thyroid Enlargement Compiled by: Prof.Anwar

Baig (AIKTC.SOP)

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Anti-thyroid drugsDrugs used for the treatment of hyperthyroidism :1.Inhibition of hormone synthesis :

Thioamides (Propylthiouracil and Methimazole).2. Blockade of hormone release :

Iodides, Iodinated contrast media. 3. Radioactive Iodine 1314. Anion Inhibitors :

Perchlorates, Thiocynates.5. Beta blocking drugs : Propranolol.6. Surgery


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Anti-thyroid drugs

peroxidase


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Thiomides1. Propylthiouracil: Protype of the group It inhibits the synthesis of the thyroid hormones but does not inactivate already formed and stored thyroxine. Labelled as goitrogens.2. Methyl thiouracil: is equal in potency to PTU. But have allergic manifestations3.Methimazole: chemically similar to PTU but 10 times more potent than PTU4.Carbimazole: as effective as PTU


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Mode of Action of ThioamidesIt interfere with:1. iodination of tyrosine2. Coupling and condensation of iodotyrosines3. Block the oxidation of iodides4. Inhibit the peroxidase enzyme systems5. Little effect on iodine trapping by thyroid gland


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Therapeucitc Uses1.Hyperthyroidism: relief but little effect on associated exophthalmos in graves disease.2.Prepration of thyrotoxic patient for surgical treatment.

Sulphonamides and related compounds possess antithyroidal activity.


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Contraindications• It crosses placenta can cause foetal

goiter.• Use should be minimized in pregnancy.• Should not be used in lactating mother.Toxicity:Goiterogenic actionAllergic action (Urticaria,purpuric rashes)Sever lucopenia and aganulocytosisHepatitis and nephritis may occur rarely


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Pharmacokinetic comparision between Propylthiouracil and Methimazole

PropylthiouracilPropylthiouracil MethimazoleMethimazole AbsorptionAbsorption AbsorbedAbsorbed fromfrom GITGIT AbsorbedAbsorbed fromfrom GITGIT

ProteinProtein bindingbinding

80- 80- toto 90% 90% MostMost ofof drugdrug isis freefree

accumulationaccumulation thyroidthyroid thyroidthyroid

ExcretionExcretion KidneysKidneys asas inactiveinactive metabolitemetabolite withinwithin 24 24 hrshrs

ExcretionExcretion slowslow,60-,60-70% 70% ofof drugdrug isis recoveredrecovered inin urineurine inin 48 48 hrshrs


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Pharmacokinetic comparision between Propylthiouracil and Methimazole

PropylthiouracilPropylthiouracil MethimazoleMethimazole HalfHalf lifelife 1.5 1.5 hrshrs ( ( shortshort

halfhalf-- lifelife))6 6 hrshrs ( ( longlong halfhalf--lifelife))

AdministrationAdministration EveryEvery 6- 8 6- 8 hrshrs AsAs aa singlesingle dosedose

PregnancyPregnancy recommendedrecommended inin pregnancypregnancy..

NotNot recommendedrecommended inin pregnancypregnancy

BreastfeedingBreastfeeding LessLess secretedsecreted inin breastbreast milkmilkRecommendedRecommended

secretedsecreted NotNot recommendedrecommended

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Drug that destroy thyroid tissue2. Radioactive Iodine

• I131 mainly used.• It emits beta and gamma radiations.• It accumulates in thyroidal gland and

destructive action is becz of beta rays.

• Gamma rays are only used to calculate the amount of Iodine present.


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Therapeutic uses• Selected cases of hyperthyroidism:

recurrence rate is low.• Thyroid carcinoma:• Daignostic use: localisation of

metastatic deposits of thyroid cancer in the lungs and bones

• Angina pectoris: occasionally


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Selection of the patients1.uncomplicated hyperthyroidsm2. recurrent or persistent hyperthyroidsm after subtotal thyroidectomy3.Failure or response to anti thyroidal drug4.Presence of severe exophthalmos

•Advantage is low mortality, uncommon recurrence•Disadvantage is incidence of hypothyroidism is high


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Contraindications

• I131 is contraindicated during pregnancy and lactation

Toxicity:• May produce many temporary but

potentially dangerous reactions like mild pain in thyroid area, swelling of thyroid gland and bone marrow depression.


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3. Drug with uncertain mode of actionIodide

• Oldest agent used in management of thyroid disorders

• Used in the treatment of iodine deficiency goiter, paradoxically when it is administered to hyperthyroid patients there is reduction in vascularity and swelling of the gland.

• Gland shrinks and symptoms improves (mechanism is ill understood)

• High iodide content in blood inhibits thyroid hormone release.

• Antagonized the ability of TSH and C-AMP to stimulate the proteolysis and hormone release.


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Clinical uses 1. Prior to thyroid surgery to decrease vascularity of the

gland .2. Following radio active iodine therapy.Examples Organic iodides as :iopanoic acid or ipodate

Precautions /toxicity:

1. Should not be used as a single therapy2. Should not be used in pregnancy

3. May produce iodism ( acniform rash, swelling of salivary glands, mucous membrane ulceration, metallic taste bleeding disorders and rarely anaphylaxis ).


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4. IONIC INHIB ITORSCertain monovalen thyroid probably because of similar hydrated ionic sizeT4/T3 cannot be synthesized. Thiocyanate also inhibits iodination at high doses. They are toxic and not used now.Thiocyanates: can cause liver, kidney, bone marrow and brain toxicity.Perchlorates:produce rashes,fever,aplastic anaemia, agranulocytosis.Nitrates: are weak drugs, can induce methemoglobinaemia and vascular effects .

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5.ADRENOCEPTOR BLOCKING AGENTS:

• Adjunctive therapy to relief the adrenergic symptoms of hyperthyroidism such as tremor, palpitation, heat intolerance and nervousness.

• E.g. Propranolol, Atenolol , Metoprolol.


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5. Antiadrenergic drug contd...• Tachycardia,palpitation,hypertension are

adrenergic mediated symptoms of thyrotoxocosis.

• To control these antiadrenergic drugs like propranolol and guanethidine are used as adjuvant therapy.

• Propranolol appears to be superior over guanethidine : releves anxiety and tension

• Propranolol reduces the peripheral conversion of T4 to T3

• Propranolol is contraindicated in asthmatic patients


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6. THYROIDECTOMY

• Sub-total thyriodectomy is the treatment of choice in very large gland or multinodular goiter


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2.antithyroidal and thyroid drugs

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