Dr.U.P.RathnakarMD.DIH.PGDHM 1

Thyroid hormones

Thyroid hormones

• T4 & T3

• T4 Thyroxine, L- thyroxine

• T3 Triiodothronine, Liothyronine

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Thyroid hormones

• Synthesis• Regulation• Actions and MOA• Uses• Pharmacology of antithyroid drugs

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4

Thyroid

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Regulation of Thyroid Hormone Synthesis

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Dopamine, glucocorticoids, and somatostatin suppress TSH

Thyroid Hormone Synthesis

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I

I

II

II

II

MIT

MIT

DIT

DIT

DIT

DIT

NIS

T4

T3

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oxidation

Iodination

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2

3

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Conversion

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2

2

NIS

Pendrin

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Transport of T4 & T3

• Secretion 60-90 µg of T4 & 10-30 µg of T3, daily.• Highly protein bound [GLOBULIN, Albumin &

prealbumin]• Free form is active[1%]• Peripheral conversion-T4 to T3- in liver & kidney[D1] • Brain and pit [D2]• Plasma t1/2 of T4 is 6-7 days• Plasma t1/2 of T3 is 1-2 days• Metabolized by conjugation

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MOA

11mRNA

Protein synthesis

Relation between T4 and T3

T4 Thyroxine

• 60-90 µg/day• Transport, storage form• Less potent, slow action• May bind –not active• l-thyroxine• Easily available,• Oral & i.v• Preferred - sustained &

uniform action, Lower risk of cardiac arrhythmias.

• 10-30 µg/day• Active form• Potent, fast action• Binds & active• Triiodothyronine {Liothyronine}

• Not easily available• Oral & i.v.• Not commonly used

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T3- Triiodothyronine

Thyroid hormone actions

•Increases BMR•Facilitates Growth & Development

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Thyroid hormone actions

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Gene transcription Protein synthesis

Metabolic ProteinsEg. Enzymes

Structural proteinsFor growth &development

Regulatory ProteinsEg. NaK ATPaseTransport pro.Receptors etc.

• Increases BMR[except CNS & gonads]• Physical and mental growth• Alters systemic functions

Thyroid hormone actions

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↑↑↑ATPase ↑↑↑ATP demand[Energy]

↑↑↑Mitochondrial activity

Fat↑↑↑Lipolysis↑↑↑ FFA↑↑↑LDL-R in liver↑↑↑CHE clearance↑↑↑Gluconeogenesis

↓Serum CHE↑↑↑ GIT function, increased apetite↑↑↑ Hyperdynamic circulation↑↑↑ Respiratory rate↑↑↑ Weight loss [Thyrotoxicosis]↑↑↑ CNS alertness, anxiety

Carbohydrate↑↑↑Absorption↑↑↑Increased utilization↑↑↑Glycogenolysis↑↑↑Gluconeogenesis

Hyperglycemia

↑↑↑ BMR & Energy demand

T4&T3 Actions

• Growth&development• Metabolism• Calorigenesis• CVS• Nervous system• Sk.Muscles• GIT• Blood• Reproduction 16

Thyroid hormonesUses

• Cretinism [Congenital Hypothyroidism]

• Adult hypothyroidism• Myxoedema coma

• Non-toxic goiter• Thyroid nodule• Papillary carcinoma of thyroid• Non-specific uses

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PreparationsL-Thyroxine [T4]Liothyronine[T3]Oral & i.v

Thyroid hormonesUses

Cretinism [Congenital Hypothyroidism]

• Thyroxine (8-12 µg/kg daily

• Should be started as early as possible,

Because mental retardation only partially reversible. Response is dramatic

Adult hypothyroidism• Start with a low dose-50

µg of l-thyroxine daily • increase every 2-3 weeks

100-200 µg/day (clinical response and TSH levels)

• Dose adjustments - made at 4-6 week intervals

• Subclinical hypothyroidism treated if there are CV risk factors

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Thyroid hormonesUses

Myxoedema coma• Emergency-mortality↑• Drug of choice is

l-thyroxine 500 µg i.v. →100 µg i.v. OD till oral is started

• Supportive therapy

Myxoedema coma• If parenteral NA-oral –500

µg →100-300 µg OD • Absorption may be

delayed in hypothyroidism

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Thyroid hormonesUses

Non-toxic goiter• Endemic or sporadic• T4 replacement therapy• Iodine supplements-

prophylaxis

Thyroid nodule• Benign with excess of

TSH• T4 to suppress TSH

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Thyroid hormonesUses

Papillary carcinoma of thyroid• In non-resectable cases-

to suppress TSH and induce temporary regression

Non-specific uses• Refractory anaemias.• Menstrual disorders,

Infertilitv not corrected bv usual treatment

• Chronic/ non healing ulcers

• Obstinate constipation

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oxidation

Iodination

1

2

3

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Conversion

61to5TSH ACTIVATES

1Ionic inhibitors

block

2Carbimazole Methimazole

Propylthiouracil

1-2-3-5Iodides

6Propranolol,

Prednisolone,Propylthiouracil

131I 2

2

NIS

Pendrin

Antithyroids drugs

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Anti-thyroid Compounds[Interfere, directly or indirectly, with the

synthesis, release, or action of thyroid hormones]

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Anti-thyroid Compounds[Therapeutically used]

Drugs ActionAntithyroid drugs [Propylthiouracil,

Methimazole, Carbimazole

Inhibit synthesis of T4 & T3

Ionic inhibitors Thiocynate, perchlorate, fluoborate

High concn of Iodides Synthesis & release of hormones[Limited period]

Radioactive iodine Damages thyroid gland with ionizing radiation

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Adjuants Beta blockers. glucocorticoids

ANTITHYROID DRUGS

• Goitrogens– Lithium:– Amiodarone:– Sulfonamides, paraaminosalicylic acid:– Phenobarbitone, phenvtoin, carbamazepine,

rifampin

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CLASSIFICATION

1. Inhibitors of iodide trapping (anion inhibitors): • Thiocyanates, perchlorates.

2. Thyroid hormone synthesis inhibitors • Propylthiouracil, methimazole, carbimazole. (Thioamides or thiourea

derivatives)

3. Hormone release inhibitors:• Iodine, iodides of Na + and K+, organic iodide.

4. Thyroid tissue-destroying agent: • Radioactive iodine (131I).

5. Others:• Propranolol, atenolol, diltiazem, dexamethasone.

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IONIC INHIBITORS

• Not used because of ADEs• Monovalant anions like iodides• Thiocynates: can cause liver, kidney, bone

marrow and brain toxicity[cabbage, cigarette smoking]

• Perchlorates: produce rashes, fever, aplastic anaemia, agranulocytosis

• Nitrates: are weak drugs, can induce methemoglobinaemia and vascular effects

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Antithyroid drugs[Popylthiouracil-Methimazole-Carbimazole]

• MOA• Inhibit peroxidase

• Oxidation of Iodides-Inhibited• Iodination of tyrosine-inhibited

• Coupling-Inhibited• Synthesis of T3&T4 inhibited

• Effective only after stores of iodinated thyroglobulin depleted.

• Propylthiouracil inhibits [5’ DI] peripheral conversion of T4 to T3 29

Antithyroid drugsPK

• Absorbed from GIT• Carbimazole is the pro-drug of methimazole• Carbimazole gets converted to methimazole• Concentrated in Thyroid• Propylthiouracil & Carbimazole Cross

placenta equally

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Pharmacokinetic Features of Anti-thyroid Drugs

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Peripheral conversion Inhibits No

[More than PTU]

Antithyroid drugsAdverse effects

• Hypothyroidism and goiter -reversible• Due to excess TSH• Dose adjustment restores TSH concentration• G.i. intolerance• Rare but serious adverse effect- aganulocytosis (1 in

500 to 1000 cases)-periodic counts-reversible.

• Rashes and joint pain.• Propylthiouracil-Hepatic failure[CI in children except

methimazole allergy]• Methimazole-aplasia cutis[fetus]

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Antithyroid drugsTherapeutic uses

1. Definitive treatment, in Graves' disease

2. With radioactive iodine, to hasten recovery while awaiting the effects of radiation

3. To control the disorder in preparation for surgical treatment

Methimazole-DOC33

Anti-thyroid DrugsUses

• Propylthiouracil: 50-150 mg TDS• Methimazole: 5-10 mg TDS• Carbimazole: 5-15 mg TDS

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Maintenance O.D

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1. Thyrotoxicosis in pregnancy

2. Pregnancy and thyrotoxicosis is unusual as anovulatory cycles are common in thyrotoxic patients

3. Autoimmune disease tends to remit during pregnancy, when the maternal immune response is suppressed.

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Thyrotoxicosis in pregnancy

3. Thyrotoxicosis is almost always -Graves' disease. 4. Antithyroid drugs can all cross the placenta to some degree,

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Thyrotoxicosis in pregnancy

5. Carbimazole -asociated with a skin defect in the child known as aplasia cutis. 6. If subtotal thyroidectomy is necessary because of poor drug compliance or drug hypersensitivity, it is most safely performed in the second trimester. Radioactive iodine is absolutely contraindicated.

Thyrotoxicosis in Pregnancy

• Historically, propylthiouracil has been preferred over methimazole because transplacental passage was thought to be lower;

• Both propylthiouracil and methimazole cross the placenta equally

• Propylthiouracil-associated liver failure in pregnancy may favor the use of methimazole,

• Carbimazole is used in the EU during pregnancy and is rarely associated with congenital abnormalities [Aplasia Cutis]

• Propylthiouracil is thought to cross into breast milk less than methimazole.

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Antithyroids and Preoperative use

• Pts rendered euthyroid-to reduce operative[Subtotal thyroidectormy] morbidity & mortality

Others• Iodides-less vascularity, less friable• Dexamethasone, propranolol-7 days

before

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Adjuant therapywith Antithyroid drugs

• No intrinsic antithyroid activity• β blockers-palpitations, tremor,anxiety• Propranolol or atenolol• Diltiazem• Dexamethasone• Radiological contrast media• Cholestyramine• Rituximab-TSI

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Anti-thyroid DrugsUses

1. Thyrotoxicosis-Grave’s & Toxic nodular• Clinical improvement takes upto 1-2 weeks• Remission-try withdrawal [Grave’s]• Remission unlikely in Toxic goiter

[-Surgery/131 indicated] Or permanent oral therapy

2. Preoperatively

3. Along with 13II

4. Thyroid storm[PTU] 41

Anti-thyroid DrugsUses

Advantages• No surgical risk, scar -

injury to parathyroids or recurrent laryngeal nerve.

• Hvpothyroidism, - is reversible.

• Can be used even in children and young

• Pregnancy

Disadvantages• Prolonged tt• Drug toxicity

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Thyroid storm (thyrotoxic crisis)[Life threatening]

• Propranolol, iodides, PTU, Prednisolone• Propranolol 1-2 mg slow i.v. may be followed by 40-80

mg oral every 6 hours .• Propylthiouracil 200-300 mg oral 6 hourly• Hydrocortisone 100 mg i.v. 8 hourly followed by oral

prednisolone)• To tide over crisis, cover any adrenal insufficiency• Diltiazem 60-720 mg BD• Rehydration, anxiolylics, external cooling and

antibiotics43

Iodides

• Inhibit all aspects of iodine metabolism by the thyroid gland.

• Acute inhibition of the synthesis of T4& T3 Wolff-Chaikoff effect

• Vascularity is reduced, gland firm.• Thyroid constipation• Symptoms reappear- ‘Thyroid escape’

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Iodides-Uses

• Lugol's solution- 5% iodine and 10% KI- 8 mg of iodine / drop

• Saturated solution of potassium iodide (SSKI) al-50 mg / drop

• Dose -16-36 mg TID

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Iodides-Uses• Before surgery-7-10 days before• Protect the thyroid from radioactive iodine fallout

following a nuclear accident, military exposure, • Uptake of radioactive iodine is inversely proportional

to the serum concentration of stable iodine.• 30-100 mg of iodide daily - decrease the thyroid

uptake of radioisotopes of iodine.• Following the Chernobyl nuclear reactor accident in

1986, 10 million children and adults in Poland were given stable iodide

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Iodides-ADEs• Acute

• Angioedema and laryngeal.• Multiple cutaneous hemorrhages may be present. • Fever, arthralgia, lymph node enlargement, and eosinophilia.

• Chronic- ‘Iodism’• Unpleasant brassy taste and burning in the mouth and throat • Coryza, sneezing, and irritation of the eyes with swelling of the eyelids • Parotid and submaxillary glands -enlarged and tender, -mistaken for mumps• Skin lesions are common • Diaarhoea• Disappear spontaneously within a few days after stopping

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Radioactive Iodine• Radioactive isotopes of Iodine-123I and 131I• 123I, α -emitter -in diagnostic studies • 131I emits both γ rays and β particles- used

therapeutically for thyroid destruction• Trapped and incorporated and deposited in the colloid

of the follicles• Destructive particles originate within the follicle and

act almost exclusively on the parenchymal cells of the thyroid, damage to surrounding tissue.

• γ radiation passes through the tissue and can be quantified by external detection 48

Radioactive IodineTherapeutic Uses

• Hyperthyroidism• Antithyroid-Discontinued 1 week before

the therapeutic dose of 131I • 80-150 µCi of 131I oral• Repeat dose after 3 months if required

• Carcinoma thyroid

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Radioactive IodineTherapeutic Uses

• Carcinoma thyroid• T4 stopped [to stimulate-TSH]• Radioactive iodine• T4 [suppress TSH]

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Radioactive IodineTherapeutic Uses

Advantages• Safe-no mortality• Not expensive• No risks of surgery• No hospitalization

Disadvantages• Long time for control• Not in young• CI pregnancy• Radiation thyroiditis

[Worsening of ophthalmopathy and hyperthyroidism]

• Increase shown in -cancer, including stomach, kidney, and breast

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Radioactive IodinePrecautions after treatment

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Adjuantsβ ADRENERGIC BLOCKERS

• Propranolol• To control symptoms of sympathetic over

activity• No effect on thyroid function• While awaiting response to carbimazole or

131I.• With iodide for preoperative preparation• Thyroid storm (thyrotoxic crisis]

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The Therapeutic Choice

• Anti-thyroid drug therapy, radioactive iodine, and subtotal thyroidectomy

• Large goiters or severe disease =definitive therapy with either surgery or radioactive iodine .

• Radioactive iodine remains the treatment of choice of many endocrinologists in the U.S.

• Many investigators consider coexisting ophthalmopathy to be a relative contraindication for radioactive iodine

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The Therapeutic Choice

• Older patients, treatment with anti-thyroid drugs is advisable before therapy with radioactive iodine,

• Subtotal thyroidectomy is advocated for Graves' disease in young patients with large goiters, children who are allergic to anti-thyroid drugs, pregnant women (usually in the second trimester) who are allergic to anti-thyroid drugs,

• Radioactive iodine or surgery is indicated for definitive therapy in toxic nodular goiter.

• Radioactive Iodine is CI in pregnancy

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Anti-thyroid Compounds

Drugs ActionAntithyroid drugs [Propylthiouracil, Methimazole, Carbimazole

Inhibit synthesis of T4 & T3

Ionic inhibitors Thiocynate, perchlorate, fluoborate

High concn of Iodides Synthesis & release of hormones[Limited period]

Radioactive iodine Damages thyroid gland with ionizing radiation

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Adjuants Beta blockers. glucocorticoids