Thyroid hormones

Dr.U.P.Rathnakar
MD.DIH.PGDHM
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Thyroid hormones
T4 & T3 T4 Thyroxine, L- thyroxine T3 Triiodothronine, Liothyronine

Thyroid hormones
Synthesis Regulation Actions and MOA Uses Pharmacology of antithyroid drugs

Thyroid

Regulation of Thyroid Hormone Synthesis

Dopamine, glucocorticoids, and somatostatin suppress TSH

Thyroid Hormone Synthesis

DIT

I T4 I DIT
DIT

I I

I T3 I
DIT MIT

I
NIS MIT 7

Conversion

NIS

6 5 4

Pendrin

3
8

oxidation

[Sick euthyroid syndrome]

Transport of T4 & T3
Secretion 60-90 g of T4 & 10-30 g 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

Protein synthesis

mRNA

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Relation between T4 and T3

T4 Thyroxine 60-90 g/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. T3- Triiodothyronine 10-30 g/day Active form Potent, fast action Binds & active Triiodothyronine {Liothyronine} Not easily available Oral & i.v. Not commonly used
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Thyroid hormone actions

Increases BMR Facilitates Growth & Development

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Thyroid hormone actions

Gene transcription Protein synthesis Structural proteins For growth & development Regulatory Proteins Eg. NaK ATPase Transport pro. Receptors etc. Metabolic Proteins Eg. Enzymes

Increases BMR[except CNS & gonads] Physical and mental growth Alters systemic functions
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Thyroid hormone actions

ATPase ATP demand [Energy] Mitochondrial activity

BMR & Energy demand

Carbohydrate Absorption Increased utilization Glycogenolysis Gluconeogenesis Hyperglycemia

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

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

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T4&T3 Actions
Growth&development Metabolism Calorigenesis CVS Nervous system Sk.Muscles GIT Blood Reproduction

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Thyroid hormones Uses

Cretinism [Congenital Hypothyroidism] Adult hypothyroidism Myxoedema coma
Non-toxic goiter Thyroid nodule Papillary carcinoma of thyroid Non-specific uses
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Preparations L-Thyroxine [T4] Liothyronine[T3] Oral & i.v

Thyroid hormones Uses

Cretinism [Congenital Hypothyroidism] Thyroxine (8-12 g/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 g of l-thyroxine daily increase every 2-3 weeks 100-200 g/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 hormones Uses

Myxoedema coma Emergency-mortality Drug of choice is l-thyroxine 500 g i.v. 100 g i.v. OD till oral is started Supportive therapy Myxoedema coma If parenteral NA-oral 500 g 100-300 g OD Absorption may be delayed in hypothyroidism

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Thyroid hormones Uses

Non-toxic goiter Endemic or sporadic T4 replacement therapy Iodine supplementsprophylaxis Thyroid nodule Benign with excess of TSH T4 to suppress TSH

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Thyroid hormones Uses

Papillary carcinoma of thyroid Non-specific uses In non-resectable cases Refractory anaemias. to suppress TSH and Menstrual disorders, induce temporary Infertilitv not corrected bv regression usual treatment Chronic/ non healing ulcers Obstinate constipation

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Conversion

1to5
TSH ACTIVATES
Antithyroids drugs NIS

1 Ionic inhibitors block 2 Carbimazole Methimazole Propylthiouracil 1-2-3-5 Pendrin Iodides 6 Propranolol, Prednisolone, Propylthiouracil 131I

6 5 4

2
oxidation

3
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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

Action

Antithyroid drugs Inhibit synthesis of T4 & T3 [Propylthiouracil, Methimazole, Carbimazole

Ionic inhibitors Thiocynate, perchlorate, fluoborate Synthesis & release of hormones [Limited period]

High concn of Iodides Radioactive iodine

Damages thyroid gland with ionizing radiation Beta blockers. glucocorticoids

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Adjuants

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 28

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 29 conversion of T4 to T3

Antithyroid drugs PK
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

Peripheral conversion

Inhibits

No

31 [More than PTU]

Antithyroid drugs Adverse 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] 32

Antithyroid drugs Therapeutic 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-DOC

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Anti-thyroid Drugs Uses

Propylthiouracil: 50-150 mg TDS Methimazole: 5-10 mg TDS Maintenance O.D Carbimazole: 5-15 mg TDS

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1. Thyrotoxicosis in pregnancy
1. Pregnancy and thyrotoxicosis is unusual as anovulatory cycles are common in thyrotoxic patients 2. 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.
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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 therapy with Antithyroid drugs

No intrinsic antithyroid activity blockers-palpitations, tremor,anxiety Propranolol or atenolol Diltiazem Dexamethasone Radiological contrast media Cholestyramine Rituximab-TSI
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Anti-thyroid Drugs Uses

1. Thyrotoxicosis-Graves & Toxic nodular Clinical improvement takes upto 1-2 weeks Remission-try withdrawal [Graves] Remission unlikely in Toxic goiter [-Surgery/131 indicated] Or permanent oral therapy 2. Preoperatively 3. Along with 13II 41 4. Thyroid storm[PTU]

Anti-thyroid Drugs Uses

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 antibiotics 43

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, -emitter -in diagnostic studies 131I emits both rays and 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. radiation passes through the tissue and can be quantified by external detection 48

Radioactive Iodine Therapeutic Uses

Hyperthyroidism Antithyroid-Discontinued 1 week before the therapeutic dose of 131I 80-150 Ci of 131I oral Repeat dose after 3 months if required Carcinoma thyroid

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Radioactive Iodine Therapeutic Uses

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

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Radioactive Iodine Therapeutic 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 Iodine
Precautions after treatment

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Adjuants 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
Antithyroid drugs [Propylthiouracil, Methimazole, Carbimazole
Ionic inhibitors

Action
Inhibit synthesis of T4 & T3

Thiocynate, perchlorate, fluoborate

Synthesis & release of hormones [Limited period]

High concn of Iodides Radioactive iodine

Damages thyroid gland with ionizing radiation Beta blockers. glucocorticoids

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Adjuants