Thyroid hormone & Thyroid inhibitors

Objectives

• List the clinical uses of thyroxine• Outline the classification of thyroid inhibitors• Describe the mechanism of action, pharmacokinetics, adverse effects

and clinical uses of antithyroid drugs• Describe the mechanism of action, adverse effects and clinical uses

of iodine and iodides

Thyroid gland• Secretes three hormones - Triiodothyronine (T3) - Tetraiodothyronine (T4, thyroxine) - Calcitonin

Biosynthesis of thyroid hormones

Steps in the synthesis1.Iodide uptake2.Oxidation and iodination3.Coupling 4.Storage and release5.Peripheral conversion of T4 to T3

6

Transport, Metabolism and Excretion •Only about 0.03-0.08% of total T4 & 0.2-0.5% of T3 exist in the free form.•Binds with-Thyroxine binding globulin-Thyroxine binding prealbumin-Albumin Metabolic inactivation of T4 and T3 occurs by deiodination and glucuronide/sulfate conjugation Occurs mainly at liverExcreted in bile and enters enterohepatic circulationFinally excreted in urine T1/2-T4 6-7days, T3 1-2 days

Relation between T4 and T3• Thyroid secretes more T4 than T3

• T4 is the major circulating hormone becauseit is 15 times more tightly bound to plasma

proteins.• T3 is 5 times more potent than T4 and acts

faster. •Peak effect of T3 comes in 1–2 days while

that of T4 takes 6–8 days.• T3 is more avidly bound to the nuclear receptor

than T4 and the T4-receptor complex is unableto activate/derepress gene transcription.

• About 1/3 of T4 is converted to T3 in thethyroid cells, liver and kidney by D1 typeof 5’deiodinase (5’DI) and released into

circulation. **T3 is the active hormone, while T4 is mainly a transport form;

functions as a prohormone of T3.

Actions of thyroid hormone• Metabolic function –Lipid: Enhance lipolysisPlasma free FA levels elevated Lipogenesis stimulated Chol metabolism stimulated Carbohydrate:Met stimulated Tissue sugar utilization increasesCompensatory glycogenolysis, gluconeogenesis and faster absorption of glucose in

intestine insulin resistance and hyperglycemia in hyperthyroidism Protein :Overall effect is catabolic Protein as energy source Negative nitrogen balance and wasting Weight loss

Growth and development :• Essential •Exerted through the protein synthesis by translation of genetic code •Cretinism in children and adults also impaired intelligence•Affects nervous system

•On GIT:• appetite & food intake. • motility of GIT diarrhea often result in hyperthyroidism

•On CVS: • Direct action on contractile elements and upregulation of beta receptors • Hyperdynamic circulation- due to demand and direct cardiac effect • cardiac output, HR, contractility • Angina, AF, CHF, systolic BP increases

•On nervous system: • excitable effect.• Has role on development of brain in fetal & 1st few weeks of postnatal life

•Muscle weakness due to protein catabolism

• Haemopoiesis: Anaemia in hypothyroidism

• Reproduction:Indirect effect on reproduction

12

13

Thyroid drugs

PharmacokineticsPharmacokinetics

Levothyroxine bioavailability – 75%

Well absorbed orally

Should be taken empty stomach

Sucralfate, iron, calcium, PPI reduces absorption

Enzyme inducers- rifampicin, phenytoin, carbamazepine- accelerates

metabolism

DRUGSDRUGS

levothyroxine (L-T4)- oral + IV

liothyronine (T3)- IV used in myxedema coma

Liothyronine:Faster onsetShorter duration of actionReserved for acute emergenciesEx; myxedema coma

ADR: Signs and symptoms of hyperthyroidism in overdose Risk of angina pectoris, cardiac dysrhythmias and cardiac failure Osteoporosis Hypersensitivity reactions- rash, pruritus, oedema

Mechanism of action

Mechanism of action of thyroid hormone on nuclear thyroid hormone receptor (TR).T3—Triiodothyronine; T4—Thyroxine; TRE—Thyroid hormone response element; RXR—Retinoid X receptor;mRNA—Messenger ribonucleic acid; 5’DI—5’Deiodinase

16

Uses- Mostly as replacement therapy 1. Cretinism : treat early as possible

8-12microgram/kg/day 2. Adult hypothyroidism:

start a low dose and increase every 2-3 wks and optimum 100-200microgram/day

3. Myxoedema coma: emergency IV T4 and low dose IV T3

4. Nontoxic goiter5. Thyroid nodule- certain nodules only

if not size reduces in 6 months stop treatment 6. Papillary carcinoma of the thyroid 7. Empirical uses- refractory anaemia, mental depression, infertility,

• Used to lower the functional capacity of the hyperactive thyroid gland

Thyrotoxicosis-Two main causes1.grave’s disease2.Toxic nodular goiter

17

Thyroid inhibitors

Classification of drugs:

1. Inhibit hormone synthesis-PTU, Methimazole, Carbimazole

2. Inhiit iodide trapping/ ionic inhibitorsthiocyanates, perchlorates, nitrates

3. Inhibit hormone releaseiodine, iodides of Na&K, organic iodide

4. Destroy thyroid tissueRadioactive iodine I-131,125,123

Thioamides/ antithyroid drugs • Prevent hormone synthesis by inhibiting the thyroid

peroxidase-catalyzed reactions and blocking iodide/ iodotyrosyl oxidation

1.Inhibit iodination of tyrosine in thyroglobulin2.Inhibit coupling of iodotyrosine residues to form T3

and T4

• Thyroid colloid depleted over the time • Do not interfere with trapping of iodide and not

modify the action of T3 and T4• Do not affect the release of T3/T4• PTU inhibits peripheral conversion of T4 to T3

PK

• Well absorbed orally• Widely distributed • Enter milk and cross placenta• Metabolized in liver and excreted in urine • Concentrated in thyroid and thyroid t1/2 is longer • Carbimazole converted to methimazole

Adverse reactions

• Intolerance• Skin rashes and joint pain • Hypothyroidism and goiter due to over treatment • An altered sense of taste • Liver damage • The most dangerous – agranulocytosis (granulocyte count <

500 cells/mm2)- rare

Use

• Control thyrotoxicosis• Clinical improvement by 1-2 wks or more • Maintenance doses titrated with clinical status of the patient

1. Definitive therapy-Grave’s disease: remission by 1-2 yrs or reinstitute if recurToxic nodular goiter: surgery/ I-131/ permanent maintenance therapy

with antithyroid drugs 2. preoperatively

3. Along with I-131

Benefit& disadvantages of antithyroid drugs Vs Surgery/radio iodine Benefit •No surgical risk•If hypothyroidism occur- reversible•Can be used in children and adults

Disadvantages•Prolonged/ life long treatment•Difficult in uncooperative ptn•Drug toxicity

Which one to prescribe during pregnancy?

Ionic inhibitors

• Monovalent anions inhibit iodide trapping into thyroid • Toxic and not clinically used now • Ex: perchlorates, thiocyanates

Iodine and Iodides• Fastest acting thyroid inhibitor • Thyroid status starts to return normal• Complete stoppage of hormone release from the gland • Thyroid gland involutes and colloid restored • Response to iodine and iodide is identical • Peak effects in 10-15 days • Thyroid escape occur following- again thyrotoxicosis • Main action- inhibition of hormone release • Wolff-Chaikoff effect: excess ioidide rapidly and briefly interferes

with iodination of tyrosil and thyronil residues of thyroglobulin resulting in reduced T3/T4 synthesis

Ex:Lugol’s solution

Cont’d• Uses:

1. Preoperative preparation2. Thyroid storm3. Prophylaxis of endemic goiter4. Antiseptic

• Adverse effect:• Acute reaction : swelling of lip, eye lid, face, angineurotic edema of larynx, fever,

joint pain, lymphadenopathy, thrombocytopenia• Chronic overdose : inflammation of mucous membrane , salivation, lacrimation,

burning sensation in the mouth, rhinorrhoea, GI intolerance

Radioactive iodine• 131I is - used for treatment of thyrotoxisis

• Administered orally in solution as sodium 131I, it is rapidly absorbed

• concentrated by the thyroid, & incorporated into storage follicles emits β particles & X rays β particles damage the thyroid cells thyroid tissue destroyed by pyknosis and necrosis replaced by fibrosis

• Use• Diagnostic purpose 25-100μ curies in thyroid function test• Therapeutic use 3-6 milli curies in toxic nodular goiter, graves disease.

• Advantage :• Easy administration• Effectiveness• Low expense• Absence of pain• In patient who have indication of operation but want to avoid operation• Once treated no chance of recurrence

• Disadvantage :• Hypothyroidism• Latent period of getting response (8-12 weeks)• Contraindicated in pregnancy • Not suitable for young patients