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Thyroid drugs

The document discusses thyroid hormones and thyroid inhibitors. It describes the synthesis and actions of thyroid hormones T3 and T4. It then outlines different classes of thyroid inhibitors including antithyroid drugs, iodine/iodides, and radioactive iodine. Antithyroid drugs like methimazole and propylthiouracil inhibit hormone synthesis while iodine/iodides inhibit hormone release. Radioactive iodine is used therapeutically to destroy the thyroid gland in conditions like Graves' disease.

Health & Medicine◦
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 synthesis 1.Iodide uptake 2.Oxidation and iodination 3.Coupling 4.Storage and release 5.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 liver Excreted in bile and enters enterohepatic circulation Finally 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 because it 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 unable to activate/derepress gene transcription. • About 1/3 of T4 is converted to T3 in the thyroid cells, liver and kidney by D1 type of 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 lipolysis Plasma free FA levels elevated Lipogenesis stimulated Chol metabolism stimulated Carbohydrate: Met stimulated Tissue sugar utilization increases Compensatory 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
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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 onset Shorter duration of action Reserved for acute emergencies Ex; 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 goiter 5. 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 causes 1.grave’s disease 2.Toxic nodular goiter 17 Thyroid inhibitors
Classification of drugs: 1. Inhibit hormone synthesis- PTU, Methimazole, Carbimazole 2. Inhiit iodide trapping/ ionic inhibitors thiocyanates, perchlorates, nitrates 3. Inhibit hormone release iodine, iodides of Na&K, organic iodide 4. Destroy thyroid tissue Radioactive 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 thyroglobulin 2.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 recur Toxic 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 preparation 2. Thyroid storm 3. Prophylaxis of endemic goiter 4. 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 •131 I is - used for treatment of thyrotoxisis •Administered orally in solution as sodium 131 I, 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
Thyroid drugs