Pharmacology of Thyroid Gland 2024-2025 PDF

Pharmacology of thyroid gland 2024-2025 Dr. Mahmood Salim Thyroid hormones The hormones secreted by the thyroid gland are thyroxine (T4), triiodothyronine (T3 ) and calcitonin. The thyroid follicular cells have specialized mechanism for the synthesis of thyroid hormones. This...

Pharmacology of thyroid gland 2024-2025 Dr. Mahmood Salim Thyroid hormones The hormones secreted by the thyroid gland are thyroxine (T4), triiodothyronine (T3 ) and calcitonin. The thyroid follicular cells have specialized mechanism for the synthesis of thyroid hormones. This is regulated by TSH secreted by anterior pituitary, which, in turn, is inhibited by the free thyroid hormone levels. The ‘C’ cells of thyroid secrete calcitonin, which is a functionally distinct hormone regulating calcium metabolism. Deficiency of thyroid hormones in children results in cretinism characterized by mental retardation and other features of hypothyroidism; in adults, it results in myxedema. Hypersecretion of these hormones also has effects on various organ systems resulting in ‘thyrotoxicosis’. Drugs used for treating hyperthyroidism are called antithyroid drugs. These drugs play an important role in the management of hyperthyroidism caused by both benign and malignant conditions of thyroid gland. Synthesis of thyroid hormones 1.Iodide trapping: Active transport of iodide ions (I-) into follicular cells of thyroid gland is known as iodide trapping and takes place by a basement membrane protein called the sodium/iodide symporter. This process can be inhibited by thiocyanates and perchlorates, which compete with iodide. 2.Oxidation and iodination: The iodide ion is oxidized to iodine by peroxidase enzyme. Iodine combines with tyrosine residues of thyroglobulin molecule and forms monoiodotyrosine (MIT) and diiodotyrosine (DIT). The peroxidase enzyme is transiently blocked by high levels of iodide in the follicular cells and persistently blocked by thiourea group of antithyroid drugs. 3. Coupling: This is the final step in the synthesis of thyroid hormones. Two molecules of DIT couple to form thyroxine (T4), and one molecule of MIT with one molecule of DIT forms triiodothyronine (T3). 1.Hormone release: Release of thyroid hormones takes place under the control of TSH. The process involves endocytosis and proteolysis of iodinated thyroglobulin and results in release of T4, T3, MIT and DIT. The process of proteolysis is also inhibited by high levels of intrafollicular iodide. 2.Peripheral conversion of T4 to T3: Most of the hormone released from thyroid is T4, which is much less potent in comparison to T3. Conversion of T4 to T3 in periphery is inhibited by propylthiouracil, iopanoic acid, propranolol and glucocorticoids. Mechanism of action Mechanism of action of thyroid hormones is similar to that of steroid hormones. Thyroxine needs to be converted into T3 inside the cell for binding to the nuclear receptor. Features of Hyperthyroidism and Hypothyroidism  Therapeutic uses: Replacement therapy in hypothyroid states 1. Cretinism and myxedema: For cretinism, treatment should be started as early as possible after birth. In young adults, full replacement doses of levothyroxine sodium. 2. Myxedema coma: This is a medical emergency and usually common in longstanding untreated myxedema cases. 1.Levothyroxine (T4): has all the action of endogenous thyroxine; it is given orally. Starting dose of levothyroxine 1.6 to 1.7mcg/kg/day. In older patient with long standing disease without cardiac disease start therapy with levothyroxine 50 mcg/day and increase after 1 month but in older cardiac patient initial dose 25mcg daily, generally taken in the morning, 30 min before eating (empty stomach). Side effect: Flushing, Diarrhea, palpitation, Myocardial infarction, Headache, anxiety, Tremor…etc 1.Liothyronine (T3): has all the actions of endogenous tri-iodothyronine; it is given I.V. is the treatment of choice for Myxoedema coma. 20mcg I.V injection followed by further injection 20 mcg three times daily until there is sustained clinical improvement. After 48-72 hr switch patient to oral levothyroxine 50mcg daily. 2.Liotrix: Mixture of levothyroxine and liothyronine, it’s better tolerated than T3 preparation and longer half life. Antithyroid Drugs These drugs reduce the level of thyroid hormones by reducing thyroid hormone synthesis or release or both. They are used in the treatment of hyperthyroid conditions. Classification 1. Thyroid hormone synthesis inhibitors (thioamides thiourea or derivatives): Propylthiouracil, methimazole, carbimazole. 1. Hormone-release inhibitors: Iodine, iodides of Na+ and K+, organic iodide. 2. Thyroid tissue-destroying agent: Radioactive iodine (I131). 3. Others: Propranolol, diltiazem, dexamethasone.  Thioamides Propylthiouracil, methimazole and carbimazole are thioamides used to treat hyperthyroidism. Their mechanism of action is depicted in Figure  Mechanism of action of thioamides 1. They inhibit thyroid peroxidase enzyme, which converts iodide to iodine. 2. They inhibit iodination of tyrosine residues in thyroglobulin. 3. They inhibit coupling of iodotyrosines (MIT and DIT). Propylthiouracil also inhibits the peripheral deiodination of T4 to T3. Pharmacokinetics Thioamides are well absorbed orally. Propylthiouracil is most rapidly absorbed. Carbimazole is converted to methimazole after absorption. They are widely distributed but get accumulated in thyroid gland. Propylthiouracil has a short half-life and needs to be given every 6–8 h. They cross the placental barrier and can cause fetal hypothyroidism. They are excreted in urine. Adverse effects Skin rashes are most common. The other side effects are joint pain, fever, hepatitis, nephritis, etc. A dangerous but rare adverse effect is agranulocytosis, which usually occurs during first few weeks or months of therapy; but it may occur later also. This may develop rapidly, so regular blood counts may not be helpful. The drugs should be stopped at the first sign of agranulocytosis, i.e. sore throat and/or fever.  Uses 1.For long-term treatment of thyrotoxicosis where surgery is not indicated or not feasible and radioactive iodine is contraindicated. 2. Along with radioactive iodine to hasten recovery in thyrotoxicosis. 3. For treatment of thyrotoxic crisis along with iodide and propranolol.  Iodine and Iodides Iodides are the oldest agents used to treat hyperthyroidism. They can inhibit all steps in the synthesis of thyroid hormones, but the major effect is inhibition of release of thyroid hormones. Preparations and uses of iodine and iodides: 1. Lugol’s iodine (5% iodine in 10% solution of KI): It is used orally preoperatively before thyroidectomy and in thyroid storm. It renders the gland firm, less vascular and decrease its size, which makes surgery convenient with less bleeding and complications. 2. As an expectorant: Potassium iodide (KI) acts as a mucolytic agent that enhances expectoration. 3. As an antiseptic: Tincture of iodine (iodine in alcohol). Adverse effects Allergic reactions: Angioedema, laryngeal oedema, arthralgia, fever, eosinophilia, and lymphadenopathy may occur acutely (type-III hypersensitivity). Chronic overdose with iodide results in iodism. The symptoms are headache, sneezing and irritation of eyes with swelling of eyelids, and sometimes pulmonary oedema can occur. These resolve after few days of stopping iodine. Hypothyroidism may also occur; use of iodides during pregnancy may cause fetal goiter.  Radioactive Iodine Therapeutically used radioactive iodine is (I)131. Sodium iodide containing (I)123 is used for diagnostic scan. Radioactive iodine gets concentrated in the same way as stable iodine in thyroid, and emits 3- rays and β-particles. The β-particles cause destruction of the follicular cells leading to fibrosis and correction of hyperthyroid state.  Uses and contraindications Radioactive iodine is used in hyperthyroidism due to adenoma or carcinoma when surgery is not feasible or contraindicated. It is contraindicated in pregnancy, patients less than 16 years and Graves disease associated with eye manifestation. Advantages 1.Treatment is simple; does not require hospitalization—can be done in the outpatient department. 2. Not expensive. 1. No risk of surgery and scar. 2. Permanently cures hyperthyroidism. Disadvantages It is slow acting and causes local soreness in the neck. Incidence of hypothyroidism is high. It is not suitable for pregnant women, children and young patients (16 years < age).  β-Adrenoceptor Blockers (β-Blockers) Although β-blockers are not strictly antithyroid drugs, they produce dramatic improvement in symptoms of thyrotoxicosis like tachycardia, palpitation and tremors. Propranolol also has an inhibitory effect on peripheral conversion of T4 to T3.  Uses 1. To control symptoms of thyrotoxicosis initially till antithyroid drugs act. 2. In thyrotoxic crisis. 3. Preoperatively before thyroid surgery.