Thyroid Disorders PDF

THYROID DISORDERS REAGAN KABUKA (B.PHARM, MPH) THYROID HORMONES The thyroid gland is a butterfly shaped endocrine gland at the front of the neck that controls the body's metabolism (how the body uses energy) The thyroid gland secretes; Thyroid hormones: - T...

THYROID DISORDERS REAGAN KABUKA (B.PHARM, MPH) THYROID HORMONES The thyroid gland is a butterfly shaped endocrine gland at the front of the neck that controls the body's metabolism (how the body uses energy) The thyroid gland secretes; Thyroid hormones: - Thyroxin (T4) and Tri-iodothyronine (T3) Thyrocalcitonin Synthesis, Storage and Release of Thyroid hormones (T3 and T4) The hypothalamus secretes thyrotropin-releasing hormone (TRH) which stimulates the anterior pituitary gland to secrete thyroid-stimulating hormone (TSH) TSH binds to specific fixed membrane-bound receptors on the thyroid cell leading to activation of adenyl cyclase resulting in increased cAMP. This leads to increase in the size, vasculature and function of the thyroid gland Iodide active uptake and concentration of by the thyroid gland is known as iodide trapping and facilitated by the effect of TSH and ATP (sources of energy). About 50% of the circulating iodide is trapped by the thyroid gland and rest excreted in urine Active trapping of iodide can be inhibited by: - 1. Monovalent chemical groups that compete with iodine e.g. Perchlorate, nitrates and Thiocyanate 2. Anaerobic conditions that cause depletion of ATP 3. Digitalis antagonizes ATPase enzyme therefore antagonize ATP utilization Iodide Metabolism Conversion of iodide into active elementary iodine by thyroid peroxidase (TPO) Organification of iodine: - Iodine combines with thyroglobulin to give mono-iodotyrosine (MID) and Di-iodotyrosine (DIT) Coupling of MID and DIT to give Tri-iodothyronine (T3) and Tetra- iodothyronine (T4). MIT and DIT are retained inside the cell and de-iodinated by thyroid de- ionidinase enzyme leading to elementary iodine producing further iodination of tyrosine. Lack of thyroid de-iodinase enzyme leads to decreased availability of iodine which results in Hypothyroidism. Release of T3 and T4 after secretion is under the function of TSH Pharmacokinetics of Thyroid hormones Irregularly absorbed orally. Better given before meals on empty stomach. Distributed all over the body The major parts of circulating T3 and T4 are protein-bound mainly to thyroxin-binding globulin T4; the bound part is 99.9% while the free active part is 0.1%. T3; the bound part is 99.6% while the free active part is 0.4%. Aspirin displaces T3 and T4 from plasma protein binding sites leading to increased free form Loss of plasma proteins decreases binding sites for T3 and T4 leading to increased free form Oestrogens increase binding of T3 and T4 leading to decreased free form Fate of Thyroid hormones The major part goes through hepatic conjugation with glucuronic acid then excreted in the bile into the intestine where the major part is excreted in the stool. The rest is deconjugated in the intestine and reabsorbed into the liver (entero-hepatic circulation) In the kidney (mainly) and the liver, they undergo oxidative deamination and transamination i.e. T3 into Tri-iodo-thyro-acetic acid while T4 into Tetra-iodo-thyro-acetic acid and excreted in the urine T4 is acted on by tissue de-iodinase leading to de-iodinatio into T3 (4 times more than T4) Pharmacodynamics of Thyroid hormones Actions and toxicity of thyroid hormones 1. Calorigenic effect- Increased basal metabolic rate which produces hyperpyrexia resulting into warmness, flushing and intolerance to heat 2. Sympathetic activity resulting into anxiety, skeletal muscle tremors and sweating 3. CVS - Direct action of the blood vessels and heart resulting in vasodilatation and tachycardia 4. Kidney: - Diuretic action 5. G.I.T: - Increased motility resulting in diarrhea and malabsorption, increased appetite but loss of weight (due to increased metabolic rate) SIGNS AND SYMPTOMS Preparations of Thyroid Hormones 1) Levothyroxin-sodium (L-T4) 100ug/day; - In the form of tablets or powder for reconstruction for injection 2) Liothyronine-sodium (T3) 25ug/day; - Stronger than T4 (4 times more T3). - Quicker onset but short duration 3) Liotrix: - T4 + T3 in a ratio of 4:1 (physiological) Therapeutic Uses of Thyroid Hormones Replacement therapy in hypothyroidism Hypothyroidism in adult (Myxoedema); Levothyroxin-sodium is used 50ug/day for 2 weeks, then 100ug/day for 2 weeks then 150ug/day for life Hypothyroidism in children (Cretinism): - Early treatment leads to better results. Levothyroxin-sodium is used and the dose is adjusted according to the age of the child Simple non-toxic goiter: - usually due to decreased thyroid hormones leading to increased TSH resulting in increased size of thyroid Hypercholesterolemia: -D-thyroxin is used in euthyroid or cardiac patients. Levothyroxin in hypothyroid patient as part of replacement therapy. Gynaecological disorders: - Amenorrhea and recurrent abortion. ANTITHYROID DRUGS Thioamides: - decrease organification resulting in decreased synthesis of thyroid hormones Ionic inhibitors e.g. Potassium perchlorate: - decrease trapping of iodide resulting in decreased synthesis of T3 and T4. Iodide therapy e.g. Lugol’s iodine: - reduces the effects of TSH on the thyroid gland and inhibits the release of T3 and T4. Radioactive 131-Iodine; - emits Beta-rays that destroy thyroid tissue Beta-blockers e.g. Propranolol Surgical: - subtotal thyroidectomy. Thioamides, Thiouracils and Thioureas 1- Propylthiouracil - 100mg t.d.s till control of symptoms then 50mg once daily orally. 2- Methimazole - 10mg t.d.s till control of symptoms then 5mg once daily orally. 3- Carbimazole - similar to Methimazole Mechanism of action of Thioamides They inhibit Organification of iodide leading to decreased synthesis of thyroid hormones. Inhibit peroxidase enzyme resulting in decreased conversion of iodide to active elementary iodine. Inhibit incorporation of iodine into thyroglobulin thereby inhibit the formation of MIT and DIT. Inhibit coupling of MIT and DIT resulting in decreased synthesis of T3 and T4. Therapeutic uses of thioamides : Drugs of choice in mild hyperthyroidism. (Moderate and severe hyperthyroidism are treated by surgery or radioactive iodine-131). Temporary control of moderate and severe hyperthyroidism till: - Preparation of patient for subtotal thyroidectomy. Side effects and toxicity of thioamides : Agranulocytosis, hypersensitivity reactions e.g. skin rash, GIT upsets, increased size and vasculature of the thyroid gland, exophthalmos, if given during pregnancy or lactation, results in cretinism, loss or depigmentation of hair, liver and kidney damage, Joint pains. Potassium perchlorate Mechanism of action: Ionic inhibitor which competes with iodine for uptake and storage by the thyroid gland leading to decreased synthesis of thyroid hormones Effects of Potassium perchlorate: Inhibit thyroid function after a latent period of 1-2 weeks, till depletion of stored colloid. Increase size and vascularity of thyroid gland due to increased TSH. Exophthalmos. Therapeutic uses of Potassium perchlorate: - Similar to thioamides: - It is used to substitute thioamides in patients allergic to them. Side effects of Potassium perchlorate: - Similar to thioamides, in addition; - Fetal aplastic anaemia Iodide Therapy Preparations: Lugol’s iodine (5% iodine in 10% potassium iodide): - 0.3ml t.d.s orally Potassium iodide: - 60mg t.d.s orally. Actions of Iodides:- A) – Antithyroid effect: Attenuate effect of TSH on the thyroid gland, decrease size and vascularity of thyroid gland, decrease endocytosis of thyroglobulin leading to colloid accumulates in the follicle lumen, decrease proteolysis of thyroglobulin, decrease release of T3 and T4 B) Saline expectorant: Na+ and K+ iodide is absorbed from stomach and intestine; secreted in all exocrine glands thereby producing irritation. They increase conjunctival, lacrimal, salivary and bronchial secretions. Iodine directly liquefies tenacious sputum Uses: - 1) – In chronic bronchitis. 2) – Pre-operative preparation (7-10 days) before subtotal thyroidectomy. 3) – Hyperthyroid crisis. Side effects: Allergic reactions. - Iodism: - Headache, conjunctivitis, rhinitis, sialadenitis and gastritis. Radioactive Iodine-131 Radioactive iodine-131 is trapped by the thyroid In the thyroid gland, radioactive iodine is converted to radioactive T3 and T4 and sored in colloid Radioactive iodide emits 2 types of rays: Iodine-131 in large dose (Beta-rays- destructive and of low penetration) and Iodine-132 in small dose (gamma-rays- non-destructive and of high penetration) N.B: - Iodine-131 half-life = 8 days; used in therapy. - Iodine-132 half-life = 2 hours; used in diagnosis Therapeutic uses of Iodine-131: 1. Moderate and severe hyperthyroidism in: - Old patients and cardiac patients. - Recurrence after surgery. - Failure of anti-thyroid drug therapy. The effect of treatment by radioactive iodide appears after 2-3 months during which, patient is temporary controlled by anti-thyroid drugs plus Beta-blocker 2. Cancer of the thyroid 3. Test the function of thyroid; use small dose of Iodine-132, then measure Gamma-rays Side effects of Radioactive Iodide: - 1- Pain and congestion at the site of the thyroid. 2- Hypothyroidism Contraindications of Radioactive Iodide therapy: - 1) – Children; leads to hypothyroidism and high chance of malignancy. 2) – Pregnancy; damage of fetal thyroid. Beta-Blockers Example: - Propranolol (oral and I.V). Advantages: - 1. Protects the heart from tachycardia, angina and arrhythmia of hyperthyroidism 2. Passes the blood-brain-barrier leading to decreased anxiety and tremors of hyperthyroidism 3. Decreased conversion of T4 to the more active T3. Uses: Orally in temporally relief of manifestations till control of hyperthyroidism by anti-thyroid drugs, surgery or radioactive iodide I.V in emergency treatment of hyperthyroid crisis Guanethidine Guanethidine eye-drops produce decreased Exophthalmos by relaxing the sympathetically innervated smooth muscle responsible for eyelid retraction. Choice of treatment of Hyperthyroidism Mild Hyperthyroidism: Thioamides or Perchlorate Propranolol orally Guanethidine eye-drops. Moderate and Severe Hyperthyroidism: - A) – Surgical treatment; subtotal thyroidectomy. B) – Radioactive Iodide-131. Preparation of patient for surgery: Sedatives e.g. Diazepam Propranolol; the resting heart rate should be less than 90 beats/ min Anti-thyroid drugs (Thioamides or Perchlorate) for 6 weeks. Stop the drug 10- 14 days before operation Lugol’s iodide 0.3 ml t.d.s for 7-10 days before operation. QUESTIONS???