Thyroid Disorders.student version pptx (1).pptx

Thyroid Disease Pharmacology Harleen Singh Pharm D. Clinical Professor Thyroid Disease Hypothyroidism, hyperthyroidism, and nodular disease, are common, affecting 5% to 15% of the general population. Females are affected three to four times more than males. Regulation of Thyroid Hormones •Regu...

Thyroid Disease Pharmacology Harleen Singh Pharm D. Clinical Professor Thyroid Disease Hypothyroidism, hyperthyroidism, and nodular disease, are common, affecting 5% to 15% of the general population. Females are affected three to four times more than males. Regulation of Thyroid Hormones •Regulation of thyroid hormone secretion. •Release of thyroid hormones is controlled by the hypothalamic– pituitary–thyroid axis. •Dashed lines represent negative feedback, rT3, reverse triiodothyronine (inactive); T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyroidstimulating hormone or thyrotropin. Follicles:The functional Units of Thyroid Gland Key thyroid Elements function : • • • • • Thyroglobulin(Tg) Tyrosine Iodine Thyroxine(T4) Triiodotyrosine(T3) Biosynthesis of T4and T3 • The process includes • Dietary iodine ingestion • Active transport and uptake of iodine by thyroid gland • Oxidation of iodine and iodination of thyroglobulin Tg) tyrosine residues • Coupling of iodotyrosine residues (MIT and DIT) to form T4 and T3 • Proteolysis of Tg with release of T4 and T3 into circulation Thyroid Hormones • T3 (triiodothyronine is four times more potent than T4(Tetraiodothyronine) • 80% of the total daily T3 production results from the peripheral deiodination of T4 to T3. •Approximately 35% to 40% of secreted T4 is converted peripheral to T3 • 45% of secreted T4 undergoes peripheral conversion to inactive reverse T3 (rT3). • T4: 0.1% free (active) and 99.9% protein-bound (inactive) • T3: 0.2% free and 99.8%, protein bound Thyroid Function Tests • Total T4 (5‐12 mcg/dL)* • Total T3 (84.6‐130.2 ng/dL)* • Free Thyroxine (0.93‐1.7 ng/dL)* • TSH (0.27‐4.2 mIU/L)* • Most sensitive indicator of Hypothyroid function • Dose to individual patient’s pituitary response • Thyroid Antibodies ‐ TPOAb, TgAb * TEG; normal values vary with the specific laboratory Thyroid peroxidase (TPO), A thyroglobulin antibodies (TgAb) Diagnostic values Hypothyroidism Hypothyroidism Hypothyroidism is a clinical syndrome that results from a deficiency of thyroid hormone. The prevalence of hypothyroidism is 1.4% to 2% in females and 0.1% to 0.2% in males. Hypothyroidism can be caused by either primary (thyroid gland) or, less commonly, by secondary (hypothalamic–pituitary) malfunction. Hashimoto thyroiditis, an autoimmune disorder, is the most common cause of primary hypothyroidism and appears to have a strong genetic predisposition. Other common causes of hypothyroidism, including drug-induced. Hypothyroidism‐ Causes • Autoimmune (Hashimoto’s thyroiditis) • Iatrogenic causes (surgical management or RAI for HTR, external radiation) • Medications • Cretinism • Iodide deficiency (or excess) • Postpartum thyroiditis • Post‐inflammatory thyroiditis • Secondary causes (pituitary or hypothalamic dysfunction) RAI: radioactive iodine, HTR: Hyperthyrodism Classifying hypothyroidism by laboratory values Type TSH level Primary Hypothyroidis m Elevated ↑ Subclinical Hypothyroidis m Elevated ↑ Secondary Hypothyroidis m Normal ←→ or Low ↓ Free T4 level Low ↓ Normal ←→ Low ↓ Common Signs/Symptoms of Hypothyroidism • Dry Skin • Dry, course hair • Brittle nails • Thickening of tongue • Face puffiness • Goiter • Delayed DTR’s • Hypertension • Bradycardia • Non‐pitting LE edema • Cholesterol/CPK • Fatigue • Cold Intolerance • Forgetfulness • Depression • Weight Gain • Heavy periods • Galactorrhea • Muscle aches • Hoarseness • Constipation Drug‐induced Hypothyroidism Iodine‐containing contrast dyes Antineoplastic Agents (ipilimumab, bexarotene, sunitinib, nivolumab) Propylthiouracil: PTU Iodinated Glycerol Amiodarone Lithium Alpha‐Interferon Anti‐thyroid Drugs (methimazole, PTU) Hypothyroidism Treatment Thyroid Hormones Analogs • Levothyroxine (T4) • Liothyronine (T3) • Desiccated thyroid hormone • (Thyroid USP; Armour, Nature, Westhroid) • Triiodothyronine (Cytomel, Triostat) • Synthetic T4/T3 combination (Liotrix—Thyrolar) Thyroid Hormone Replacement • Goals     Provide resolution of symptoms Achieve normalization of T4 levels Avoid overtreatment (esp. in the elderly) Maintenance of the same generic preparation (i.e., maintenance of an identifiable formulation of levothyroxine) Thyroid Replacement Products: T4 MOA: Activation of nuclear receptors results in gene expression with RNA formulation and protein synthesis Euthyrox, Levoxyl, Synthroid, Tirosint, Tirosint‐SOL, Unithroid, Generics • Rationale for use •Stable, pure, and predictable potency • Serum T3 concentration controlled physiologically •Long half‐life, allows daily dosing • Twelve doses available •Different products may not be therapeutically equivalent. • Mean replacement dosage of 1.6 mcg/kg of body weight per day (if no underlying thyroid function) typically recommended Levothyroxine Dosing • Appropriate pace of replacement depends on  Duration of the hypothyroidism  Severity of the hypothyroidism  Presence of other, associated medical disorders • Use T4 initial doses of 12.5 mcg to full replacement dose. • Titrate dose to normalization of TSH level (primary disease); check TSH 6–8 weeks after each dose change, every 3– 6 T4 – Drug Interactions • Decrease in T4 absorption (take T4 1 hour before or 4‐6 hours after) • Cholestyramine, Colestipol, Colesevelam • Calcium • Ferrous sulfate • Sucralfate • Aluminum hydroxide • Magnesium • Increase in T4 metabolism (increase T4 dose) • Rifampin • Traditional anti‐epileptics (Phenytoin, CBM, PB) •Increase TBG in blood •Estrogen, Raloxifene, Tamoxifen, Heroin, Methadone At Risk Populations • Patients especially at risk with inconsistent T4 dosing: • Pregnant women (TSH goal of under 2.5 or 3 mIU/L; increase T4 replacement by 30% with first detection of pregnancy) • Infants (T4 dose of 10–15 mcg/kg) • Thyroid cancer patients (target TSH of 0.1–0.2) • Patients with preexisting cardiac disease and older persons (start low, 12.5 mcg and go slow, 12.5‐mcg increments every 6–8 weeks) • Patients with preexisting Osteoporosis Case 1 A 63-year-old woman has Hashimoto disease. Her thyroid laboratory values today include TSH 10.6 mIU/L (normal 0.5– 4.5 mIU/L) and free T4 0.5 ng/dL (normal 0.8–1.9 ng/dL). She feels consistently rundown and has dry skin that does not respond to the use of hand creams. Which is the best drug for initial treatment of her condition? A. Levothyroxine. B. Liothyronine. C. Desiccated thyroid. D. Methimazole. Hyperthyroidi sm Hyperthyroidism Hyperthyroidism or thyrotoxicosis is the hypermetabolic syndrome that occurs from excessive thyroid hormone production. Hyperthyroidism affects about 1.3% of the U.S. population (0.5% clinical disease and 0.7% subclinical hyperthyroidism). The condition is more prevalent in females and white patients and increases with age Hyperthyroidism ‐ Causes • Toxic diffuse goiter (Graves’ disease) • Toxic adenoma (uninodular goiter) • Toxic multinodular goiter (Plummer’s disease) • Iodine induced HTR (Jod‐Basedow) • Excessive ingestion of thyroid hormone (factitious) • Drugs (amiodarone) • Tumor (excessive pituitary TSH or trophoblastic disease) • Painful subacute thyroiditis • Silent thyroiditis, including lymphocytic and postpartum variations Case 2 • Mrs. L. is a 38‐year‐old woman with newly diagnosed Graves’ disease who experiences fatigue, heat intolerance, tremor, and palpitations. • She has no significant medical history and is currently taking no medications. • Laboratory results include the following: TSH less than 0.01 mIU/L (0.4–4); FT4 3.3 ng/dL (0.7–1.9); and TT3 368 ng/dL (80–180). Case 2 continued Initiation of which of the following regimens will reduce her symptoms within hours? A. PTU 100 mg 3 times/day B. Methimazole 10 mg 2 times/day C. Lugol’s solution 10 drops 3 times/day D. Nadolol 40 mg 2 times/day Laboratory Values • Both T3, T4 ↑ • TSH ↓ • I131 uptake ↑ • TRs antibodies ↑ • ECG – Tachycardia, arrhythmia • USG – Diffuse Goiter Common Signs & Symptoms of Hyperthyroid Disease • Flushed, Moist Skin • Increased HR, Tremor • Thinning of hair • Proptosis, lid lag • Pretibial myxedema • Palmar erythema • Brisk DTR’s • Goiter • Weakness, fatigue • Nervousness • Muscle aches • Weight Loss • Heat Intolerance • Palpitations • Amenorrhea • Diarrhea • Insomnia Uptake of Radioiodine by the Thyroid N Engl J Med. 2011;364(6):542-550. doi:10.1056/NEJMct1007101 Goiter Drug‐Induced Hyperthyroidism IODINE‐ CONTAINING CONTRAST DYES AMIODARONE ALPHA‐ INTERFERON THYROID HORMONE (T3, T4) IODINATED GLYCEROL Hyperthyroidi sm Treatment Hyperthyrodism Treatment Radioactive iodine(131I) • Most common treatment of Graves’ disease in US • Contraindication in pregnancy and in nursing mothers • Very high risk of subsequent hypothyroidism Surgery: • TOC for thyroid cancer, respiratory or swallowing difficulties • Find an experienced surgeon! • Results in Hypothyroidism • Other Risks Antithyroid pharmacotherapy Beta blockers Mechanism of action: Manage sympathetic‐mediated symptoms. Inhibit peripheral T4 conversion (propranolol, nadolol). Very quick onset of effect (hours) Dose: • Propranolol 120–160 mg/day in three or four divided doses; maximum 640 mg/day • Nadolol 80 mg/day in one or two divided doses; maximum 320 mg/day • Used until more specific antithyroid therapy takes effect Adverse effects: Hypotension, Bradycardia, Fatigue Contraindications: COPD, Asthma, HF Thioamides Mechanism of action: Mechanism of action: Inhibits iodination and synthesis of thyroid hormones; propylthiouracil can block T4 /T3 conversion in the periphery as well at high doses . Delayed effect (weeks) Dose: • Propylthiouracil(PTU): 300–600 mg/day in two or three divided doses; preferred in first trimester of pregnancy, lactation and thyroid storm • Methimazole (Tapazole): 30–60 mg/day in one or two divided doses; longer half‐life, better adherence, LESS HEPATOTOXICITY • Often used before RAI therapy or surgery; may use for 18–24 Thioamides (cont.) Adverse effects: • Benign: Rash, fever, arthralgias • Severe: Agranulocytosis, hepatitis • Hepatotoxicity risk (boxed warning for PTU) Patient information: • Report fever, sore throat, flulike symptoms, abdominal pain, dark urine, or lightly colored stool. • When getting a prescription for thioamide, be sure to get one for a complete blood cell count (agranulocytosis). Iodides Mechanism of action: Block thyroid hormone release. Inhibit organification. Inhibit the peripheral conversion of T4 to T3, Decrease gland size/vascularity Rapid onset (days) Dose • Saturated solution of potassium iodide (38 mg/drop): 1–5 drops in juice three times daily for 10 days before surgery • Lugol solution (potassium iodide and iodine; 6 mg/drop): 3–5 drops in juice three times Daily for 10 days before surgery • Radiographic iodinated contrast agents: 1 g orally daily (Telepaque/Oragrafin/ Hypaque) • Most commonly used for patients with Graves disease before surgery and in thyroid storm Iodides Adverse Effects/Contraindications Adverse effects • Dose‐related toxicity (iodism) • Metallic taste • “Escape” phenomenon • Allergic reactions Contraindications • Pregnancy • Prior to RAI therapy • Patients with nodular goiter or adenomas Case 2 continued Initiation of which of the following regimens will reduce her symptoms within hours? A. PTU 100 mg 3 times/day B. Methimazole 10 mg 2 times/day C. Lugol’s solution 10 drops 3 times/day D. Nadolol 40 mg 2 times/day References •Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid. 2017;27(3):315–389. doi:10.1089/thy.2016.0457 (128) •Bekkering GE, Agoritsas T, Lytvyn L, et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019;365: l2006. (172) •Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement. Thyroid. 2014;24(12):1670–1751. doi:10.1089/thy.2014.0028 (32) •Ross DS. Radioiodine therapy for hyperthyroidism. N Engl J Med. 2011;364: 542–550. (196) •Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343–1421. doi:10.1089/thy.2016.0229 (33) •Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21(10):1081–1125. doi:10.1089/thy.2011.0087 (38) Questions?