Thyrotoxicosis (hyperthyroidism)

Introduction: Thyrotoxicosis is any syndrome caused by excess thyroid hormone and can be related to excess hormone production (hyperthyroidism).

Pathophysiology: Thyrotoxicosis results when tissues are exposed to excessive levels of T4,

T3, or both. Hyperthyroidism, which is one cause of thyrotoxicosis, refers to overproduction of thyroid hormone by the thyroid gland.

TSH-secreting pituitary tumors release biologically active hormone that is unresponsive to normal feedback control.

Graves’ disease is the most common cause of hyperthyroidism; it results from the action of thyroid-stimulating antibodies (TSAb) directed against the thyrotropin receptor on the surface of thyroid cell.

Clinical presentation: Subtle and slowly progressive, patient may seek medical attention only after long period of thyrotoxicosis or owing to an acute complication such as atrial fibrillation.

*Symptoms: Nervousness, anxiety, palpitations, emotional lability, easy fatigability, heat intolerance, weight loss concurrent with increased appetite, increased frequency of bowel movements, proximal muscle weakness (noted on climbing stairs or arising from a sitting position), and scanty or irregular menses in women.

*Sign: Physical signs include warm, smooth, moist skin and unusually fine hair; onycholysis, lid lag, tachycardia at rest, occasional gynecomastia in men; fine tremor of the protruded tongue and outstretched hands; and hyperactive deep tendon reflexes.

Thyroid storm is a life-threatening medical emergency characterized by decompensated thyrotoxicosis, high fever (often>39.4°C [103°F]), tachycardia, tachypnea, dehydration, delirium, coma, nausea, vomiting, and diarrhea. Precipitating factors include infection, trauma, surgery, radioactive iodine (RAI) treatment, and withdrawal from antithyroid drugs.

Diagnosis: The diagnosis of hyperthyroidism is based upon thyroid function test. Low TSH level (less than 0.5 mIU /L or µIU /mL) signifies thyrotoxicosis. FT4 is elevated in overt hyperthyroidism but may be normal in mild

hyperthyroidism. Increased radioiodine uptake in the thyroid indicates increased

hormone production by the thyroid gland. Almost all patients with graves’ disease will have positive TSHR-SAbs

and positive anti-TPOAbs. Low RAIU indicates excess thyroid hormone not by thyroid gland

hyperfunction, this may see in painful thyroiditis, painless thyroiditis, Struma ovarii and follicular cancer.

Treatment:

*Goals of treatment: 1.Eliminate excess thyroid hormone.

2.Minimize symptoms and long-term consequences.

3.Provide individualized therapy based on the type and severity of disease, patient age and gender, existence of nonthyroidal conditions, and response to previous therapy.

Nonpharmacology: Surgical removal of the thyroid gland should be considered in patients

with a large gland (>80 g), severe ophthalmopathy, or lack of remission on antithyroid drug treatment.

If thyroidectomy is planned, propylthiouracil (PTU) or methimazole is usually given until the patient is biochemically euthyroid (usually 6–8 weeks), followed by addition of iodides (500 mg/day) for 10–14 days before surgery to decrease vascularity of the gland. Levothyroxine may be added to maintain the euthyroid state while thionamides are continued.

Complication of surgery: 1.Hypothyroidism, 2.Recurrent laryngeal nerve injury, 3.Airway obstruction, 4.Wound infection. Pharmacology:

THIOUREAS (THIONAMIDES): o Propylthiouracil(PTU) and Methimazole

*Mechanism of action PTU and methimazole block thyroid hormone synthesis by inhibiting the peroxidase enzyme system of the thyroid, preventing oxidation of trapped iodide and by inhibiting coupling of MIT and DIT to form T4 and T3. PTU (but not methimazole) also inhibits peripheral conversion of T4 to T3.

*Initial dose Usual initial doses include PTU 300 to 600 mg daily (usually in three or four divided doses) or methimazole 30 to 60 mg daily given in three divided doses. Evidence exists that both drugs can be given as a single daily dose.

*Maintenance dose Typical daily maintenance doses are PTU 50 to 300 mg and

methimazole 5 to 30 mg. Continue therapy for 12 to 24 months to induce long-term remission.

Improvement in symptoms and laboratory abnormalities should occur within 4 to 8 weeks, at which time a tapering regimen to maintenance doses can be started.

*Monitoring Monitor patients every 6 to 12 months after remission.

*Adverse effects Major adverse effects include agranulocytosis (with fever, malaise,

gingivitis, or pharyngeal infection, aplastic anemia, lupus-like syndrome, polymyositis, GI intolerance, hepatotoxicity, and hypoprothrombinemia.

Minor adverse reactions include pruritic maculopapular rashes, arthralgias, fever, and benign transient leukopenia (white blood cell count <4000/mm3 or 4 × 109/L).

Because of the risk of hepatotoxicity dont use the PTU as first line therapy unless in

1- First trimester of pregnancy 2- Intolerance to methimazole 3- Thyroid storm

IODIDES *Mechanism of action

Acutely blocks thyroid hormone release, inhibit thyroid hormone biosynthesis by interfering with intrathyroidal iodide use, and decreases size and vascularity of the gland.

*Dosage form Potassium iodide is available as a saturated solution (SSKI, 38 mg iodide per drop) or as Lugol`s solution, containing 6.3 mg of iodide per drop.

*Dose: Typical starting dose of SSKI is 3 to 10 drops daily (120–400 mg) in water or juice. When used to prepare a patient for surgery, it should be administered 7 to 14 days preoperatively. Symptom improve occur within 2-7 days of initial therapy.

*Adverse effects: Hypersensitivity reactions (skin rashes, drug fever, rhinitis, conjunctivitis), salivary gland swelling, “iodism” (metallic taste, burning mouth and throat, sore teeth and gums, symptoms of a head cold, and sometimes stomach upset and diarrhea), and gynecomastia. Iodides are often used as adjunctive therapy to prepare a patient with Graves’ disease for surgery before 7-14 days. SSKI should not be used before but rather 3 to 7days after RAI treatment so the RAI can concentrate in the thyroid.

ADRENERGIC BLOCKERS o Propranolol and Nadolol

*β-Blockers are used to ameliorate thyrotoxic symptoms such as palpitations, anxiety, tremor, and heat intolerance, they have no effect on peripheral thyrotoxicosis or prevent thyroid storm. *β-Blockers are usually used as adjunctive therapy with antithyroid drugs and RAI or iodide. The only conditions for which β-blockers are primary therapy for thyrotoxicosis are those associated with thyroiditis. *Initial Dose: -Propranolol dose 20 to 40 mg orally four times daily is effective for most patients (heart rate <90 beats/min). -Younger or more severely toxic patients may require 240 to 480 mg/day. *Contraindications: 1.Decompensated heart failure unless it is caused solely by tachycardia. 2.Sinus bradycardia. 3.Concomitant therapy with monoamine oxidase inhibitors or tricyclic antidepressants. 4.Patients with spontaneous hypoglycemia.

Centrally acting sympatholytic (eg, clonidine) and calcium channel antagonists (eg, diltiazem) may be useful for symptom control when contraindications to β-blockade exist.

*Adverse effects: Side effects include nausea, vomiting, anxiety, insomnia, lightheadedness, bradycardia, and hematologic disturbances.

RADIOACTIVE IODINE (RAI): o Sodium iodide–131 is an oral liquid that concentrates in the

thyroid and initially disrupts hormone synthesis by incorporating into thyroid hormones and thyroglobulin

*USES: Agent of choice for Graves’ disease, toxic autonomous nodules, and toxic multinodular goiters. *Dose: -The goal of therapy is to destroy overactive thyroid cells, and a single dose of 4000 to 8000 rad (40–80 Gy) results in a euthyroid state in 60% of patients at 6 months or sooner. -A second dose of RAI should be given 6 months after the first RAI treatment if the patient remains hyperthyroid. -Patients with cardiac disease and elderly patients are often treated with thionamides prior to RAI ablation because thyroid hormone levels transiently increase after RAI treatment due to release of preformed thyroid hormone. -Antithyroid drugs are not routinely used after RAI because their use is associated with a higher incidence of posttreatment recurrence or persistent hyperthyroidism. -If iodides are administered, they should be given 3 to 7 days after RAI to prevent interference with uptake of RAI in the thyroid gland. *Adverse effects: Hypothyroidism commonly occurs months to years after RAI. The acute, short-term side effects include mild thyroidal tenderness and dysphagia. *Contraindication: Pregnancy is an absolute contraindication to use of RAI.

PREGNANCY

- PTU is considered the drug of choice during the first trimester of pregnancy, with the lowest possible doses used to maintain the maternal T4 level in the high-normal range. - To prevent fetal goiter and suppression of fetal thyroid function, PTU is usually prescribed in daily doses of 300 mg or less and tapered to 50 to 150 mg daily after 4 to 6 weeks. - PTU doses of less than 200 mg daily are unlikely to produce fetal goiter. -During the second and third trimesters, when the critical period of organogenesis is complete, MMI is thought to be the drug of choice because of the greater risk of hepatotoxicity with PTU.

Neonatal and Pediatric Hyperthyroidism -Some babies of hyperthyroid mothers will be hyperthyroid due to placental transfer of TSAbs, which stimulates thyroid hormone production in utero and postpartum; this is likely if the maternal TSAb titers were quite high. The disease is usually expressed 7 to 10 days postpartum and treatment with antithyroid drugs (PTU 5 to 10 mg/kg/day or MMI 0.5 to 1 mg/kg/day) may be needed for as long as 8 to 12 weeks until the antibody is cleared. -Iodide (potassium iodide one drop per day or Lugol’s solution one to three drops per day) and sodium iodate may be used for the first few days to acutely inhibit hormone release. -Childhood hyperthyroidism has classically been managed with either PTU or MMI. THYROID STORM

Initiate the following therapeutic measures promptly: (1) Suppression of thyroid hormone formation and secretion. (2) Antiadrenergic therapy. (3) Administration of corticosteroids. (4) Treatment of associated complications or coexisting factors that may have precipitated the storm.

Iodides, which rapidly block the release of preformed thyroid hormone, should be administered after a thionamide is initiated to inhibit iodide utilization by the overactive gland.

Antiadrenergic therapy with the short-acting agent esmolol is preferred because it can be used in patients with pulmonary disease or at risk for cardiac failure and because its effects can be rapidly reversed.

Corticosteroids are generally recommended, but there is no convincing evidence of adrenocortical insufficiency in thyroid storm; their benefits may be attributed to their antipyretic action and stabilization of blood pressure (BP).

General supportive measures, including acetaminophen as an antipyretic (avoid aspirin or other nonsteroidal anti-inflammatory drugs, which may displace bound thyroid hormone), fluid and electrolyte replacement, sedatives, digoxin, antiarrhythmics, insulin, and antibiotics should be given as indicated.

**EVALUATION OF THERAPEUTIC OUTCOMES

After therapy (surgery, thionamides, or RAI) for hyperthyroidism has been initiated, evaluate patients monthly until they reach a euthyroid condition.

Assess for clinical signs of continuing thyrotoxicosis or development of hypothyroidism.

If T4 replacement is initiated, the goal is to maintain both the free T4

level and the TSH concentration in the normal range. Once a stable dose of T4 is identified, monitor the patient every 6 to 12 months.

Reference: JosephT. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey.Pharmacotherapy a pathophysiologic approach.10th ed .Newyork: McGraw-Hill Education;2017.Chapter 75 , Thyroid disorders ; p 3293-352.

Done by PharmD students: Dima Qanadilo

Amna Friehat Batool Dallou

Supervised By clinical pharmacist: Dr.Eshraq Al-Abweeny