1. Lecture -2 Endocrine and Metabolic Disorders Thyroid Disorders
University of Nizwa
College of Pharmacy and Nursing
School of Pharmacy
PHARMACOTHERAPY II
PHCY 410
Lecture -2 Endocrine and Metabolic Disorders Thyroid Disorders
Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

2. Course Outcome
Upon completion of this lecture the students will be able to
Classify thyroid disorders based on etiology and its diagnostic criteria.
Develop skills to monitor drug therapy in hypo and hyperthyroid patients.
Develop pharmaceutical care plan for managing patients with thyroid disorders.

3. Hyperthyroidism and hypothyroidism are the clinical and biochemical syndromes resulting from increased and decreased thyroid hormone production, respectively.
Triiodothyronine (T3) and thyroxine (T4) are the two biologically active thyroid hormones produced by the thyroid gland in response to hormones released by the pituitary and hypothalamus.
The hypothalamic thyrotropin-releasing hormone (TRH) stimulates release of thyrotropin (i.e., thyroid-stimulating hormone [TSH]) from the pituitary in response to low circulating levels of thyroid hormone.
TSH in turn promotes hormone synthesis and release by increasing thyroid activity.

4. Thyroid Hormone Physiology

6. Thyroid disorders are very common, with women more affected than men
Thyroid disorders are very common, with women more affected than men. It is divided into hypothyroidism and hyperthyroidism.
A- Hypothyroidism
Hypothyroidism is a clinical syndrome that usually results from a deficiency of the thyroid hormone.
The thyroid gland failure causes primary hypothyroidism and the causes include chronic autoimmune thyroiditis (Hashimoto’s disease), iatrogenic (physician induced) hypothyroidism, iodine deficiency, enzyme defects and goitrogens.
Pituitary failure (secondary hypothyroidism) is an uncommon cause resulting from pituitary tumors, tuberculosis and autoimmune mechanisms.

7. Signs & Symptoms of Hypothyroidism and Hyperthyroidism

9. DRUG-INDUCED HYPOTHYROIDISM
Iodides and iodide-containing compounds (i.e., povidone iodine, amiodarone, iodinated contrast media) can produce hypothyroidism and goiter in patients with underlying thyroid abnormalities.
Lithium-induced hypothyroidism and goiter have been reported in 5% to 50% of patients on chronic therapy.
Thiocyanate-induced hypothyroidism can result from long-term use of nitroprusside in patients with renal insufficiency.
It inhibits iodide transport and reduces hormone synthesis.
Plants such as rutabagas, cabbage, and turnips contain thiocarbamides that are metabolized in the body to thiocyanates.
These dietary goitrogens do not produce a significant degree of hypothyroidism unless large amounts are ingested raw over a long period.

10. Investigations 1) History: symptoms such as fatigue, weight gain, impaired memory, constipation and cold intolerance. 2) Physical examination: - Dry skin and hair, hypertension, and bradycardia - Extreme cases may present with myxedema coma (hypotension, coma, hypothermia) 3) Lab investigations: A rise in the TSH level is the first evidence of primary hypothyroidism. Pituitary failure (secondary hypothyroidism) should be suspected in a patient with decreased levels of T4 and inappropriately normal or low TSH levels.

11. Thyroid Function Tests
Total T4
Total T3
TSH
Normal
mcg/dl
60-181ng/dl
milliIU/L
Hypothyroid
Low
High
Hyperthyroid

12. The goal of therapy is to reverse the signs and symptoms of hypothyroidism and normalize the TSH and free thyroxine levels.
Therapeutic Choices
Pharmacologic Choices
1) Levothyroxine (L-T4)
The goal of L-T4 replacement therapy is to normalize the TSH level. Dosages average is 1.6 µg/kg/day in adults.
Dosage adjustment is made every four to six weeks as needed, as it usually takes six weeks to attain a new steady state after dosage adjustments.
In the elderly, or in patients with coronary artery disease, start with a dose as low as 12.5 µg/day as tolerated, and titrate every four weeks.

13. In young, healthy patients with disease of short duration, l-thyroxine can be administered in nearly full replacement doses (e.g., 100–150 g daily) without fear of precipitating cardiac toxicity.
Long-standing and severe myxedema, older adults, and in patients with cardiac disease (i.e., angina, CHF), are extremely sensitive to the metabolic effects of thyroid hormone,
Hence minute doses of l-thyroxine must be started cautiously to avoid cardiovascular complications of heart failure, angina, tachycardia, and myocardial infarction.
Angina should be controlled before l-thyroxine therapy is attempted. If medically indicated, coronary bypass surgery can be performed safely in hypothyroid patients before l-thyroxine replacement.

14. 2) Liothyronine (Triiodothyronine, T3)
T3 needs to be dosed multiple times a day because of its shorter half-life (e.g., 1.5 days compared to 7 days for levothyroxine).
A combination of L-T4 (Levothyroxine) and T3 is occasionally used for replacement therapy, with little or no benefit.
Goiter
Hypothyroidism

15. Myxedema Coma
Myxedema coma is a rare consequence of decompensated hypothyroidism.
Clinical features include hypothermia, advanced stages of hypothyroid symptoms, and altered sensorium ranging from delirium to coma.
The initial treatment is intravenous bolus levothyroxine 300 to 500 mcg followed by 100 µg iv daily.
Corticosteroids, such as hydrocortisone 100 mg iv Q8H (to prevent adrenal crisis).
Supportive therapy and passive rewarming as required.

16. Hypothyroidism in Pregnancy
Hypothyroidism during pregnancy leads to an increased rate of stillbirths.
Thyroid hormone is necessary for fetal growth and must come from the maternal side during the first 2 months of gestation.
Although liothyronine can cross the placental membrane slightly better than levothyroxine, the latter is considered to be the drug of choice.
Requirements for L-T4 replacement may increase by up to 50% during pregnancy to maintain TSH at 1 to 3 mU/mL.
GOITROUS THYROID DISEASE
Many goitrous glands contain one or more nodules. The introduction of iodide supplementation has eliminated goiter as a major medical problem.

17. B- Hyperthyroidism
Hyperthyroidism (thyrotoxicosis) is defined as the syndrome of excessive thyroid hormone production.
Thyroid storm: a life-threatening medical emergency characterized by severe thyrotoxicosis as well as other signs and symptoms.
Thyroid storm can be precipitated by many causes including:
Radioactive iodine
Infection
Trauma
Surgery
Over-replacement of thyroid hormone
Withdrawal from antithyroid drugs

18. Causes of Hyperthyroidism
Graves' disease: most common cause of hyperthyroidism
(It is an autoimmune disorder caused by an abnormal thyroid receptor IgG-stimulating immunoglobulin (e.g., TRab) that binds to the TSH receptor to cause uncontrolled thyroid hormone production)
Toxic nodules
Iodine excess
Iatrogenic: over treatment with thyroid hormones    
Metastatic thyroid cancer  
TSH–producing pituitary adenoma

19. Therapeutic Choices
Non-pharmacologic Choices
Consider thyroid surgery in patients with thyroid nodules, thyroid cancer, and occasionally in patients with Graves’ disease.
Medical therapy is frequently initiated prior to surgery to make the patient euthyroid if possible.

20. Pharmacologic Choices 1- Radioactive iodine (131I) to ablate thyroid tissue in patients with Graves’ disease, and toxic nodules.
131I is contraindicated in pregnancy, and inducing hypothyroidism is the main risk associated with its use.
2- Thioamides used as long-term primary therapy for Graves hyperthyroidism, especially in adolescents and children.
Methimazole (MMI) and propylthiouracil (PTU) decrease the production of thyroid hormones; PTU can also block the conversion of T4 to T3.
PTU (drug of choice) or methimazole (congenital skin defects i.e. aplasia cutis) can be safely used in pregnancy. In lactating women, PTU is preferred over methimazole because insignificant amounts of PTU are excreted in milk.

21. Methimazole given as a single daily dose, improves patient adherence and is more potent than PTU(100 mg PTU = 10 mg methimazole).
Duration of action of methimazole is 24 to 36 hours, permitting once-daily administration. The intrathyroidal duration of PTU is much shorter, requiring initial dosing every 6 to 8 hours to be effective.
PTU is preferred over methimazole in patients with thyroid storm or severe hyperthyroidism because it blocks peripheral conversion of T4 to T3 and have a faster onset of action.
Tapering of thioamide dose should not begin until symptoms are reduced and T4 levels are normal, usually 6 to 8 weeks (based on elimination of existing thyroid stores; t1/2 = 7 days).

22. Hepatocellular and obstructive hepatitis have been reported with both agents.
Hepatocellular damage is more common with PTU, and obstructive jaundice occurs with methimazole, especially at doses greater than 40 mg per day.
Agranulocytosis (<500 polymorphonuclear neutrophil leukocytes) is the most serious (but rare) adverse reaction to the thioamides.

23. Beta-adrenergic blockers used adjunctively in the management of hyperthyroidism to ameliorate the symptoms of adrenergic excess.
Nonselective agents such as propranolol can decrease the conversion of T4 to T3.
When propranolol is given orally in doses of 20 to 40 mg three to four times a day as necessary, symptomatic relief of palpitations, tachycardia, anxiety, sweating, tremor, and diarrhea occurs.
Avoid beta-blockers in patients with asthma.
Calcium-channel blockers, particularly Oral diltiazem(120 mg three times daily or 60 mg q.i.d), might be a useful alternative when beta-blockers are contraindicated (e.g., in patients with asthma, insulin-dependent diabetes).

24. Iodides provide symptomatic relief of thyrotoxicosis, their clinical use has been largely succeeded by the thioamides and beta-blockers.
Iodine, in the form of oral Lugol’s solution (5% iodine and 10% potassium iodide) contains 8 mg iodide per drop or iv sodium iodide, blocks thyroid hormone release.
It can be used in acute management of severe hyperthyroidism.
Iodides are routinely given 10 to 14 days before surgery to facilitate surgical removal of the hyperplastic gland by decreasing its vascularity and increasing its firmness.

25. NONPHARMACOLOGIC THERAPY
Preoperatively, the combination of beta-blockers and iodides can also be used, although the established regimen of thioamides and iodides is preferable.
Corticosteroids can be used as adjuvant therapy in treatment-resistant cases.
NONPHARMACOLOGIC THERAPY
Surgery. Thyroidectomy is considered the treatment option of choice for patients in whom RAI or thioamides are contraindicated;
in those with large goiters, causing cosmetic disfigurement, respiratory distress, or swallowing difficulties
in those with suspected malignancies; and in selected children and pregnant women.

26. Thyroid Storm
Thyroid storm is characterized by highlighting of the hyperthyroid symptoms and the acute onset of high fever(>39.4oC).
If untreated, cardiovascular collapse and shock can occur.
Gastrointestinal symptoms can be profound, producing diarrhea, vomiting, abdominal pain, and liver enlargement.
Central nervous system involvement can cause agitation and psychosis, leading to apathy, stupor, and coma.

27. The following therapeutic measures should be instituted promptly:
suppression of thyroid hormone formation and secretion
(2) antiadrenergic therapy
(3) administration of corticosteroids
(4) treatment of associated complications or coexisting factors that precipitated the storm.
PTU in large doses is the preferred thionamide because it interferes with the production of thyroid hormones and blocks the peripheral conversion of T4 to T3.
If patients are unable to take medications orally, the tablets can be crushed into suspension and instilled by gastric or rectal tube