Chapter 55 - Drugs For Thyroid Disorders

CHAPTER 55

DRUGS

FOR

THYROID DISORDERS

Thyroid hormones have profound effects on metabolism, cardiac function, growth and development. - stimulate the metabolic rate of most cells, increase the force and rate of cardiac contraction - promote maturation - severe deficiency can produce dwarfism and permanent mental impairment Thyroid drugs are the most misused drugs in the diet industry.

I.

THYROID PHYSIOLOGY

A.

CHEMISTRY & NOMENCLATURE - thyroid gland produces two active hormones: triiodothyronine (T3) thyroxine (T4, tetraiodothyronine) - T3 is more potent than T4 - the body secretes more T4 than T3 and converts it to T3 as needed

B.

THYROID HORMONE ACTIONS - thyroid hormones are protein bound - synthetic drugs are better than natural drugs to mimic the natural thyroid hormone actions 1. Stimulation of Energy Use – elevates the basal metabolic rate, resulting in increased oxygen consumption and increased heat production 2. Stimulation of the Heart – increases both the rate and force of contraction, resulting in increased cardiac output and increased oxygen demand 3. Promotion of Growth and Development – essential for normal development of the brain and other components of the nervous system, and have a significant impact on maturation of skeletal muscle

II.

THYROID PATHOPHYSIOLOGY

A. HYPOTHYROIDISM – mild deficiency of thyroid hormone; malfunction of the thyroid gland - myxedema - severe deficiency in adults - cretinism – hypothyroidism in infancy 1.

Hypothyroidism in Adults a. Clinical Presentation - produces pale, puffy and expressionless facial characteristics, cold and dry skin, hair is brittle and loss occurs, heart rate and temperature are lowered, patient

may have complaints of lethargy, fatigue, and intolerance to cold - mentality is impaired - thyroid enlargement (goiter) may occur if reduced levels of T3 and T4 promote excessive release of TSH (thyroid stimulating hormone) b. Causes - usually due to malfunction of the thyroid itself - in iodine sufficient countries, the principal cause is chronic autoimmune thyroiditis (Hasimoto’s disease) - other causes are insufficient iodine in the diet, surgical removal of the thyroid and destruction of the thyroid by radioactive iodine - may also result from insufficient secretion of TSH and TRH (thyrotropin releasing hormone) c. Therapeutic Strategy - requires replacement therapy with thyroid hormones and treatment must continue for life - standard replacement regimen consists of levothyroxine (T4) alone - when adequate, doses eliminate all signs and symptoms of deficiency 2.

Hypothyroidism During Pregnancy - maternal hypothyroidism can result in permanent neuropsychologic deficits in the child - congenital hypothyroidism can cause mental retardation and other developmental problems - in the absence of fetal hypothyroidism, maternal hypothyroidism can decrease IQ and other aspects of neuropsychologic function - limited largely to the first trimester, a time during which the fetus is unable to produce thyroid hormones on its own - maternal hypothyroidism must be diagnosed and treated very early - symptoms of hypothyroidism are often nonspecific (irritability, tiredness, poor concentration, etc.) – or there may be no symptoms at all - recommended routine screening as soon as pregnancy is confirmed - thyroid hormone levels should be monitored and dosage increased as needed 3.

Hypothyroidism in Infants a. Clinical Presentations - causes mental retardation and derangement

of growth - the child develops a large and protruding tongue, potbelly, and dwarfish stature

- development of the nervous system, bones, teeth, and muscles is impaired - cretinism usually results from a failure in thyroid development - other causes include autoimmune disease, severe iodine deficiency, TSH deficiency, and exposure to radioactive iodine in utero - requires replacement therapy with thyroid hormones - if treatment is initiated within a few days of birth, physical and mental development will be normal - if treatment is delayed for several months, some permanent retardation will be evident - treatment must continue for life B.

HYPERTHYROIDISM - elevated levels of thyroid hormones - thyrotoxic crisis – extremely high levels of thyroid hormone 1.

Graves’ Disease (Barbara Bush has this disease) - most common cause of excessive thyroid hormone secretion - occurs most frequently in women 20 to 40 yrs. old (incidence in females is 6 times greater than males) - results from elevated levels of thyroid hormone - heartbeat is rapid and strong, and dysrhythmias and angina may develop - central nervous system is stimulated, resulting in rapid thought flow and rapid speech, nervousness and insomnia - skeletal muscles may weaken and atrophy - metabolic rate is raised, resulting in increased heat production, increased body temperature, intolerance to heat and skin that is warm and moist - appetite is increased; however, despite increased food consumption, weight loss occurs is caloric intake fails to match the increased metabolic rate - patients often present with exophthalmos (protrusion of the eyeballs) Cause: - thyroid stimulating immuglobulins (TSIs) which are antibodies produced by an autoimmune process - increase thyroid activity by stimulating receptors for TSH on the thyroid gland (mimic the effects of TSH on thyroid function)

- not responsible for exophthalmos Treatment (directed at decreasing production of thyroid hormones): a) surgical removal of thyroid tissue b) destruction of thyroid tissue with radioactive iodine (preferred treatment for adults) c) suppression of thyroid hormone synthesis with antithyroid drugs (preferred treatment for younger patients) - Propranolol (suppresses tachycardia) and nonradioactive (inhibits synthesis and release of thyroid hormones) iodine may be used as adjunctive therapy 2.

Toxic Nodular Goiter (Plummer’s Disease) - result of thyroid adenoma - results from elevated levels of thyroid hormone - heartbeat is rapid and strong, and dysrhythmias and angina may develop - central nervous system is stimulated, resulting in rapid thought flow and rapid speech, nervousness and insomnia - skeletal muscles may weaken and atrophy - metabolic rate is raised, resulting in increased heat production, increased body temperature, intolerance to heat and skin that is warm and moist - appetite is increased; however, despite increased food consumption, weight loss occurs is caloric intake fails to match the increased metabolic rate - persistent condition that rarely undergoes spontaneous remission Treatment (directed at decreasing production of thyroid hormones): a) surgical removal of thyroid tissue, which provides long-term control (preferred) b) destruction of thyroid tissue with radioactive iodine, which provides long-term control (preferred) c) suppression of thyroid hormone synthesis with antithyroid drugs (symptoms return rapidly when drugs are withdrawn) 3.

Thyrotoxic Crisis (Thyroid Storm) - occurs when levels of thyroid hormone become extremely high - characterized by hyperthermia, severe tachycardia, and profound weakness - unconsciousness, coma, and heart failure may ensue

- can be caused by excessive production of endogenous thyroid hormones or by overdose with thyroid hormones during replacement therapy - can be life threatening and requires immediate treatment - high doses of potassium iodide or strong iodine solution are given to suppress thyroid hormone release - propylthiouracil is given to suppress thyroid hormone synthesis and conversion of T4 to T3 in the periphery - propranolol is given to reduce heart rate - additional measures include sedation, cooling, and giving clucocorticoids and IV fluids

III.

THYROID FUNCTION TESTS

A.

SERUM (BLOOD) T4 TEST - measures total (bound plus free) thyroxine - useful for initial screening of thyroid function: levels of T4 will be low in hypothyroid patients levels of T4 will be high in hyperthyroid patients - can also be used to monitor thyroid hormone replacement therapy: T4 levels should rise B.

SERUM (BLOOD) T3 TEST - measures total (bound plus free) triiodothyronine - useful for diagnosing hyperthyroidism because in this disorder levels of T3 often rise sooner and to a greater extent than levels of T4 - can also be employed to monitor thyroid hormone replacement therapy: T3 levels should increase C.

SERUM (BLOOD) TSH - most sensitive method for diagnosing hypothyroidism because very small reductions in serum T3 and T4 cause a dramatic rise in serum TSH - even when the degree of hypothyroidism is minimal, it will be reflected by an abnormally high TSH level - can also be used to distinguish primary hypothyroidism (high TSH levels) from secondary hypothyroidism (hypothyroidism resulting from anterior pituitary dysfunction; low TSH levels)

IV.

THYROID HORMONE PREPARATIONS

FOR

HYPOTHYROIDISM

A.

LEVOTHYROXINE (T4) – (trade names: Levothroid, Levoxyl, Synthroid) - synthetic preparation of thyroxine (T4) - the drug of choice for most patients who require thyroid hormone replacement - highly protein bound with half-life of about 7 days - indicated for all forms of hypothyroidism, regardless of cause - levothyroxine and other thyroid hormones should not be taken to treat obesity Adverse Effects: in appropriate doses, rarely causes adverse effects - excessive doses, thyrotoxicosis may result (symptoms: tachycardia, angina, tremor, nervouseness, insomnia, hyperthermia, heat intolerance, and sweating) Drug Interactions: Absorption Reduction: Cholestyramine (Questran) Calcium supplements (Tums, Os-Cal) Sucralfate (Carafate) Aluminum containing antacids (Maalox, Mylanta) Iron supplements (ferrous sulfate) - to ensure adequate absorption, patients should separate administration of levothyroxine and these drugs by 3 – 4 hours Metabolism Increase: Phenytoin (Dilantin) Rifampin (antibiotic) sertraline (Zoloft) Phenobarbital - patients taking these drugs may need to increase levothyroxine dosage - levothyroxine accelerates the degradation of vitamin K dependent clotting factors Warfarin effects are enhanced, therefore, dosage should be reduced - thyroid hormones increase cardiac responsiveness to catecholamines (epinephrine, dopamine, dobutamine), increasing the risk of catecholamine-induced dysrhythmias Others: can increase requirements for insulin and digitalis, therefore, dosages may need to be increased

V.

DRUGS

FOR

HYPERTHYROIDISM

A.

PROPYTHIOURACIL (PTU) - inhibits thyroid hormone synthesis - rapidly absorbed following oral administration - short half-life of about 75 minutes, therefore must be administered several times a day - can cross the placenta and can enter the breast milk - can be used alone as the sole form of therapy for Graves’ disease - used as an adjunct to radiation therapy - administered to control hyperthyroidism until the effects of radiation become manifest - given to suppress thyroid hormone synthesis in preparation for thyroid gland surgery - given to patients experiencing thyrotoxic crisis Adverse Effects: relatively rare agranulocytosis is the most serious toxicity - reaction is rare and usually develops during the 1st 2 months of therapy - sore throat and fever may be the earliest indications - patients should be instructed to report these immediately hypothyroidism – occurs in high doses pregnancy and lactation – PTU crosses the placenta and has caused neonatal hypothyroidism and goiter - PTU enters the breast milk others – rash, nausea, arthralgia, headache, dizziness and paresthesias B.

RADIOACTIVE IODINE (131I) – (TRADE NAME: IODOTOPE) - radioactive isotope of stable iodine that emits a combination of beta particles and gamma rays - half-life of 8 days - can be used to destroy thyroid tissue in patients with hyperthyroidism (Graves’ Disease) - objective is to produce clinical remission without causing complete destruction of the thyroid gland - patients over the age of 30 may be candidates for this therapy - children are inappropriate candidates - pregnant and lactating mothers are inappropriate candidates