THYROID AND ANTITHYROID DRUGS

Dr. S. A. Ziai

Intake is 150 mcg/day200 mcg during pregnancy

Rapidly absorbed

ECF

75mcg/day

Sodium/Iodide Symporter

Iodide organification

Pendred’s Syndrome

Thyroglobulin

T4:T3 = 5:1

65% Iodine

59% Iodine

To normalize:1. Growth & development2. Body temperature3. Energy levels

Table . Summary of thyroid hormone kinetics.

Variable T4 T3

Volume of distribution 10 L 40 L

Extrathyroidal pool 800 mcg 54 mcgDaily production 75 mcg 25 mcg

Fractional turnover per day 10% 60%

Metabolic clearance per day 1.1 L 24 L

Half-life (biologic) 7 days 1 daySerum levels    

  Total5-12 mcg/dL (64-164 nmol/L)

70-132 ng/dL (1.1-2.0 nmol/L)

  Free 0.7-1.86 ng/dL (9-24 pmol/L)

0.23-0.42 ng/dL (3.5-6.47 pmol/L)

Amount bound 99.96% 99.6%Biologic potency 1 4Oral absorption 80% 95%

Demonstration of the Wolff-Chaikoff block induced by iodide in the rat. Animals were given increasing doses of stable iodide. There was at first an increase in total organification, but then, as the dose was increased further, a depression of organification of iodide and an increase in the free iodide present in the thyroid gland occurred.

Wolff-Chaikoff block

Table. Typical values for thyroid function tests.

Name of Test Normal Value1

Results in Hypothyroidis

m

Results in Hyperthyroidis

mTotal thyroxine by RIA (T4 [RIA])

5-12 mcg/dL (64-154 nmol/L)

Low High

Total triiodothyronine by RIA (T3 [RIA])

70-132 ng/dL (1.1-2.0 nmol/L)

Normal or low High

Free T4 (FT4)0.7-1.86 mg/dL (9-24 pmol/L)

Low High

Free T3 (FT3)0.2-0.42 ng/dL (3-6.5 pmol/L)

Low High

Thyrotropic hormone (TSH)0.5-5.0 uIU/mL (0.5-5.0 mIU/L)

High2 Low

123I uptake at 24 hours 5-35% Low HighThyroglobulin autoantibodies (Tg-ab)

< 1 IU/mL Often present Usually present

Thyroid peroxidase antibodies (TPA)

< 1 IU/mL Often present Usually present

Isotope scan with 123I or 99mTcO4

Normal patternTest not indicated

Diffusely enlarged gland

Fine-needle aspiration biopsy (FNA)

Normal patternTest not indicated

Test not indicated

Serum thyroglobulin < 56 ng/mLTest not indicated

Test not indicated

Serum calcitoninMale: < 8 ng/L (< 2.3 pmol/L); female: < 4 ng/L (< 1.17 pmol/L)

Test not indicated

Test not indicated

TSH receptor-stimulating antibody (thyroid stimulating immunoglobulin)

< 125%Test not indicated

Elevated in Graves' disease

1Results may vary with different laboratories.2Exception is central hypothyroidism

Table. Drug effects and thyroid function.Drug Effect Drugs

Change in thyroid hormone synthesis

 

Inhibition of TRH or TSH secretion without induction of hypothyroidism or hyperthyroidism

Dopamine, levodopa, corticosteroids, somatostatin, metformin, bexarotene

 

Inhibition of thyroid hormone synthesis or release with the induction of hypothyroidism (or occasionally hyperthyroidism)

Iodides (including amiodarone), lithium, aminoglutethimide, thioamides, ethionamide

Alteration of thyroid hormone transport and serum total T3 and T4 levels, but usually no modification of FT4 or TSH

  Increased TBGEstrogens, tamoxifen, heroin, methadone, mitotane, fluorouracil

  Decreased TBG Androgens, glucocorticoids

 Displacement of T3 and T4 from TBG with transient hyperthyroxinemia

Salicylates, fenclofenac, mefenamic acid, furosemide

Alteration of T4 and T3 metabolism with modified serum T3 and T4 levels but not FT4 or TSH levels

 Induction of increased hepatic enzyme activity

Nicardipine, imatinib, protease inhibitors, phenytoin, carbamazepine, phenobarbital, rifampin, rifabutin

 Inhibition of 5¢-deiodinase with decreased T3, increased rT3

Iopanoic acid, ipodate, amiodarone, b blockers, corticosteroids, propylthiouracil, flavonoids, starvation

Other interactions

  Interference with T4 absorption

Cholestyramine, colestipol, ciprofloxacin, aluminum hydroxide, sucralfate, sodium polystyrene sulfonate, raloxifene, ferrous sulfate, calcium carbonate, bran, soy

 

Induction of autoimmune thyroid disease with hypothyroidism or hyperthyroidism

Interferon-a, interleukin-2, interferon-b, lithium, amiodarone

Effect of thyroid function on drug effects

  AnticoagulationLower doses of warfarin required in hyperthyroidism, higher doses in hypothyroidism

  Glucose control

Increased hepatic glucose production and glucose intolerance in hyperthyroidism; impaired insulin action and glucose disposal in hypothyroidism

  Cardiac drugsHigher doses of digoxin required in hyperthyroidism; lower doses in hypothyroidism

  Sedatives; analgesics

Increased sedative and respiratory depressant effects from sedatives and opioids in hypothyroidsim; converse in hyperthyroidism

Thyroid hormones

Levo (L) isomers T4 80% absorbed and best absorption in

the duodenum and ileum (T3~95%) Modified by food, drugs, and intestinal flora Impaired by severe myxedema with ileus

Enzyme inducers in euthyroids T4 replacement medication

MOA

TR-LBD, T3 receptor ligand-binding domain TR-DBD, T3 receptor DNA-binding domain RXR-LBD, retinoid X receptor ligand-binding domainRXR-DBD, retinoid X receptor DNA-binding domain5'DI, 5'deiodinase.T3 receptors (10times more affinity than T4)•c-erb oncogene family, steroids, vitamin A &D•In two forms a & b

Protein synthesis e.g. Na+/K+ ATPase

Effects of Thyroid Hormones Critical for nervous, skeletal, &

reproductive tissue Protein synthesis Potentiation of GH secretion & action

Deficiency in early life mental retardation & dwarfism (congenital cretinism)

Pervasive influence on metabolism of drugs, carbohydrates, fats, proteins, & vitamins

Secretion & degradation of all other hormones CA, Cortisol, estrogens, Testosterone,

insulin

Thyroid hyperactivity

sympathetic nervous system overactivity (especially in the CVS) CA levels are not increased increased numbers of b receptors enhanced amplification of the b receptor signal Usefulness of b blockers in:

Lid lag & retraction Tremor Excessive sweating Anxiety nervosness

Thyroid Preparations

Synthetic Levothyroxine (T4)

Drug of choice for HRT: stability, content uniformity, low cost, lack of allergenic foreign

protein, easy laboratory measurement of serum levels, and long half-life (7 days), which permits once-daily administration

liothyronine (T3) It is best used for short-term suppression of TSH shorter half-life (24 hours), which requires multiple daily

doses; its higher cost; and the greater difficulty of monitoring ; greater risk of cardiotoxicity, T3 should be avoided in patients with cardiac disease

Liotrix shelf life ~ 2 years and must be stored in dark bottles

Thyroid Preparations

Animal origin desiccated thyroid

Advantage: Low cost

Disadvantages: protein antigenicity, product instability, variable

hormone concentrations, and difficulty in laboratory monitoring

shelf life is not known; kept dry 100 mg of desiccated thyroid = 100 mcg

of levothyroxine = 37.5 mcg of liothyronine

Table. Manifestations of thyrotoxicosis and hypothyroidism.System Thyrotoxicosis Hypothyroidism

Skin and appendages

Warm, moist skin; sweating; heat intolerance; fine, thin hair; Plummer's nails; pretibial dermopathy (Graves' disease)

Pale, cool, puffy skin; dry and brittle hair; brittle nails

Eyes, face

Retraction of upper lid with wide stare; periorbital edema; exophthalmos; diplopia (Graves' disease)

Drooping of eyelids; periorbital edema; loss of temporal aspects of eyebrows; puffy, nonpitting facies; large tongue

Cardiovascular system

Decreased peripheral vascular resistance, increased heart rate, stroke volume, cardiac output, pulse pressure; high-output heart failure; increased inotropic and chronotropic effects; arrhythmias; angina

Increased peripheral vascular resistance; decreased heart rate, stroke volume, cardiac output, pulse pressure; low-output heart failure; ECG: bradycardia, prolonged PR interval, flat T wave, low voltage; pericardial effusion

Respiratory system

Dyspnea; decreased vital capacity

Pleural effusions; hypoventilation and CO2 retention

Gastrointestinal system

Increased appetite; increased frequency of bowel movements; hypoproteinemia

Decreased appetite; decreased frequency of bowel movements; ascites

Central nervous system

Nervousness; hyperkinesia; emotional lability

Lethargy; general slowing of mental processes; neuropathies

Musculoskeletal system

Weakness and muscle fatigue; increased deep tendon reflexes; hypercalcemia; osteoporosis

Stiffness and muscle fatigue; decreased deep tendon reflexes; increased alkaline phosphatase, LDH, AST

Renal systemMild polyuria; increased renal blood flow; increased glomerular filtration rate

Impaired water excretion; decreased renal blood flow; decreased glomerular filtration rate

Hematopoietic system

Increased erythropoiesis; anemia1

Decreased erythropoiesis; anemia1

Reproductive system

Menstrual irregularities; decreased fertility; increased gonadal steroid metabolism

Hypermenorrhea; infertility; decreased libido; impotence; oligospermia; decreased gonadal steroid metabolism

Metabolic system

Increased basal metabolic rate; negative nitrogen balance; hyperglycemia; increased free fatty acids; decreased cholesterol and triglycerides; increased hormone degradation; increased requirements for fat- and water-soluble vitamins; increased drug metabolism

Decreased basal metabolic rate; slight positive nitrogen balance; delayed degradation of insulin, with increased sensitivity; increased cholesterol and triglycerides; decreased hormone degradation; decreased requirements for fat- and water-soluble vitamins; decreased drug metabolism

1The anemia of hyperthyroidism is usually normochromic and caused by increased red blood cell turnover. The anemia of hypothyroidism may be normochromic, hyperchromic, or hypochromic and may be due to decreased production rate, decreased iron absorption, decreased folic acid absorption, or to autoimmune pernicious anemia. (LDH, lactic dehydrogenase; AST, aspartate aminotransferase.)

Thioamides

Methimazole is about ten times more potent than PTU

Thioamides

PTU rapidly and incompletely (50-80%) absorbed, distributed in total body water and accumulate in thyroid gland.

Inactive PTU excreted as glucoronide in kidney within 24 hrs. Methimazole is completely absorbed and excreted slower than

PTU, 65-70% of a dose is recovered in the urine in 48 hours. Half-life: 1.5 hrs for PTU and 6 hrs for methimazole Half-life has little influence on the duration of the antithyroid

action PTU every 6-8 hours & methimazole every 24 hours pregnancy category D (evidence of human fetal risk based on

adverse reaction data from investigational or marketing experience)

PTU is preferable in pregnancy Both thioamides are secreted in low concentrations in breast milk

but are considered safe for the nursing infant

Thioamides

Inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification

They block coupling of the iodotyrosines PTU and (to a much lesser extent)

methimazole inhibit the peripheral deiodination of T4 and T3

Synthesis rather than the release of hormones is affected the onset requiring 3-4 weeks before stores of T4 are depleted.

Thioamides

Adverse reactions to the thioamides occur in 3-12% of treated patients

Early nausea and gastrointestinal distress An altered sense of taste or smell may occur with methimazole The most common adverse effect is a maculopapular pruritic rash (4-

6%), at times accompanied by systemic signs such as fever The most dangerous complication is agranulocytosis (granulocyte

count < 500 cells/mm3) It occurs in 0.1-0.5% of patients taking thioamides the risk may be increased in older patients and in those receiving high-

dose methimazole therapy (> 40 mg/d) rapidly reversible when the drug is discontinued broad-spectrum antibiotic therapy may be necessary G-CSF, may hasten recovery of the granulocytes

The cross-sensitivity between propylthiouracil and methimazole is about 50%

Anion Inhibitors

perchlorate (ClO4-), pertechnetate (TcO4

-), and thiocyanate (SCN-)

Block uptake of iodide by the gland through competitive inhibition of the iodide transport mechanism

ClO4- block thyroidal reuptake of I- in patients

with iodide-induced hyperthyroidism (eg, amiodarone-induced hyperthyroidism)

ClO4- is rarely used clinically because it is

associated with aplastic anemia

Iodides

Today they are rarely used (before thioamides introduction in the 1940s)

They inhibit: Organification Hormone release (in pharmacologic dose

(>6mg/day)) inhibition of thyroglobulin proteolysis

the size and vascularity of the hyperplastic gland preoperative preparation for surgery

In susceptible individuals, iodides can induce hyperthyroidism (jodbasedow phenomenon) or precipitate hypothyroidism

Iodides

Thyroid storm Symptoms rapidly improved within 2-7 days.

Disadvantages: increase in intraglandular stores of iodine delay onset of thioamide therapy prevent use of radioactive iodine therapy for several weeks should not be used alone (escape of gland from the iodide

block in 2-8 weeks) withdrawal may severe exacerbation of thyrotoxicosis cross the placenta and can cause fetal goiter Iodism; uncommon & reversible

acneiform rash (similar to that of bromism), swollen salivary glands, mucous membrane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic taste, bleeding disorders and, rarely, anaphylactoid reactions

Iodinated Contrast Media Diatrizoate orally Iohexol orally or intravenously Valuable treatment of hyperthyroidism (not labeled)

Rapidly inhibit the conversion of T4 to T3

Inhibition of hormone release due to the iodine released Relatively nontoxic Useful adjunctive therapy in the treatment of thyroid

storm and offer valuable alternatives when iodides or thioamides are contraindicated

May not interfere with 131I retention as much as iodides

Radioactive Iodine

131I Orally in solution as sodium 131I

Rapidly absorbed Concentrated by the thyroid Incorporated into storage follicles Emission of b rays with an effective half-life of 5 days Penetration range of 400-2000 mm

Destruction of the thyroid parenchyma, within a few weeks after administration

Advantages of radioiodine include easy administration, effectiveness, low expense, and absence of pain

Should not be administered to pregnant women or nursing mothers

Beta blockers

Metoprolol, propranolol, atenolol Propranolol has been the b blocker most

widely studied and used in the therapy of thyrotoxicosis

Beta blockers cause clinical improvement of hyperthyroid symptoms but do not alter thyroid hormone levels

HYPOTHYROIDISM

Table . Etiology and pathogenesis of hypothyroidism.

Cause Pathogenesis GoiterDegree of

Hypothyroidism

Hashimoto's thyroiditis

Autoimmune destruction of thyroid

Present early, absent later

Mild to severe

Drug-induced1 Blocked hormone formation2 Present Mild to

moderateDyshormonogenesis

Impaired synthesis of T4 due to enzyme deficiency

Present Mild to severe

Radiation, 131I, x-ray, thyroidectomy

Destruction or removal of gland Absent Severe

Congenital (cretinism)

Athyreosis or ectopic thyroid, iodine deficiency; TSH receptor-blocking antibodies

Absent or present Severe

Secondary (TSH deficit)

Pituitary or hypothalamic disease Absent Mild

1Iodides, lithium, fluoride, thioamides, aminosalicylic acid, phenylbutazone, amiodarone, perchlorate, ethionamide, thiocyanate, cytokines (interferons, interleukins), bexarotene, etc.

Dr. Hakaru Hashimoto

There is evidence of humoral immunity in the presence of antithyroid antibodies and lymphocyte sensitization to thyroid antigens

Management

Levothyroxine Infant 1-6 months of age is 10-15 mcg/kg/d Adult is about 1.7 mcg/kg/d > 65 years of age may require less thyroxine Thyroxine should be administered on an empty stomach Its long half-life of 7 days permits once daily dosing It takes 6-8 weeks to reach ss levels in the bloodstream Children should be monitored for normal growth and

development Serum TSH and free thyroxine should be measured at

regular intervals (0.5-2.5 mU/L)

Management

In older patients, and in patients with underlying cardiac disease, start treatment with reduced dosages, and if angina pectoris or cardiac arrhythmia develops, it is essential to stop or reduce the dose of thyroxine immediately

In children, restlessness, insomnia, and accelerated bone maturation and growth may be signs of thyroxine toxicity

In adults, increased nervousness, heat intolerance, episodes of palpitation and tachycardia, or unexplained weight loss

Chronic overtreatment with T4, particularly in elderly patients, can increase the risk of atrial fibrillation and accelerated osteoporosis

Management

MYXEDEMA AND CORONARY ARTERY DISEASE Myxedema frequently occurs in older persons Correction of myxedema must be done cautiously to avoid

provoking arrhythmia, angina, or acute myocardial infarction

If coronary artery surgery is indicated, it should be done first

MYXEDEMA COMA It is associated with progressive weakness, stupor,

hypothermia, hypoventilation, hypoglycemia, hyponatremia, water intoxication, shock, and death

It is a medical emergency The patient should be treated in ICU It is important to give all preparations intravenously

Management

HYPOTHYROIDISM AND PREGNANCY Hypothyroid women frequently have anovulatory cycles (usefulness

in infertile euthyroid patients?) Early development of the fetal brain depends on maternal thyroxine Increase in the thyroxine dose (about 30-50%) is required to

normalize the serum TSH level during pregnancy Elevated maternal TBG levels

SUBCLINICAL HYPOTHYROIDISM Elevated TSH level and normal thyroid hormone levels found in 4-10% of the general population but increases to 20% in

women older than age 50 Therapy should be considered for patients with TSH levels greater

than 10 mU/L DRUG-INDUCED HYPOTHYROIDISM

Levothyroxine therapy if the offending agent cannot be stopped

HYPERTHYROIDISM

Grave's Disease or diffuse toxic goiter

Helper T lymphocytes stimulate B lymphocytes to synthesize antibodies to thyroidal antigens

TSH-R Ab [stim] = TSI Spontaneous remission occurs but some

patients require years of antithyroid therapy

Grave's Disease Orbital fibrocytes

Management

1. ANTITHYROID DRUG THERAPY useful in young patients with small glands and mild disease Methimazole is preferable to propylthiouracil (except in

pregnancy) begun with divided doses, shifting to maintenance therapy

with single daily doses when the patient becomes clinically euthyroid

There is a 50-68% incidence of relapse Laboratory tests most useful in monitoring the course of

therapy are serum FT3, FT4, and TSH levels In 2nd year or with maintenance therapy TSH begins to drive

the gland Levothyroxine, 50-150 mcg TSH control

A minor rash can often be controlled by antihistamine therapy Agranulocytosis is often heralded by sore throat or high fever

Management

2. THYROIDECTOMY Treatment of choice for patients with very large glands or multinodular

goiters Patients are treated with antithyroid drugs until euthyroid (about 6

weeks). In addition, for 10-14 days prior to surgery, they receive saturated solution of potassium iodide, 5 drops twice daily, to diminish vascularity of the gland and simplify surgery.

About 80-90% of patients will require thyroid supplementation following near-total thyroidectomy

3. RADIOACTIVE IODINE 131I is the preferred treatment for most patients over 21 years of age In patients with underlying heart disease or severe thyrotoxicosis and

in elderly patients, it is desirable to treat with antithyroid drugs (preferably methimazole) until the patient is euthyroid, 5-7 days before the appropriate dose of 131I is administered

Iodides should be avoided to ensure maximal 131I uptake levothyroxine

Adjuncts to antithyroid therapy Propranolol, 20-40 mg orally every 6

hours Diltiazem (in asthma) Propranolol is gradually withdrawn as

serum thyroxine levels return to normal Adequate nutrition and vitamin

supplements are essential Barbiturates accelerate T4 breakdown

(by hepatic enzyme induction) and may be helpful both as sedatives and to lower T4 levels

Toxic Uninodular Goiter & Toxic Multinodular Goiter

Occur often in older women with nodular goiters

Single toxic adenomas surgical excision of the adenoma or

radioiodine therapy Toxic multinodular goiter

Treated with methimazole or propylthiouracil followed by subtotal thyroidectomy

Subacute Thyroiditis

spontaneously resolving hyperthyroidism Supportive therapy is usually all that is

necessary Propranolol for tachycardia Aspirin or nonsteroidal anti-inflammatory

drugs to control local pain and fever Corticosteroids may be necessary in severe

cases to control the inflammation

Thyroid Storm

A life-threatening syndrome Propranolol, 1-2 mg slowly intravenously or 40-

80 mg orally every 6 hours or diltiazem Potassium iodide, 10 drops orally daily, or

iodinated contrast media, 1 g orally daily propylthiouracil, 250 mg orally every 6 hours or

400 mg every 6 hours as a retention enema Hydrocortisone, 50 mg intravenously every 6

hours (shock & T4 to T3 conversion inhibition) If not respond, plasmapheresis or peritoneal

dialysis

Ophthalmopathy

Elevation of the head Artificial tears Smoking cessation A short course of prednisone Eyelid or eye muscle surgery may be

necessary to correct residual problems after the acute process has subsided

Dermopathy

Dermopathy or pretibial myxedema will often respond to topical corticosteroids

Lugol's solution

Lugol's iodine, also known as Lugol's solution, first made in 1829, is a solution of iodine named after the French physician J.G.A. Lugol.

Lugol's iodine solution is often used as an antiseptic and disinfectant, a starch indicator, to replenish iodine deficiency, to protect the thyroid gland from radioactive materials (e.g. "fallout"), and for emergency disinfection of drinking water

It consists of 5% iodine (I2) and 10% potassium iodide (KI) in 85% distilled water with a total iodine content of 130 mg/mL

Amiodarone-Induced Thyrotoxicosis

3% of patients receiving amiodarone will develop hyperthyroidism

Two types Iodine-induced (type I), which often occurs in

persons with underlying thyroid disease (eg, multinodular goiter)

An inflammatory thyroiditis (type II) that occurs in patients without thyroid disease due to leakage of thyroid hormone into the circulation

Since it is not always possible to differentiate between the two types, thioamides and glucocorticoids are often administered together

Nontoxic goiter

Goiter due to iodide deficiency is best managed by prophylactic administration of iodide

The optimal daily iodide intake is 150-200 mcg Iodized salt and iodate used as preservatives in

flour and bread are excellent sources of iodine in the diet

Iodized poppyseed oil IM Goiter due to ingestion of goitrogens in the diet

is managed by elimination of the goitrogen or by adding sufficient thyroxine to shut off TSH stimulation