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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