Thyroid and Antithyroid Drugs

By:Bohlooli S, PhD

School of Medicine, Ardabil University of Medical Sciences (ArUMS)

THYROID PHYSIOLOGY Iodide Metabolism

The recommended daily adult iodide (I-) intake is 150 mcg

Biosynthesis of Thyroid Hormones Transport of Thyroid Hormones

thyroxine-binding globulin (TBG) about 0.04% of total T4 and 0.4% of

T3 exist in the free form.

Biosynthesis of thyroid hormones

Peripheral metabolism of thyroxine

Evaluation of Thyroid Function

THYROID-PITUITARY RELATIONSHIPS

AUTOREGULATION OF THE THYROID GLAND

ABNORMAL THYROID STIMULATORS

Name of Test Normal Value1 Results in Hypothyroidism

Results in Hyperthyroidism

Total 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 High

Thyroglobulin 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 pattern Test not indicated Diffusely enlarged gland

Fine-needle aspiration biopsy (FNA)

Normal pattern Test not indicated Test not indicated

Serum thyroglobulin < 56 ng/mL Test not indicated Test not indicated

Serum calcitonin Male: < 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 imunoglobulin)

< 125% Test not indicated Elevated in Graves' disease

Typical values for thyroid function tests

The hypothalamic-pituitary-thyroid axis

BASIC PHARMACOLOGY

THYROID HORMONES

Chemistry Are levo (L) isomers Dextro (D) isomer of thyroxine,

dextrothyroxine, has approximately 4% of the biologic activity of the L isomer

Pharmacokinetics Mechanism of Action

Summary of thyroid hormone kinetics.

Variable T4 T3

Volume of distribution 10 L 40 L

Extrathyroidal pool 800 mcg 54 mcg

Daily 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 day

Serum levels    

  Total5-12 mcg/dL (64-164 nmol/L)

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

  Free0.7-1.86 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 4

Oral absorption 80% 95%

Model of the interaction of T3 with the T3 receptor

Effects of Thyroid Hormones

The thyroid hormones are responsible for : Optimal growth Development Function Maintenance of all body tissues

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

Manifestations of thyrotoxicosis and hypothyroidism (1)

Manifestations of thyrotoxicosis and hypothyroidism (2)

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 system Mild 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

System Thyrotoxicosis Hypothyroidism

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

Manifestations of thyrotoxicosis and hypothyroidism (3)

System Thyrotoxicosis Hypothyroidism

Thyroid Preparations

Synthetic: levothyroxine, liothyronine, liotrix

Animal origin desiccated thyroid

ANTITHYROID AGENTS

Thioamides Anion Inhibitors Iodides Iodinated Contrast Media Radioactive Iodine Adrenoceptor-Blocking Agents

Thioamides

Thioamides

Pharmacokinetics Propylthiouracil is rapidly absorbed

and the bioavailability is 50-80% Methimazole is completely absorbed Both thioamides cross the placental

barrier

Thioamides; Pharmacodynamics

Act by multiple mechanisms Prevent hormone synthesis by

inhibiting the thyroid peroxidase Inhibiting the peripheral

deiodination of T4 and T3 The onset of these agents is slow,

often requiring 3-4 weeks

Thioamides: Toxicity: Occur in 3-12% of treated patients Nausea and gastrointestinal distress The most common adverse effect is a

maculopapular pruritic rash (4-6%) Rare adverse effects include:

an urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy, hypoprothrombinemia, exfoliative dermatitis, polyserositis, and acute arthralgia.

Hepatitis can be fatal The most dangerous complication is

agranulocytosis

Anion Inhibitors

Perchlorate (ClO4-) Pertechnetate (TcO4-) Thiocyanate (SCN-)

Iodides

Inhibit organification Hormone release Decrease the size and vascularity

of the hyperplastic gland

Iodinated Contrast Media

diatrizoate iohexol inhibit the conversion of T4 to T3 inhibition of hormone release

Radioactive Iodine

131I is the only isotope used for treatment of thyrotoxicosis

therapeutic effect depends on emission of rays

Adrenoceptor-Blocking Agents

Metoprolol Propranolol Atenolol effective therapeutic adjuncts in

the management of thyrotoxicosis

CLINICAL PHARMACOLOGY OF THYROID & ANTITHYROID DRUGS

HYPOTHYROIDISMHYPERTHYROIDISM

Thyroid Storm Ophthalmopathy

Dermopathy

Cause Pathogenesis GoiterDegree of Hypothyroidi

sm

Hashimoto's thyroiditis

Autoimmune destruction of thyroid

Present early, absent later

Mild to severe

Drug-induced1 Blocked hormone formation2 Present Mild to moderate

DyshormonogenesisImpaired synthesis of T4 due to

enzyme deficiencyPresent 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

Etiology and pathogenesis of hypothyroidism