thyroid and antithyroid drugs by: bohlooli s, phd school of medicine, ardabil university of medical...
TRANSCRIPT
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.
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
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%
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
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
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