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Anti-Thyroid Drugs

  • he normal thyroid gland secretes sufficient amounts of the thyroid hormones—triiodothyronine (T3) and tetraiodothyronine (T4, thyroxine)—to normalize growth and development, body temperature, and energy levels. These hormones contain 59% and 65% (respectively) of iodine as an essential part of the molecule. Calcitonin, the second type of thyroid hormone, is important in the regulation of calcium metabolism
  • The recommended daily adult iodide (I–)  intake is 150 mcg (200 mcg during pregnancy). The thyroid gland removes about 75 mcg a day from this pool for hormone synthesis, and the balance is excreted in the urine. If iodide intake is increased, the fractional iodine uptake by the thyroid is diminished.
  1. Synthesis:
    1. The first step is the transport of iodide into the thyroid gland by an intrinsic follicle cell basement membrane protein called the sodium/iodide symporter (NIS). This can be inhibited by such anions as thiocyanate (SCN–), pertechnetate (TcO4–), and perchlorate (ClO4–).
    2. At the apical cell membrane a second I– trans- port enzyme called pendrin controls the flow of iodide across the membrane. Pendrin is also found in the cochlea of the inner ear. If pendrin is deficient or absent, a hereditary syndrome of goiter and deafness, called Pendred’s syndrome, ensues.
    3. At the apical cell membrane, iodide is oxidized by thyroidal peroxidase to iodine, in which form it rapidly iodinates tyrosine residues within the thyroglobulin molecule to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). This process is called iodide organification. Thyroidal peroxidase is transiently blocked by high levels of intrathyroidal iodide and blocked more persistently by thioamide drugs. Two molecules of DIT combine within the thyroglobulin molecule to form L-thyroxine (T4). One molecule of MIT and one molecule of DIT combine to form T3.
    4. Thyroxine, T3, MIT, and DIT are released from thyroglobulin by exocytosis and proteolysis of thyroglobulin at the apical colloid border. The MIT and DIT are then deiodinated within the gland, and the iodine is reutilized. This process of proteolysis is also blocked by high levels of intrathyroidal iodide.
    5. The ratio of T4 to T3 within thyroglobulin is approximately 5:1, so that most of the hormone released is thyroxine. Most of the T3 circulating in the blood is derived from peripheral metabolism of thyroxine.
  1. Transport:
  • T4 and T3 in plasma are reversibly bound to protein, primarily thyroxine-binding globulin (TBG). Only about 0.04% of total T4 and 0.4% of T3 exist in the free form.
  1. Metabolism:
  • The primary pathway for the peripheral metabolism of thyroxine is deiodination. Deiodination of T4 may occur by monodeiodination of the outer ring, producing T3, which is three to four times more potent than T4. Alternatively, deiodination may occur in the inner ring, producing reverse T3, or rT3, which is metabolically inactive.
  • Drugs such as amiodarone, iodinated contrast media, βεtα blockers, and corticosteroids, and severe illness or starvation inhibit the 5’-deiodinase necessary for the conversion of T4 to T3, resulting in low T3 and high rT3 levels in the serum.

  T4 T3
VOLUME OF DISTRIBUTION 10L 40L
EXTRATHYROIDAL POOL 800 mcg 54 mcg
DAILY PRODUCTION 75 mcg 25 mcg
FRACTIONAL TURNOVER 10 % 60 %
METABOLIC CLEARANCE 1.1 L 24L
HALF LIFE 7 days 1 day
BIOLOGIC POTENCY 1 4
SERUM LEVELS-TOTAL 4.8-10.4 mcg/dl
62-134 nmol/L
60-180 ng/dl
0.92-2.79nmol/L
SERUM LEVELS-FREE 0.8-2.7 ng/dl
10.3-34.7 pmol/L
230-430 pg/dl
3.5-6.47 pmol/L
PROTEIN BOUND 99.96 % 99.6 %
ORAL ABSORPTION 80 % 95 %


Thyroid Function Test:

TEST HYPOTHYROIDISM HYPERTHYROIDISM
TOTAL T4 Low High
TOTAL T3 Normal/Low High
FREE T4 Low High
FREE T3 Low High
TSH High (Except Central Hypothyroidism) Low
I-123 UPTAKE Low High
THYROGLOBIN AUTOANTIBODIES Often + Often +
THYROID PEROXIDASE ANTIBODIES Often + Often +
ISOTOPE SCAN (123-I or Tc99mO4) - Enlarged Gland
TSH RECEPTOR STIMULATING ANTIBODY/ THYROID STIMULATING ANTIBODY (TSI) Hashimotto Disease Graves Disease

Anti-Thyroid Drugs:

  1. Thionamides
     
    a. Propylthiouracil                              
     
    b. Methimazole                            
     
    c. Carbimazole
  1. Iodine
     
    a. Lugol’s iodine                               
     
    b. Potassium Iodide
  2. Radioactive iodine
    1. Iodine 131
  3. Beta blockers
     
    a. Propranolol
  1. Radio-contrast media
     
    a. Iodipate                            
     
    b. Iponic acid
​1. Thionamides 

MAO: Inhibit iodo-tyrosyl coupling (Inhibit thyroid peroxidase).

P/K
  1. Well absorbed.                                                                
  2. High hepatic first pass.   
  3. Carbimazole---Methemazole (active metabolite).     
  4. Methemazole-M/potent, longest acting.    
  5. PTU shortest acting, maximally protein bound.

Uses

DOCs

  1. Graves disease                                                
  2. Nodular Goiter                
  3. Drug induced hyperthyroidism                    
  4. Also used to make patients hypothyroid before surgery
  5. Thyroid storm (PTU)                                      
  6. Hyperthrydism in pregnancy (PTU)
An important drawback of antithryoid drugs is that they take 1-4 weeks (around a month) before they become clinically effective. Therefore they are often started with beta-blockers to reduce the latency of onset of clinical effects.

Side effects

  1. MC-rashes
  2. Angioedema
  3. Agranulocytosis
    1. Stop when neutrophils <500 cells cmm
  4. Hypothyroidism
  5. Relapse (major problem)
  1. Courses of I131 are given along with anithryoids are given to reduce the rate of relapse
2. Radiocontrast Media
  1. Fast acting                                                                        
  2. Inhibit organifification   
  3. Hypersensitivity is a major problem                            
  4. Adrenaline should be around
3. Lugol’s Iodine (5%)
  1. Fastest acting anti-thyroid drug                                    
  2. Inhibits release of thyroid hormones                         
  3. Rebound is common

Use

  • To make the gland firm before surgery

S/E

  1. Angioedema                    
  2. Iodine overload
4. Iodine131 (Radioactive Iodine)
  1. Rapidly acting drug
  2. Liberates x-rays & gamma rays (AIPG’ 2001, 2005, 2007, AIIMS’ 2003)
  3. Relapse rate is lower than antithryoid drugs
  4. Carcinogenic
  5. Secondary cancer can occur (PCT-MC) (Very remote chance though according to Mayo Clinic Studies)
  6. Avoided in anyone <22 years, pregnancy
  7. PCT -sensitive to thyroid hormones (T4 is the DOC)

 
5. Propanolol
Inhibition of beta-adrenoreceptors
Inhibit T4 to T3 conversion (only propranolol).

use: Hyperthyroidism, especially thyroid storm adjunct to control tachycardia, hypertension, and atrial fibrillation.





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