Treatment of Hyperthyroidism

Amit Nayak

Hyperthyroidism

• The increased oxygen demand leads to an increased heart rate and increased cardiac output and, thereby, places strain on the heart

• Exaggerated catabolic processes lead to decreased serum cholesterol and to poor glucose tolerance and glucosuria

• excessive calorigenic effect produced by catabolic processes causes anorexia and poor thermoregulation

Antithyroid Drugs for the Treatment of Hyperthyroidism

• Iodide• Methimazole, Propylthiouracil, and Related

Compounds

Iodide• Inhibition of the release of thyroid hormone by iodide is the basis for its

use in hyperthyroidism. • Iodide decreases the vascularity of the enlarged thyroid gland and also

lowers the elevated BMR. • It also has been suggested that excess iodide might change the

conformation of thyroglobulin, making the protein less susceptible to thyroidal proteolysis.

• the role of iodide in hyperthyroidism has been relegated to that of preparation for thyroid surgery.

• Iodide, as Lugol's solution (Strong Iodine Solution USP) or as saturated potassium iodide solution, is administered for approximately 2 weeks to ensure decreased vascularity and firming of the gland.

• Iodism, a side effect of iodine administration, is apparently an allergic react ion characterized by dermatological and common cold- like symptoms

Methimazole, Propylthiouracil, and Related Compound

• Thionamides are the most important class of antithyroid compounds in clinicalpract ice used in nondestructive therapy of hyperthyroidism

• potent inhibitors of TPO, which is responsible for the iodination of tyrosine residues of thyroglobulin and the coupling of iodotyrosine residues to form iodothyronines

• no effect on the iodide pump or on thyroid hormone release

Contd….Chemically, the grouping R-CS-N- as been referred to as thioamide, thionamide, thiocarbamide, or if R is N, as it is in thiouracil, PTU, and MMI, it is called a thioureylene. This structure may exist in either the thioketo or thioenol tautomer ic forms.

SAR

• The study of 6-alkylthiouracil showed maximal antithyroid activity with 6-propylthiouracil . 6-Methylthiouracil has less than one- tenth the activity of PTU.

• The C2 thioketo/ thioenol group and an unsubstituted N1 position are essential for activity

• The enolic hydroxyl group at C4 in PTU and the presence of alkyl group at C5 and C6 enhance the inhibitory potency

SAR Contd…

• Methimazole has more TPO inhibitory activity and is longer -acting than PTU but , in contrast to PTU, is not able to inhibit the peripheral deiodination of T4, presumably because of the presence of the methyl group at N1 position. The suggested maintenance dosages listed in USP DI are 50 to 800 mg daily for PTU and 5 to 30 mg daily for MMI

• Efforts to improve the taste and decrease the rate of release of MMI led to the development of 1-carbethoxy-3-methylthioimidazole (carbimazole) . Carbimazole, the pro-drug derivative of methimazole, gives rise to methimazole in vivo and is used in the same dosage

Side-Effects

• The side effects of thioamides include diarrhea, vomiting, jaundice, skin rashes, and at times, sudden onset of agranulocytosis. There does not appear to be a great difference in toxicity among the compounds currently in use