O Antithyroid Drugs

Hyperthyroidism (excessive production of thyroid hormones) usually requires surgery, but before surgery the patient must be prepared by preliminary abolition of the hyperthyroidism through the use of antithyroid drugs. Thiourea and related compounds show an antithyroid activity, but they are too

toxic for clinical use. The more useful drugs are 2-thiouracil derivatives and a closely related 2-thioimidazole derivative. All of these appear to have a similar mechanism of action (i.e., prevention of the iodination of the precursors of thyroxine and triiodothyronine). The main difference in the compounds lies in their relative toxicities.

These compounds are absorbed well after oral administration and excreted in the urine.

The 2-thiouracils, 4-keto-2-thiopyrimidines, are undoubtedly tautomeric compounds and can be represented as follows:

Some 300 related structures have been evaluated for antithyroid activity, but of these, only the 6-alkyl-2-thiouracils and closely related structures possess useful clinical activity. The most serious adverse effect of thiouracil therapy is agranulocytosis.

Propylthiouracil, USP. Propylthiouracil, 6-propyl-2-thiouracil (Propacil), is a stable, white, crystalline powder with a bitter taste. It is slightly soluble in water but readily soluble in alkaline solutions (salt formation).

This drug is useful in the treatment of hyperthyroidism. There is a delay in appearance of its effects because propyl-thiouracil does not interfere with the activity of thyroid hormones already formed and stored in the thyroid gland. This lag period may vary from several days to weeks, depending on the condition of the patient. The need for three equally spaced doses during a 24-hour period is often stressed, but evidence now indicates that a single daily dose is as effective as multiple daily doses in the treatment of most hyper-thyroid patients.81

Methimazole, USP. Methimazole, 1-methylimidazole-2-thiol (Tapazole), occurs as a white to off-white, crystalline powder with a characteristic odor and is freely soluble in water. A 2% aqueous solution has a pH of 6.7 to 6.9. It should be packaged in well-closed, light-resistant containers.

Methimazole is indicated in the treatment of hyperthyroidism. It is more potent than propylthiouracil. The side effects are similar to those of propylthiouracil. As with other antithyroid drugs, patients using this drug should be under medical supervision. Also, like the other antithyroid drugs, methimazole is most effective if the total daily dose is subdivided and given at 8-hour intervals.

#review questions#

1. Nitroglycerin can be used as an antianginal agent because of its vasodilator effects. Also, nitroglycerin is a liquid used in dynamite; why does not Mrs. Smith blow up when using this drug as a vasodilator?

a. It is not really the same nitroglycerin as the one used to make dynamite.

b. Nitroglycerin must be used while it is fresh so it will not detonate.

c. There are stabilizers added to nitroglycerin that prevent its detonation.

d. Nitroglycerin is very dilute when used as an antiangi-nal agent so it will not detonate.

2. Although the agent shown here (Losartan [Cozaar]) has some pharmacological effects, one of its metabolites is reported to be more potent. Identify this metabolite.

a. V-dealkylation that releases the imidazole ring (V-de-imidazole metabolite)

b. oxidation of the 5-methanol to a carboxylic acid c. oxidation of the aromatic (benzene) ring to a phenol d. oxidation of the omega-1 carbon on the 2-position alkyl side chain e. None of the above is true because only the parent compound is active.

CH2CH2CH2CH;

4. Highlight the difference between digoxin and digitoxin and point out the two primary reasons why one is more toxic than the other.

a. sulfhydryls: S-nitrosothiols b. amidase; carboxylic acids and amines c. esterases; carboxylic acids and alcohols d. hydroxyl residues; O-nitrosoalcohols

3. After a patient is administered an organic nitrate, these are then metabolized to nitric oxide (NO) by first reacting with_to form_.

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