Medical Pharmacology Chapter 30:  Thyroid and Antithyroid Drugs

• Overview

  • Purpose:

    • Reduction of thyroid activity.

    • Reduction of hormone effects.

  • Approach:

    • Use drugs that change tissue response to thyroid hormones.

    • Destroy the the thyroid with surgical or radiation interventions.

  • Definition:

    • "Goitrogens" --

      1. Compounds that suppress T₃ and T₄ secretion

      2. Thereby increasing TSH

      3. Increased TSH levels produces thyroid gland enlargement (goiter)

  • Antithyroid drugs include:

    • Thioamides.

    • Iodides.

    • Radioactive iodine.

• Thioamides

  • Major drugs for thyrotoxicosis:

    • Propylthiouracil

      • Rapidly absorbed

      • Bioavailability: 50 -- 80% (incomplete absorption/large first-pass effect).

      • Metabolism: glucuronidation by the liver; excreted by the kidney.

      • Sort half-life (1.5 hours) but accumulated by the thyroid.

      • Crosses placental barrier (increased protein binding compared to methimazole makes propylthiouracil preferable for use in pregnancy since less free drug is available to cross into the fetus).

    • Methimazole

      • About 10 times more active than propylthiouracil

      • Well absorbed

      • Accumulated by the thyroid

      • Crosses the placental barrier

    • Mechanism of Action:  thioamides

      1. Major action: inhibits thyroidal peroxidase-catalyzed reactions, blocking iodine organification: -- thus preventing hormone synthesis.

      2. Propylthiouracil and methimazole (too a much reduced degree) inhibit peripheral deiodination of T₄ and T₃

      3. Slow onset of pharmacological effect

    •   Toxicity:

      • Frequency of adverse effects: 3-12%.

      • Most common: maculopapular pruritic rash.

      • Most serious potential reaction: agranulocytosis -- risk 0.3% - 0.6 % of patients; reversible upon discontinuation; cross sensitivity between propylthiouracil and methimazole

      • possibly increased risk in:

        • Elderly.

        • Patients receiving high-dose methimazole.

• Anion Inhibitors

  • Competitive inhibition:

    • Perchlorate.

    • Pertechnetate.

    • Thiocyanate.

  • Major clinical use:  potassium perchlorate ( not often used because of the possibility of causing aplastic anemia).

    • Blockade of thyroid gland reuptake of I^- in patients with iodide-induced hyperthyroidism.

• Iodides

  • Rarely used now as monotherapy

  • Actions on the thyroid:

    • Inhibit organification.

    • Inhibition of hormone release is the major action.

      • Mechanism: perhaps inhibition of thyroglobulin proteolysis.

    • Decreased thyroidal size and vascularity.

    • May induce hyperthyroidism (Jod-Basedow effect).

    • May precipitate hypothyroidism.

  • Clinical Considerations

    • May be useful in short-term management of thyroid storm.

    • Maybe helpful in preoperative preparation for surgery (due to reduction in gland vascularity, size, and fragility).

    •   Major disadvantages:

      1.  Iodide therapy increases intraglandular iodine concentration.

         • May delay initiation of thioamides treatment.

         • May delay use of radioactive iodine treatment.

      2.   Chronic iodide used in pregnancy: avoid -- iodide crosses the placenta and may cause fetal goiter.

      3.   Iodide as monotherapy: not appropriate; iodide block lasts only 2-8 weeks; withdrawal at this time may exacerbate thyrotoxicosis.

    • Iodide use, if at all, should be initiated only after thioamide treatment and not used if radioactive iodine therapy is planned.

• Iodinated Radiographic Contrast Media

  • Useful in management of hyperthyroidism (off label use).

  • Ipodate and iopanoic acid inhibit T₄ to T₃ conversion in:

    • Kidney.

    • Liver.

    • Pituitary gland.

    • Brain.

  • Additional mechanism: iodine release-mediated inhibition of hormone release.

  • Clinical Use:

    1. Adjunctive treatment of thyroid storm.

    2. Alternatives if thioamides and iodides are contraindicated.

  •  Toxicity:  similar to iodides; relatively nontoxic.

• Radioactive Iodine

  • ¹³¹I is the radioactive isotope used for treating thyrotoxicosis.

  • Mechanism of Action:

    • Rapidly absorbed, concentrated in the thyroid.

    • Incorporated into thyroid follicles.

    • β emission (electron) is the basis for therapeutic efficacy.

    • Thyroid parenchymal destruction occurs within a few weeks.

  • Therapeutic Advantages for radioiodine:

    1. Good efficacy.

    2. Easy to administer.

    3. Low expense.

    4. Pain free treatment.

  •  Contraindication:

    • ¹³¹I-- not administered to pregnant women or nursing mother;¹³¹I crosses placental barrier and excreted in breast milk.

• Adrenergic receptor blocking drugs

  • Rationale: reduction of sympathetic manifestations in thyrotoxicosis

    • Applicable drugs:

      • β-adrenoceptor blockers.

      • Guanethidine.

    • Agent of choice:  propranolol (Inderal, nonselective β-receptor antagonist)

Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and Antithyroid Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 619-633.

Wartofsky, L., Diseases of the Thyroid, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2012-2034