Thyroid Page 2

Thyroid preparations:
- Synthetic:
  - levothyroxine
  - liothyronine
  - liotrix
- Animal origin:
  - dessicated thyroid-- never justifiable; many disadvantages {protein antigenicity; product instability and variable hormone concentration; difficulty in lab assessment}
- Preparations of choice: synthetic levothyroxine:
  - Applications:
    - thyroid replacement
    - suppression therapy
  - Rationale:
    1. low-cost
    2. stability
    3. non-allergenic (no foreign protein)
    4. serum levels readily obtained
    5. long half-life (seven days) -- supports once-daily dosing
    6. since T₄ is converted to T₃ inside the cell, T₄ administration produces both hormones
- Liothyronine -- more active than levothyroxine but not recommended because of:
  1. shorter half-life (multiple dosing)
  2. more costly
  3. higher hormonal activity enhances cardiotoxicity (T₃ -- contraindicated in patients with cardiac disease)
  4. most appropriate use: short-term TSH suppression

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Antithyroid Drugs:

Overview
- Purpose:
  - reduction of thyroid activity
  - reduction of hormone effects
- Approach:
  - use drugs that change tissue response to thyroid hormones
  - destroy 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

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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
    - short 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
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  - 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: (since synthesis, not release is affected, a month may be required before T₄ stores are depleted.)
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  - Toxicity:
    - Frequency of adverse effects: 3-12%.
    - Most common: maculopapular pruritic rash
    - Rare: urticarial rash, vasculitis, arthralgia, lupus-like reaction, hepatitis, lymphadenopathy, cholestatic jaundice, hypoprothrombinemia, polyserositis.
    - 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
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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

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Iodides
- rarely used now as monotherapy
- Actions on the thyroid:
  - inhibit organification
  - inhibit hormone release-- major action
    - Mechanism: perhaps inhibition of thyroglobulin proteolysis
  - decreased thyroidal size and vascularity
  - may induce hyperthyroidism (jodbasedow)
  - 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

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Iodinated Radiographic Contrast Media
- Useful in management of hyperthyroidism (off label use)
- Ipodate and iopanoic acid inhibit T₄T₃ 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.

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Radioactive Iodine:
- ¹³¹I is the radioactive isotope used for treating thyrotoxicosis.
- Mechanism of Action:
  - rapidly absorbed, concentrated in the thyroid
  - incorporated into thyroid follicles
  - beta emission is the basis for therapeutic efficacy
  - Thyroid parenchymal destruction occurs within a few weeks. Pathology:
    - epithelial swelling, necrosis
    - follicular disruption
    - leukocyte infiltration
    - edema
- 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.

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Adrenergic receptor blocking drugs:
- Rationale: reduction of sympathetic manifestations in thyrotoxicosis:
  - Applicable drugs:
    - beta adrenoceptor blockers
    - guanethidine
  - Agent of choice: propranolol (nonselective beta-receptor antagonist)

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