Page 704 - Basic _ Clinical Pharmacology ( PDFDrive )

690 SECTION VII Endocrine Drugs

TABLE 38–2 Typical adult values for thyroid function tests.

Name of Test Normal Value 1 Results in Hypothyroidism Results in Hyperthyroidism
Total thyroxine (T 4 ) 4.8–10.4 mcg/dL (62–134 nmol/L) Low High
Total triiodothyronine (T 3 ) 59–156 ng/dL Normal or low High
(0.9–2.4 nmol/L)
Free T 4 (FT 4 ) 0.8–1.4 ng/dL (10–18 pmol/L) Low High
Free T 3 (FT 3 ) 169–371 ng/dL (2.6–5.7 pmol/L) Low High
Thyrotropic hormone (TSH) 0.45–4.12 μIU/mL High 2 Low
(0.45–4.12 mIU/L)
123
I uptake at 24 hours 5–35% Low High
Antithyroglobulin antibodies (Tg-Ab) <200 IU/mL Often present Usually present
Thyroperoxidase antibodies (ATPO) ≤100 WHO units Often present Usually present
Isotope scan with 123 I or 99m TcO 4 Normal pattern Test not indicated Diffusely enlarged gland
Fine-needle aspiration (FNA) biopsy Normal pattern Test not indicated Test not indicated
Serum thyroglobulin Women: 1.5–38.5 mcg/L Test not indicated Test not indicated
Men: 1.4–29.2 mcg/L
TSH receptor-stimulating antibody or Negative <140% of baseline Test not indicated Elevated in Graves’ disease
thyroid-stimulating immunoglobulin (TSI)
1
Results may vary with different laboratories.
2 Exception is central hypothyroidism.

The synthetic dextro (d) isomer of thyroxine, dextrothyroxine, is restored. Thus, the concentration of total and bound hormone
has approximately 4% of the biologic activity of the l-isomer as will increase, but the concentration of free hormone and the
evidenced by its lesser ability to suppress TSH secretion and cor- steady-state elimination will remain normal. The reverse occurs
rect hypothyroidism. when thyroid binding sites are decreased.

Pharmacokinetics Mechanism of Action
Thyroxine is absorbed best in the duodenum and ileum; absorp- A model of thyroid hormone action is depicted in Figure 38–4,
tion is modified by intraluminal factors such as food, drugs, which shows the free forms of thyroid hormones, T and T ,
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3
gastric acidity, and intestinal flora. Oral bioavailability of current dissociated from thyroid-binding proteins, entering the cell
preparations of l-thyroxine averages 70 to 80% (Table 38–1). by the active transporters (eg, monocarboxylate transporter
In contrast, T is almost completely absorbed (95%). T and T 8 [MCT8], MCT10, and organic anion transporting polypep-
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4
3
absorption appears not to be affected by mild hypothyroidism but tide [OATP1C1]). Transporter mutations can result in a clinical
may be impaired in severe myxedema with ileus. These factors are syndrome of mental retardation, myopathy, and low serum T
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important in switching from oral to parenteral therapy. For par- levels (Allan-Herndon-Dudley syndrome). Within the cell, T is
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enteral use, the intravenous route is preferred for both hormones. converted to T by 5′-deiodinase, and the T enters the nucleus,
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3
In patients with hyperthyroidism, the metabolic clearances of where T binds to a specific T thyroid receptor protein, a member
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T and T are increased and the half-lives decreased; the opposite of the c-erb oncogene family. (This family also includes the steroid
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is true in patients with hypothyroidism. Drugs that induce hepatic hormone receptors and receptors for vitamins A and D.) The T
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microsomal enzymes (eg, rifampin, phenobarbital, carbamaze- receptor exists in two forms, α and β. Mutations in both α and
pine, phenytoin, tyrosine kinase inhibitors, HIV protease inhibi- β genes have been associated with generalized thyroid hormone
tors) increase the metabolism of both T and T (Table 38–3). resistance. Cigarette smoking and environmental agents (eg, poly-
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Despite this change in clearance, the normal hormone concentra- chlorinated biphenyls) also may interfere with receptor action.
tion is maintained in the majority of euthyroid patients as a result Differing concentrations of receptor forms in different tissues may
of compensatory hyperfunction of the thyroid. However, patients account for variations in T effect on these tissues.
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dependent on T replacement medication may require increased Most of the effects of thyroid on metabolic processes appear
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dosages to maintain clinical effectiveness. A similar compensation to be mediated by activation of nuclear receptors that lead to
occurs if binding sites are altered. If TBG sites are increased by increased formation of RNA and subsequent protein synthesis, eg,
pregnancy, estrogens, or oral contraceptives, there is an initial shift increased formation of Na+/K+-ATPase. This is consistent with
of hormone from the free to the bound state and a decrease in its the observation that the action of thyroid is manifested in vivo
rate of elimination until the normal free hormone concentration with a time lag of hours or days after its administration.