Chapter 30:  Thyroid and Antithyroid Drugs

Thyroid Physiology and Pharmacology

• Overview

  • Thyroid -- exocrine gland

  • Two hormones types released:

    • thyroxine and triiodothyronine

    • calcitonin

  • Thyroxine and triiodothyronine are important in:

    1. growth

    2. development

    3. maintaining normal body temperature

    4. energy metabolism regulation

• Non-Physiological Thyroid Simulation:

  • Graves' disease:

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

• Chemistry of thyroid hormones:

  • Active isomer -- levo (L-form) -- thyroxine, triiodothyronine, reverse iodothyronine (reverse T₄)

• Pharmacokinetics:

  • T₄ -- well absorbed from the ileum and duodenum following oral administration-- about 80% absorbed on average

  • Modification of absorption:

    • food

    • drugs (e.g., sucralfate, iron, aluminum-containing antacids)

  • T₃ -- almost completely absorbed (95%) following oral administration

  •  T₄ and T₃ absorption may be impaired by myxedema (may require parenteral administration {IV}, as a result)

  • Factors that alter T₄ and T₃ clearance:

    • hyperthyroidism: increases 

    • hypothyroidism: decreases 

    • Drugs (hepatic microsomal enzymes inducers): Clearance is enhanced; Euthyroid state may be maintained because of thyroid hyperfunction.

      • phenobarbital

      • carbamazepine (Tegretol)

      • phenytoin (Dilantin)

      • rifampin

  • Increases in the number of TBG binding sites (due to pregnancy, estrogen use, oral contraceptive use)

    • more thyroid hormone is bound; elimination rate declines (only free hormone can be eliminated); normal hormone concentration would be eventually restored

• Mechanism of Hormone Action:

  1. Unbound T₄ and T₃ diffuse into the cell (passive diffusion, possibly active transport)

  2. Inside cell:

     3. T₄ converted to T₃

     4. T₃ is transported to the  cell nucleus where T₃ binds to a specific T₃ nuclear receptor

• Thyroid hormones: metabolic actions

  • nuclear receptor activation results in  increased RNA and protein synthesis: examples --

    • increased Na/K ATPase  causes  increased ATP turnover, increased oxygen consumption --calorigenic effect

* * Adapted from Table 38-4, Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and Antithyroid Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 625.

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

• Thyroid preparations:

  • Synthetic:

    • levothyroxine

    • liothyronine

    • liotrix

  • Animal origin:

    • dessicated thyroid-- never justifiable; many disadvantages {protein antigenicity; product instability and variable hormone concentration; difficulty and 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

• 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

      • 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

    • 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

    • 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

• 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

    • beta emission 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:

      • beta adrenoceptor blockers

      • guanethidine

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

• Overview: hypothyroidism

  1. cause: inadequate thyroid hormone synthesis

  2. Cretinism -- when hypothyroidism is present from birth and accompanied by developmental abnormalities

  3. Myxedema: severe hypothyroidism associated with:

     • deposition of hydrophilic mucopolysaccharides in the dermis (ground substance) and other tissues-- causing:

       • facial feature thickening

       • doughy skin induration

• Pretibia myxedema

• Hypothyroidism: pathogenesis

  1. inadequate thyroid hormone synthesis causes TSH hypersecretion which results in goiter

  2. if this compensatory physiological response is insufficient, goitrous hypothyroidism occurs

  • Causes of goitrous hypothyroidism (North America)

    • most common cause: Hashimoto's disease 

      • Mechanism:

        1. defective binding of iodide

        2. abnormal secretion of iodoproteins

    • Iodide-induced goiter with or without hypothyroidism: intrinsic defect inorganic binding mechanism

      • Euthyroid patients with Graves' disease {particularly following surgery or radioiodine therapy}, patients with Hashimoto's disease, and normal fetuses are particularly susceptible to iodide-induced goiter.

(Right) Struma lymphomatosa in Hashimoto thyroiditis, gross. Note: diffuse, pale yellow infiltrate affecting the entire thyroid. The yellow infiltrate is caused by an influx of lymphocytes, which may form follicles. Normal thyroid (Left)

KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

• Hypothyroidism: Clinical presentation

  • Neonates (note that cretinism may be present at birth, but usually is apparent within the first few months after birth as a function of the extent of thyroid failure)

    • manifestations:

      • physiologic jaundice

      • constipation

      • somnolence

      • feeding problems

    • Since early clinical diagnosis may be difficult and early treatment is necessary to ensure normal intellectual development,all neonates should be screened for hypothyroidism by measuring serum T₄ or TSH

  • Young Children:

    • coarse features, protruding tongue, broad, flat nose, widely set eyes, dry skin, coarse hair. impaired mental development, retarded bone age, epiphyseal dysgenesis, delayed dentition.

  • Older Child:

    • retardation of linear growth, delayed puberty

    • poor school performance

  • Adult:

    • fatigue, lethargy, constipation, cold intolerance,

    • slowing of intellectual and motor activity

    • lessened appetite; increased weight

    • dry skin; dry hair (may fall out)

    • deeper, hoarser voice

    • With Advanced Disease: (florid myxedema)

      • dull, expressionless facies, sparse hair, periorbital puffiness , large tongue, rough and doughy skin (cool, pale)

      • enlarged heart (dilation, pericardial effusion)

      • adynamic ileus

      •  Without treatment: myxedema coma possible with respiratory depression and increased P_CO2

  • Laboratory Tests:

    • single most useful: serum TSH

      • increased levels in thyroprivic and goitrous

      • normal or undetectable in pituitary or hypothalamic hypothyroidism

        • in hypothalamic hypothyroidism: TSH hypersecretion is associated with hypersecretion of other pituitary hormones

    • All hypothyroidism:

      • decreased serum T₄ and free T₄I

      • serum T₃ may be decreased  less than serum serum T₄

    • Some other abnormal laboratory results:

      • increase serum cholesterol (hypothyroidism of thyroid origin)

      • increased creatinine phosphokinase

      • increased aspartate transaminase

      • indications of pernicious anemia

• Pharmacological treatment:

  • Synthetic hormones:

    • levothyroxine, preferred

    • liothyronine

    • liotrix (combination of new L-thyroxine and liothyronine)

  • Neonatal, infantile, and juvenile hypothyroidism: early full replacement therapy vital to improve likelihood of:

    • normal intellectual development

    • normal growth

  • If neonatal, infantile, and juvenile presentations result from pituitary and hypothalamic hypothyroidism, treatment with hydrocortisone should precede thyroid replacement therapy:

    • Rationale:acute adrenocortical insufficiency may because by the increase in metabolic rate with increase glucocorticoid clearance following thyroid hormonal treatment

  • Adults:

    • rapid treatment desirable especially in patients with:

      1.  myxedema coma

      2.  hypothyroid patients needing to undergo emergency surgery (these patients have extreme sensitivity to CNS depressants);

         • IV levothyroxine with hydrocortisone may be appropriate

    • to patients with myxedema coma and systemic illness may have reduced ability to convert T₄ to T₃. In these cases supplemental liothyronine may be added to levothyroxine.

*- Thyroprivic: refering to lack of thyroidhormone (e.g. removal of the gland or suppression of glandular function)

Thyrotoxicosis

• Definition:clinical, physiological, biochemical consequences when tissues respond to excess thyroid hormone

• Most important causes: those associated with prolonged hormone overproduction by the thyroid.

• Causes:

  • Extra-pituitary unregulated thyroid stimulation:

    1. Graves' disease

    2. Hashimoto's disease

    3. trophoblastic tumor

  • Chronic thyroiditis

  • Excessive TSH secretion by pituitary tumor (rare)

  • Autonomous thyroid gland hyperfunction

  • Ingestion of meat contaminated with animal thyroids ("hamburger toxicosis")

• Hyperthyroidism is only associated with conditions in which thyroidal hyperfunction leads to thyrotoxicosis.

Graves' disease

• Three major presentations:

  • hyperthyroidism with diffuse goiter

  • dermopathy

  • ophthalmopathy

• Thyroid Pathology :

  • soft, enlarged, vascular

  • Parenchymal hypertrophy/hyperplasia

  • Lymphocytic infiltration (suggesting the immunological nature of the disease)

"Diffuse toxic goiter of Graves disease, gross, showing symmetric, non-nodular hypervascular enlargement of the thyroid"

1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

• Graves' disease: other involvements

  • generalized lymphoid hyperplasia and infiltration

  • spleenic or thymic enlargement

  • Thyrotoxicosis associated with:

    • skeletal muscle fiber degeneration

    • cardiac enlargement

    • diffuse liver fibrosis with fatty infiltration

    • skeletal decalcification

    • body tissue loss

• Ophthalmopathy:characterized by --

  1. inflammatory orbital content infiltrate (lymphocytes, mast cells, plasma cells)

  2. enlargement of orbital musculature (lymphocytes infiltration, mucopolysaccharides, edema, fat)

  3. eventually -- muscle fiber degeneration; loss of striations; fibrosis

• Dermopathy:

  • dermal thickening (lymphocytes infiltration; mucopolysaccharides)

• Clinical Presentations:-- Thyrotoxicosis

  • Common manifestations (thyrotoxicosis)

    • nervousness, insomnia, tremors, frequent bowel movements, heat intolerance, sweating, emotional instability

    • weight loss despite adequate or increased appetite

    • muscle weakness

    • oligomenorrhea/amenorrhea in premenstrual women

    • dyspnea

    • palpitations

    • exacerbation of angina/cardiac failure (older patients)

  • Ocular Presentations: -- distinct from ophthalmopathy associated with Graves' disease; ocular signs mainly due to excessive sympathetic stimulation

    • characteristics stare (widening palprebral fissures)

    • lid lag

    • infrequent blinking

    • failure to wrinkle brow upon upward gaze

  • Cardiovascular effects:

    • wide pulse pressure

    • sinus tachycardia

    • atrial arrhythmias (particularly atrial fibrillation)

    • systolic murmurs

    • occasionally heart failure

• Clinical Presentations: Graves' disease

  • Common manifestations:

    • hyperfunctioning goiter

      • asymmetric, lobular

    • ophthalmopathy

      • Two components: spastic and mechanical

        • spastic-- stare, lid lag, lid retraction

        • proptosis (sensitive to antiadrenergic agents) including:

          1. ophthalmoplegia

          2. periorbital swelling

          3. conjunctivitis

          4. corneal ulceration, optic neuritis, optic atrophy

    • Diagnosis:

      • in addition to physical manifestations described earlier:

        • undetectable TSH

        • Usually increased values of T₄ and T₃.

• Thyroid Storm:

  •  Fulminating increase in symptoms of thyrotoxicosis

  • "Medical storm" is now likely to be seen in undertreated patients.

  •  Precipitated by surgery or complicating illness, often sepsis.

  • Presenting syndrome:

    • extreme irritability

    • coma or delirium

    • high fever, 41^oC

    • tachycardia

    • hypotension

    • vomiting

    • diarrhea

  • Treatment:

    • manage dehydration: IV glucose/Saline, vitamin B complex

    • glucocorticoids (possible reduction in adrenal reserve; increase glucocorticoid requirement and thyrotoxicosis

    • digitalis may be required to control elevated ventricular rates in the presence of atrial fibrillation

    • Block hormone synthesis by large dose propylthiouracil; followed by large doses of iodine, oral or parenteral; sodium ipodate may be used instead of iodine

    • Propranolol (adrenergic antagonist) important in the absence of CHF

    • Combination treatment with propylthiouracil, iodine, dexamethasone is likely to result in serum T₃ levels returning to normal within one to two days.

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