Anesthesia Pharmacology Chapter 24:  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

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* * 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.

• 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.

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)

• 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