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Thyroxine
Thyroxine Brian L. Furman Strathclyde Institute for Biomedical Sciences, Glasgow, UK ã 2007 Elsevier Inc. All rights reserved.
Introduction Thyroxine (T4) is the main secretory product of the thyroid follicle cells and is converted to the active hormone, triiodothyronine (T3), in the tissues under the influence of microsomal deiodinase enzymes, which remove the iodine from the ‘‘outer’’ ring (5’deiodination). Removal of the iodine from the ‘‘Inner’’ ring, or tyrosyl ring (5-deiodination), produces an inactive substance known as reverse triiodothyronine (rT3) Hernandez and St Germain (1997). T4 is highly (>99%) bound to plasma protein (mostly to thyroidbinding globulin and transthyretin—formerly known as thyroid-binding pre-albumin), with only a small amount of free hormone (FT4) available for biological activity. The classical effects of thyroxine in maintaining the metabolic activity of tissues by maintaining the production of key enzymes are generally accepted as mediated via nuclear thyroid hormone receptors, which bind the active T3. Around 30 genes have been described that are regulated by thyroid hormones, including sarcoplasmic reticulum calcium ATPase, alpha-myosin heavy chain, malic enzyme Yen (2001), and uncoupling proteins Barbe et al (2001) (http://www.fasebj.org/cgi/doi/10.1096/fj.00-0502fje). However, there is evidence for rapid, nongenomic actions of thyroid hormones mediated via nonnuclear, cell surface, G-protein coupled receptors. These actions can be produced by T4 without conversion to T3. Some of these actions seem to be mediated via the mitogen-activated protein kinase (MAP kinase) cascade and are concerned with modulating the actions of growth factors and certain cytokines Davis et al (2002). A potent, nongenomic action in activating cardiac myocyte sodium channels was demonstrated by Huang et al. (1999), and this action was shared by T4 and T3, as well as some other iodinated tyrosines, but not by rT3. Huang et al (1999) There is also evidence for direct, nongenomic effects of thyroid hormones on mitochondrial function, via mitochondrial receptors Wrutniak-Cabello et al (2001).
Nomenclature Name of the Clinical Form Related Names Source: EMTREE
Thyroxine sodium beta[(3,5 diiodo 4 hydroxyphenoxy)3,5diiodophenyl]alanine; dextro levo thyroxine; dextro,levo thyroxine; dlthyroxine; 3 [4 (4 hydroxy 3,5 diiodophenoxy) 3,5 diiodophenyl]alanine; metathyroxine; ortho thyroxine; sodium thyroxine; 3,3’,5,5’ tetraiodothyronine; 3,5,3’,5’ tetraiodothyronine; tetraiodothyronine; 3,5,3’,5’tetraiodothyronine sodium; t 4 hormone; T4 hormone; thyrosine; thyrox; thyroxene; thyroxin; thyroxinal; thyroxine sodium; thyroxine sodium salt; tyroxine; levothyroxine; 2-Amino-3-[4-(4-hydroxy-3,5diiodo-phenoxy)-3,5-diiodo-phenyl]-propionic acid; 2Amino-3-[4-(4-hydroxy-3,5-diiodo-phenoxy)-3,5-diiodophenyl]-propionic acid; 3,5,3’,5’ tetraiodothyronine sodium; beta[(3,5 diiodo 4 hydroxyphenoxy)3,5 diiodophenyl]alanine; dl thyroxine; meta thyroxine
1
2
Thyroxine
Chemical Names CAS Number
3 [4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]-alanine 7488-70-2
Basic Chemistry Chemical Structure Structure
Chemical Formula Properties Physical Properties
Molecular Weight Solubility
C15 H11 I4 N O4
Thyroxine sodium is an odorless; almost white to pale brownishyellow, hygroscopic, amorphous, or crystalline powder. It should be stored at 2–8oC in airtight containers and protected from light Parfitt (1999). 776.855 It is very slightly soluble in water or alcohol and practically insoluble in acetone, ether, or chloroform. It is soluble in aqueous solutions of alkali hydroxides Parfitt (1999).
Human Pharmacokinetics Thyroxine is absorbed from the gastro-intestinal tract, although its absorption is variable. In the plasma, it is extensively bound to plasma proteins, mostly to thyroid-binding globulin but also to albumin and pre-albumin. There are numerous ways that it is metabolized, including 5’-deiodination (to produce the active T3), 5-deiodination (producing inactive rT3), deamination, decarboxylation, and ether bond cleavage. It may also be conjugated via the hydroxyl group to form sulfates or glucuronides Hernandez and St Germain (1997). The liver is a major site of metabolism, although deiodination to T3 probably occurs in most tissues. In the presence of normal thyroid function, the plasma half-life of thyroxine is about 6–7 days, this being prolonged in hypothyroidism and shortened in hyperthyroidism.
Targets-Pharmacodynamics The classical effects of thyroxine (through T3) are mediated by specific nuclear thyroid receptors (TR), of which there are two main types (TRalpha and TRbeta) Brent (1994). Target Name(s): Thyroid receptors after conversion to T-3
Thyroxine
Therapeutics Thyroxine is used in all diseases associated with clinical hypothyroidism, in which it will reverse the signs and symptoms of hypothyroidism. The dose is titrated for individual patients depending on clinical response and measurement of plasma-free thyroid-hormone concentration. The usual starting dose is 50–100 mg daily, as a single dose, by mouth and this is adjusted at 3–4 weekly intervals as required. In most patients, all signs and symptoms, including normalization of the serum concentrations of thyrotrophin, are relieved by doses of 75–150 mg daily. Lower doses are used in the elderly and in the presence of cardiac disease to minimize the risk of precipitating angina, myocardial infarction, or congestive heart failure as a consequence of the increased metabolic rate and the demand for an increased cardiac output. The long time between dose adjustments reflects the slow onset and long duration of action of the hormone as well as its long plasma half-life. As gastro-intestinal absorption is variable, thyroxine should be taken on an empty stomach. It is also given by injection in myxedema coma Shapiro and Surks (2001).
Contraindications Thyroxine is contraindicated in the presence of hyperthyroidism.
Adverse Effects The adverse effects of thyroxine are exactly predictable from the known consequences of thyrotoxicosis and include anginal pain, cardiac arrhythmias, palpitations, tachycardia, tachypnoea, diarrhoea, vomiting, tremors, restlessness, excitability, insomnia, flushing, sweating, excessive weight loss, and headache.
Agent-Agent Interactions Agent name
Mode of Interaction
Digoxin Propranolol Rifampicin
Reduced plasma concentration of digoxin. Reduced plasma concentration of propranolol. Reduced plasma concentration of thyroxine due to increased metabolism. Reduced plasma concentration of thyroxine due to increased metabolism. Reduced plasma concentration of thyroxine due to increased metabolism. Reduced plasma concentration of thyroxine due to increased metabolism. Reduced plasma concentration of thyroxine due to increased metabolism. Increased effect of anticoagulants. Reduced plasma concentration of thyroxine due to reduced absorption. Reduced plasma concentration of free thyroxine due to increased formation of plasma thyroid-binding proteins.
Carbamazepine Phenytoin Barbiturates Chloroquine Anticoagulants Cholestyramine Oral contraceptives
3
4
Thyroxine
Journal Citations Brent, G.A., 1994. The molecular basis of thyroid hormone action. N. Engl. J. Med., 331(13), 847–853. Barbe, P., Larrouy, D., Boulanger, C., Chevillotte, E., Viguerie, N., Thalamas, C., Trastoy, M.O., Roques, M., Vidal, H., Langin, D., 2001. Triiodothyronine-mediated up-regulation of UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes. FASEB J., 15(1), 13–15. Davis, P.J., Tillmann, H.C., Davis, F.B, Wehling, M., 2002. Comparison of the mechanisms of nongenomic actions of thyroid hormone and steroid hormones. J. Endocrinol. Invest., 25(4), 377–388. Hernandez, A., St Germain, D.L., 1997. Selenodeiodinases and their role in thyroid hormone activation and inactivation. Curr. Opin. Endocrinol. Diabetes, 4(5), 333–340. Huang, C.J., Geller, H.M., Green, W.L., Craelius, W., 1999. Acute effects of thyroid hormone analogs on sodium currents in neonatal rat myocytes. J. Mol. Cell Cardiol., 31(4), 881–893. Wrutniak-Cabello, C., Casas, F., Cabello, G., 2001. Thyroid hormone action in mitochondria. J. Mol. Endocrinol., 26(1), 67–77.
Book Citations Yen, P.M., 2001. Thyroid physiology: Hormone action, receptors and postreceptor events. Becker, K.L. (Ed.), Principles and Practice of Endocrinology and Metabolism, Edition 3, pp. 321–325, Lippincott Williams and Wilkins, Philadelphia, PA. Parfitt, K., 1999. Parfitt, K. (Ed.), Martindale: The Complete Drug Reference, Edition 32. , Pharmaceutical Press, London. Shapiro, L.E., Surks, M.I., 2001. Hypothyroidism. Becker, K.L. (Ed.), Principles and Practice of Endocrinology and Metabolism, Edition 3, pp. 445–454, Lippincott Williams and Wilkins, Philadelphia, PA.
Introduction Thyroxine (T4) is the main secretory product of the thyroid follicle cells and is converted to the active hormone, triiodothyronine (T3), in the tissues under the influence of microsomal deiodinase enzymes, which remove the iodine from the ‘‘outer’’ ring (5’deiodination). Removal of the iodine from the ‘‘Inner’’ ring, or tyrosyl ring (5-deiodination), produces an inactive substance known as reverse triiodothyronine (rT3) Hernandez and St Germain (1997). T4 is highly (>99%) bound to plasma protein (mostly to thyroidbinding globulin and transthyretin—formerly known as thyroid-binding pre-albumin), with only a small amount of free hormone (FT4) available for biological activity. The classical effects of thyroxine in maintaining the metabolic activity of tissues by maintaining the production of key enzymes are generally accepted as mediated via nuclear thyroid hormone receptors, which bind the active T3. Around 30 genes have been described that are regulated by thyroid hormones, including sarcoplasmic reticulum calcium ATPase, alpha-myosin heavy chain, malic enzyme Yen (2001), and uncoupling proteins Barbe et al (2001) (http://www.fasebj.org/cgi/doi/10.1096/fj.00-0502fje). However, there is evidence for rapid, nongenomic actions of thyroid hormones mediated via nonnuclear, cell surface, G-protein coupled receptors. These actions can be produced by T4 without conversion to T3. Some of these actions seem to be mediated via the mitogen-activated protein kinase (MAP kinase) cascade and are concerned with modulating the actions of growth factors and certain cytokines Davis et al (2002). A potent, nongenomic action in activating cardiac myocyte sodium channels was demonstrated by Huang et al. (1999), and this action was shared by T4 and T3, as well as some other iodinated tyrosines, but not by rT3. Huang et al (1999) There is also evidence for direct, nongenomic effects of thyroid hormones on mitochondrial function, via mitochondrial receptors Wrutniak-Cabello et al (2001).
Nomenclature Name of the Clinical Form Related Names Source: EMTREE
Thyroxine sodium beta[(3,5 diiodo 4 hydroxyphenoxy)3,5diiodophenyl]alanine; dextro levo thyroxine; dextro,levo thyroxine; dlthyroxine; 3 [4 (4 hydroxy 3,5 diiodophenoxy) 3,5 diiodophenyl]alanine; metathyroxine; ortho thyroxine; sodium thyroxine; 3,3’,5,5’ tetraiodothyronine; 3,5,3’,5’ tetraiodothyronine; tetraiodothyronine; 3,5,3’,5’tetraiodothyronine sodium; t 4 hormone; T4 hormone; thyrosine; thyrox; thyroxene; thyroxin; thyroxinal; thyroxine sodium; thyroxine sodium salt; tyroxine; levothyroxine; 2-Amino-3-[4-(4-hydroxy-3,5diiodo-phenoxy)-3,5-diiodo-phenyl]-propionic acid; 2Amino-3-[4-(4-hydroxy-3,5-diiodo-phenoxy)-3,5-diiodophenyl]-propionic acid; 3,5,3’,5’ tetraiodothyronine sodium; beta[(3,5 diiodo 4 hydroxyphenoxy)3,5 diiodophenyl]alanine; dl thyroxine; meta thyroxine
1
2
Thyroxine
Chemical Names CAS Number
3 [4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]-alanine 7488-70-2
Basic Chemistry Chemical Structure Structure
Chemical Formula Properties Physical Properties
Molecular Weight Solubility
C15 H11 I4 N O4
Thyroxine sodium is an odorless; almost white to pale brownishyellow, hygroscopic, amorphous, or crystalline powder. It should be stored at 2–8oC in airtight containers and protected from light Parfitt (1999). 776.855 It is very slightly soluble in water or alcohol and practically insoluble in acetone, ether, or chloroform. It is soluble in aqueous solutions of alkali hydroxides Parfitt (1999).
Human Pharmacokinetics Thyroxine is absorbed from the gastro-intestinal tract, although its absorption is variable. In the plasma, it is extensively bound to plasma proteins, mostly to thyroid-binding globulin but also to albumin and pre-albumin. There are numerous ways that it is metabolized, including 5’-deiodination (to produce the active T3), 5-deiodination (producing inactive rT3), deamination, decarboxylation, and ether bond cleavage. It may also be conjugated via the hydroxyl group to form sulfates or glucuronides Hernandez and St Germain (1997). The liver is a major site of metabolism, although deiodination to T3 probably occurs in most tissues. In the presence of normal thyroid function, the plasma half-life of thyroxine is about 6–7 days, this being prolonged in hypothyroidism and shortened in hyperthyroidism.
Targets-Pharmacodynamics The classical effects of thyroxine (through T3) are mediated by specific nuclear thyroid receptors (TR), of which there are two main types (TRalpha and TRbeta) Brent (1994). Target Name(s): Thyroid receptors after conversion to T-3
Thyroxine
Therapeutics Thyroxine is used in all diseases associated with clinical hypothyroidism, in which it will reverse the signs and symptoms of hypothyroidism. The dose is titrated for individual patients depending on clinical response and measurement of plasma-free thyroid-hormone concentration. The usual starting dose is 50–100 mg daily, as a single dose, by mouth and this is adjusted at 3–4 weekly intervals as required. In most patients, all signs and symptoms, including normalization of the serum concentrations of thyrotrophin, are relieved by doses of 75–150 mg daily. Lower doses are used in the elderly and in the presence of cardiac disease to minimize the risk of precipitating angina, myocardial infarction, or congestive heart failure as a consequence of the increased metabolic rate and the demand for an increased cardiac output. The long time between dose adjustments reflects the slow onset and long duration of action of the hormone as well as its long plasma half-life. As gastro-intestinal absorption is variable, thyroxine should be taken on an empty stomach. It is also given by injection in myxedema coma Shapiro and Surks (2001).
Contraindications Thyroxine is contraindicated in the presence of hyperthyroidism.
Adverse Effects The adverse effects of thyroxine are exactly predictable from the known consequences of thyrotoxicosis and include anginal pain, cardiac arrhythmias, palpitations, tachycardia, tachypnoea, diarrhoea, vomiting, tremors, restlessness, excitability, insomnia, flushing, sweating, excessive weight loss, and headache.
Agent-Agent Interactions Agent name
Mode of Interaction
Digoxin Propranolol Rifampicin
Reduced plasma concentration of digoxin. Reduced plasma concentration of propranolol. Reduced plasma concentration of thyroxine due to increased metabolism. Reduced plasma concentration of thyroxine due to increased metabolism. Reduced plasma concentration of thyroxine due to increased metabolism. Reduced plasma concentration of thyroxine due to increased metabolism. Reduced plasma concentration of thyroxine due to increased metabolism. Increased effect of anticoagulants. Reduced plasma concentration of thyroxine due to reduced absorption. Reduced plasma concentration of free thyroxine due to increased formation of plasma thyroid-binding proteins.
Carbamazepine Phenytoin Barbiturates Chloroquine Anticoagulants Cholestyramine Oral contraceptives
3
4
Thyroxine
Journal Citations Brent, G.A., 1994. The molecular basis of thyroid hormone action. N. Engl. J. Med., 331(13), 847–853. Barbe, P., Larrouy, D., Boulanger, C., Chevillotte, E., Viguerie, N., Thalamas, C., Trastoy, M.O., Roques, M., Vidal, H., Langin, D., 2001. Triiodothyronine-mediated up-regulation of UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes. FASEB J., 15(1), 13–15. Davis, P.J., Tillmann, H.C., Davis, F.B, Wehling, M., 2002. Comparison of the mechanisms of nongenomic actions of thyroid hormone and steroid hormones. J. Endocrinol. Invest., 25(4), 377–388. Hernandez, A., St Germain, D.L., 1997. Selenodeiodinases and their role in thyroid hormone activation and inactivation. Curr. Opin. Endocrinol. Diabetes, 4(5), 333–340. Huang, C.J., Geller, H.M., Green, W.L., Craelius, W., 1999. Acute effects of thyroid hormone analogs on sodium currents in neonatal rat myocytes. J. Mol. Cell Cardiol., 31(4), 881–893. Wrutniak-Cabello, C., Casas, F., Cabello, G., 2001. Thyroid hormone action in mitochondria. J. Mol. Endocrinol., 26(1), 67–77.
Book Citations Yen, P.M., 2001. Thyroid physiology: Hormone action, receptors and postreceptor events. Becker, K.L. (Ed.), Principles and Practice of Endocrinology and Metabolism, Edition 3, pp. 321–325, Lippincott Williams and Wilkins, Philadelphia, PA. Parfitt, K., 1999. Parfitt, K. (Ed.), Martindale: The Complete Drug Reference, Edition 32. , Pharmaceutical Press, London. Shapiro, L.E., Surks, M.I., 2001. Hypothyroidism. Becker, K.L. (Ed.), Principles and Practice of Endocrinology and Metabolism, Edition 3, pp. 445–454, Lippincott Williams and Wilkins, Philadelphia, PA.