Hyperthyroidism and Antithyroid Medications - Essay Example

Hyperthyroidism refers to any condition in which there is too much thyroid hormone in the body due to an overactive thyroid gland (American Thyroid Association 2005a). There are several possible options for treating hyperthyroidism. These include antithyroid drugs, beta blockers, radioactive iodine, iodides, and surgery (Reid & Wheeler 2005a). The American Thyroid Association (2005b) added that there is no single best treatment for patients with hyperthyroidism since the treatment may depend on factors such as age, type and severity of hyperthyroidism, and the medical condition of the patient. In the US, two antithyroid medications are being used, propylthiouracil (PTU) and methimazole, while in Europe and Asia, carbimazole which has a similar action to methimazole, is being used (Fenton 2006a). Carbimazole is converted to methimazole inside the body (Ross 2008a). The three antithyroid medications mentioned belong to the class of compounds known as thionamides and these medications inhibit thyroid hormone biosynthesis by decreasing the oxidation of iodide and iodination of tyrosine (Fenton 2006b). PTU also blocks the conversion of T4 (thyroxine) hormone to the more metabolically active T3 (triiodothyronine) hormone (MedicineNet 2005a). The chemical IUPAC name of methimazole is 1-methyl-3H-imidazole-2-thione, its chemical formula is C4H6N2S, its average molecular weight is 114.1688 g/mol, its melting point is 146 degrees Celsius, its experimental water solubility is 275g/L, and it has a half life of five to six hours (DrugBank 2007a). The following statements describe the mechanism of action of methimazole: ‘Methimazole binds to thyroid peroxidase and thereby inhibits the conversion of iodide to iodine. Thyroid peroxidase normally converts iodide to iodine (via hydrogen peroxide as a cofactor) and also catalyzes the incorporation of the resulting iodide molecule onto both the three and/or five positions of the phenol rings of tyrosines found in thyroglobulin. Thyroglobulin is degraded to produce thyroxine (T4) and triiodothyronine (T3), which are the main hormones produced by the thyroid gland. So methimazole effectively inhibits the production of new thyroid hormones.’ (DrugBank 2007b) The chemical IUPAC name of propylthiouracil is 6-propyl-2-sulfanylidene-1H-pyrimidin-4-one, its chemical formula is C7H10N2OS, its average molecular weight is 170.2321 g/mol, its melting point is 219 °C, its experimental water solubility is 219 °C, and its half life is two hours (DrugBank 2007c). The chemical IUPAC name of carbimazole is ethyl 3-methyl-2-sulfanylideneimidazole-1-carboxylate, its chemical formula is C7H10N2O2S, its average molecular weight is 186.2315 g/mol, and its melting point is 123.5 °C (DrugBank 2007d). ‘Methimazole can be administered once per day. Methimazole may be initially prescribed at doses ranging from 10 to 40 milligrams per day. Once the hyperthyroidism is under control, doses of five to 15 milligrams per day are sufficient to control hyperthyroidism... PTU requires an average of 16.8 weeks to effectively lower T4 levels. PTU must be taken two to three times per the day, and several tablets are usually needed to achieve an effective dose. A dose of 300 to 600 milligrams per day may be recommended initially. Once the hyperthyroidism is under control, 100 to 200 milligrams per day are sufficient to control hyperthyroidism in most people.’ (Ross 2008b) A major hazard of using the three medications (methimazole, propylthiouracil, and carbimazole) is an occasional suppression of the production of white blood cells by the bone marrow, which happens rarely to patients but patients are still advised to see a doctor when they develop a fever, sore throat, or other signs of infection (MedicineNet 2005b). ‘The main shortcoming of antithyroid drugs is that the underlying hyperthyroidism often comes back after they are discontinued’ (Endocrine Web 2005a). However, according to Ross (2008c) several factors such as antibodies to TSH receptors, individual factors, dose of antithyroid drug, and duration of treatment with an antithyroid drug may play a role for prolonged remission of hyperthyroidism for some patients. Some of the symptoms of hyperthyroidism are nervousness, irritability, increased perspiration, heart racing, hand tremors, anxiety, difficulty sleeping, thinning of skin, fine brittle hair, and muscular weakness especially in the upper arms and thighs (American Thyroid Association 2005c). These symptoms can be reduced by using medications called beta blockers (e.g. propranolol) but beta blockers do not decrease the amount of thyroid hormone in the body (Endocrine Web 2005b). Reid and Wheeler (2005b) stated that ‘therapy with propranolol should be initiated at 10 to 20 mg every six hours and that the dose should be increased progressively until symptoms are controlled.’ ‘Propranolol is a white, odourless crystalline powder. It is soluble one in 20 of water or alcohol, slightly soluble in chloroform, and practically insoluble in ether. It is only stable at acidic pH and decomposes rapidly when alkaline. Solutions are most stable at pH 3. In aqueous solutions propranolol decomposes with oxidation of the isopropylamine side-chain.’ (Tritsch et al 1991) The chemical IUPAC name of propranolol is 1-naphthalen-1-yloxy-3-(propan-2-ylamino) propan-2-ol, its chemical formula is C16H21NO2, its average molecular weight is 259.3434 g/mol, its melting point is 163-164°C, its experimental water solubility is 0.070 mg/mL, and its half life is four hours (DrugBank 2008a). For the illustration of the following, please see Figure 5. ‘The structure of propranolol can be divided into six binding regions. Region A is a naphthalene ring. Unsubstituted aromatic rings such as this can participate in either induced dipole-induced dipole bonds or hydrophobic bonds. They could bind to nonpolar, hydrocarbon rings or acyclic chains present on the receptor. Region B is ether oxygen which possesses a partial negative charge and can function as a hydrogen bond acceptor. This group could bind to hydrogen bond donors or positively charged groups present on the receptor to form hydrogen bonds or ion-dipole bonds, respectively. Region C is an acyclic hydrocarbon chain which would bind similarly to the naphthalene ring in region A. It should be noted that aromatic rings prefer to bind with other aromatic rings, but are able to bind to acyclic chains if necessary. In contrast, acyclic hydrocarbon chains prefer to bind to other acyclic hydrocarbon chains, but can bind to aromatic rings. This particular hydrocarbon chain may not contribute much to the binding since it is not isolated. Rather it serves as the support for a number of hydrophilic functional groups with electronegativities significantly different than hydrogen and carbon. Region D is a secondary alcohol which can participate in hydrogen bonds with a variety of functional groups present on a receptor. The partially positive hydrogen of the alcohol can act as a hydrogen bond donor, while the partially negative oxygen can act as a hydrogen bond acceptor. Additionally the alcohol can participate in ion-dipole interactions with either acids or bases present on the receptor molecule by using the partially positive hydrogen atom or the partially negative oxygen atom, respectively. Region E is a secondary amine. This basic functional group can become ionized and participate in ionic or ion-dipole bonds. The unionized amine can act as either a hydrogen bond donor or acceptor by using either the hydrogen atom or the unshared pair of electrons on the nitrogen atom, respectively. The final portion of propranolol, Region F, is a propyl chain which can participate in bonds similar to those outlined for region C with the exception that bonding here is more likely because the propyl group is isolated and relatively unhindered sterically.’ (Harrold 1998a) The most recommended permanent treatment of hyperthyroidism is radioactive iodine (Endocrine Web 2005c). ‘131I (radioactive iodine) is administered orally in one to two doses’ (Fenton 2006c). ‘Radioactive iodine (commonly called radioiodine) is a form of iodine chemically identical to nonradioactive iodine. Therefore, the thyroid gland, which takes up iodine to make thyroid hormone, cannot distinguish between the two. However, the nucleus of a radioactive iodine molecule has excess energy and gives off radiation that can have effects on the cells in which it is concentrated. When radioiodine is given, the thyroid gland cannot tell if the iodine is radioactive or not, and collects it in the normal way in proportion to the activity of the thyroid. Radioiodine thus accumulates in the cells that make thyroid hormone and remains there long enough to radiate the gland and to slow thyroid production. Radioiodine that is not retained by the thyroid gland is secreted rapidly by the body (within two or three days), primarily through the kidneys into the urine.’ (Becker et al 1993) ‘Iodine is a nonmetallic, purplish-black crystalline solid’ (U.S. Environmental Protection Agency n.d.). Iodine-129 and -131 are the most important radioactive isotopes in the environment (U.S. Environmental Protection Agency n.d.). Glenn T. Seaborg and John Livingood discovered radioactive iodine-131 (U.S. Environmental Protection Agency n.d.). ‘Both iodine-129 and iodine-131 are produced by the fission of uranium atoms during operation of nuclear reactors and by plutonium (or uranium) in the detonation of nuclear weapons’ (U.S. Environmental Protection Agency 2008 n.d). Iodine-131 has a half-life of about eight days and emits beta particles upon radioactive decay (U.S. Environmental Protection Agency 2008 n.d.). Another option for treating hyperthyroidism is by using iodides. ‘Iodides block the peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and inhibit hormone release. Iodides are not used in the routine treatment of hyperthyroidism because of paradoxical increases in hormone release that can occur with prolonged use. Organic iodide radiographic contrast agents (e.g., iopanoic acid or sodium ipodate) are used more commonly than the inorganic iodides (e.g., potassium iodide).’ (Reid & Wheeler 2005c) Fontanilla et al (2001) cited by Reid and Wheeler (2005d) stated that the dosage of iodides is one gram per day for up to 12 weeks. ‘Sodium ipodate and sodium iopanoic acid are iodinated contrast agents that act by liberating iodide’ (Fenton 2006d). ‘Sodium ipodate contains 308 mg iodine/cap, whereas sodium iopanoic acid contains 333 mg iodine/cap’ (Fenton 2006e). The appearance of potassium iodide is in the form of white crystals, its boiling point is 1330 degrees Celsius, its melting point is 680 degrees Celsius, and it is odourless (Environmental Health and Safety 2006). Potassium iodide has a formula weight of 166.003 and can be synthesized by having the hydroxide react with hydroiodic acid by which the resulting salt can be purified by recrystallization (Winter n.d.). Both radioactive iodine and iodides have contraindications and complications. According to Reid and Wheeler (2005d) the following are the contraindications and complications of radioactive iodine: ‘Delayed control of symptoms; posttreatment hypothyroidism in majority of patients with Graves disease regardless of dosage (82 percent after 25 years); contraindicated in patients who are pregnant or breastfeeding; can cause transient neck soreness, flushing, and decreased taste; radiation thyroiditis in 1 percent of patients; may exacerbate Graves ophthalmopathy; may require pretreatment with antithyroid drugs in older or cardiac patients’ The following are the contraindications and complications of iodides, according to Reid and Wheeler (2005e): ‘Paradoxical increases in hormone release with prolonged use; common side effects of sialadenitis, conjunctivitis, or acneform rash; interferes with the response to radioactive iodine; prolongs the time to achieve euthyroidism with antithyroid drugs’ According to Becker et al (1993), radioactive iodine treatment is safe since radioiodine can deliver sufficient radiation to the thyroid gland to slow its function while delivering only a small amount to the rest of the body. However, in order to protect people from absorbing radioactive iodine during a nuclear emergency, the American Thyroid Association recommends the use of potassium iodide (American Thyroid Association 2002). Figure 1: Chemical Structure of Methimazole (DrugBank 2007e) Figure 2: Chemical Structure of Carbimazole (DrugBank 2007f) Figure 3: Chemical Structure of Propylthiouracil (DrugBank 2007g) Figure 4: Chemical Structure of Propranolol (DrugBank 2008b) Figure 5: Six Binding Regions of propranolol (Harrold 1998b) Figure 6: Crystal Structure of Potassium Iodide (Winter n.d.) List of References American Thyroid Association, 2002, American Thyroid Association Endorses Potassium Iodide for Radiation Emergencies, American Thyroid Association, accessed 9 May 2008, American Thyroid Association, 2005, Hyperthyroidism, American Thyroid Association, accessed 9 May 2008, Becker, D., Hurley, J., & Detres, R., 1993, Radioactive Iodine Treatment of Hyperthyroidism, Thyroid Foundation of Canada, accessed 9 May 2008, DrugBank, 2007, Carbimazole, DrugBank, accessed 12 May 2008, DrugBank, 2007, Methimazole, DrugBank, accessed 12 May 2008, DrugBank, 2008, Propranolol, DrugBank, accessed 12 May 2008, DrugBank, 2007, Propylthiouracil, DrugBank, accessed 12 May 2008, Endocrine Web, 2005, Treatment of Hyperthyroidism: Drugs, Iodine, and Surgery as Treatments for Hyperthyroid Problem, Endocrine Web and Norman Endocrine Surgery Clinic, accessed 11 May 2008, Environmental Health & Safety, 2006, Potassium Iodide, Mallinckrodt Baker Inc., accessed 12 May 2008, Fenton, C., 2006, Hyperthyroidism, eMedicine, accessed 10 May 2008, Harrold, M., 1998, ‘Importance of Functional Group Chemistry in the Drug Selection Process: A Case Study,’ American Journal of Pharmaceutical Education, Vol. 62, accessed 12 May 2008, MedicineNet, 2005, Hyperthyroidism (overactive thyroid gland) Symptoms, Causes, Diagnosis, and Treatment, MedicineNet, Inc. accessed 10 May 2008, Reid, R. & Wheeler, S., 2005, ‘Hyperthyroidism: Diagnosis and Treatment,’ American Family Physician, Vol. 72, No. 4, accessed 12 May 2008, Ross, D., 2008, Patient information: Antithyroid drugs, UpToDate, Inc., accessed 11 May 2008, Tritsch, L., Dahlet, M., Sauder, P., Kopferschmitt, J., Flesch, F., & Jaeger, A., 1991, Propranolol, International Programme on Chemical Safety, accessed 12 May 2008, U.S. Environmental Protection Agency, n.d., Iodine, U.S. Environmental Protection Agency, accessed 12 May 2008, Winter, M., n.d., Potassium, The University of Sheffield and WebElements Ltd, accessed 12 May 2008, Read More