Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Pharmacognosy wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Adherence (medicine) wikipedia , lookup
Drug interaction wikipedia , lookup
Toxicodynamics wikipedia , lookup
Prescription costs wikipedia , lookup
Psychopharmacology wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Neuropharmacology wikipedia , lookup
Psychedelic therapy wikipedia , lookup
Update Article Drugs and Thyroid Joe George*, Shashank R Joshi* Abstract Drugs can affect thyroid functional status in numerous ways. They may influence thyroid homeostasis at any level from their synthesis, secretion, transport or end-organ action resulting in hypothyroidism or hyperthyroidism. Amiodarone is an important drug in this group. The effects of amiodarone on thyroid function result from iodine release and intrinsic drug properties. Both amiodarone-induced thyrotoxicosis (AIT) and amiodarone -induced hypothyroidism (AIH) may develop in apparently normal thyroid glands or in glands with preexisting, clinically silent abnormalities. Treatment of AIH consists of thyroxine replacement while continuing or discontinuing amiodarone therapy. In type I AIT the main medical treatment consists of simultaneous administration of thionamides and potassium perchlorate, while in type II AIT, glucocorticoids are the most useful therapeutic option. It is important to evaluate patients before and during amiodarone therapy. The list of drugs affecting thyroid function is long with new drugs being added. Some of them are clinically important while others just produce diagnostic dilemmas. The possible effect of drugs on the results of thyroid-function tests should always be considered while making decisions regarding patient care. © INTRODUCTION T esting of thyroid function is becoming common in clinical practice. Many patients tested, are on multiple medications for various medical conditions. This is particularly true of elderly patients. It is widely recognized that certain drugs can alter thyroid hormone measurements and can cause confusing laboratory test results in subjects without thyroid disease. Certain other drugs affect thyroid function directly or indirectly and produce manifest disease. As awareness for thyroid disease is increasing and thyroid function testing is becoming part of routine evaluation protocols, the recognition of such abnormalities is also increasing. Therefore, the possible effect of these drugs both on the results of thyroid-function tests and on the effectiveness of treatment must always be considered in decisions regarding patient care. Although most drug induced changes in thyroid hormone homeostasis are transient, they produce puzzling and at the same time fascinating problems for physicians and endocrinologists alike. Drugs affecting Thyroid Function A large number of compounds may affect thyroid function. The list is rapidly growing with the array of new drugs coming into therapeutic armamentarium. Rather than presenting an exhaustive review, the more *Department of Endocrinology, Seth G.S. Medical College and KEM Hospital, Mumbai. © JAPI VOL. 55 MARCH 2007 commonly encountered compounds are listed1 (Tables 1 & 2) with those enjoying wider use and those with significant effect being considered in detail. Drugs may influence thyroid homeostasis at four different levels.2 They may alter the synthesis and/or secretion of thyroid hormone, may change the serum concentrations of thyroid hormones by acting at the level of binding proteins or by competing for their hormone binding sites, may modify cellular uptake and metabolism of thyroid hormone or may interfere with hormone action at the target tissue. AMIODARONE Amiodarone is an iodine-rich drug widely used for the management of atrial and ventricular arrhythmias.3 Being a category Type-III anti-arrhythmic, its main mechanism of action is to block myocardial potassium channels. Although itÊs cardiac side effects are less frequent than those associated with other antiarrhythmics, it has potentially marked effects on cornea, lungs, liver, skin, and the thyroid 4. It is a benzofuranic derivative with a structural similarity to T3 and T4 (Fig. 1). It can produce both hypo and hyperthyroidism. Each molecule of amiodarone contains two iodine atoms, which constitute approximately 37% of its mass. Hence, a patient taking a 200-mg daily dose of amiodarone ingests 75 mg of organic iodine each day. 10% of the molecule is deiodinated daily. So a maintenance daily dose of 200 to 600 mg results in approximately 721 mg iodide each day. The optimal www.japi.org 215 daily iodine intake advised is 150 to 300 øgm. Thus Amiodarone therapy results in iodine intake 50-100 times higher than the daily requirement. Furthermore, amiodarone is distributed in several tissues, including adipose tissue, liver, lung, and, to a lesser extent, kidneys, heart, skeletal muscle, thyroid, and brain, from which it is slowly released.5 This results in a prolonged terminal elimination half-life of around 100 days; the drug and its metabolites remaining available for a long period after withdrawal.5 Amiodarone effects on the thyroid gland and thyroid hormone metabolism are unique. These can be divided into intrinsic effects resulting from the inherent properties of the compound and iodine-induced effects (due solely to the pharmacologic effects of a large iodine load) [Table 3]. Majority of patients receiving amiodarone have thyroid function tests within the physiological range. Because the thyroid gland is exposed to an extraordinary load of iodine, adjustments are made in thyroidal iodine handling and hormone metabolism in order to maintain normal function, the reflection of which is seen in serum thyroid hormone levels. These alterations in serum thyroid function tests can be divided into acute (<3 months) and chronic (>3 a) Amiodarone b) Thyroxine (T4) c) Triiodothyronine (T3) Fig. 1 : Structure of Amiodarone and thyroid hormones. Table 1 : Drugs that influence thyroid function : transfer protein and extra thyroidal metabolism Mechanism of interference Drugs Altering thyroid hormone serum transfer proteins Increase Thyroid Binding Globulin (TBG) concentration Decrease TBG concentration Interfere with thyroid hormone binding to TBG and/ or transthyretin Agents that alter extra-thyroidal metabolism of thyroid hormone Inhibit conversion of T4 to T3 Increased hepatic metabolism Drugs that decrease T4 absorption or enhance excretion Estrogen, Tamoxifen Heroin, Methadone Clofibrate 5- Flurouracil, Mitotane Perphenazine Androgens Anabolic steroids (eg. Danazol) Glucocorticoids Slow release nicotinic acid Frusemide Fenoflenac Mefanamic acid Salicylates Phenytoin Diazepam Sulphonylureas Free fatty acids Heparin PTU Glucocorticoids Propranolol Iodinated contrast agents Amiodarone Clomipramine Phenobarbital Rifampicin Phenytoin Carbamazepine Cholestyramine, Colestipol Aluminium hydroxide Ferrous sulphate Sucralfate Amiodarone (Adapted and reproduced from Surks MI, Siewert R. Drugs and Thyroid Function. NEJM 1995;333:1688-94) 216 www.japi.org © JAPI VOL. 55 MARCH 2007 Table 2 : Drugs that influence thyroid function : Synthesis, secretion, action Mechanism of interference Drugs Drugs that affect synthesis or / and secretion of hormone Decreased T3/T4 synthesis /secretion Increased T3/T4 synthesis /secretion Decreased TSH concentration / response to TRH Increase TSH concentration / response to TRH Drugs that affect hormone action at the target tissue Lithium Iodide Thionamides (Propylthiouracil, Methimazole, Carbimazole) Thiocyanate Perchlorate Amiodarone Cytokines (IFN-γ, IL-2, GM-CSF) Aminoglutethimide Iodide Amiodarone Cytokines (IFN-γ, IL-2, GM-CSF) T4, T3 Glucocorticoids Growth hormone Octreotide, somatostatin Opiates Dopamine L- dopa, Bromocriptine Pimozide Phentolamine Thioridazine Methysergide Cyproheptadine Iodine Lithium Dopamine antagonists Iodide Amiodarone (Adapted and reproduced from Surks MI, Siewert R. Drugs and Thyroid Function. NEJM 1995;333:1688-94) Table 3 : Effect of Amiodarone on the Thyroid gland : Postulated Mechanisms Intrinsic Drug Effects IodineInduced Effects Inhibition of thyroid hormone entry into cells Inhibition of type 1 and type 2 5Ê deiodinase. (Total & FreeT4, rT3,T3, TSH) Decreased T3 binding to its receptor Failure to escape from Wolff-Chaikoff effect. Iodine induced potentiation of autoimmunity. In patients with underlying autonomous nodules or latent GravesÊ disease, produces hyperthyroidism (Jod Basedow Effect) Thyroid cytotoxicity (Destructive thyroiditis) (Adapted and reproduced from Basaria S, Cooper DS. Amiodarone and the thyroid. The American J Medicine 2005;118:706-14) months) phases that follow amiodarone exposure6 (Table 4). Indeed, more than 50% of patients who receive long-term amiodarone therapy show abnormal results on thyroid function test, though the majority remains clinically euthyroid. Occasionally, amiodarone can also cause goiter without apparent thyroid dysfunction. Although the majority of patients given amiodarone remain euthyroid, some develop thyroid dysfunction, i.e., thyrotoxicosis and hypothyroidism. Amiodaroneinduced thyrotoxicosis (AIT) appears to occur more frequently in geographical areas with low iodine intake, whereas Amiodarone induced hypothyroidism (AIH) is more frequent in iodine-sufficient areas.7-9 In a study carried out simultaneously in Italy (moderately low iodine intake) and United States (normal iodine intake), it was found that the incidence of AIT was about 10% in © JAPI VOL. 55 MARCH 2007 Table 4 : Effects of amiodarone on thyroid hormone profile in euthyroid subjects Parameters Duration of Treatment < 3 months > 3 months T4 / Free T4 T3 / Free T3 Reverse T3 TSH 50% 15-20% 200% 20-50%, remain <20 mU/L Normal TBG 20-40% above baseline 15-20% Remains >150% Normal Normal (Adapted and reproduced from Basaria S, Cooper DS. Amiodarone and the thyroid. The American J Medicine 2005;118:706-14) former and 2% in the latter, while the incidence of AIH was 5% in Italy and 22% in the United States. In general, the various published studies report an overall incidence www.japi.org 217 of AIT ranging from 1% to 23% and of AIH ranging from 1% to 32%.10 India is currently predominantly iodine sufficient though pockets of iodine deficiency still exist. Thus, irrespective of iodine intake, it may be estimated that the overall incidence of amiodaroneinduced thyroid dysfunction be between 2% and 24%,10 most commonly in the range of 1418%.11 AMIODARONE INDUCED THYROTOXICOSIS (AIT) AIT may develop, often suddenly and explosively, early or after many years of amiodarone treatment.12 Trip et al.13 observed that the average length of amiodarone treatment before the occurrence of AIT was about 3 yr, with a probability of disease slightly increasing with duration of therapy. An interesting feature of AIT is that it may develop even many months after drug withdrawal, due to tissue storage of the drug and its metabolites with slow release.8 There are no parameters that predict AIT including daily or cumulative dose of the drug.13 It is said to have a male to female ratio of 3:1.14.15 The pathogenesis of AIT is not completely delineated. The disease may develop both in a normal thyroid gland and in a gland with preexisting abnormalities. Two main forms of AIT exist. Type I AIT usually occurs in abnormal thyroid glands and is due to iodine induced excessive thyroid hormone synthesis and release; type II AIT is a destructive thyroiditis leading to release of preformed thyroid hormones from the damaged thyroid follicular cells. The relative prevalence of the two forms of AIT is unknown, but it may depend on the ambient Table 5 : Classification of Amiodaroneinduced thyrotoxicosis Type 1 Underlying thyroid Yes abnormality Thyroid autoantibodies Often present Goitre Often present Thyroidal radioactive Low, rarely normal iodine uptake or increased Serum IL-6 Slightly concentrations increased Cytologic findings ? Abundant colloid, histiocytes Pathogenic mechanism Excessive Thyroid hormone synthesis Colour flow Normal/increased Doppler pattern blood flow Response to thionamides Yes (Poor) Response to perchlorate Yes Response to Glucocorticoids Probably No Subsequent Hypothyroidism Unlikely Type 2 No Usually absent Usually absent Low Markedly increased Destructive Thyroiditis Decreased blood flow No No Yes Possible (Adapted and reproduced from Bartalena L, Grasso L, Bragioni S, et al. Serum interleukin-6 in Amiodarone induced thyrotoxicosis. J Clin Endocrinol Metab 1994;78:42327) 218 iodine intake. Definitions of AIT may not be absolute, and mixed forms with features of both type I and type II exist. Nevertheless, identifying the different subgroups has important management implications. AIT may not manifest with classical symptoms of thyrotoxicosis due to the antiadrenergic action of amiodarone and its impairment of conversion of T4 to T3. Goiter and local tenderness may be present or absent. Worsening of the underlying cardiac disorder in a patient on Amiodarone may herald onset of AIT.16 Diagnosis of AIT may be difficult in patients with severe non thyroidal illness, because the latter may dominate and confuse the clinical picture. Over and above this differentiating between the two types of AIT at times is impossible17 (Table 5). Treatment of AIT is a major challenge. The high intra thyroidal iodine content reduces/blunts the effectiveness of carbimazole / methimazole therapy.8 The generally low or suppressed RAIU makes radioiodine therapy an unattractive option. Surgical option is often complicated by the underlying cardiac condition and the thyrotoxic state. Overall it is difficult to lay down a definite protocol of management. We have tried to make a few suggestions18 (Table 6) which would work Table 6 : Treatment of Amiodarone-induced Thyroid disease protocol Type I AIT Thionamides ( carbinazole 30-60 mg/day or methimazole 3040 mg/day) in combination with potassium perchlorate (1 g/day for 1640 days). Discontinue amiodarone if possible. After restoration of euthyroidism and normalization of urinary iodine excretion, definitive treatment of the underlying thyroid abnormalities by either radioiodine or thyroidectomy. If amiodarone cannot be withdrawn and medical therapy is unsuccessful, consider total thyroidectomy. Type II AIT Glucocorticoids for 23 months (starting dose, prednisone 40 mg/day or equivalent). Discontinue amiodarone if possible. In mixed forms add thionamides and potassium perchlorate. After restoration of euthyroidism, follow-up for possible spontaneous progression to hypothyroidism. If amiodarone cannot be withdrawn and medical therapy is unsuccessful, consider total thyroidectomy. Amiodarone-induced hypothyroidism Underlying Thyroid Abnormalities (Usually HashimotoÊs Thyroiditis) Amiodarone therapy can be continued. L-T4 replacement therapy is added. Apparently Normal Thyroid Gland If amiodarone cannot be discontinued, L-T4 replacement therapy is initiated. If amiodarone is withdrawn, strict follow-up is required for possible spontaneous restoration of euthyroidism. A short course of potassium perchlorate (1 g/day for 1030 days) can be given to accelerate return to euthyroidism. (Adapted and reproduced from Martino. E, Bartalena L, Bogazzi F, Braverman LE. The Effects of Amiodarone on the Thyroid. Endocrine Reviews 2001;22:24054) www.japi.org © JAPI VOL. 55 MARCH 2007 as a skeleton on which management should be based. Finally each patient is different and treatment needs to be individualized accordingly. In type I AIT thionamides should be given to block further organification of iodine and synthesis of thyroid hormones. Larger than usual daily doses of methimazole (4060 mg) or propylthiouracil (600800 mg) are often necessary since the iodine-rich gland is usually resistant to these drugs. In addition, potassium perchlorate should be given if available to decrease the entrance of iodine into the thyroid and to deplete intrathyroidal iodine stores.19 The limitation of potassium perchlorate is its toxicity, particularly agranulocytosis, aplastic anemia and renal side effects. A complete blood count should be done every few weeks in patients receiving thionamide and perchlorate to detect this potentially fatal side effect. In addition, potassium perchlorate should be withdrawn once euthyroidism is achieved; usually by 6 weeks. Adding lithium carbonate (9001350 mg/day for 46 weeks) to propylthiouracil is an additional option worth mentioning.20 Treatment with lithium should always be accompanied by drug monitoring to maintain serum lithium concentrations within the therapeutic range of 0.61.2 mEq/l. Type II AIT, being a destructive thyroiditis does not respond to above treatment. Steroids are the best option because of their membrane-stabilizing and anti-inflammatory effects.21 They have been employed in AIT at different doses (1580 mg prednisone or 36 mg dexamethasone daily) and different time schedules (712 weeks).10,11,22 If thyrotoxicosis recurs on tapering steroid, it must be reinstituted. When distinction between type 1 and 2 is not possible or when they coexist in the same patient, a stepwise treatment approach is advised beginning with an antithyroid drug and potassium perchlorate. After 1 month of treatment, if patient doesnÊt show any response, perchlorate is discontinued and prednisolone is added. Tapering of steroid is done once serum free T4 concentration normalizes. Antithyroid drug in this case can be tapered and discontinued when urinary iodide excretion is < 200 øg daily.23 One of the most difficult problems in management of AIT is to decide on continuing or discontinuing amiodarone. It can be a double edged sword. Literature is full of conflicting opinion.18 But most experts advocate withdrawal of amiodarone, when feasible, although some patients with mild disease and response to thionamide and/or glucocorticoid therapy may be continued with treatment. In cases in which withdrawal of amiodarone is not feasible and medical therapy has failed, thyroidectomy represents a useful alternative. Definitive treatment of the underlying thyroid disorder will usually be required in most type I AIT patients; this can mostly be accomplished by radioiodine, provided the RAIU values improve. Most type II patients will © JAPI VOL. 55 MARCH 2007 remain euthyroid after resolution of the thyrotoxicosis. In patients with a history of AIT in whom amiodarone becomes necessary after it has been discontinued, ablation of the thyroid with radioiodine before resuming amiodarone should be strongly considered. AMIODARONE INDUCED HYPOTHYROIDISM (AIH) The risk of developing AIH is independent of the daily or cumulative dose of amiodarone. However, the risk is greater in the elderly, iodine sufficiency, HashimotoÊs thyroiditis, females and those with positive thyroid microsomal or thyroglobulin antibodies. AIH may be transient or persistent; the latter is almost always associated with an underlying thyroid disorder.9 AIH is usually an early event and it is uncommon after the first 18 months of amiodarone treatment.13 The most likely pathogenic mechanism is that the thyroid gland of these patients, damaged by preexisting HashimotoÊs thyroiditis, is unable to escape from the acute Wolff-Chaikoff effect after an iodine load24 and to resume normal thyroid hormone synthesis. These patients have a positive perchlorate discharge test cementing the theory of defective hormonogenesis.8 Similar to spontaneous hypothyroidism, AIH patients frequently have vague symptoms and signs, such as fatigue, cold intolerance, mental sluggishness, and dry skin. In patients already on thyroxine replacement therapy, the dose may need to be increased due to the inhibition of the generation of T3 from T4 induced by amiodarone25. Laboratory findings are similar to those in spontaneous hypothyroidism, with decreased serum free T4 and increased serum TSH concentrations. Management of AIH does not have the complexity observed with AIT (Table 6). If amiodarone is necessary for the underlying cardiac disorder, it can be continued in association with thyroxine replacement. If discontinuance of amiodarone therapy is feasible, spontaneous remission of hypothyroidism often occurs, particularly in patients without underlying thyroid abnormalities8. In view of the fact that these patients often have severe underlying cardiac disease, it is advisable to maintain the serum TSH concentration in the upper half of the normal range. Monitoring of thyroid function in amiodaronetreated patients It is essential to carefully evaluate patients before and during amiodarone therapy. A reasonable protocol is given in Fig. 2.18 It is ideal to monitor thyroid function every 6-12 weeks with free T3, free T4 and TSH. Amiodarone in pregnancy and lactation If amiodarone therapy is required, it can be administered during pregnancy, although it may cause changes in fetal thyroid function. Among pregnant women treated with amiodarone, abnormalities in www.japi.org 219 Fig. 2 : Recommendations for following patients receiving amiodarone therapy. (Adapted and reproduced from Martino. E, Bartalena L, Bogazzi F, Braverman LE. The Effects of Amiodarone on the Thyroid. Endocrine Reviews 2001;22:24054) thyroid function were found in 20% neonates, 3% of whom had transient hyperthyroxinemia and 17% had AIH. Congenital hypothyroidism related to amiodarone therapy in the mother is likely to be transient, but thyroxine therapy should be promptly started for the fear of motor and mental sub normalcy. Amiodarone is secreted in the milk. Breast feeding is not absolutely contraindicated but thyroid function in the neonate must be carefully monitored for the possible occurrence of AIH. Iodine and Iodinated Drugs As seen in the previous section, thyroid hormone secretion can either be increased or decreased in response to iodinated drugs (Table 3). In addition to amiodarone, there are many iodine containing organic compounds used in clinical practice that are partially deiodinated in vivo and therefore can affect thyroid function like substance : Saturated Solution Potassium iodine (amount of iodine - 38 mg/drop; LugolÊs Iodine (amount of iodine - 6.3 mg/drop); Amiodarone (amount of iodine - 75mg/tablet); Iodoquinol(amount of iodine - 104 mg/tablet); Povidone Iodine (amount of iodine - 10 mg/ml); Theophylline elixir (amount of iodine - 6.6 mg/ ml); Iopanoic acid (amount of iodine - 333mg/tablet); Ipodate Sodium (amount of iodine - 308 mg/capsule); Intravenous radiographic contrast (amount of iodine - 140 380 mg/ml); Tincture Iodine (amount of iodine - 40mg/ml). The risks posed by the use of radiographic contrast agents for coronary angiography or computed 220 tomography is of particular concern because of the dose consumed and the widespread use of these procedures. These agents even with, minimal deiodination (e.g., only 0.1 percent) will result in the release of as much as 14 to 175 mg of iodide. Although the inhibitory effect of iodine on thyroidal hormone synthesis and secretion is spontaneously reversible after several days, the abnormalities in T4 and TSH may persist for up to 2 weeks following an acute iodine load. Long standing abnormalities occur though less frequently. Cytokines Thyroid dysfunction may develop in patients with chronic inflammatory disorders or tumors who receive long-term treatment with cytokines. Administration of interferonÊs (α and β), interleukins and granulocyte macrophage colony stimulating factor (GM-CSF) has been associated with both hyper and hypo function of thyroid gland.2 In addition, cytokines are known to result in appearance or increase in titer of thyroid autoantibody. But appearance of antibody without thyroid dysfunction is much more common during therapy. Interferon- α is associated with the development of anti microsomal (antithyroperoxidase) antibodies in 20 percent of patients, and some have transient hyperthyroidism, hypothyroidism, or both.26 Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Thyroid dysfunction usually appears after 3 months of treatment and may persist even after discontinuation. Interleukin-1 (IL-1) and TNF-α are known to inhibit iodine organification and hormone release as well as to modulate thyroglobulin production and thyrocyte growth. Interferon γ increases expression of the MHC class II molecules on cell surface which lead to initiation of autoimmunity.27 Therapy with interleukin-2 is associated with transient painless thyroiditis in about 20 percent of patients.28 Lithium Lithium interference with thyroid function occurs mainly at the level of hormone secretion. Additional effects on iodine trapping, release and coupling have also been described. Long-term lithium treatment results in goiter in up to 50 percent of patients, sub clinical hypothyroidism in up to 34%, and overt hypothyroidism in up to 15% percent.29 This can appear abruptly even after many years of treatment. This makes it mandatory to test thyroid function once or twice a year in these patients.30 Presence of thyroid autoantibody increases the risk of development of hypothyroidism; 50 percent of those with autoantibody and 15 percent of those without antibodies have sub clinical hypothyroidism.31 The inhibitory effect of lithium on thyroid hormone secretion has been utilized in treatment of thyrotoxicosis in selected situations. Lithium treatment is also associated rarely with thyrotoxicosis. It is not common and occurs mainly after www.japi.org © JAPI VOL. 55 MARCH 2007 long term use. Mechanism is unclear but is thought to involve either autoimmune or destructive thyroiditis.32 Transient euthyroid hyperthyroxinemia has been reported after discontinuation of lithium treatment.33 NSAID Salicylates (in doses of >2.0 g per day) inhibit the binding of T4 and T3 to TBG and transthyretin.34 The initial effect is an increase in serum free T4 concentrations. When therapeutic serum concentrations are sustained, salicylates result in a 20 to 30 percent decrease in serum total T4 concentrations and normal serum free T4 concentrations. Other NSAIDs also displace T4 from its binding sites, particularly fenoflenac. Frusemide Frusemide has no effect at the usual therapeutic concentrations, but large intravenous doses (more than 80 mg) result in a transient increase in serum free T4 concentrations and a decrease in serum total T4 concentrations.35 The mechanism is reported to be inhibition of T4 binding to its carrier proteins. Heparin Large doses of heparin alter the distribution of T4 between plasma and its rapidly exchangeable tissue pools increasing the former and decreasing the latter. Thus serum free T4 concentrations increase transiently after the administration of heparin. This increase is caused by the inhibition of protein binding of T4 by the free fatty acids generated as a result of the ability of heparin to activate lipoprotein lipase.36 These changes are of diagnostic but not clinical consequence. Ferrous Sulphate, Sucralfate, Aluminium Hydroxide Drugs can alter thyroid hormone availability by inhibition of absorption at the intestinal level. This has been seen in T4 treated patients with hypothyroidism who are given aluminum hydroxide, ferrous sulfate or sucralfate. This interference seems to occur in relatively few patients on replacement. Still it is prudent to advise all patients to take their T4 and other medications at different times. Antiepileptic drugs Cytochrome P450 complex (CYP3A) consist of enzymes responsible for oxidative and reducing reactions. Some of these enzymes are induced by antiepileptic drug phenytoin, phenobarbital and carbamazepine. This can produce marked reductions in thyroid hormone levels. Metabolic clearance rate and the hepatic metabolism of T4 increases there by resulting in increased dose requirement in hypothyroid patients on replacement therapy. Phenytoin and carbamazepine cause a decrease of 20 to 40 percent in serum total and free T4 concentrations and a smaller decrease in serum total and free T3 concentrations in patients who have no thyroid disease. The effect on TSH concentration is less impressive.37 Rifampicin is one of the most potent inducers of hepatic mixed function oxygenases. It produces changes similar to that produced by phenytoin and other antiepileptic drugs. Propranalol Beta receptor antagonists are useful drugs in the symptomatic treatment of thyrotoxicosis. Small decreases in serum T3 concentrations occur in patients treated with large doses (>160 mg per day) of propranolol, and a few have small increase in serum T4 concentration.38 The reduction in T3 by propranolol is mainly due to a reduction in its generation from T4. The clinical benefits of β receptor antagonists in thyrotoxicosis are not related to this action. Action of propranolol on thyroxine metabolism is not shared by metoprolol, atenolol or labetalol.39 Still these drugs are effective in providing symptomatic relief of thyrotoxicosis. The patients on β receptor antagonists are clinically euthyroid and have normal serum TSH concentrations. Steroids Dexamethasone has several effects on thyroid hormone physiology. Both large acute therapy and moderate chronic therapy can suppress TSH secretion from anterior pituitary.40 Large doses of glucocorticoids cause a 30 percent reduction in serum T3 concentrations within several days through its inhibitory action on 5Ê deiodinase enzyme.41 T4 secretion is also reduced with high dose steroid therapy. Long-term therapy also decreases production of TBG. Estrogen The most common causes of an increase in serum TBG concentrations in routine practice are an increase in estrogen production and administration of estrogen.42 Estrogens increase sialylation of TBG, which decreases its rate of clearance and raises its serum concentration. The increase of TBG in serum is dose-dependent. The usual doses of ethinyl estradiol (20 to 35 mg per day) and conjugated estrogen (0.625 mg per day) raise serum TBG concentrations by approximately 30 to 50 percent and serum T4 concentrations by 20 to 35 percent.43 The increases begin within two weeks, and a new steady state is attained in four to eight weeks. In women with hypothyroidism who are receiving T4 and become pregnant, an increase of 25 to 50% percent in the dose is needed, on average, to maintain normal serum TSH concentrations. Tamoxifen has weak estrogen-agonist effects in the liver and raises serum TBG concentrations slightly. CONCLUSION Thyroid function testing is becoming part of routine evaluation protocols. Therefore, the possible effect of these drugs on the results of thyroid-function tests must always be considered in decisions regarding patient care. Although most drug induced changes in thyroid Rifampicin © JAPI VOL. 55 MARCH 2007 www.japi.org 221 hormone homeostasis are transient, they can produce panic and result in unnecessary treatment. Knowledge of the site of drug interaction and the physiologic features of the thyroid hormone system should enable the clinician to anticipate changes that may occur in thyroid homeostasis. Knowledge of drugs that increase the risk of thyroid abnormalities would help in monitoring those patients at high risk and would lead to early diagnosis and treatment. REFERENCES 1. Surks MI, Siewert R. Drugs and Thyroid Function. NEJM 1995;333:1688-94. 2. Meier CA, Burger AC. Effects of drugs and other substances on thyroid hormone synthesis and metabolism. In Braverman LE, Utiger RD ed. Werner and IngbarÊs the thyroid: a fundamental and clinical text. Lippincott Williams and Wilkins. 2005;229 46. 3. Reiffel JA, Estes III NA, Waldo AL, Prystowsky EN, Di Bianco R. A consensus report on antiarrhythmic drug use. Clin Cardiol 1994;17:10316. 4. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects of low dose amiodarone: a meta-analysis. J Am Coll Cardiol 1997;30:7918. 5. Holt DW, Tucker GT, Jackson PR, Storey GCA. Amiodarone pharmacokinetics. Am Heart J 1983;106:84347. 6. Basaria S, Cooper DS. Amiodarone and the thyroid. The American J Medicine 2005;118:706-14. 7. Martino E, Safran M, Aghini-Lombardi F, Rajatanavin R, Lenziardi M, Fay M, Pacchiarotti A, Aronin A, Macchia E, Haffajee C, Baschieri L, Pinchera A, Braverman LE. Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 1984;101: 2834 8. Martino E, Aghini-Lombardi F, Mariotti S, Bartalena L, Braverman L, Pinchera A. Amiodarone: a common source of iodine induced thyrotoxicosis. Horm Res 1987;26:15871. 9. Martino E, Aghini-Lombardi F, Mariotti S, Bartalena L, Lenziardi M, Ceccarelli C, Bambini G, Safran M, Braverman LE, Pinchera A. Amiodarone iodine-induced hypothyroidism: risk factors and follow-up in 28 cases. Clin Endocrinol (Oxf) 1987;26:22737. 10. Harjai KJ, Licata AA. Effects of amiodarone on thyroid function. Ann Intern Med 1997;126:6373. 11. Lombardi A, Martino E, Braverman LE. Amiodarone and the thyroid. Thyroid Today 1990;13:17. 12. Newnham HH, Topliss DJ, Legrand BA, Chosich N, Harper RW, Stockigt JR. Amiodarone-induced hyperthyroidism: assessment of the predictive value of biochemical testing and response to combined therapy with propylthiouracil and perchlorate. Aust NZ J Med 1988;18:3744. 13. Trip MD, Wiersinga WM, Plomp TA. Incidence, predictability, and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism. Am J Med1991;91:50711. 14. Albert SG, Alves LE, Rose EP. Thyroid dysfunction during chronic amiodarone therapy. J Am Coll Cardiol 1987;9: 17583. 15. Harjai KJ, Licata AA. Amiodarone-induced hyperthyroidism: a case series and brief review of literature. Pacing Clin Electrophysiol 1996;19:154854. 16. 222 Keidar S, Grenadier E, Palant A. Amiodarone-induced thyrotoxicosis: four cases and a review of the literature. Postgrad J Med 1980;56:35658. 17. Bartalena L, Grasso L, Bragioni S, et al. Serum interleukin-6 in Amiodarone induced thyrotoxicosis. J Clin Endocrinol Metab 1994;78:42327. 18. Martino. E, Bartalena L, Bogazzi F, Braverman LE. The Effects of Amiodarone on the Thyroid. Endocrine Reviews 2001;22:240 54. 19. Wolff J. Perchlorate and the thyroid gland. Pharmacol Rev 1998;50:89105. 20. Dickstein G, Shechner C, Adawi F, Kaplan J, Baron E, Ish-Shalom S. Lithium treatment in amiodarone-induced thyrotoxicosis. Am J Med 1997;102:45458. 21. Bartalena L, Brogioni S, Grasso L, Bogazzi F, Burelli A, Martino E. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study. J Clin Endocrinol Metab 1996;81:293033. 22. Wiersinga WM. Amiodarone and the thyroid. In: Weetman AP, Grossman A. (eds) Pharmacotherapeutics of the Thyroid Gland. Springer Verlag, Berlin, 1997;22587. 23. Erdogan MF, Gulec S, Tutar E, et al. A stepwise approach to the treatment of amiodarone induced thyrotoxicosis. Thyroid 2003;13:205. 24. Braverman LE, Ingbar SH, Vagenakis AG, Adams L, Maaloof F. Enhanced susceptibility to iodide myxedema in patients with HashimotoÊs disease. J Clin Endocrinol Metab 1971;32:51521. 25. Figge J, Dluhy RG. Amiodarone-induced elevation of thyroid stimulating hormone in patients receiving levothyroxine for primary hypothyroidism. Ann Intern Med 1990;113:55355. 26. Baudin E, Marcellin P, Pouteau M, et al. Reversibility of thyroid dysfunction induced by recombinant alpha interferon in chronic hepatitis C. Clin Endocrinol (Oxf) 1993;39:657-61. 27. Kung AWC, Jones BM, Lai CL. Effects of interferon-gamma therapy on thyroid function, T-lymphocyte subpopulations and induction of autoantibodies. J Clin Endocrinol Metab 1990;71:12304. 28. Vassilopoulou-Sellin R, Sella A, Dexeus FH, Theriault RL, Pololoff DA. Acute thyroid dysfunction (thyroiditis) after therapy with interleukin-2. Horm Metab Res 1992;24:434-8. 29. Lazarus JH. The effects of lithium therapy on thyroid and thyrotropin releasing hormone. Thyroid 1998;8:909-913. 30. Kirov.G. Thyroid disorders in Lithium treated patients. J Affect Disorders 1998;50:33-40. 31. Bocchetta A, Bernardi F, Pedditzi M, et al. Thyroid abnormalities during lithium treatment. Acta Psychiatr Scand 1991;83:193-8. 32. Miller KK, Daniels GH. Association between lithium use and thyrotoxicosis caused by silent thyroiditis. Clin Endocrinol (Oxf) 2001;55:501-08. 33. Stratakis CA, Chrousos GP. Transient elevation of serum thyroid hormone levels following Lithium discontinuation. Eur J Pediatrics 1996;155:939-41. 34. L a r s e n P R . S a l i c y l a t e - i n d u c e d i n c r e a s e s i n f r e e triiodothyronine in human serum: evidence of inhibition of triiodothyronine binding to thyroxine-binding globulin and thyroxine-binding prealbumin. J Clin Invest 1972;51: 1125- 34. 35. Stockigt JR, Lim CF, Barlow JW, et al. Interaction of furosemide with serum thyroxine binding sites: in vivo and in vitro studies and comparison with other inhibitors. J Clin Endocrinol Metab 1985;60:1025-31. 36. Mendel CM, Frost PH, Kunitake ST, Cavalieri RR. Mechanism of the heparin induced increase in the concentration of free thyroxine in plasma. J Clin Endocrinol Metab 1987;65: 1259-64. 37. Smith PJ, Surks MI. Multiple effects of diphenylhydantoin on www.japi.org © JAPI VOL. 55 MARCH 2007 effects of dexamethasone on serum concentrations of 3,3Ê5Êtriiodothyronine (reverse T3) and 3,3_5-triiodothyronine (T3). J Clin Endocrinol Metab 1975;41:911-20. the thyroid hormone system. Endocr Rev 1984;5:514-24. 38. Kristensen BO, Weeke J. Propranolol-induced increments in total and free serum thyroxine in patients with essential hypertension. Clin Pharmacol Ther 1977;22:864-7. 42. 39. Murchison LE, How J, Bewsher PD. Comparison of propranolol and metoprolol in the management of hyperthyroidism. Br J Clin Pharmacol 1979;8:581-87. 40. Knopp RH, Bergelin RO, Wahl PW, Walden CE, Chapman MB. Clinical chemistry alterations in pregnancy and oral contraceptive use. Obstet Gynecol 1985;66:682-90. Wilber JF, Utiger RD. The effect of glucocorticoids on thyrotropin secretion. J Clin Invest 1969;48:2086-90. 41. Chopra IJ, Williams DE, Orgiazzi J, Solomon DH. Opposite Announcement 4th Infectious Disease Certificate Course - IDCC -2007 PD Hinduja National Hospital and Medical Research Centre, Mumbai, India In collaboration with Henry Ford Health System, Detroit, MI, USA 26th Aug (Sunday) to 2nd September (Sunday) 2007 8.30 am to 5.00 pm Objective: Diagnosis, Management and Prevention of Infectious Diseases. Focus: Acute febrile illnesses (including Dengue, Enteric, Malaria), Tuberculosis, HIV, Infections in ICU/ Pediatrics/ Immunocompromised, Organ Specific Infections Format: Ward Rounds, Archived Cases, Interactive Lectures, Work Mats, Microbiology Discussions, Visit to Infectious Disease Hospital Credit hours: 55 hours of Category 1 credit towards the American Medical Association PhysicianÊs Recognition Award. Eligibility: Post graduates in Medicine/ Pediatrics and Microbiology (Final year postgraduates may also be considered) Registration procedure: Candidates to send short bio data with Demand Draft/ Cheque of Rs 3,000/- or 100 USD in favor of PD Hinduja National Hospital and Medical Research Centre payable at Mumbai. (Outstation cheques will not be accepted) Candidates to make their own arrangement for accommodation Last date for registration: 30th June 2007 Course Information/ Detailed Programme: www.hindujahospital.com/IDCC2007 Inquiries: 022-24447704 or [email protected] Course Coordinators: Dr FD Dastur /Dr Rajeev Soman/ Dr Camilla Rodrigues/ Dr Tanu Singhal © JAPI VOL. 55 MARCH 2007 www.japi.org 223