Thyroid Hormones and Thyroid Inhibitors

 Chapter -18 

Thyroid Hormones and Thyroid Inhibitors

THYROID HORMONE

• The thyroid gland secretes 3 hormones—thyroxine (T4), triiodothyronine (T3) and calcitonin. The former two are produced by thyroid follicles, have similar biological activity and the term ‘thyroid hormone’ is restricted to these only. Calcitonin produced by interfollicular ‘C’ cells is chemically and biologically entirely different. It is considered along with parathormone, (Ch. 24) with which it regulates calcium metabolism.

• The physiological significance of thyroid gland was recognized only after Graves and Basedow (1835, 1840) associated the clinical features of the ‘Graves’ disease’ with swelling of thyroid gland and Gull (1874) correlated myxedema with its atrophy. Kendall (1915) obtained crystalline thyroxine and suggested its chemical formula which was confirmed in 1926. Thyroxine was the first hormone to be synthesized in the laboratory. Later, as T4 could not account for all the biological activity of thyroid extract, search was made and more potent T3 was discovered in 1952.

CHEMISTRY AND SYNTHESIS

• Both T4 and T3 are iodine containing derivatives of thyronine which is a condensation product of two molecules of the amino acid tyrosine. Thyroxine; is 3, 5, 3´, 5´–tetraiodothyronine while T3 is 3, 5, 3´ triiodothyronine.

• The thyroid hormones are synthesized and stored in the thyroid follicles as part of thyroglobulin Bulin molecule—which is a glycoprotein synthesized by thyroid cells, MW 660 Kd, contains 10% sugar. The synthesis, storage and release of T4 and T3 is summarized in Fig. 18.1 and involves the following processes.

1. Iodide uptake The total body content of I2, obtained from food and water, is 30–50 mg, out of which about 1/5 is present in the thyroid. Concentration of iodide in blood is low (0.2–0.4 μg/dl) but thyroid cells have an active transport process (Na+: I¯ symporter or NIS) to concentrate this anion; this trapping is stimulated by TSH to exceed a gradient of more than 100 fold. The I2 content of thyroid gland somehow regulates the uptake mechanism: meagre store activating and large store inhibiting it. The iodide concentrating mechanism is not peculiar to thyroid; skin, salivary glands, gastric mucosa, intestine, mammary glands and placenta also possess it, but uptake in these organs is not stimulated by TSH.

2. Oxidation and iodination Iodide trapped by follicular cells is carried across the apical membrane by another transporter termed ‘pendrin’ and oxidized by the membrane bound thyroid peroxidase enzyme to iodinium (I+) ions or hypoiodous acid (HOI) or enzyme-linked hypoiodate (E-OI) with the help of H2O2. These forms of iodine combine avidly with tyrosil residues of thyroglobulin, apparently without any enzymatic intervention, to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) while the residues are still attached to the thyroglobulin chains.

3. Coupling Pairs of iodinated tyrosil residues couple together (Fig. 18.2) to form T3 and T4.

• Normally much more T4 than T3 is formed, but during I2 deficiency relatively more MIT is available and a greater proportion of T3 is formed. Thus, more active hormone is generated with lesser amount of I2.

• Coupling is an oxidative reaction and is catalyzed by the same thyroid peroxidase.

• Thyroglobulin is the most efficient protein in supporting coupling by providing favorable spatial configuration to facilitate the reaction. Oxidation of iodide and coupling are both stimulated by TSH.

4. Storage and release Thyroglobulin containing iodinated tyrosyl and thronal residues is transported to the interior of the follicles and remains stored as thyroid colloid till it is taken back into the cells by endocytosis and broken down by lysosomal proteases. The T4 and T3 so released is secreted into circulation while MIT and DIT residues are DE iodinated and the iodide released is reutilized. The uptake of colloid and proteolysis are stimulated by TSH: the quiescent gland has follicles distended with colloid and cells are flat or cubical, while the TSH stimulated gland has columnar cells and colloid virtually disappears.

• Normal human thyroid secretes 60–90 μg of T4 and 10–30 μg of T3 daily.

5. Peripheral conversion of T4 to T3 Peripheral tissues, especially liver and kidney, convert T4 to T3. About 1/3 of T4 secreted by thyroid undergoes this change and most of the T3 in plasma is derived from liver. Target tissues take up T3 from circulation for their metabolic need, except brain and pituitary which take up T4 and convert it to T3 within their own cells. Almost equal amounts of 3, 5, 3´ triiodothyronine (normal T3 : active) and 3, 3´, 5´ triiodothyronine (reverse T3: inactive) are produced in the periphery. Propylthiouracil (but not carbimazole), propranolol (high doses), amiodarone and glucocorticoids inhibit peripheral conversion of T4 to T3 (except in brain and pituitary).

TRANSPORT, METABOLISM AND EXCRETION

Thyroid hormones are avidly bound to plasma proteins—only 0.03–0.08% of T4 and 0.2–0.5% of T3 are in the free form. Almost all protein bound    

iodine (PBI) in plasma is thyroid hormone, of which 90–95% is T4 and the rest T3. Binding occurs to 3 plasma proteins. In the order of affinity for T4, these are:

• Thyroxine binding globulin (TBG) 

• Thyroxine binding prealbumin (transthyretin) 

•  Albumin

The normal concentration of PBI is 4–10 μg/ dl; only 0.1–0.2 μg/dl of this is T3, rest is T4. During pregnancy thyroxine binding globulin is increased—PBI levels are elevated, but there is no effect on thyroid status as the concentration of free hormone remains unaltered.

Only the free hormone is available for action as well as for metabolism and excretion. Metabolic inactivation of T4 and T3 occurs by deiodination and glucuronide/sulfate conjugation of the hormones as well as of their deiodinase products. Liver is the primary site (also salivary glands and kidneys). The conjugates are excreted in bile. A significant fraction is deconjugated in intestines and reabsorbed (enterohepatic circulation) to be finally excreted in urine

Plasma t½ of T4 is 6–7 days, while that of T3 is 1–2 days. The half-lives are shortened in hyperthyroidism and prolonged in hypothyroidism due respectively to faster and slower metabolism

REGULATION OF SECRETION

• The secretion of hormones from the thyroid is controlled by anterior pituitary by the elaboration of thyrotropin (see p. 240). The relation between the two glands is depicted in Fig. 18.3. The negative feedback by the thyroid hormones is exercised directly on the pituitary as well as through hypothalamus. The action of TRH on pituitary and that of TSH on thyroid cells is mediated by enhanced cAMP synthesis. High concentration of TSH also acts via IP3/DAG–increased intracellular Ca2+ pathway in the thyroid cells.

ACTIONS

The actions of T4 and T3 are qualitatively similar and are nicely depicted in the features of hypo and hyperthyroidism. They affect the function of practically all body cells.

1. Growth and development T4 and T3 are essential for normal growth and development. The most remarkable action is metamorphosis of tadpole to frog: the tail is used-up to build lungs, limbs and other organs. The action cannot be broadly labelled as catabolic or anabolic. It is exerted through a critical control of protein synthesis in the translation of the genetic code. Congenital deficiency of T4 and T3 resulting in cretinism emphasizes their importance. The milestones of development are delayed and practically every organ and tissue of the body suffers. The greatest sufferer, however, is the nervous system. Retardation and nervous deficit is a consequence of paucity of axonal and dendritic ramification, synapse formation and impaired myelination. In adult hypothyroidism also, intelligence is impaired and movements are slow.

2. Intermediary metabolism Thyroid hormones have marked effect on lipid, carbohydrate and protein metabolism.

• Lipid T4 and T3 indirectly enhance lipolysis by potentiating the action of catecholamines and other lipolytic hormones, probably by suppressing a phosphodiesterase → increased cAMP: plasma free fatty acid levels are elevated. Lipogenesis is also stimulated. All phases of cholesterol metabolism are accelerated, but its conversion to bile acids dominates. Thus, hyperthyroidism is characterized by hypocholesterolemia. LDL levels in blood are reduced.

• Carbohydrate Carbohydrate metabolism is also stimulated. Though utilization of sugar by tissues is increased (mainly secondary to increased BMR), glycogenolysis and gluconeogenesis in liver as well as faster absorption of glucose from intestines more than compensate it → hyper glycaemia and diabetic-like state with insulin resistance occur in hyperthyroidism.

• Protein Synthesis of certain proteins is increased, but the overall effect of T3 is catabolic—increased amounts of protein being used as energy source. Prolonged action results in negative nitrogen balance and tissue wasting. Weight loss is a feature of hyperthyroidism. T3, T4 in low concentrations inhibit mucoprotein synthesis which so characteristically accumulates in myxedema

3. Callogenesis T3 and T4 increase BMR by stimulation of cellular metabolism and resetting of the energy stat. This is important for maintaining body temperature. However, metabolic rate in brain, gonads, uterus, spleen and lymph nodes is not significantly affected. The mechanism of callogenesis was believed to be uncoupling of oxidative phosphorylation: excess energy being released as heat. However, this occurs only at very high doses and is not involved in mediating the physiological actions of T3, T4. Dinitrophenol uncouples oxidative phosphorylation but has no thyroid-like activity.

4. CVS T3 and T4 cause a hyperdynamic state of circulation which is partly secondary to increased peripheral demand and partly due to direct cardiac actions. Heart rate, contractility and output are increased resulting in a fast, bounding pulse. T3 and T4 stimulate heart by direct action on contractile elements (increasing the myosin fraction having greater Ca2+ ATPase activity) and probably by up regulation of β adrenergic receptors. Atrial fibrillation and other irregularities are common in hyperthyroidism. Thyroid hormones can also precipitate CHF and angina. BP, specially systolic, is often raised. Myocardial O2 consumption can be markedly reduced by induction of hypothyroidism.

5. Nervous system T3, T4 have profound functional effect on CNS. Mental retardation is the hallmark of cretinism; sluggishness and other behavioral features are seen in myxoedema. Hyperthyroid individuals are anxious, nervous, excitable, exhibit tremors and hyperreflexia.

6. Skeletal muscle Muscles are flabby and weak in myxoedema, while thyrotoxicosis produces increased muscle tone, tremor and weakness due to myopathy.

 7. GIT Propulsive activity of gut is increased by T3/T4. Hypothyroid patients are often constipated, while diarrhea is common in hyperthyroidism.

8. Kidney T3 and T4 do not cause diuresis in euthyroid individuals, but the rate of urine flow is often increased when myxoedematous patients are treated with it.

9. Haemopoiesis Hypothyroid patients suffer from some degree of anaemia which is restored only by T4 treatment. Thus, T4 appears to be facilitatory to erythropoiesis.

10.Reproduction Thyroid has an indirect effect on reproduction. Fertility is impaired in hypothyroidism and women suffer from oligomenorrhoea. Normal thyroid function is required for maintenance of pregnancy and lactation.

Mechanism of action

• Both T3 and T4 penetrate cells by active transport and produce majority of their actions by combining with a nuclear thyroid hormone receptor (TR) which belongs to the steroid and retinoid superfamily of intracellular receptors. Two TR isoform families (TRα and TRβ) have been identified. Both bind T3 and function in similar manner, but their tissue distribution differs, which may account for quantitative differences in the sensitivity of different tissues to T3.

• In contrast to the steroid receptor, the TR resides in the nucleus even in the unliganded inactive state. It is bound to the ‘thyroid hormone response element’ (TRE) in the enhancer region of the target genes along with corepressors (Fig. 18.4). This keeps gene transcription suppressed. When T3 binds to the ligand-binding domain of TR, it heterodimerizes with retinoid X receptor (RXR) and undergoes a conformation change releasing the corepressor and binding the coactivator. This induces gene transcription → production of specific mRNA and a specific pattern of protein synthesis → various metabolic and anatomic effects.

• Many of the effects, e.g. tachycardia, arrhythmias, raised BP, tremor, hyperglycemia are mediated, at least partly, by sensitization of adrenergic receptors to catecholamines. Induction of adenylyl cyclase, proliferation of β adrenoceptors and a better coupling between these two has been demonstrated.

• Apart from the nuclear T3 receptor, other sites of thyroid hormone action have been described. It acts on cell membrane to enhance amino acid and glucose entry and on mitochondria to increase oxygen consumption. At these sites T4 appears to be equipotent to T3, while at the nuclear receptor T4 has much lower affinity, and even when bound to the TR, T4 does not promote gene transcription.

 Relation between T4 and T3

• Thyroid secretes more T4 than T3, but in iodine deficient state this difference is reduced. 

• T4 is the major circulating hormone because it is 15 times more tightly bound to plasma proteins. 

• T3 is 5 times more potent than T4 and acts faster. Peak effect of T3 comes in 1–2 days while that of T4 takes 6–8 days. 

• T3 is more avidly bound to the nuclear receptor than T4 and the T4-receptor complex is unable to activate/derepress gene transcription. 

• About 1/3 of T4 is converted to T3 in the thyroid cells, liver and kidney by D1 type of 5’deiodinase (5’DI) and released into circulation. In addition, T3 is generated within the target cells (skeletal muscle, heart,

brain, pituitary) by another type (D2) of 5’DI. Thus, it may be cocluded that T3 is the active hormone, while T4 is mainly a transport form; functions as a prohormone of T3. However, it may directly produce some nongenomic actions.

Preparations

• l-thyroxine sod.: ELTROXIN, ROXIN 100 μg tab. THYRONORM, THYROX 25 μg, 50 μg, 100 μg tabs. Triiodothyronine (Liothyronine) 5, 25 μg tab—25 μg is equivalent to 100 μg of l-thyroxine: not freely available in India. It is occasionally used i.v. along with l-thyroxine in myxoedema coma.

• Oral bioavailability of l-thyroxine is ~ 75%, but severe hypothyroidism can reduce oral absorption. It should be administered in empty stomach to avoid interference by food. Sucralfate, iron and calcium also reduce l-thyroxine absorption. Enzyme inducers like rifampin, phenytoin and

• carbamazepine accelerate metabolism of T4; dose of l-thyroxine may need enhancement. Clinically, l-thyroxine is preferred for all indications over liothyronine because of more sustained and uniform action as well as lower risk of cardiac arrhythmias.

USES

The most important uses of thyroid hormone are as replacement therapy in deficiency states:

1. Cretinism It is due to failure of thyroid development or a defect in hormone synthesis (sporadic cretinism) or due to extreme iodine deficiency (endemic cretinism). It is usually detected during infancy or childhood. Treatment with thyroxine (8–12 μg/kg) daily should be started as early as possible, because mental retardation that has already ensued is only partially reversible. Response is dramatic: physical growth and development are restored and further mental retardation is prevented.

2. Adult hypothyroidism This is one of the commonest endocrine disorders which develops as a consequence of thyroiditis, thyroidectomy; may accompany simple goiter if iodine deficiency is severe or may be idiopathic. Important drugs that can cause hypothyroidism are 131I, iodides, lithium and amiodarone. Treatment with T4 is most gratifying. It is often wise to start with a low dose—50 μg of thyroxine daily and increase every 2–3 weeks to an optimum of 100–200 μg/day (adjusted by clinical response and serum TSH levels). Further dose adjustments are made at 4–6-week intervals needed for reaching steady-state. Individualization of proper dose is critical, aiming at normalization of serum TSH levels. Increase in dose is mostly needed during pregnancy.

Subclinical hypothyroidism characterized by euthyroid status and raised TSH level (>10 mU/ L) should be treated with T4 if other cardiovascular risk factors are present; otherwise replacement therapy is optional.

3. Myxoedema coma It is an emergency; characterized by progressive mental de due to acute hypothyroidism: carries significant mortality. Rapid thyroid replacement is crucial. Though liothyronine (T3) acts faster, its use is attended by higher risk of cardiac arrhythmias, angina, etc. Drug of choice is l-thyroxine (T4) 200– 500 μg i.v. followed by 100 μg i.v. OD till oral therapy can be instituted. Some authorities recommend adding low dose i.v. T3 10 μg 8 hourly in younger patients with no arrhythmia or ischaemia. Alternatively oral T4 500 μg loading dose followed by 100–300 μg daily may be used, but in severe hypothyroidism, oral absorption is delayed and inconsistent.

Corticosteroids to cover attendant adrenal insufficiency, ventilatory and cardiovascular support, correction of hyponatraemia, hypoglycaemia, etc. are the other measur

4. Nontoxic goiter It may be endemic or sporadic. Endemic is due to iodine deficiency which may be accentuated by factors present in water (excess calcium), food or milk (goitrin, thiocyanates). A defect in hormone synthesis may be responsible for sporadic cases. In both types, deficient production of thyroid hormone leads to excess TSH → thyroid enlarges, more efficient trapping of iodide occurs and probably greater proportion of T3 is synthesized → enough hormone to meet peripheral demands is produced. Thus, treatment with T4 is in fact replacement therapy in this condition also, despite no overt hypothyroidism. Full maintenance doses must be given. Most cases of recent diffuse enlargement of thyroid regress. Long-standing goiters with degenerative and fibrotic changes and nodular goiter respond poorly or not at all. Therapy may be withdrawn after a year or so in some cases if adequate iodine intake is ensured. Others need life-long therapy.

Endemic goiter and cretinism due to iodine deficiency in pregnant mother is preventable by ensuring daily ingestion of 150–200 μg of iodine. This is best achieved by iodizing edible salt. In India iodization of table salt (100 μg iodine/g salt) is required under the National Programme, but recently mandatory iodization rule has been withdrawn.

5. Thyroid nodule Certain benign functioning nodules regress when TSH is suppressed by T4 therapy. Nonfunctional nodules and those nonresponsive to TSH (that are associated with low TSH levels) do not respond. T4 therapy should be stopped if the nodule does not decrease in size within 6 months and when it stops regressing.

6. Papillary carcinoma of thyroid It is often responsive to TSH. In nonresectable cases, full doses of T4 suppress TSH production and may induce temporary regression. 

7. Empirical uses T4 has been sometimes used in the following conditions without any rationale; response is unpredictable.

• Refractory anemias..

• Menstrual disorders, infertility not corrected by usual treatment.

• Chronic/non healing ulcers.

• Obstinate constipation..

• Thyroxine is not recommended for obesity and as a hypocholesterolemia agent

THYROID INHIBITORS

• These are drugs used to lower the functional capacity of the hyperactive thyroid gland.

• Thyrotoxicosis is due to excessive secretion of thyroid hormones. The two main causes are Graves’ disease and toxic nodular goiter. Graves’ disease is an autoimmune disorder: IgG class of antibodies to the TSH receptor are detected in blood. They bind to and stimulate thyroid cells and produce other TSH like effects. Due to feedback inhibition, TSH levels are low. The accompt ponying exophthalmos is due to autoimmune inflammation of periorbital tissues.

• Toxic nodular goiter, which produces thyroid hormone independent of TSH, mostly supervenes on old nontoxic goiters. It is more common in the elderly; ocular changes are generally absent.

CLASSIFICATION

1. Inhibit hormone synthesis (Antithyroid drugs)

• Propylthiouracil, Methimazole, Carbimazole.

2. Inhibit iodide trapping (Ionic inhibitors)

• Thiocyanates (–SCN), Perchlorates (–ClO4), Nitrates (–NO3).

3. Inhibit hormone release

• Iodine, Iodides of Na and K, Organic iodide.

4. Destroy thyroid tissue

Radioactive iodine (131I, 125I, 123I).

Compounds in groups 1 and 2 may be collectively called goitrogens.

In addition, certain drugs used in high doses for prolonged periods cause hypothyroidism/goiter as a side effect:

• Lithium: inhibits thyroid hormone release. 

• Amiodarone: inhibits peripheral conversion of T4 to T3; also interferes with thyroid hormone action. 

• Sulfonamides, paraaminosalicylic acid: inhibit thyroglobulin iodination and coupling reaction. 

• Phenobarbitone, phenytoin, carbamazepine, rifampin: induce metabolic degradation of T4/T3

Goitrin—found in plants (cabbage, turnip, mustard, etc.), is the cause of goiter in cattle who feed on these plants. May contribute to endemic goiter in certain iodine deficient regions.

ANTITHYROID DRUGS

By convention, only the synthesis inhibitors are called antithyroid drugs, though this term has also been applied to all thyroid inhibitors.

Thiourea derivatives were found to produce goiter and hypothyroidism in rats in the 1940s. Open chain compounds were found to be toxic. Subsequently, methyl and propyl thiouracil and thioimidazole derivatives methimazole and carbimazole were found to be safe and effective.

Antithyroid drugs bind to thyroid peroxidase and prevent oxidation of iodide/iodotyrosyl residues, thereby.

• Inhibit iodination of tyrosine residues in thyroglobulin 

• Inhibit coupling of diiodotyrosine residues to form T3 and T4

Action 

• has been observed at lower concentration of antithyroid drugs than action

• Thyroid colloid is depleted over time and blood levels of T3/T4 are reduced.

• They do not interfere with trapping of iodide and do not modify the action of T3 and T4 on peripheral tissues or on pituitary. Goiter is not

• the result of potentiation of TSH action on thyroid, but is due to increased TSH release as a consequence of reduction in feedback inhibition. No goiter occurs if antithyroid drugs are given to hypophysectomised animals or if T4 is given along with them. Antithyroid drugs do not affect release of T3 and T4—their effects are not apparent till thyroid is depleted of its hormone content.

• Propylthiouracil also inhibits peripheral conversion of T4 to T3 by D1 type of 5’DI, but not by D2 type. This may partly contribute to its effects. Methimazole and carbimazole do not have this action (Table 18.1) and may even antagonize that of propylthiouracil

• Pharmacokinetics All antithyroid drugs are quickly absorbed orally, widely distributed in the body, enter milk and cross placenta; are metabolized in liver and excreted in urine primarily as metabolites. All are concentrated in thyroid: intrathyroid t½ is longer: effect of a single dose lasts longer than would be expected from the plasma t½. Carbimazole acts largely by getting converted to methimazole in the body.   

• Adverse effects Hypothyroidism and goiter can occur due to overtreatment, but is reversible on stopping the drug. It is indicated by enlargement of thyroid, and is due to excess TSH production. Goiter does not develop with appropriate doses which restore T4 concentration to normal so that feedback TSH inhibition is maintained.   Important side effects are: g.i. intolerance, skin rashes and joint pain. Loss or graying of hair, loss of taste, fever and liver damage are infrequent. A rare but serious adverse effect is agranulocytosis (1 in 500 to 1000 cases); It is mostly reversible. There is partial cross reactivity between propylthiouracil and carbimazole.

• Preparations and dose Propylthiouracil: 50–150 mg TDS followed by 25–50 mg BD–TDS for maintenance. PTU 50 mg tab. Methimazole: 5–10 mg TDS initially, maintenance dose 5–15 mg daily in 1–2 divided doses. Carbimazole: 5–15 mg TDS initially, maintenance dose 2.5–10 mg daily in 1–2 divided doses, NEO MERCAZOLE, THYROZOLE, ANTITHYROX 5 mg tab.

• Carbimazole is more commonly used in India. Propylthiouracil (600–900 mg/day) may be preferred in thyroid storm for its inhibitory action on peripheral conversion of T4 to more active T3. It is also used in patients developing adverse effects with carbimazole.

• Use Antithyroid drugs control thyrotoxicosis in both Graves’ disease and toxic nodular goiter. Clinical improvement starts after 1–2 weeks or more (depending on hormone content of thyroid gland). Iodide loaded patients are less responsive. Maintenance doses are titrated on the basis of clinical status of the patient. The following strategies are adopted.

(i) As definitive therapy

• Remission may occur in up to half of the patients of Graves’ disease after 1–2 years of treatment: the drug can then be withdrawn. If symptoms recur—treatment is reinstituted. This is preferred in young patients with a short history of Graves’ disease and a small goiter.

• Remissions are rare in toxic nodular goiter: surgery (or 131I) is preferred. However, in frail elderly patient with multinodular goiter who may be less responsive to 131I, permanent maintenance therapy with antithyroid drugs can be employed.

• Preoperatively Surgery in thyrotoxic patients is risky. Young patients with florid hyperthyroidism and substantial goiter are rendered euthyroid with carbimazole before performing subtotal thyroidectomy.

• Along with 131I Initial control with antithyroid drug—1 to 2 weeks gap—radioiodine dosing—resume antithyroid drug after 5–7 days and gradually withdraw over 3 months as the response to 131I develops. This approach is preferred in older patients who are to be treated with 131I but require prompt control of severe hyperthyroidism. This will also prevent initial hyperthyroidism following 131I due to release of stored T4.

Advantages of antithyroid drugs over surgery/ 131I are:

• No surgical risk, scar or chances of injury to parathyroids or recurrent laryngeal nerve. 
• Hypothyroidism, if induced, is reversible. 
• Can be used even in children and young adults. 

Disadvantages are: 

1. Prolonged (often life long) treatment is needed because relapse rate is high. 
2. Not practicable in uncooperative/unintelligent patient. 
3. Drug toxicity.

During pregnancy thyroidectomy and 131I are contraindicated. With antithyroid drugs risk of foetal hypothyroidism and goiter is there. However, low doses of propylthiouracil are preferred: its greater protein binding allows less transfer to the fetus. For the same reason it is to be preferred in the nursing mother. However, some reports of safety of methimazole during pregnancy have appeared.

IONIC INHIBITORS

• Certain monovalent anions inhibit iodide trapping by the thyroid probably because of similar hydrated ionic size— T4/T3 cannot be synthesized. Thiocyanate also inhibits iodination at high doses. Their relative inhibitory potency is—

• SCN 1: CLO4 10: NO3 1/30

• They are toxic and not used now. Thiocyanates: can cause liver, kidney, bone marrow and brain toxicity.

• Perchlorates: produce rashes, fever, aplastic anaemia, agranulocytosis.

• Nitrates: are weak drugs, can induce methemoglobinaemia and vascular effects.

IODINE AND IODIDES

• Though iodine is a constituent of thyroid hormones, it is the fastest acting thyroid inhibitor. It is reduced in the intestines to iodide and the response to iodine or iodides is identical. The gland, if enlarged, shrinks, becomes firm and less vascular. The thyroid status starts returning to normal at a rate commensurate with complete stoppage of hormone release from the gland. The gland itself involutes and colloid is restored. With daily administration, peak effects are seen in 10–15 days, after which ‘thyroid escape’ occurs and thyrotoxicosis may return with greater vengeance. Worsening of hyperthyroidism especially occurs in multinodular goiter.

• All facets of thyroid function seem to be affected, but the most important action is inhibition of hormone release— ‘thyroid constipation’. Endocytosis of colloid and proteolysis of thyroglobulin comes to a halt. The mechanism of action is not clear. It appears to be a direct action on thyroid cells, though attenuation of TSH and cAMP induced thyroid stimulation has been demonstrated. Excess iodide inhibits its own transport in thyroid cells and may alter the redox potential of cells, thus interfering with iodination → reduced T3/T4 synthesis ( WolffChaikoff effect).

• Preparations and dose Lugo’s solution (5% iodine in 10% Pot. iodide solution): LUGOL’S SOLUTION, COLLOID IODINE 10%: 5–10 drops/day. COLLOSOL 8 mg iodine/5 ml liq. Iodide (Sod. /Pot.) 100–300 mg/day (therapeutic), 5–10 mg/ day (prophylactic) for endemic goiter.

Uses

• Preoperative preparation for thyroidectomy generally given for 10 days just preceding surgery. The aim is to make the gland firm, less vascular and easier to operate on. Though iodide itself will lower the thyroid status, it cannot be relied upon to attain eothyridids which is done by use of carbimazole before starting iodide. Propranolol may be given additionally for rapid control of symptoms. 

• Thyroid storm Lugo’s iodine (6–10 drops) or iodine containing radiocontrast media (hopanoid acid/ipodate) orally are used to stop any further release of T3/T4 from the thyroid and to decrease T4 to T3 conversion.

• Prophylaxis of endemic goiter It is generally used as “iodized salt”. 

• Antiseptic As tincture iodine, etc. see Ch. 65.

Adverse effects

• Acute reaction It occurs in sensitive individuals only swelling of lips, eyelids, angioedema of larynx (may be dangerous), fever, joint pain, petechial hemorrhages, thrombocytopenia, lymphadenopathy. 

• Chronic overdose (iodism) Inflammation of mucous membranes, salivation, rhinorrhea, sneezing, lacrimation, swelling of eyelids, burning sensation in mouth, headache, rashes, gig symptoms, etc. The symptoms regress on stopping iodide ingestion. Long-term use of high doses can cause hypothyroidism and goiter.

• Iodide may cause flaring of acne in adolescents. Given to pregnant or nursing may be responsible for fetal/infantile goiter and hypothyroidism.

RADIOACTIVE IODINE

• The stable isotope of iodine is 127I. Its radioactive isotopes of medicinal importance are:

• 131I: physical half-life is 8 days—most commonly used in medicine.

• 123I: physical half-life is 13 hours—only rarely used diagnostically.

• 125I: physical half-life is 60 days. Their chemical behaviour is similar to the stable isotope.

• 131I emits X-rays as well as β particles. The former are useful in tracer studies, as they traverse the tissues and can be monitored by a counter, while the latter are utilized for their destructive effect on thyroid cells. 131I is concentrated by thyroid, incorporated in colloid—emits radiation from within the follicles. The β particles penetrate only 0.5–2 mm of tissue. The thyroid follicular cells are affected from within, undergo pyknosis and necrosis followed by fibrosis when a sufficiently large dose has been administered, without damage to neighbouring tissues. With carefully selected doses, it is possible to achieve partial ablation of thyroid.

• It is used as sodium salt of 131I dissolved in water and taken orally.

• Diagnostic 25–100 μ curie is given; counting or scanning is done at intervals. No damage to thyroid cells occurs at this dose.

• Therapeutic The most common indication is hyperthyroidism due to Graves’ disease or toxic nodular goiter. The average therapeutic dose is 3–6 m curie—calculated on the basis of previous tracer studies and thyroid size. Higher doses are generally required for toxic multinodular goiter than for Graves’ disease. The response is slow— starts after 2 weeks and gradually increases, reaching peak at 3 months or so. Thyroid status is evaluated after 3 months, and a repeat dose, if needed, is given. About 20–40% patients require one or more repeat doses. 

Advantages

• Treatment with 131I is simple, conveniently given on outpatient basis and inexpensive. 

• No surgical risk, scar or injury to parathyroids/recurrent laryngeal nerves. 

• Once hyperthyroidism is controlled, cure is permanent.

Disadvantages

• Hypothyroidism: About 5–10% patients of Graves’ disease treated with 131I become hypothyroidy every year (up to 50% or more patients may ultimately require supplemental thyroxine treatment). This probably reflects the natural history of Graves’ disease, because only few patients of toxic nodular goiter treated with 131I develop hypothyroidism. Moreover, eventual hypothyroidism is a complication of subtotal thyroidectomy/prolonged carbimazole therapy as well.

• Long latent period of response.

• Contraindicated during pregnancy—fetal thyroid will also be destroyed resulting in cretinism, other abnormalities if given during first trimester.

• Not suitable for young patients: they are more likely to develop hypothyroidism later and would then require lifelong T4 treatment. Genetic damage/cancer is also feared, though there is no evidence for it.    

• 131I is the treatment of choice after 25 years of age and if CHF, angina or any other contraindication to surgery is present.    

• Metastatic carcinoma of thyroid (especially papillary or those cases of follicular which concentrate iodine), 131I may be used as palliative therapy after thyroidectomy. Much higher doses are required and prior stimulation with TSH is recommended.

β ADRENERGIC BLOCKERS.

Propranolol (and other nonselective β blockers) have emerged as an important form of therapy to rapidly alleviate manifestations of thyrotoxicosis that are due to sympathetic overactivity: palpitation, tremor, nervousness, severe myopathy, sweating. They have little effect on thyroid function and the hypermetabolic state. They are used in hyperthyroidism in the following situations.

1. While awaiting response to carbimazole or 131I. 
2. Along with iodide for preoperative preparations before subtotal thyroidectomy. 
3. Thyroid storm (thyrotoxic crisis): It is an emergency due to decompensated hyperthyroidism. Vigorous treatment with the following is indicated:

• Nonselective β blockers are the most valuable measure: afford dramatic symptomatic relief. In addition, they reduce peripheral conversion of T4 to T3. Propranolol 1–2 mg slow i.e., may be followed by 40–80 mg oral every 6 hours. 

• Propylthiouracil 200–300 mg oral 6 hourly: reduces hormone synthesis as well as peripheral T4 to T3 conversion. 

• Kopaonik acid (0.5–1 g OD oral) or ipodate are iodine containing radiocontrast media. They are potent inhibitors of thyroid hormone release from thyroid, as well as of peripheral T4 to T3 conversion. 

• Corticosteroids (hydrocortisone 100 mg i.e., 8 hourly followed by oral prednisolone): help to tide over crisis, cover any adrenal insufficiency and inhibit conversion of T4 to T3 in periphery. 

• Diltiazem 60–120 mg BD oral may be added if tachycardia is not controlled by propranolol alone. 

• Rehydration, anxiolytics, external cooling and appropriate antibiotics are the other measures.