Thyroid Inhibitors

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 accompanying 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)

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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;

       i.    Inhibit iodination of tyrosine residues in thyroglobulin

     ii.     Inhibit coupling of iodotyrosine residues to form T₃ and T₄.

Action (ii) has been observed at lower concentration of antithyroid drugs than action (i). 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 T ₄ 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.

As definitive therapy (a) Remission may occur in upto 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:

·        Prolonged (often life long) treatment is needed because relapse rate is high.

·        Not practicable in uncooperative/unintelligent patient.

·        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 foetus. For the same reason it is to be preferred in the nursing mother. However, some reports of safety of methimazole during pregnancy have appeared.

Propylthiouracil is also used in thyroid storm.

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

Lugol’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

1. 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 euthyroidism which is done by use of carbimazole before starting iodide. Propranolol may be given additionally for rapid control of symptoms.

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

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

4. Antiseptic  As tincture iodine, etc. see Ch. No. 65.

Adverse Effects

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

2. Chronic overdose (iodism) Inflammation of mucous membranes, salivation, rhinorrhoea, sneezing, lacrimation, swelling of eyelids, burning sensation in mouth, headache, rashes, g.i. symptoms, etc. The symptoms regress on stopping iodide ingestion.

Longterm use of high doses can cause hypothyroidism and goiter.

Iodide may cause flaring of acne in adolescents. Given to pregnant or nursing mothers, it may be responsible for foetal/infantile goiter and hypothyroidism.

RADIOACTIVE IODINE

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

¹³¹ I: 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 hypothyroid every year (upto 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—foetal 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.

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.

       i.            While awaiting response to carbimazole or ¹³¹I.

 ii.    Along with iodide for preoperative preparation before subtotal thyroidectomy.

  iii.            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.v. 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.

•           Iopanoic 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.v. 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, anxiolylics, external cooling and appropriate antibiotics are the other measures.