Thyroid hormones, antithyroid drugs

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Chapter 37 Thyroid hormones, antithyroid drugs

Diana C. Brown

Synopsis

• Thyroid hormones (thyroxine/levothyroxine T4, liothyronine T3).

• Use of thyroid hormone: treatment of hypothyroidism.

• Antithyroid drugs and hyperthyroidism: thionamides, drugs that block sympathetic autonomic activity, iodide and radio-iodine 131I, preparation of patients for surgery, thyroid storm (crisis), exophthalmos.

• Drugs that cause unwanted hypothyroidism.

• Calcitonin (see Ch. 39).

Thyroid hormones

L-Thyroxine (T4 or tetra-iodo-l-thyronine) and lio-l-thyronine (T3 or tri-iodo-l-thyronine) are the natural hormones of the thyroid gland. T4 is a less active precursor of T3, which is the major mediator of physiological effect. In this chapter, T4 for therapeutic use is referred to as levothyroxine (the rINN; see p. 69).

For convenience, the term ‘thyroid hormone’ is used to comprise T4 plus T3. Both forms are available for oral use as therapy.

Calcitonin

See page 639.

Physiology and pharmacokinetics

Thyroid hormone synthesis requires oxidation of dietary iodine, followed by iodination of tyrosine to mono- and di-iodotyrosine; coupling of iodotyrosines leads to formation of the active molecules, tetra-iodothyronine (T4 or L-thyroxine) and tri-iodothyronine (T3 or l-thyronine).

These active thyroid hormones are stored in the gland within the molecule of thyroglobulin, a major component of the intrafollicular colloid. They are released into the circulation following reuptake of the colloid by the apical cells and proteolysis. The main circulating thyroid hormone is T4. About 80% of the released T4 is de-iodinated in the peripheral tissues to the biologically active T3 (30–35%) and biologically inactive ‘reverse’ T3 (45–50%); thus most circulating T3 is derived from T4. Further de-iodination, largely in the liver, leads to loss of activity.

In the blood both T4 and T3 are extensively (99.9%) bound to plasma proteins (thyroxine binding globulin (TBG) and transthyretin (TTR), albumin and lipoproteins). The concentration of TBG is raised by oestrogens (physiological or pharmacological) and prolonged use of neuroleptics. The concentration of TBG is lowered by adrenocortical and androgen (including anabolic steroid) therapy and by urinary protein loss in the nephrotic syndrome. Phenytoin and salicylates compete with thyroid hormone for TBG binding sites. Effects such as these would interfere with the assessment of the clinical significance of measurements of total thyroid hormone concentration but the availability of free thyroid hormone assay largely avoids such complicating factors. Normal values are: free T4 9–25 picomol/L, free T3 3–9 picomol/L.

T4 and T3 are well absorbed from the gut, except in myxoedema coma when parenteral therapy is required.

T4 (levothyroxine)

A single dose reaches its maximum effect in about 10 days (its binding to plasma proteins is strong as well as extensive) and passes off in 2–3 weeks (t½ 7 days in euthyroid, 14 days in hypothyroid and 3 days in hyperthyroid subjects).

T3 (liothyronine)

is about five times as biologically potent as T4; a single dose reaches its maximum effect in about 24 h (its binding to plasma proteins is weak) and passes off in 1 week (t½ 2 days in euthyroid subjects).

Pharmacodynamics

Thyroid hormone passes into the cells of target organs. T4 is de-iodinated to T3, which combines with specific nuclear receptors and induces characteristic metabolic changes:

• Protein synthesis during growth.

• Increased metabolic rate with raised oxygen consumption.

• Increased sensitivity to catecholamines with proliferation of β-adrenoceptors (particularly important in the cardiovascular system).

Levothyroxine for hypothyroidism

The main indication for levothyroxine is treatment of thyroxine deficiency (cretinism, adult hypothyroidism) from any cause. The adult requirement of hormone is remarkably constant, and dosage does not usually have to be altered once the optimum has been found. Patients should be monitored annually. Monitoring needs to be more frequent in children, who may need more as they grow. Similarly, pregnant women should be monitored monthly, and require a 50–100% increase in their normal dose of levothyroxine.

Early treatment of neonatal hypothyroidism (cretinism) (1 in 5000 births) is important if permanent mental defect is to be avoided. It must be lifelong.

Hypothyroidism due to panhypopituitarism requires replacement with glucocorticoids as well as with thyroid hormone. Use of levothyroxine alone can cause acute adrenal insufficiency.

Small doses of levothyroxine in normal subjects merely depress pituitary thyroid-stimulating hormone (TSH) production and consequently reduce the output of thyroid hormone by an equivalent amount.

Levothyroxine is used in some countries for the treatment of non-toxic nodular goitre, on the assumption that nodular thyroid tissue growth is dependent on TSH. The treatment is not curative. Levothyroxine should not be used to treat obesity (see Obesity, p. 602).

Treatment of hypothyroidism

Levothyroxine tablets

contain pure L-thyroxine sodium and should be used.

The initial oral dose in healthy patients under the age of 60, without cardiac disease, is 50–100 micrograms/day. In the old and patients with heart disease or multiple coronary risk factors, this level should be achieved gradually (to minimise cardiovascular risk due to a sudden increase in metabolic demand), starting with 12.5–25 micrograms daily for the first 2–4 weeks, and then increasing by 12.5 micrograms monthly until normal TSH levels are achieved.

The usual replacement dose at steady state in patients with complete thyroid failure, is 1.6 micrograms/kg/day, 100–200 micrograms per day given as a single dose. This is usually sufficient to reduce plasma TSH to normal (0.3–3.5 mU/L), which is the best indicator of adequate treatment. Patients who appear to need increasing doses with fluctuating TSH levels, are probably not taking their tablets consistently; the possibility of malabsortion or other drug interaction should be excluded. The maximum effect of a dose is reached after about 10 days and passes off over about 2–3 weeks. Absorption is more complete and less variable if levothyroxine is taken at the same time every day, one hour before breakfast.

Tablets containing physiological mixtures of levothyroxine and liothyronine are not sufficiently evaluated to recommend in preference to levothyroxine alone.

Hypothyroid patients tend to be intolerant of drugs in general owing to slow metabolism.

Liothyronine tabs

Liothyronine is the most rapidly effective thyroid hormone, a single dose giving maximum effect within 24 h and passing off over 24–48 h. It is not routine treatment for hypothyroidism because its rapid onset of effect can induce heart failure. Its main uses are myxoedema coma and psychosis, both rare conditions. A specialised use is during the withdrawal of levothyroxine replacement (to permit diagnostic radioiodine scanning) in patients with thyroid carcinoma.

Myxoedema coma follows prolonged total hormone deficiency and constitutes an emergency. Liothyronine 5–20 micrograms is given intravenously every 12 h. Intravenous therapy is mandatory because drug absorption is impaired. Intravenous hydrocortisone should be given to cover the possibility of coexisting adrenocortical insufficiency.

Subclinical hypothyroidism

Subclinical hypothyroidism is defined as an elevated serum TSH concentration in the presence of normal free T4 and free T3. Although termed subclinical, 25% of patients have symptoms of hypothyroidism and cognitive disturbance. Meta-analyses of population based studies show a higher incidence of ischaemic heart disease and mortality in subjects younger than 65 years. Indications for treatment are pregnancy, ovarian dysfunction/infertility, symptoms of hypothyrodism, TSH ≥ 10 mU/L, TSH < 10 mU/L and positive thyroid antibodies and patients with high risk of cardiovascular disease.

Adverse effects

of thyroid hormone parallel the increase in metabolic rate. The symptoms and signs are those of hyperthyroidism. Symptoms of myocardial ischaemia, atrial fibrillation or heart failure are liable to be provoked by too vigorous therapy or in patients having serious ischaemic heart disease who may even be unable to tolerate optimal therapy. Should they occur, discontinue levothyroxine for at least a week, and recommence at lower dose. Only slight overdose may precipitate atrial fibrillation in patients aged over 60 years.

In pregnancy

a hypothyroid patient on thyroxine replacement should be assessed with a preconception TSH level measurement and free T4 and TSH should be checked once pregnancy is confirmed. Monthly measurements of free T4 and TSH are recommended. Optimal replacement therapy is essential in the first trimester when the athyroid fetus is dependent on maternal supply to ensure normal neuro-intellectual development. An average 50% increase in dose of levothyroxine is required and ideally patients should anticipate this increase. Some endocrinologists advise patients to increase their daily dose by 30% or 25–50 micrograms per day. Post delivery, patients revert to their preconception dose. Breast feeding is not contraindicated.

Antithyroid drugs and hyperthyroidism

Drugs used for the treatment of hyperthyroidism include:

• Thionamides, which block the synthesis of thyroid hormone.

• Iodine: radioiodine, which destroys the cells that make thyroid hormone; iodide, an excess of which reduces the production of thyroid hormone temporarily (it is also necessary for the formation of hormone, and both excess and deficiency can cause goitre).

Thionamides (thiourea derivatives) carbimazole, methimazole, propylthiouracil

Mode of action (Fig. 37.1)

The major action of thionamides is to reduce the formation of thyroid hormone by inhibiting oxidation and organification (incorporation into organic form) of iodine (iodotyrosines) and coupling of iodotyrosines. Maximum effect is delayed until existing hormone stores are exhausted (weeks, see below). With high dose, reduced hormone synthesis leads to hypothyroidism.

image

Fig. 37.1 Effects of antithyroid drugs. The multiple effects of antithyroid drugs include inhibition of thyroid hormone synthesis and a reduction in both intrathyroid immune dysregulation and (in the case of propylthiouracil) the peripheral conversion of thyroxine to tri-iodothyronine. Tyrosine-Tg, tyrosine residues in thyroglobulin; 1+, the iodinating intermediate; TPO, thyroid peroxidase.

(Adapted from Cooper D S 2005 Antithyroid drugs. New England Journal of Medicine 352:905–917.)

Carbimazole and methimazole

(the active metabolite of carbimazole) (t½ 6 h) and propylthiouracil (t½ 2 h) are commonly used, but the t½ matters little because the drugs accumulate in the thyroid and act there for 30–40 h; thus a single daily dose suffices.

Propylthiouracil

(PTU) differs from other members of the group in that it also inhibits peripheral conversion of T4 to T3, but only at high doses used in treatment of thyroid storm (see p. 594). PTU differs from the other thionamides in its apparent radio-protective effect when used prior to radioiodine treatment.

Carbimazole is the drug of choice in the UK. PTU is used when a patient develops side-effects to carbimazole. PTU is not recommended in children because of the increased risk of severe hepatotoxicity and death.

Immunosuppression

In patients taking antithyroid drugs, serum concentrations of antithyrotropin receptor antibodies decrease with time, as do other immunologically important molecules, including intracellular adhesion molecule 1, and soluble interleukin-2 and interleukin-6 receptors. There is an increased number of circulating suppressor T cells and a decreased number of helper T cells. Antithyroid drugs may also induce apoptosis of intrathyroidal lymphocytes.

Doses

• Carbimazole 40 mg total/day is given orally (or methimazole 30 mg) until the patient is euthyroid (usually 4–6 weeks). Then either titrate (titration regimen) by decrements initially of 10 mg every 4–6 weeks to a maintenance dose of 5–10 mg/day, or continue (block–replace regimen) 40 mg once daily, and add levothyroxine 100 micrograms/day, with monitoring of free T4 and TSH.

• Propylthiouracil

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