A Textbook of Clinical Pharmacology and Therapeutics

deficiency. Potassium iodide (3 mg daily p.o.) prevents further
enlargement of the gland, but seldom actually shrinks it.
Iodized salt is used to prevent this type of endemic goitre in
areas where the diet is iodine deficient, according to a defined
World Health Organization (WHO) policy.
Preoperative treatment with Lugol’s iodine solution (an
aqueous solution of iodine and potassium iodide) in combination
with carbimazole or propylthiouracil (see below) is
used to reduce the vascularity of the gland and inhibit thyroid
hormone release. This action of iodine in inhibiting thyroid
hormone release is only maintained for one to two weeks,
after which thyroid hormone release is markedly increased if
the cause of the hyperthyroidism has not been dealt with.
THYROXINE AND TRI-IODOTHYRONINE
Use
L-Thyroxine is used in the treatment of uncomplicated hypothyroidism,
the dose being individualized according to serum
TSH. The dose is titrated every four weeks until the patient has
responded clinically and the TSH level has fallen to within the
normal range. Excessive dosage may precipitate cardiac complications,
particularly in patients with ischaemic heart disease in
whom the starting dose should be reduced. If angina pectoris
limits the dose of thyroxine, the addition of a beta-blocker (e.g.
atenolol) will allow further increments in thyroxine dosage.
Long-term overdosage is undesirable and causes osteoporosis,
as well as predisposing to cardiac dysrhythmias.
Congenital hypothyroidism is treated similarly and thyroxine
must be given as early as possible. In the UK, the adoption
of the Guthrie test has greatly facilitated the early detection of
neonatal hypothyroidism.
The rapid action of T3 is useful in treating myxoedema coma.
It is given intramuscularly while starting maintenance therapy
with thyroxine. Hypothyroidism sometimes coexists with Addison’s
disease (also autoimmune in aetiology) and hydrocortisone
is given empirically to patients with myxoedema coma.
Hypothyroidism may result from hypopituitarism. This is
also treated with oral thyroxine in the usual doses. Glucocorticosteroid
replacement must be started first, otherwise
acute adrenal insufficiency will be precipitated.
Mechanism of action
Thyroxine is a prohormone. After entering cells it is converted
to T3, which binds to the thyroid hormone nuclear receptor
and the ligand–receptor complex increases transcription of
genes involved in the following cellular functions:
• stimulation of metabolism – raised basal metabolic rate;
• promotion of normal growth and maturation, particularly
of the central nervous system and skeleton;
• sensitization to the effects of catecholamines.
Adverse effects
The adverse effects of the thyroid hormones relate to their
physiological functions and include cardiac dysrhythmia,
angina, myocardial infarction and congestive cardiac failure.
ANTITHYROID DRUGS 293
Tremor, restlessness, heat intolerance, diarrhoea and other features
of hyperthyroidism are dose-dependent toxic effects of
these hormones. Chronic thyroxine excess is an insidious
cause of osteoporosis.
Pharmacokinetics
Thyroid hormones are absorbed from the gut. The effects of T4 are not usually detectable before 24 hours and maximum
activity is not attained for many days during regular daily
dosing. T3 produces effects within six hours and peak activity
is reached within 24 hours. The t1/2 of T4 is six to seven days in
euthyroid individuals, but may be much longer than this in
hypothyroidism, and that for T3 is two days or less. It is unnecessary
to administer thyroid hormone more frequently than
once a day. The liver conjugates thyroid hormones, which
undergo enterohepatic recirculation.
Key points
Iodine and thyroid hormones
• Iodized salt is used to prevent endemic goitre in regions
where the diet is iodine-deficient. Lugol’s iodine (a
solution of iodine in aqueous potassium iodide) is also
used pre-operatively to reduce the vascularity of the
thyroid.
• Thyroxine (T 4) is used as a physiological replacement in
patients who are hypothyroid. It is converted in the
tissues to the more active tri-iodothyronine (T 3).
• T 3 has a shorter elimination half-life than T 4 and is
therefore used for emergency treatment of
myxoedema coma (often with glucocorticoids because
of the possibility of coexisting hypoadrenalism).
ANTITHYROID DRUGS
CARBIMAZOLE
Use
Carbimazole is used to treat hyperthyroidism. The patient is
usually rendered euthyroid within four to six weeks, and the
dose is then reduced. Treatment is maintained for one to two
years and the drug is then gradually withdrawn. If relapse
occurs, the dose is raised until clinical improvement is
restored. If dosage adjustment proves difficult, smoother control
may be obtained by giving a replacement dose of thyroxine
together with a blocking dose of carbimazole.
Mechanism of action
The action of carbimazole is via its active metabolite methimazole,
which is a substrate-inhibitor of peroxidase and is
itself iodinated and degraded within the thyroid, diverting
oxidized iodine away from thyroglobulin and decreasing thyroid
hormone biosynthesis. Methimazole is concentrated by
cells with a peroxidase system (salivary gland, neutrophils
and macrophage/monocytes, in addition to thyroid follicular
cells). It has an immunosuppressive action within the thyroid