Thyroxine Sodium
Levothyroxine Sodium
An odourless almost white to pale brownish-yellow. hygro-
scopic. amorphous or crystalline powder. It may assume a
slight pink colour on exposure to light. It may be obtained
from the thyroid gland of domesticated animals used for food
by man or be prepared synthetically.
Very slightly soluble in water: slightly soluble in alcohol (I
in 300); practically insoluble in acetone, in chloroform, and
in ether. It dissolves in aqueous solutions of alkali hydroxides
and in hot solutions of alkali carbonates. A saturated solution
in water has a pH of about 8.9. Store at 2ยฐ to 8ยฐ in airtight
containers. Protect from light.
Adverse Effects and Treatment
The adverse effects of thyroxine are generally asso-
ciated with excessive dosage and correspond to
symptoms of hyperthyroidism. They may include
tachycardia, palpitations, anginal pain. headache.
nervousness, excitability. insomnia, tremors, muscle
weakness and cramps, heat intolerance, sweating,
flushing, fever, weight loss, menstrual irregularities,
diarrhoea, and vomiting. These adverse reactions
usually disappear after dosage reduction or tempo-
rary withdrawal of treatment. Thyroid storm has oc-
casionally been reported following massive or
chronic intoxication and convulsions, cardiac ar-
rhythmias, heart failure, coma. and death have oc-
curred.
In acute overdosage. gastric lavage or emesis induc-
tion should be considered to reduce gastro-intestinal
absorption. Treatment is usually symptomatic and
supportive; propranolol may be useful in controlling
the symptoms of sympathetic overactivity. Thyrox-
ine overdosage requires an extended follow-up peri-
od as symptoms may be delayed for several days due
to the gradual peripheral conversion of thyroxine to
tri-iodothyronine.
Carcinogenicity. An association between the use of thyroid
hormones and an increased risk of breast cancer in women
was proposed by Kapdi and Wolfe. A further analysis by
Mustacchi and Greenspan of the data from the same group of
patients did not confirm such an association nor did later stud-
ies by Wallace et all, Shapiro et al. and Hoffman et all.
Effects on the bones. Hyperthyroidism is a known risk fac-
tor for osteoporosis and some studies have indicated that
women receiving long-term thyroxine therapy may have de-
creased bone density or accelerated bone mineralisation and
thus be at greater risk of developing osteoporosis. The bone
changes were greatest in those who had some degree of over-
treatment resulting in subclinical hyperthyroidism (usually
indicated by low TSH concentrations) and therefore strict at-
tention to monitoring of therapy by using sensitive TSH as-
says, and possibly the use of bone studies, has been
advised. Conversely, Franklyn et at found no effect of
long-term thyroxine treatment on bone density and neither
did Ross when he gave thyroxine short term to postmenopau-
sal women with subclinical hypothyroidism. However, in an-
other study loss of bone density did occur in
postmenopausal women taking relatively high doses of thy-
roxine (1.6 ng or more per kg body-weight daily) long term
and appeared to be prevented by oestrogen replacement ther-
apy.
Effects on the nervous system. Two children aged 8 and
11 years developed pseudotumour cerebri (benign intracrani-
al hypertension) shortly after the initiation of thyroxine ther-
apy for hypothyroidism. There have been further reports on
individual children and infants.
Partial complex status epilepticus. with confusion, agitation.
and continuous myoclonic jerks in the left side of the face and
left hand, was seen in a hypothyroid patient with Turner's
syndrome who was receiving treatment with thyroxine for
mvxoedema 5 The condition responded to anticonvul-
sant therapy: the patient subsequently remained seizure-free
on a reduced dose of thyroxine and concomitant phenytoin.
Hypersensitivity. A hypersensitivity reaction to synthetic
thyroid hormones was reported in a 63-year-old hypothyroid
woman with Hashimoto's thyroiditis. Fever, eosinophilia,
and liver dysfunction developed after replacement treatment
with liothyronine or thyroxine. but disappeared when therapy
was discontinued. After an interval of 4 months liothyronine
was gradually reintroduced without adverse effect.
Urticaria and angioedema has been described in one patient
who received thyroid and thyroxine. In a further case similar
reactions were attributed to the presence of sunset yellow as
colouring agent in the proprietary thyroxine preparation.
Overdosage. The clinical features and management of over-
dosage with thyroid drugs have been reviewed. Although ag-
gressive therapy is not normally justified in asymptomatic
patients, various regimens have been tried.
Binimelis and colleagues have described six adults who in-
gested massive doses of thyroxine ranging from 70 to
1200 mg over 2 to 12 days due to an error in the pharmaceu-
tical preparation. All the patients developed symptoms of
thyrotoxicosis within 3 days of taking the first dose. Treat-
ment to reduce the conversion of L-thyroxine to L-tri-iodothy-
ronine was tried using propranolol 120 to 140 mg daily, with
hydrocortisone 400 mg daily, and in 3 patients, propylthio-
uracil 400 to 1200 mg daily, but the benefits of such therapy
were considered doubtful. Seven to 10 days after the first dose
of thyroxine, all 6 patients developed neurological complica-
tions and 5 went into coma. Cardiac disturbances were also
noted; 2 had left ventricular failure and 3 developed severe
arrhythmias. As clinical status deteriorated, plasmapheresis
and charcoal haemoperfusion were both found to increase the
elimination of L-thyroxine from serum. Plasmapheresis ap-
peared to be the more effective procedure, though the magni-
tude of the extraction of L-thyroxine depended on the serum
concentration of L-thyroxine. One patient died of septic shock
and acute renal failure; the other 5 recovered after troubled
courses.
In a further study of 41 children aged I to 5 years who had
accidentally ingested estimated amounts of thyroxine sodium
ranging from 0.05 to 13 mg, symptoms of hyperthyroidism
occurred in only 11 between 12 hours and 11 days after inges-
tion. Treatment was limited to initial measures to decrease ab-
sorption; no adverse effect was considered severe enough to
warrant specific symptomatic treatment and all symptoms
fully resolved within 14 days. These findings appeared to be
consistent with previous reports, although Kulig et al* had
described a 2-year-old boy who developed clinical signs of
hyperthyroidism and suffered 2 episodes of tonic-clonic sei-
zures 7 days after the ingestion of up to 18 mg of thyroxine
sodium. However, since serious complications appeared to be
uncommon and most symptoms remitted without treatment, a
conservative approach to the management of acute thyroxine
overdosage in children was recommended.
Precautions
Thyroxine is contra-indicated in untreated hyperthy-
roidism. It should be used with extreme caution in
patients with cardiovascular disorders including an-
gina, heart failure, myocardial infarction. and hyper-
tension; lower initial doses, smaller increments, and
longer intervals between increases should be used as
necessary. An ECG performed before starting treat-
ment with thyroxine may help to distinguish under-
lying myocardial ischaemia from changes induced
by hypothyroidism. Thyroxine should also be intro-
duced very gradually in elderly patients and those
with long-standing hypothyroidism to avoid any
sudden increase in metabolic demands. It should not
be given to patients with adrenal insufficiency with-
out adequate corticosteroid cover otherwise the thy-
roid replacement therapy might precipitate an acute
adrenal crisis. Care is also required when thyroxine
is given to patients with diabetes mellitus or diabetes
insipidus.
Tests of thyroid function are subject to alteration by
a number of nonthyroidal clinical conditions and by
a wide variety of drugs, some of which are men-
tioned under Interactions, below.
Adrenocortical insufficiency. Thyroid-hormone replace-
ment without concomitant treatment with corticosteroids may
precipitate acute adrenocortical insufficiency in patients with
impaired adrenocortical function, including those with sub-
clinical or unrecognised adrenocortical disease. Adrenocor-
tical insufficiency should be suspected in patients who
develop symptoms of lassitude, malaise, weight loss. and hy-
potension; prompt diagnosis and replacement of corticoster-
oids could prevent the development of a potentially fatal
crisis. In commenting on this report. Davis and SheppardL
point out that a raised concentration of thyroid-stimulating-
honnone alone may not necessarily imply hypothyroidism in
patients with chronic adrenocortical insufficiency. Even con-
firmed hypothyroidism in these patients may not be perma-
nent.
Cardiovascular disorders. There is a complex relationship
between the heart and thyroid. Cardiovascular abnormalities
may be associated with hypothyroidism as well as with thy
roxine replacement therapy, hence the need for caution.
Myasthenia. Thyroid hormones may occasionally precipi-
tate or exacerbate a pre-existing myasthenic syndrome.
Pregnancy and breast feeding. Most authorities consider
that thyroid hormones do not readily cross the placenta. Pla-
cental transfer has been reported, but in amounts so limited
that a mother with physiological concentrations of thyroxine
and tri-iodothyronine would not provide normal thyroid hor-
mone concentrations to a fetus with congenital hypothy-
roidism.
Minimal amounts of thyroid hormone are distributed into
breast milk. There is insufficient thyroid hormone to meet
the biological needs of a suckling infant with a nonfunction-
ing thyroid gland but it has been suggested that thyroxine in
breast milk might mask any hypothyroidism in the suckling
newborn.
Interactions
As thyroid status influences metabolic activity and most body
systems, correction of hypothyroidism with thyroid agents
may affect other disease states and their treatment. In hy-
pothyroid diabetics for instance, the initiation of thyroid re-
placement therapy may increase their insulin or oral
hypoglycaemicโs requirements. Thyroid status can also affect
drug metabolism and clearance. Studies have indicated that
plasma concentrations of propranolol are reduced in hyper-
lhy.oidism compared with the euthyroid state, probably due
to increased clearance and hypothyroid patients receiving
chronic propranolol therapy have had a reduction in plasma-
propranolol concentrations when given thyroxine treatment
(propranolol can also reduce the activity of thyroxine, see be-
low). Similarly, serum-digoxin concentrations appear to be
lower in hyperthyroidism and higher in hypothyroidism
which may contribute in part to the observed insensitivity of
hyperthyroid patients to digoxin therapy although other
mechanisms have been proposed.
Thyroid status can itself be altered by a number of disease
states such as chronic active liver disorders and by a range of
drugs. Some drugs such as lithium and iodide act directly on
the thyroid gland and inhibit the release of thyroid hormones
leading to clinical hypothyroidism.
Enzyme-induction by drugs such as chloroquine, ri-
fampicin, carbamazepine, phenytoin or
barbiturates enhances thyroid hormone metabolism result-
ing in reduced serum concentrations of thyroid hormones.
Therefore, patients on thyroid replacement therapy may re-
quire an increase in their dose of thyroid hormone if these
drugs are given concurrently and a decrease if the enzyme-
inducing drug is withdrawn.
Other drugs such as amiodarone and propranolol may
inhibit the de-iodination of thyroxine to tri-iodothyronine re-
sulting in a decreased concentration of tri-iodothyronine with
a concomitant rise in the concentration of inactive reverse tri-
iodothyronine.
The protein binding of thyroid hormones may be altered by
drug treatment. For example, oral contraceptives may in-
duce an oestrogen-dependent rise in thyroxine-binding glob-
ulin and the total thyroid hormone bound to it, whereas
androgen administration reduces the concentration of the
binding globulin, and has resulted in clinical hyperthyroidism
when given to postmenopausal women maintained on thyrox-
ine replacement therapy. Drugs such as phenytoin, car-
banw'epine. and enclo/enac2? may reduce protein binding
by displacing the thyroid hormones from their plasmi-bind-
ing sites. As thyroid hormones are highly protein bound,
changes in binding might be expected to influence require-
ments in thyroid replacement therapy, but in practice there is
little clinical evidence of any problems except with thyroid-
function testing (see below).
Cholestyramine, an anionic exchange resin, significantly re-
duces the absorption of ingested thyroxine by binding with
thyroid hormones in the gastro-intestinal tract. The malab-
sorption of thyroxine is minimised by allowing an interval of
4 to 5 hours to elapse between the ingestion of the two
drugs. A similar effect has been observed with sodium pol-
ystyrene sulphonate. Sucralfate also reduces absorption of
thyroxine from gastro-intestinal tract as does aluminium
hydroxide, calcium carbonate, and ferrous sulphate,
Thyroid hormone enhance the effects of oral anticoagulants.
Patients on anticoagulants therapy therefore require careful
monitoring when treatment with thyroid agents is initiated or
altered as the oral anticoagulant dose may need to be
adjusted.
(see under the interactions of Warfarin).
Thyroid agents increase metabolic demands and should there-
fore be used with caution with drugs known to influence car-
diac function, such as the sympathomimetics, as they may
enhance this effect. In addition, thyroid hormones may in-
crease receptor sensitivity to catecholamines. Such a mecha-
nism has been proposed to explain the increase in response to
tricyclic antidepressants observed when
thyroid agents are given concurrently.
Isolated reports of drugs interacting with thyroid agents in-
clude ketamine (severe hypertension and tachycardia) and
lovastatin.
Pharmacokinetics
Thyroxine is variably but adequately absorbed from
the gastro-intestinal tract following oral administra-
tion. Fasting increases absorption. Once in the circu-
lation, thyroxine is extensively protein bound,
principally to thyroxine-binding globulin (TBG) but
also to a lesser extent to thyroxine-binding pre-albu-
min (TBPA) or to albumin. Thyroxine has a plasma
half-life in euthyroidism of about 6 to 7 days:
half-life is prolonged in hypothyroidism and re-
duced in hyperthyroidism.
Thyroxine is primarily metabolised in the liver and
kidney to tri-iodothyronine (liothyronine) and,
about 40%, to inactive reverse tri-iodothyronine,
both of which undergo further deiodination to inac-
live metabolites. Further metabolites result from the
deamination and decarboxylation of thyroxine to
tetrac.
Thyroxine is reported to undergo enterohepatic re-
cycling and excretion in the faeces.
The distribution of thyroid hormones across the pla-
centa and into breast milk is discussed under Preg-
nancy and Breast Feeding (above).
Uses and Administration
Thyroxine is a thyroid hormone used as re-
placement therapy in the treatment of hypothy-
roidism . It is given in conditions such as
diffuse non-toxic goitre and Hashimoto's thyroiditis to
suppress the secretion
of thyroid-stimulating hormone (TSH) and hence
prevent or reverse enlargement of the thyroid gland.
Thyroxine is also used to suppress TSH production
in the treatment of thyroid carcinoma and as
a diagnostic agent for the differential diagnosis of
hyperthyroidism. It is given with antithyroid drugs
in the management of hyperthyroidism.
The peak therapeutic effect of regular oral adminis-
tration of thyroxine may not be achieved until after
several weeks and there is a slow response to chang-
es in dosage. Similarly, effects may persist for sev-
eral weeks after withdrawal. Thyroxine is given as
the sodium salt in a single daily dose. Its absorption
can be irregular and it is probably best taken on an
empty stomach, usually before breakfast.
The dose of thyroxine sodium for the treatment of
any thyroid disorder should be individualised on the
basis of clinical response and biochemical tests and
should be monitored regularly.
In hypothyroidism the initial adult dose of thyrox-
ine sodium is 50 to 100 ng daily by mouth increased
by increments of 25 to 50 ng every 4 weeks or more
until the thyroid deficiency is corrected and a main-
tenance dose is established. The adult maintenance
dose is usually between 100 and 200 ug daily. In
elderly patients, in those with cardiovascular disor-
ders, or in those with severe hypothyroidism of long
standing, treatment should be introduced more grad-
ually: an initial dose of 25 to 50 ng daily increased
by increments of 25 ng at intervals of 4 weeks may
be appropriate.
In children, individualisation of dosage and moni-
toring of treatment is especially important. One sug-
gested regimen for the treatment of congenital
hypothyroidism is 25 ng initially and increased by
increments of 25 ng every 2 to 4 weeks until mild
toxic symptoms appear, at which time the dosage is
slightly reduced. Similar doses may be used for ju-
venile myxoedema except that children over I year
of age may be given 2.5 to 5 ng per kg body-weight
daily initially.
Thyroxine sodium may also be given by the naso-
gastric route or by intravenous injection. It has also
been given intramuscularly. In myxoedema (hy-
pothyroid) coma a suggested dose by intravenous
injection is 200 to 500 ng initially, followed by daily
supplements of 100 to 200 ng until the patient is eu-
thyroid and can tolerate administration by mouth.
Administration. There has been controversy over the
bioequivalence or otherwise of different brands of thyroxine.
Most studies and reports have come from the USA and results
may have depended to some extent on the particular brands
compared. Formulations may also have changed which makes
comparison of results difficult. A recently published study'
concluded that 2 generic thyroxine products were bioequiva-
lent and interchangeable with 2 branded products.
Depression. While thyroid hormones may increase the ac-
tivity of tricyclic antidepressants, as mentioned under Interac-
tions (see above), the benefits in the treatment of refractory
depression are debatable. A meta-analysis' of 8 stud-
ies involving 292 patients treated with liothyronine in addi-
tion to tricyclic antidepressants indicated that such therapy
was effective in a subgroup of cases but that the small number
of patients studied made additional placebo-controlled data
desirable. It was also noted that current trends in the treatment
of depression favoured drugs other than tricyclics. so that fu-
ture trials with liothyronine may need to investigate combina-
tion treatment with selective serotonin reuptake inhibitors.
Obesity. Thyroid drugs have been tried in the treatment of
obesity in euthyroid patients, but they produce only
temporary weight loss, mainly of lean body-mass, and can
produce serious adverse effects, especially cardiac complica-
tions. Hypothyroidism has also been reported2 when these
drugs were withdrawn from previously euthyroid patients be-
ing treated for simple obesity. It has also been notedthat thy-
roxine is probably being abused by some athletes to promote
weight loss.
Urticaria. There is some suggestion that chronic urticaria
may be associated with thyroid autoimmunity and
that treatment with thyroid hormones may result in clinical
remission. In one study, a nine-year-old boy was successful-
ly treated for chronic urticaria with thyroxine therapy at doses
of 50 to 100 mcg daily. The workers advised screening for thy-
roid function and anti-thyroid microsomal antibodies in cases
of chronic urticaria as these patients may benefit from thyroid
hormone therapy.