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Drugs and Thyroid
Joe George*, Shashank R Joshi*
Abstract
Drugs can affect thyroid functional status in numerous ways. They may influence thyroid homeostasis
at any level from their synthesis, secretion, transport or end-organ action resulting in hypothyroidism or
hyperthyroidism. Amiodarone is an important drug in this group. The effects of amiodarone on thyroid
function result from iodine release and intrinsic drug properties. Both amiodarone-induced thyrotoxicosis
(AIT) and amiodarone -induced hypothyroidism (AIH) may develop in apparently normal thyroid glands or
in glands with preexisting, clinically silent abnormalities. Treatment of AIH consists of thyroxine replacement
while continuing or discontinuing amiodarone therapy. In type I AIT the main medical treatment consists of
simultaneous administration of thionamides and potassium perchlorate, while in type II AIT, glucocorticoids
are the most useful therapeutic option. It is important to evaluate patients before and during amiodarone
therapy. The list of drugs affecting thyroid function is long with new drugs being added. Some of them are
clinically important while others just produce diagnostic dilemmas. The possible effect of drugs on the results
of thyroid-function tests should always be considered while making decisions regarding patient care. ©
INTRODUCTION
T
esting of thyroid function is becoming common in
clinical practice. Many patients tested, are on
multiple medications for various medical conditions.
This is particularly true of elderly patients. It is widely
recognized that certain drugs can alter thyroid hormone
measurements and can cause confusing laboratory test
results in subjects without thyroid disease. Certain other
drugs affect thyroid function directly or indirectly and
produce manifest disease. As awareness for thyroid
disease is increasing and thyroid function testing is
becoming part of routine evaluation protocols, the
recognition of such abnormalities is also increasing.
Therefore, the possible effect of these drugs both on the
results of thyroid-function tests and on the effectiveness
of treatment must always be considered in decisions
regarding patient care. Although most drug induced
changes in thyroid hormone homeostasis are transient,
they produce puzzling and at the same time fascinating
problems for physicians and endocrinologists alike.
Drugs affecting Thyroid Function
A large number of compounds may affect thyroid
function. The list is rapidly growing with the array of
new drugs coming into therapeutic armamentarium.
Rather than presenting an exhaustive review, the more
*Department of Endocrinology, Seth G.S. Medical College and
KEM Hospital, Mumbai.
© JAPI VOL. 55 MARCH 2007
commonly encountered compounds are listed1 (Tables
1 & 2) with those enjoying wider use and those with
significant effect being considered in detail.
Drugs may influence thyroid homeostasis at four
different levels.2 They may alter the synthesis and/or
secretion of thyroid hormone, may change the serum
concentrations of thyroid hormones by acting at the
level of binding proteins or by competing for their
hormone binding sites, may modify cellular uptake and
metabolism of thyroid hormone or may interfere with
hormone action at the target tissue.
AMIODARONE
Amiodarone is an iodine-rich drug widely used for the
management of atrial and ventricular arrhythmias.3 Being
a category Type-III anti-arrhythmic, its main mechanism
of action is to block myocardial potassium channels.
Although itÊs cardiac side effects are less frequent than
those associated with other antiarrhythmics, it has
potentially marked effects on cornea, lungs, liver, skin,
and the thyroid 4. It is a benzofuranic derivative with a
structural similarity to T3 and T4 (Fig. 1). It can produce
both hypo and hyperthyroidism.
Each molecule of amiodarone contains two iodine
atoms, which constitute approximately 37% of its
mass. Hence, a patient taking a 200-mg daily dose
of amiodarone ingests 75 mg of organic iodine each
day. 10% of the molecule is deiodinated daily. So a
maintenance daily dose of 200 to 600 mg results in
approximately 721 mg iodide each day. The optimal
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215
daily iodine intake advised is 150 to 300 øgm. Thus
Amiodarone therapy results in iodine intake 50-100
times higher than the daily requirement. Furthermore,
amiodarone is distributed in several tissues, including
adipose tissue, liver, lung, and, to a lesser extent,
kidneys, heart, skeletal muscle, thyroid, and brain, from
which it is slowly released.5 This results in a prolonged
terminal elimination half-life of around 100 days; the
drug and its metabolites remaining available for a long
period after withdrawal.5
Amiodarone effects on the thyroid gland and
thyroid hormone metabolism are unique. These can be
divided into intrinsic effects resulting from the inherent
properties of the compound and iodine-induced effects
(due solely to the pharmacologic effects of a large
iodine load) [Table 3]. Majority of patients receiving
amiodarone have thyroid function tests within the
physiological range. Because the thyroid gland is
exposed to an extraordinary load of iodine, adjustments
are made in thyroidal iodine handling and hormone
metabolism in order to maintain normal function, the
reflection of which is seen in serum thyroid hormone
levels. These alterations in serum thyroid function tests
can be divided into acute (<3 months) and chronic (>3
a) Amiodarone
b) Thyroxine (T4)
c) Triiodothyronine (T3)
Fig. 1 : Structure of Amiodarone and thyroid hormones.
Table 1 : Drugs that influence thyroid function : transfer protein and extra thyroidal metabolism
Mechanism of interference
Drugs
Altering thyroid hormone
serum transfer proteins
Increase Thyroid Binding Globulin
(TBG) concentration
Decrease TBG concentration
Interfere with thyroid hormone binding
to TBG and/ or transthyretin
Agents that alter extra-thyroidal
metabolism of thyroid hormone
Inhibit conversion of T4 to T3
Increased hepatic metabolism
Drugs that decrease T4 absorption
or enhance excretion
Estrogen, Tamoxifen
Heroin, Methadone
Clofibrate
5- Flurouracil, Mitotane
Perphenazine
Androgens
Anabolic steroids (eg. Danazol)
Glucocorticoids
Slow release nicotinic acid
Frusemide
Fenoflenac
Mefanamic acid
Salicylates
Phenytoin
Diazepam
Sulphonylureas
Free fatty acids
Heparin
PTU
Glucocorticoids
Propranolol
Iodinated contrast agents
Amiodarone
Clomipramine
Phenobarbital
Rifampicin
Phenytoin
Carbamazepine
Cholestyramine, Colestipol
Aluminium hydroxide
Ferrous sulphate
Sucralfate
Amiodarone
(Adapted and reproduced from Surks MI, Siewert R. Drugs and Thyroid Function. NEJM 1995;333:1688-94)
216
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© JAPI VOL. 55 MARCH 2007
Table 2 : Drugs that influence thyroid function : Synthesis, secretion, action
Mechanism of interference
Drugs
Drugs that affect synthesis
or / and secretion of hormone
Decreased T3/T4 synthesis /secretion
Increased T3/T4 synthesis /secretion
Decreased TSH concentration
/ response to TRH
Increase TSH concentration
/ response to TRH
Drugs that affect hormone
action at the target tissue
Lithium
Iodide
Thionamides (Propylthiouracil,
Methimazole, Carbimazole)
Thiocyanate
Perchlorate
Amiodarone
Cytokines (IFN-γ, IL-2, GM-CSF)
Aminoglutethimide
Iodide
Amiodarone
Cytokines (IFN-γ, IL-2, GM-CSF)
T4, T3
Glucocorticoids
Growth hormone
Octreotide, somatostatin
Opiates
Dopamine
L- dopa, Bromocriptine
Pimozide
Phentolamine
Thioridazine
Methysergide
Cyproheptadine
Iodine
Lithium
Dopamine antagonists
Iodide
Amiodarone
(Adapted and reproduced from Surks MI, Siewert R. Drugs and Thyroid Function. NEJM 1995;333:1688-94)
Table 3 : Effect of Amiodarone on the Thyroid gland : Postulated Mechanisms
Intrinsic Drug Effects
IodineInduced Effects
Inhibition of thyroid hormone entry into cells
Inhibition of type 1 and type 2 5Ê deiodinase.
(Total & FreeT4, rT3,T3, TSH)
Decreased T3 binding to its receptor
Failure to escape from Wolff-Chaikoff effect.
Iodine induced potentiation of autoimmunity.
In patients with underlying autonomous nodules or latent GravesÊ
disease, produces hyperthyroidism (Jod Basedow Effect)
Thyroid cytotoxicity (Destructive thyroiditis)
(Adapted and reproduced from Basaria S, Cooper DS. Amiodarone and the thyroid. The American J Medicine 2005;118:706-14)
months) phases that follow amiodarone exposure6
(Table 4). Indeed, more than 50% of patients who receive
long-term amiodarone therapy show abnormal results
on thyroid function test, though the majority remains
clinically euthyroid. Occasionally, amiodarone can also
cause goiter without apparent thyroid dysfunction.
Although the majority of patients given amiodarone
remain euthyroid, some develop thyroid dysfunction,
i.e., thyrotoxicosis and hypothyroidism. Amiodaroneinduced thyrotoxicosis (AIT) appears to occur more
frequently in geographical areas with low iodine intake,
whereas Amiodarone induced hypothyroidism (AIH)
is more frequent in iodine-sufficient areas.7-9 In a study
carried out simultaneously in Italy (moderately low
iodine intake) and United States (normal iodine intake),
it was found that the incidence of AIT was about 10% in
© JAPI VOL. 55 MARCH 2007
Table 4 : Effects of amiodarone on thyroid hormone
profile in euthyroid subjects
Parameters
Duration of Treatment
< 3 months
> 3 months
T4 / Free T4
T3 / Free T3
Reverse T3
TSH
50%
15-20%
200%
20-50%, remain
<20 mU/L
Normal
TBG
20-40% above baseline
15-20%
Remains >150%
Normal
Normal
(Adapted and reproduced from Basaria S, Cooper DS. Amiodarone
and the thyroid. The American J Medicine 2005;118:706-14)
former and 2% in the latter, while the incidence of AIH
was 5% in Italy and 22% in the United States. In general,
the various published studies report an overall incidence
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217
of AIT ranging from 1% to 23% and of AIH ranging
from 1% to 32%.10 India is currently predominantly
iodine sufficient though pockets of iodine deficiency
still exist. Thus, irrespective of iodine intake, it may
be estimated that the overall incidence of amiodaroneinduced thyroid dysfunction be between 2% and 24%,10
most commonly in the range of 1418%.11
AMIODARONE INDUCED THYROTOXICOSIS
(AIT)
AIT may develop, often suddenly and explosively,
early or after many years of amiodarone treatment.12 Trip
et al.13 observed that the average length of amiodarone
treatment before the occurrence of AIT was about 3 yr,
with a probability of disease slightly increasing with
duration of therapy. An interesting feature of AIT is
that it may develop even many months after drug
withdrawal, due to tissue storage of the drug and its
metabolites with slow release.8 There are no parameters
that predict AIT including daily or cumulative dose of
the drug.13 It is said to have a male to female ratio of
3:1.14.15
The pathogenesis of AIT is not completely delineated.
The disease may develop both in a normal thyroid gland
and in a gland with preexisting abnormalities. Two
main forms of AIT exist. Type I AIT usually occurs in
abnormal thyroid glands and is due to iodine induced
excessive thyroid hormone synthesis and release; type
II AIT is a destructive thyroiditis leading to release of
preformed thyroid hormones from the damaged thyroid
follicular cells. The relative prevalence of the two forms
of AIT is unknown, but it may depend on the ambient
Table 5 : Classification of Amiodaroneinduced
thyrotoxicosis
Type 1
Underlying thyroid
Yes
abnormality
Thyroid autoantibodies
Often present
Goitre
Often present
Thyroidal radioactive
Low, rarely normal
iodine uptake
or increased
Serum IL-6
Slightly
concentrations
increased
Cytologic findings
?
Abundant colloid, histiocytes
Pathogenic mechanism
Excessive Thyroid
hormone synthesis
Colour flow
Normal/increased
Doppler pattern
blood flow
Response to thionamides
Yes (Poor)
Response to perchlorate
Yes
Response to
Glucocorticoids
Probably No
Subsequent
Hypothyroidism
Unlikely
Type 2
No
Usually absent
Usually absent
Low
Markedly
increased
Destructive
Thyroiditis
Decreased
blood flow
No
No
Yes
Possible
(Adapted and reproduced from Bartalena L, Grasso L, Bragioni S,
et al. Serum interleukin-6 in Amiodarone induced thyrotoxicosis. J
Clin Endocrinol Metab 1994;78:42327)
218
iodine intake. Definitions of AIT may not be absolute,
and mixed forms with features of both type I and type II
exist. Nevertheless, identifying the different subgroups
has important management implications.
AIT may not manifest with classical symptoms
of thyrotoxicosis due to the antiadrenergic action of
amiodarone and its impairment of conversion of T4
to T3. Goiter and local tenderness may be present or
absent. Worsening of the underlying cardiac disorder
in a patient on Amiodarone may herald onset of AIT.16
Diagnosis of AIT may be difficult in patients with severe
non thyroidal illness, because the latter may dominate
and confuse the clinical picture. Over and above this
differentiating between the two types of AIT at times is
impossible17 (Table 5).
Treatment of AIT is a major challenge. The high
intra thyroidal iodine content reduces/blunts the
effectiveness of carbimazole / methimazole therapy.8 The
generally low or suppressed RAIU makes radioiodine
therapy an unattractive option. Surgical option is often
complicated by the underlying cardiac condition and
the thyrotoxic state. Overall it is difficult to lay down
a definite protocol of management. We have tried to
make a few suggestions18 (Table 6) which would work
Table 6 : Treatment of Amiodarone-induced Thyroid
disease protocol
Type I AIT
Thionamides ( carbinazole 30-60 mg/day or methimazole 3040
mg/day) in combination with potassium perchlorate (1 g/day
for 1640 days).
Discontinue amiodarone if possible.
After restoration of euthyroidism and normalization of urinary
iodine excretion, definitive treatment of the underlying thyroid
abnormalities by either radioiodine or thyroidectomy.
If amiodarone cannot be withdrawn and medical therapy is
unsuccessful, consider total thyroidectomy.
Type II AIT
Glucocorticoids for 23 months (starting dose, prednisone 40
mg/day or equivalent).
Discontinue amiodarone if possible.
In mixed forms add thionamides and potassium perchlorate.
After restoration of euthyroidism, follow-up for possible
spontaneous progression to hypothyroidism.
If amiodarone cannot be withdrawn and medical therapy is
unsuccessful, consider total thyroidectomy.
Amiodarone-induced hypothyroidism
Underlying Thyroid Abnormalities (Usually HashimotoÊs
Thyroiditis) Amiodarone therapy can be continued. L-T4
replacement therapy is added.
Apparently Normal Thyroid Gland
If amiodarone cannot be discontinued, L-T4 replacement
therapy is initiated. If amiodarone is withdrawn, strict
follow-up is required for possible spontaneous restoration
of euthyroidism. A short course of potassium perchlorate (1
g/day for 1030 days) can be given to accelerate return to
euthyroidism.
(Adapted and reproduced from Martino. E, Bartalena L, Bogazzi
F, Braverman LE. The Effects of Amiodarone on the Thyroid.
Endocrine Reviews 2001;22:24054)
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© JAPI VOL. 55 MARCH 2007
as a skeleton on which management should be based.
Finally each patient is different and treatment needs to
be individualized accordingly.
In type I AIT thionamides should be given to block
further organification of iodine and synthesis of thyroid
hormones. Larger than usual daily doses of methimazole
(4060 mg) or propylthiouracil (600800 mg) are often
necessary since the iodine-rich gland is usually resistant
to these drugs. In addition, potassium perchlorate
should be given if available to decrease the entrance
of iodine into the thyroid and to deplete intrathyroidal
iodine stores.19 The limitation of potassium perchlorate is
its toxicity, particularly agranulocytosis, aplastic anemia
and renal side effects. A complete blood count should be
done every few weeks in patients receiving thionamide
and perchlorate to detect this potentially fatal side effect.
In addition, potassium perchlorate should be withdrawn
once euthyroidism is achieved; usually by 6 weeks.
Adding lithium carbonate (9001350 mg/day for 46
weeks) to propylthiouracil is an additional option worth
mentioning.20 Treatment with lithium should always be
accompanied by drug monitoring to maintain serum
lithium concentrations within the therapeutic range of
0.61.2 mEq/l.
Type II AIT, being a destructive thyroiditis does
not respond to above treatment. Steroids are the best
option because of their membrane-stabilizing and
anti-inflammatory effects.21 They have been employed
in AIT at different doses (1580 mg prednisone or 36
mg dexamethasone daily) and different time schedules
(712 weeks).10,11,22 If thyrotoxicosis recurs on tapering
steroid, it must be reinstituted.
When distinction between type 1 and 2 is not
possible or when they coexist in the same patient, a
stepwise treatment approach is advised beginning
with an antithyroid drug and potassium perchlorate.
After 1 month of treatment, if patient doesnÊt show any
response, perchlorate is discontinued and prednisolone
is added. Tapering of steroid is done once serum free T4
concentration normalizes. Antithyroid drug in this case
can be tapered and discontinued when urinary iodide
excretion is < 200 øg daily.23
One of the most difficult problems in management
of AIT is to decide on continuing or discontinuing
amiodarone. It can be a double edged sword. Literature
is full of conflicting opinion.18 But most experts advocate
withdrawal of amiodarone, when feasible, although
some patients with mild disease and response to
thionamide and/or glucocorticoid therapy may be
continued with treatment. In cases in which withdrawal
of amiodarone is not feasible and medical therapy has
failed, thyroidectomy represents a useful alternative.
Definitive treatment of the underlying thyroid disorder
will usually be required in most type I AIT patients; this
can mostly be accomplished by radioiodine, provided
the RAIU values improve. Most type II patients will
© JAPI VOL. 55 MARCH 2007
remain euthyroid after resolution of the thyrotoxicosis.
In patients with a history of AIT in whom amiodarone
becomes necessary after it has been discontinued,
ablation of the thyroid with radioiodine before resuming
amiodarone should be strongly considered.
AMIODARONE INDUCED HYPOTHYROIDISM
(AIH)
The risk of developing AIH is independent of the
daily or cumulative dose of amiodarone. However,
the risk is greater in the elderly, iodine sufficiency,
HashimotoÊs thyroiditis, females and those with positive
thyroid microsomal or thyroglobulin antibodies. AIH
may be transient or persistent; the latter is almost always
associated with an underlying thyroid disorder.9 AIH is
usually an early event and it is uncommon after the first
18 months of amiodarone treatment.13
The most likely pathogenic mechanism is that the
thyroid gland of these patients, damaged by preexisting
HashimotoÊs thyroiditis, is unable to escape from the
acute Wolff-Chaikoff effect after an iodine load24 and
to resume normal thyroid hormone synthesis. These
patients have a positive perchlorate discharge test
cementing the theory of defective hormonogenesis.8
Similar to spontaneous hypothyroidism, AIH patients
frequently have vague symptoms and signs, such as
fatigue, cold intolerance, mental sluggishness, and
dry skin. In patients already on thyroxine replacement
therapy, the dose may need to be increased due to the
inhibition of the generation of T3 from T4 induced by
amiodarone25. Laboratory findings are similar to those
in spontaneous hypothyroidism, with decreased serum
free T4 and increased serum TSH concentrations.
Management of AIH does not have the complexity
observed with AIT (Table 6). If amiodarone is
necessary for the underlying cardiac disorder, it can be
continued in association with thyroxine replacement.
If discontinuance of amiodarone therapy is feasible,
spontaneous remission of hypothyroidism often occurs,
particularly in patients without underlying thyroid
abnormalities8. In view of the fact that these patients
often have severe underlying cardiac disease, it is
advisable to maintain the serum TSH concentration in
the upper half of the normal range.
Monitoring of thyroid function in amiodaronetreated patients
It is essential to carefully evaluate patients before
and during amiodarone therapy. A reasonable protocol
is given in Fig. 2.18 It is ideal to monitor thyroid function
every 6-12 weeks with free T3, free T4 and TSH.
Amiodarone in pregnancy and lactation
If amiodarone therapy is required, it can be
administered during pregnancy, although it may cause
changes in fetal thyroid function. Among pregnant
women treated with amiodarone, abnormalities in
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219
Fig. 2 : Recommendations for following patients receiving amiodarone
therapy. (Adapted and reproduced from Martino. E, Bartalena L, Bogazzi
F, Braverman LE. The Effects of Amiodarone on the Thyroid. Endocrine
Reviews 2001;22:24054)
thyroid function were found in 20% neonates, 3% of
whom had transient hyperthyroxinemia and 17% had
AIH. Congenital hypothyroidism related to amiodarone
therapy in the mother is likely to be transient, but
thyroxine therapy should be promptly started for the
fear of motor and mental sub normalcy.
Amiodarone is secreted in the milk. Breast feeding is
not absolutely contraindicated but thyroid function in
the neonate must be carefully monitored for the possible
occurrence of AIH.
Iodine and Iodinated Drugs
As seen in the previous section, thyroid hormone
secretion can either be increased or decreased in
response to iodinated drugs (Table 3). In addition to
amiodarone, there are many iodine containing organic
compounds used in clinical practice that are partially
deiodinated in vivo and therefore can affect thyroid
function like substance : Saturated Solution Potassium
iodine (amount of iodine - 38 mg/drop; LugolÊs Iodine
(amount of iodine - 6.3 mg/drop); Amiodarone (amount
of iodine - 75mg/tablet); Iodoquinol(amount of iodine
- 104 mg/tablet); Povidone Iodine (amount of iodine - 10
mg/ml); Theophylline elixir (amount of iodine - 6.6 mg/
ml); Iopanoic acid (amount of iodine - 333mg/tablet);
Ipodate Sodium (amount of iodine - 308 mg/capsule);
Intravenous radiographic contrast (amount of iodine
- 140 380 mg/ml); Tincture Iodine (amount of iodine
- 40mg/ml). The risks posed by the use of radiographic
contrast agents for coronary angiography or computed
220
tomography is of particular concern because of the dose
consumed and the widespread use of these procedures.
These agents even with, minimal deiodination (e.g.,
only 0.1 percent) will result in the release of as much
as 14 to 175 mg of iodide. Although the inhibitory
effect of iodine on thyroidal hormone synthesis and
secretion is spontaneously reversible after several days,
the abnormalities in T4 and TSH may persist for up to
2 weeks following an acute iodine load. Long standing
abnormalities occur though less frequently.
Cytokines
Thyroid dysfunction may develop in patients with
chronic inflammatory disorders or tumors who receive
long-term treatment with cytokines. Administration
of interferonÊs (α and β), interleukins and granulocyte
macrophage colony stimulating factor (GM-CSF) has
been associated with both hyper and hypo function
of thyroid gland.2 In addition, cytokines are known
to result in appearance or increase in titer of thyroid
autoantibody. But appearance of antibody without
thyroid dysfunction is much more common during
therapy. Interferon- α is associated with the development
of anti microsomal (antithyroperoxidase) antibodies
in 20 percent of patients, and some have transient
hyperthyroidism, hypothyroidism, or both.26 Patients
who have antithyroid antibodies before treatment are
at higher risk for thyroid dysfunction during treatment.
Thyroid dysfunction usually appears after 3 months of
treatment and may persist even after discontinuation.
Interleukin-1 (IL-1) and TNF-α are known to inhibit
iodine organification and hormone release as well as
to modulate thyroglobulin production and thyrocyte
growth. Interferon γ increases expression of the
MHC class II molecules on cell surface which lead to
initiation of autoimmunity.27 Therapy with interleukin-2
is associated with transient painless thyroiditis in about
20 percent of patients.28
Lithium
Lithium interference with thyroid function occurs
mainly at the level of hormone secretion. Additional
effects on iodine trapping, release and coupling have
also been described. Long-term lithium treatment results
in goiter in up to 50 percent of patients, sub clinical
hypothyroidism in up to 34%, and overt hypothyroidism
in up to 15% percent.29 This can appear abruptly even
after many years of treatment. This makes it mandatory
to test thyroid function once or twice a year in these
patients.30 Presence of thyroid autoantibody increases
the risk of development of hypothyroidism; 50 percent
of those with autoantibody and 15 percent of those
without antibodies have sub clinical hypothyroidism.31
The inhibitory effect of lithium on thyroid hormone
secretion has been utilized in treatment of thyrotoxicosis
in selected situations.
Lithium treatment is also associated rarely with
thyrotoxicosis. It is not common and occurs mainly after
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© JAPI VOL. 55 MARCH 2007
long term use. Mechanism is unclear but is thought to
involve either autoimmune or destructive thyroiditis.32
Transient euthyroid hyperthyroxinemia has been
reported after discontinuation of lithium treatment.33
NSAID
Salicylates (in doses of >2.0 g per day) inhibit the
binding of T4 and T3 to TBG and transthyretin.34 The
initial effect is an increase in serum free T4 concentrations.
When therapeutic serum concentrations are sustained,
salicylates result in a 20 to 30 percent decrease in serum
total T4 concentrations and normal serum free T4
concentrations. Other NSAIDs also displace T4 from its
binding sites, particularly fenoflenac.
Frusemide
Frusemide has no effect at the usual therapeutic
concentrations, but large intravenous doses (more
than 80 mg) result in a transient increase in serum
free T4 concentrations and a decrease in serum total
T4 concentrations.35 The mechanism is reported to be
inhibition of T4 binding to its carrier proteins.
Heparin
Large doses of heparin alter the distribution of T4
between plasma and its rapidly exchangeable tissue
pools increasing the former and decreasing the latter.
Thus serum free T4 concentrations increase transiently
after the administration of heparin. This increase is
caused by the inhibition of protein binding of T4 by
the free fatty acids generated as a result of the ability of
heparin to activate lipoprotein lipase.36 These changes
are of diagnostic but not clinical consequence.
Ferrous Sulphate, Sucralfate, Aluminium Hydroxide
Drugs can alter thyroid hormone availability by
inhibition of absorption at the intestinal level. This has
been seen in T4 treated patients with hypothyroidism
who are given aluminum hydroxide, ferrous sulfate or
sucralfate. This interference seems to occur in relatively
few patients on replacement. Still it is prudent to advise
all patients to take their T4 and other medications at
different times.
Antiepileptic drugs
Cytochrome P450 complex (CYP3A) consist of
enzymes responsible for oxidative and reducing
reactions. Some of these enzymes are induced by
antiepileptic drug phenytoin, phenobarbital and
carbamazepine. This can produce marked reductions
in thyroid hormone levels. Metabolic clearance rate and
the hepatic metabolism of T4 increases there by resulting
in increased dose requirement in hypothyroid patients
on replacement therapy. Phenytoin and carbamazepine
cause a decrease of 20 to 40 percent in serum total and
free T4 concentrations and a smaller decrease in serum
total and free T3 concentrations in patients who have
no thyroid disease. The effect on TSH concentration is
less impressive.37
Rifampicin is one of the most potent inducers of
hepatic mixed function oxygenases. It produces changes
similar to that produced by phenytoin and other
antiepileptic drugs.
Propranalol
Beta receptor antagonists are useful drugs in the
symptomatic treatment of thyrotoxicosis. Small decreases
in serum T3 concentrations occur in patients treated with
large doses (>160 mg per day) of propranolol, and a
few have small increase in serum T4 concentration.38
The reduction in T3 by propranolol is mainly due to a
reduction in its generation from T4. The clinical benefits
of β receptor antagonists in thyrotoxicosis are not related
to this action. Action of propranolol on thyroxine
metabolism is not shared by metoprolol, atenolol or
labetalol.39 Still these drugs are effective in providing
symptomatic relief of thyrotoxicosis. The patients on β
receptor antagonists are clinically euthyroid and have
normal serum TSH concentrations.
Steroids
Dexamethasone has several effects on thyroid
hormone physiology. Both large acute therapy and
moderate chronic therapy can suppress TSH secretion
from anterior pituitary.40 Large doses of glucocorticoids
cause a 30 percent reduction in serum T3 concentrations
within several days through its inhibitory action on 5Ê
deiodinase enzyme.41 T4 secretion is also reduced with
high dose steroid therapy. Long-term therapy also
decreases production of TBG.
Estrogen
The most common causes of an increase in serum
TBG concentrations in routine practice are an increase
in estrogen production and administration of estrogen.42
Estrogens increase sialylation of TBG, which decreases
its rate of clearance and raises its serum concentration.
The increase of TBG in serum is dose-dependent. The
usual doses of ethinyl estradiol (20 to 35 mg per day)
and conjugated estrogen (0.625 mg per day) raise serum
TBG concentrations by approximately 30 to 50 percent
and serum T4 concentrations by 20 to 35 percent.43 The
increases begin within two weeks, and a new steady
state is attained in four to eight weeks. In women with
hypothyroidism who are receiving T4 and become
pregnant, an increase of 25 to 50% percent in the dose
is needed, on average, to maintain normal serum TSH
concentrations. Tamoxifen has weak estrogen-agonist
effects in the liver and raises serum TBG concentrations
slightly.
CONCLUSION
Thyroid function testing is becoming part of routine
evaluation protocols. Therefore, the possible effect of
these drugs on the results of thyroid-function tests must
always be considered in decisions regarding patient
care. Although most drug induced changes in thyroid
Rifampicin
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221
hormone homeostasis are transient, they can produce
panic and result in unnecessary treatment. Knowledge of
the site of drug interaction and the physiologic features
of the thyroid hormone system should enable the
clinician to anticipate changes that may occur in thyroid
homeostasis. Knowledge of drugs that increase the risk
of thyroid abnormalities would help in monitoring those
patients at high risk and would lead to early diagnosis
and treatment.
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Announcement
4th Infectious Disease Certificate Course - IDCC -2007
PD Hinduja National Hospital and Medical Research Centre, Mumbai, India
In collaboration with Henry Ford Health System, Detroit, MI, USA
26th Aug (Sunday) to 2nd September (Sunday) 2007
8.30 am to 5.00 pm
Objective: Diagnosis, Management and Prevention of Infectious Diseases.
Focus: Acute febrile illnesses (including Dengue, Enteric, Malaria), Tuberculosis, HIV, Infections in
ICU/ Pediatrics/ Immunocompromised, Organ Specific Infections
Format: Ward Rounds, Archived Cases, Interactive Lectures, Work Mats, Microbiology Discussions, Visit
to Infectious Disease Hospital
Credit hours: 55 hours of Category 1 credit towards the American Medical Association PhysicianÊs
Recognition Award.
Eligibility: Post graduates in Medicine/ Pediatrics and Microbiology (Final year postgraduates may also
be considered)
Registration procedure: Candidates to send short bio data with Demand Draft/ Cheque of Rs 3,000/- or
100 USD in favor of PD Hinduja National Hospital and Medical Research Centre payable at Mumbai.
(Outstation cheques will not be accepted)
Candidates to make their own arrangement for accommodation
Last date for registration: 30th June 2007
Course Information/ Detailed Programme: www.hindujahospital.com/IDCC2007
Inquiries: 022-24447704 or [email protected]
Course Coordinators:
Dr FD Dastur /Dr Rajeev Soman/ Dr Camilla Rodrigues/ Dr Tanu Singhal
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223