CORTICOSTEROIDS
The adrenal cortex synthesises a number of steroids,
which may be divided into corticosteroids. based on
a 21-carbon nucleus, and sex corticoids, primarily
androgens.-based on a 19-carbon nucleus. The corti-
costeroids are traditionally divided into those with
predominantly glucocorticoid actions, of which cor-
tisol (hydrocortisone) is the most important endog-
enous example, and those which are primarily
mineralocorticoid. of which aldosterone is much the
most important.
The endogenous glucocorticoids are under regulato-
ry control from the hypothalamus and pituitary, via
the releasing hormones corticorelin and
corticotrophin or ACTH . In return the
glucocorticoids act to inhibit production and release
of these releasing hormones by a negative feedback
mechanism. The system is known collectively as the
hypothalamic-pituitary-adrenal (HPA) axis. Aldos-
terone secretion, by contrast, is under the control of
the renin-angiotensin system.
The main mineralocorticoid actions are on fluid
and electrolyte balance. They enhance sodium reab-
sorption in the kidney and hence expand the extra-
cellular fluid volume, and they enhance renal
excretion of potassium and H*.
The glucocorticoid actions are wide-ranging. They
have potent anti-inflammatory and immunosuppres-
sive effects, at least partly through inhibition of the
release of various cytokines. and it Is primarily these
that are made use of clinically . They
also have profound metabolic.effects: blood glucose
concentrations are maintained or increased by a de-
crease in peripheral glucose utilization and an in-
crease in gluconeogenesis: glycogen deposition,
protein breakdown, and lipolysis are increased, and
effects on calcium uptake and excretion lead to a de-
crease in body calcium stores. Glucocorticoids play
a facilitative or permissive role in the function of
many other active endogenous substances, and have
effects on the function of cardiovascular system,
kidneys, skeletal muscle and CNS.
Many synthetic congeners and derivatives of the
corticosteroids are available. The main corticoster-
oids used systemically are hydroxy compounds (al-
cohols). They are relatively insoluble in water and
the sodium salt of the phosphate or succinate ester is
generally used to provide water-soluble forms for
injections or solutions. Such esters are readily hy-
drolysed in the body.
Various structure-activity relationships are under-
stood for the corticosteroids and have been made use
' of in the development of new compounds. The pres-
ence of a hydroxyl group at position 11 seems to be
essential for glucocorticoid activity, while a hy-
droxyl at position 21 is required for mineraloconi-
coid activity. Fluorination at position 9 enhances
both mineralocorticoid and glucocorticoid activity.
Substitution at carbon 16 (as in betamethasone. dex-
amethasone. or mamcinolone) virtually eliminates
mineralocorticoid activity. Esterification of corti-
cosleroids at the 17 or 21 positions with fatty acids
generally increases the topical activity. The forma-
tion of cyclic acetonides at the 16 and 17 positions
further increases topical anti-inflammatory activity,
usually without increasing systemic glucocorticoid
activity.
In the medical and pharmacological literature the
names of unesterified corticosteroids have frequent-
ly been used indiscriminately for both the unesteri-
fied and esterified forms and it is not always
apparent to which form reference is being made.
The unesterified form is sometimes qualified by the
phrase 'free alcohol'.
Adverse Effects of Corticosteroids
The adverse effects of corticosteroids may result
from unwanted mineralocorticoid or glucocorticoid
actions, or from inhibition of the hypothalamic-pitu-
itary-adrenal axis.
Mineralocorticoid adverse effects are manifest in
the retention of sodium and water, with oedema and
hypertension, and in the increased excretion of po-
tassium with the possibility of hypokalaemic alkalo-
sis. In susceptible patients, cardiac failure may be
induced. Disturbances of electrolyte balance are
common with the naturally occurring corticoster-
oids. such as cortisone and hydrocortisone. but are
less frequent with many synthetic glucocorticoids.
which have little or no mineralocofticoid activity.
Adverse glucocorticoid effects lead to mobilisation
of calcium and phosphorus, with osteoporosis*and
spontaneous fractures: muscle wasting and nitrogen
depletion: and hyperglyca5mia with accentuation or
precipitation of the diabetic state. The insulin re-
quirements of diabetic patients are increased. In-
creased appetite is often reported.
Impaired tissue repair and immune function can lead
to delayed wound healing, and increased suscepti-
bility to infection. Increased susceptibility to all
kinds of infection, including septicaemia, tuberculo-
sis, fungal infections, and viral infections, has been
reported in patients on corticosteroid therapy. Infec-
tions may also be masked by the anti-inflammatory,
analgesic, and antipyretic effects of glucocorticoids.
Recent attention has focussed on the increased se-
verity of varicella, with a possible fatal outcome in
non-immune patients receiving systemic corticos-
teroid therapy.
- Other adverse effects include amenorrhoea, hyper-
hidrosis, skin thinning, ocular changes including de-
velopment of glaucoma and cataract, mental and
neurolpgical disturbances, benign intracranial hy-
pertension. acute panceatitis and avascular necrosis of bone.
An increase in the coagulability of the
blood may lead to thromboembolic complications.
Peptic ulceration has been reported but reviews of
the literature do not always agree that corticoster-
oids are responsible for an increased incidence.
The negative feedback effects of glucocorticoids on
the hypothalamic-pituitary-adrenal (HPA) axis may
lead to adrenal atrophy, in some cases after therapy.
for as little as 7 days. This produces secondary
adrenocortical insufficiency, which may become
manifest following overly rapid withdrawal of treat-
ment or be precipitated by some stress such as infec-
tion or trauma. Patients vary considerably in the
degree and duration of adrenal suppression follow-
ing a given course of corticosteroid, but adrenal at-
rophy may persist for months or years, and
withdrawal should be gradual in those who have
been treated for any length of time (see also With-
drawal, below). High doses of corticosteroids ad-
ministered during pregnancy may cause fetal or
neonatal adrenal suppression. Although the precise
mechanism is uncertain, growth retardation may fol-
low the administration of even relatively small doses
of corticosteroids to children.
Large doses of corticosteroids, or of corticotrophin.
may produce Cushingoid symptoms typical of hyper
activity of adrenal cortex, with moonface,
sometimes with hirsutism,buffalo hump, flushing,
increased bruising, ecchymoses, striae, and acne. Rapid intra-
venous administration of large doses of corticoster-
oids may cause cardiovascular collapse.
Hypersenshivity reactfons ave occurred with corti-
costeroids, mainly when administered topically.
Adverse effects occur, in general, fairly equally with
all systemic corticosteroid preparations and their in-
cidence rises steeply if dosage increases much
above physiological values, traditionally considered
to be about 7.5 mg daily of prednisolone or its
equivalent (see under Uses and Administration, be-
low, for equivalent doses of other corticosleroids).
Short courses at high dosage for emergencies appear
to cause fewer side-effects than prolonged courses
with lower doses.
Most topically applied corticosteroids may, under
certain circumstances, be absorbed in sufficient
amounts to produce systemic effects. The topical ap-
plication of corticosteroid preparations to the eyes
has produced corneal ulcers, raised intra-ocular
pressure, and reduced visual function. Application
of corticosteroids to the skin has led to loss of skin
collagen and subcutaneous atrophy; local hypopig-
mentation of deeply pigmented skins has been re-
ported following both the intradermal injection and
topical application of potent corticosteroids.
Intrathecal administration (including inadvertent in-
trathecal administration after attempted epidural in-
jection) has been associated with arachnoiditis.
Adrenal suppression. The inhibition of hypothalamic-pi-
tuitary-adrenocortical function associated with corticosteroid
administration may persist for a year or more after treatment
is withdrawn and may cause acute adrenocortical insufficien-
cy with circulatory collapse during stress. The degree of sup-
pression depends on a number of factors, including length of
treatment, time of day of administration, type of corticoster-
oid preparation used. route of administration, dose adminis-
tered. and dosing interval. In general, suppression of secretion
of adrenocorticotrophic hormone and atrophy of the adrenal
gland become progressively more definite as doses of corti-
cosleroid exceed physiological amounts (see under Uses and
Administration, below), and as the duration of therapy in-
creases (significant suppression is likely in patients recieving
more then 3 weeks of therapy,). It is less when the corticoster
oid is given as a single dose in the morning, and even less if
this morning dose is given on alternate days or less frequently.
In patients taking high enough doses of corticosteroids to sup
press the adrenals the dose should be increased during any
form of stress (for example, illness or surgery), and those
treated within the last 2 or 3 months should be restarted on
therapy. Where the interval since treatment is greater than 3
months, resumption of treatment depends on clinical assess-
ment of signs of adrenocortical insufficiency.
To avoid precipitating acute adrenocortical insufficiency,
withdrawal of corticosteroid treatment should be earned out
gradually, differing regimens being used according to the dis-
ease being treated and the duration of therapy. Examples of
withdrawal regimens that have been used are described under
withdrawal below.
Adrenal suppression may occur after very shoit courses of
high-dose therapy and since many patients undergoing such
therapy will be under continuing stress when the drugs arc
stopped, gradual withdrawal of corticosteroids over 5 to 7
days is preferable.
It should also be remembered that corricostcroid-induced ad-
renal suppression has been associated not only with systemic
therapy, but has followed topical application ofcorticosteroid
preparations, particularly those containing potent coiticoster-
oids. Adrenal suppression has also been associated with the
use of inhalants, and the topical application of eye drops, eye
ointments, and nasal preparations.
EffectS on bones and joints. Corticosteroid-induced avas-
cular necrosis of bone is an uncommon but disabling compli-
cation of therapy. The incidence may vary in patients with
different disease states; alcoholics, and patients with collagen
disease (especially systemic lupus erythematosus) may have
increased susceptibility.~ There may be a relationship with
corticosteroid dose: even short courses of high-dose corticos-
teroids may be associated with its development.There is
also a report of avascular necrosis associated with topical ap-
plication of corticosteroids.
Corticosteroids may also produce osteoporosis. A review' of
data obtained from studies published between 1970 and 1990
established that osteoporosis is a common consequence of
long term treatment with corticosteroids, occurring in ap-
proximately 50% of patients. Bone loss is more rapid during
the early stages of therapy and is most rapid in areas of the
skeleton containing the greatest proportion of trabecular bone
such as the spine, hip, distal radius, pelvis, and ribs.
Reviews and guidelines' on the prevention and management
of corticosteroid-induced osteoporosis suggest that the dose
should be minimised, as doses above 7.5 mg of prednisolone
or prednisone (or the equivalent) are associated with more
significant bone loss and increased fracture risk. Alternate*
day therapy, although desirable for its reduced effect on the
hypothalamic-pituitary-adrenal axis, does not reduce the risk
of bone loss. Patients should maintain an adequate intake of
calcium and vitamin D, should take regular exercise, and
avoid smoking and excessive alcohol intake. Hormone re-
placement therapy is advocated in postmenopausal women.
In high risk patients in whom hormone replacement therapy
is inappropriate or contra-indicated the prophylactic use of
bisphosphonates. calcitriol. or calcitonin should be consid-
ered. A thiazide diuretic may be helpful in controlling hyper-
calciuria in patients not receiving calcitriol. Whether some
conicosteroids have reduced effects on the bone is unclear.
Effects on carbohydrate and protein metabolism :
Conicosteroids produce glucose intolerance and protein
catabolism.
Effects on the cardiovascular system. Corticosteroids
have been recognized cardiovascular effects arising from induced
changes to electrolyte balance and enhancement of vascular
reactivity causing hypertension.
Effects on the cerebrovascular system. Despite being
used in high doses to treat benign intracranial hypertension.
corticosteroids may also occasionally cause this disorder.
Children receiving long-term therapy are mainly affected, an
increase in dosage often being responsible. Symptoms usual-
ly subside when dosage is reduced.'
Effects on the eyes : Ocular adverse effects of conicoster-
oids include raised intra-ocular pressure. Most reports impli-
cate prolonged topical administration to the eye or lace.
Young children (less than 8 years of age) may be at increased
risk.Increases in intra-ocular pressure appear to be less
marioed in patients receiving systemic corticosteroids.s How-
ever. there is evidence of an increased risk in patients receiv-
ing inhaled corticosteroids.~ Again, prolonged or high-dose
administration seems to be generally implicated. A recent
study in elderly patients has also demonstrated a dose-related
increase in the risk of raised intra-ocular pressure or open-
angle glaucoma.
Topical administration of corticosteroids to patients with oc-
ular herpes simplex infection can alleviate the symptoms but
allow the infection to develop with the risk of irreversible cor-
neal scarring' that may lead to loss of vision, or even loss of
the eye. Warnings have been sounded about the ocular risks
of applying conicosteroid ointments to skin near the eyes."
Cataract formation is another risk from corticosteroid use and
some references to case reports are given below;?·)9-*''' this
hazard is associated with systemic corticosteroid absorption.
Again, there is evidence that cataract formation may also be
associated with use of inhaled corticosteroids. 12.Is Individual
susceptibility to this effect appears to vary. but it may be more
important than dosage and duration of treatment. Again, chil-
dren may be more likely to develop cataract than adults'
Systemic corticosteroid use has also been associated with
damage to the retinal pigment epithelial barrier, predisposing
the patient to serous retinal detachment.
Effects on the gastro-intestinal tract :It has long been
considered that treatment with corticosteroids might lead to
peptic ulcers. Some years ago a review of the data then avail-
able suggested that since an ulcer developed in I % of control
patients not receiving steroids, the W incidence for patients
receiving steroids did not warrant the prophylactic uie of anti-
ulcer drugs in all patients. ' Others have found little evidence
of an increased risk of peptic ulcer produced by corticoster-
oids alone although there is some increase in risk associated
with the concomitant Use of corticosteroids and NSAIDs.? It
haa been suggested that it might be prudent to avoid such
combination therapy whenever possible.
Doubt has therefore been cast on the prophylactic value of
anti-ulcer therapy given concomitantly with corticoster-
oids.If an ulcer does develop and there is good reason to
continue with steroid therapy then corticosteroids may be
continued along with some form of nicer therapy. '
Then have been several reports of corticosteroids being asso-
elated with gastro-intestinal perforation. There is a risk that
the anti-inflammatory properties of corticosteroids may mask
the signs of perforation and delay diagnosis with potentially
fatal results.
Effects on growth. ,Corticosteroids impair normal growth
in children when given systemically. and although alternate
day therapy may reduce the effect on growth it does not abol-
ish it. Recent concerns have centered on the possible effects of
inhaled corticosteroids on growth.'" Some studies have not
found an effect of inhaled corticosteroids on growth, and in
general this appears to be so when doses arc modest, even if
treatment is prolonged. Others have found that inhaled
corticosteroids, particularly in high doses, do appear to have
some effect on growth parameters, but it is unclear wheth-
er this has long-term effects on the child's ultimate height.
and the alternative in children requiring such high-dose ther-
oy is likely to be an oral corticosteroid, with its consequent
effects.
Effects on immune response. Owing to their immuno-
suppressant effect administration of corticosteroids in doses
greater than those required for physiological replacement
therapy is associated with increased susceptibility to infec-
tion. aggravation of existing infection, and activation of latent
infection. An additional problem is that the anti-inflammatory
effect of corticosteroids may mask symptoms until the infec-
tion has progressed to an advanced stage: the altered response
of the body may also permit the bizarre spread of infections,
frequently in aberrant forms, such as disseminated parasitic
infections. The risk is greater in patients receiving high doses.
or associated therapy with other immunosuppressants such as
cytotoxic agents, and in those who are already debilitated.
Children receiving high doses of corticosteroid are at special
risk from childhood ailments, such as chickenpox. but vacci
nation with living organisms is contra-indicated since infec-
tion may be induced (killed vaccines or toxoids may be given
but the response may be reduced). This increased susceptibil
ity to infection coupled with masking of symptoms may also
be caused by topical or local corticosteroid therapy. Thus.
topical application to the skin has led to unusual changes such
as atypical ringworm infection. Fungal infections, generally
restricted to the upper respiratory tract, are associated with.
corticosteroid inhalations. Severe damage to the eye has fol-
lowed the ocular use of corticosteroids in herpetic infections.
and a similar generalised spread of herpes infection may fol-
low application to the mouth in the presence of herpes infec-
tion.
Conversely, the effect of corticosteroids on the symptoms and
course of some infections may be life-saving (see Uses and
Administration, below). Before embarking on a long-term
course of corticosteroid therapy general measures for the re-
duction of risk of infection include a diligent search for active ,
or quiescent infection and, where appropriate, prevention or
eradication of the infection before starting, or concurrent ad-
ministration of chemoprophylaxis during corticosteroid treat-
ment.
Effects on lipid metabolism, Glucocorticoids have potent
effects on lipid metabolism, facilitating the effects of growth.
hormone and endogenous stimulants of lipolysis. As a result
they increase both high- and low-density lipoprotein choles-
terol concentrations in the blood.
Hydroxychloroquine has been reported to counter the effects,
of corticosteroids on lipid metabolism in patients with rheu-
matoid arthritis or systemic lupus erythematosus—see p.432.-
On prolonged administration glucocorticoids also have a dra-
matic effect on body fat distribution, resulting in the charac-
teristic Cushingoid appearance of moon face. and increased .
fat at the back of the neck and supraclavicular area.
Effetts on mental state. Reviews and reports ofthe effects
of corticosteroids on mental state L-6 suggest a causative link
. between corticosteroid therapy, particularly in high doses,
and certain cases of mental disturbance. These disturbances
have included psychosis, euphoria, and depression. Impair-
ment of memory has been associated with pulsed intravenous
methylpradnisolone.
Effects on the neonate. Various adverse effects have been
reported in premature neonates given corticosteroids, see un-
der Dexamethasone.
Effects on the nervous system. Paraesthesia md irrita-
tion, most commonly occurring in the anogenital region, have
been associated with the intravenous administration of dex-
amethasone sodium phosphate' and hydrocortisone sodium
phosphate.' but not with hydrocortisone sodium succinate.'
Further comments and discussions on this topic are listed be-
Low, Also listed below are references to epidural lipomato-
sis with severe neurological complications following
systemic corticosteroid therapy.
Effects on the pancreas. Acute pancreatitis has been asso-
ciated with corticosteroid use.1.3 although evidence support-
ing the association has been challenged on a number of
grounds, both clinical and experimental.
EFFECTS ON THE SKIN : Topical corticosteroids are associated
with a number of local adverse effects on the skin. principally
due to their antiproliferative effects on keratinocytes and fl-
broblasts (leading to skin thinning and atrophy), and to possi-
ble interference with the skin flora (leading to increased risk
of superinfection or opportunistic infection).' Skin thinning is
more likely if corticosteroids are applied under occlusion
(this is especially true of halogenated corticosteroids which
are more resistant to inactivation by enzymes in the epider-
mis). Striae, which occur usually in intertriginous areas such
as axillae and groin where skin is thin. moist, and occluded.
are the most readily appreciable manifestation of skin atro-
phy, and are irreversible, unlike more minor degrees of atro-
phy. Other local adverse effects include telangectasias and purpura.
The balance between benefit and the likelihood oflocal or systemic
side effects following topical application of corticosteroids will
depend on the chemical structure of the drug (i.e. its lipophilicity
and resistance to enzymic degradation), the formulation of the
vehicle, the way in which it is applied, and the nature of the skin to
be treated.
Skin thinning and puipura have also been reported in patients
receiving inhaled corticosteroids."
The adverse skin effects arising from systemic corticosteroids
also include striae and-skin thinning as well as acneiform
eruptions. Somewhat counter-intuitively a case-control study
has suggested an increased risk of Stevens-Johnson syndrome
or toxic epidermal necrolysis in patients receiving corticoster-
oids, particularly in the period shortly after beginning therapy.
Elfects on the voice. Dysphonia may be associated-with
inhaled corticosteroids. Although oropharyngeal candidia-
sis may be one possible cause of such hoarseness, most pa-
tients with dysphonia are reported not to have candidiasis
Hypersenstivity and anaphylaxis : There have been occa-
sional reports of hypersensitivity reactions, and sometimes
anaphylaxis. caused by corticosteroids. Reactions have oc-
curred with any route, although the topical route is mainly
involved. It has been observed that the incidence of hypersen-
sitivity is increasing' and it has been suggested that a lack of
response in chronic-eczema might be due to a reaction to the -
corticosteroid treatment.'
Tumour lysis syndrome. Reports of corticosteroid-in-
duced tumour lysis syndrome are in nthe literature.
Treatment of Adverse Effects of Cortico-
steroids
The adverse effects of corticosteroids are nearly al-
ways due to their use in excess of normal physiolog-
ical requirements. They should be treated
symptomatically,where possible the dosage being
reduced or the drug slowly withdrawn.
The treatment of acute adrenocortical insufficiency
in corticosteroid-treated patients, whether due to ac-
cidental abrupt withdrawal of the corticosteroid or
the inability of the patient's adrenals to cope with
the increased stress of infection or accidental or sur-
gical trauma, is described under Adrenocortical
Insufficiency.
Withdrawal of Corticosteroids
The use of pharmacological doses of corticosteroids
suppresses the endogenous secretion of cortico-
trophin by the anterior pituitary, with the result that
the adrenal cortex becomes atrophied. Sudden with-
drawal or reduction in dosage, or an increase in cor-
ticosteroid requirements associated with the stress
of infection, or accidental or surgical trauma, may
then precipitate acute adrenocortical insufficiency;
deaths have followed the abrupt withdrawal of cor-
ticosteroids. For the emergency treatment of acute
adrenal insufficiency caused byabrupt withdrawal
of corticosteroids, see under Adrenocortical Insuffi-
ciency.
In some instanced. Withdrawal symptoms may in-
volve or resemble a clinical relapse of the disease for
which the patient has been undergoing treatment.
Other effects that may occur during withdrawal or
change of corticosteroid therapy include benign in-
tracranial hypertension with headache and vomiting
and papilloedema caused by cerebral oedema.
Latent rhinitis or eczema may be unmasked.
Duration of treatment and dosage are important fac-
tors in determining suppression of the pituitary-ad-
renal response to stress on cessation of
corticosteroid treatment, artd individual liability to
suppression is also important.
Following short courses at moderate doses it may be
appropriate to withdraw corticosteroids without ta-
pering the dose (see below). However, after high-
dose or prolonged therapy, withdrawal should be
gradual, the rate depending upon the individual pa-
tient's response, the dose, the disease being treated.
and the duratiori of therapy. Recommendations for
initial reduction stated interms ofprednisolone,
have varied from as little as steps of I mg monthly
to 2.5 to 5 mg every 2 to 7 days. Provided the disease
is unlikely to relapse the dose of systemic corticos-
teroid may be reduced rapidly to physiological val-
ues; dose reduction should then be slower to allow
recovery of pituitary-adrenal function. Symptoms
attributable to over-rapid withdrawal should be
countered by resuming a higher dose and continuing
the reduction at a slower rate. The administration of
corticotrophin does not help to re-establish adrenal
responsiveness.
This gradual withdrawal of corticosteroid therapy
permits a return of adrenal function adequate for
daily needs, but .years may sometimes be required
for the return of function necessary to meet the
stress of infection, surgical operations, or trauma.
On such occasions patients with a history of recent
corticosteroid withdrawal should be protected by
means of supplementary corticosteroid therapy as
described under Precautions, below.
In the UK. the Committee on Safety of Medicines recom-
mends that moderate dosage with corticosteroids (up to
40 mg daily of prednisolone. or equivalent), for up to 3
weeks, may be stopped without tapering provided that the"
original disease is unlikely to relapse, although prophylactic
cover may be required for any stress within a week of finish-
ing the course.' However, it should be borne in mind that in-
dividuals vary widely in their response to corticosteroids and
their ability to tolerate withdrawal. Gradual withdrawal
should be considered, even after shorter courses, if higher
doses are given, or in patients with other risk factors for
adrenocortical insufficiency, including those who have had
repeated courses of systemic corticosteroids, those who re-
ceive a course within one year of finishing long-term corticos-
teroid therapy, or those who regularly take doses in the
evening, when their suppressive effect is greater. Withdrawal
should not be abrupt in any patient who receives systemic cor-
ticosteroids for more than 3 weeks.
How dose reduction is carried out depends largely on the like-
lihood of relapse of the original disease. If this is unlikely, the
dose of systemic corticosteroid may be reduced rapidly to
physiological values (traditionally considered to be 7.5 mg of
prednisolone daily or equivalent). It should then be reduced
more slowly to allow the hypothalamic-pituitary-adrenal axis
to recover.' Where disease relapse is a possibility even the
initial reduction may need to be more cautious. Long-term
treatment may require withdrawal over many months (such as
a reduction of I mg in the daily dose of prednisolone every 3
to 4 weeks).
In reviews of the inhibition of hypolfhalamic-pituitary-adren-
ocortical function associated with corticosteroid administra-
tion. further regimens for corticosteroid withdrawal are
described For example, patients who have been treated for
weeks or months may have their daily dose ofprednisolone
reduced by 2.5 to 5 mg every 2 or 3 days, or. for those on
longer-term treatment, the reduction may be more gradual at
a rate of 2.5 mg every I to 3 weeks and possibly less. When
the dose has reached 10 mg daily decrement* may be made
with I-mg tablets. Another approach may be to convert daily
therapy gradually into alternate-day therapy by progressively
reducing the amount of corticosteroid received on every sec-
ond day, and once alternate-day therapy is established the'
dose may be further reduced until, for example, a dose of
1 mg on alternate days for one week is attained.
Precautions for Corticosteroids
Corticosteroids should only be used systemically
with great caution in the presence of congestive
heart failure, recent myocardialinfarction, or hyper-
tension. in patients with diabetes mdlitus, epilepsy
(but see below for use in infantile seizures), glauco-
ma. hypothyroidism, liver~ilure, osteoporosis, pep-
tic ulceration, psychoses or severe affective"
disorders, and renal impairment. Children may be at
increased risk of some adverse effects; in addition,
corticosteroids may cause growth retardation, and
prolonged administration is rarely justified. The eld-
erly too may be at greater risk from adverse effects.
Corticosteroids are usually contra-indicated in the
presence of acute infections uncontrolled by appro-
priate antimicrobial chemotherapy. Similarly, pa-
tients already receiving corticosteroid therapy are
more susceptible to infection, the symptoms of
which, moreover, may be masked until an advanced
stage has been reached. Patients with active or
doubtfully quiescent tuberculosis should not be giv-
en corticosteroids except, very rarely, as adjuncts to
treatment with antitubercular drugs. Patients with
quiescent tuberculosis should be observed closely
and should receive chemoprophylaxis if corticoster-
oid therapy is prolonged.
The risks of chickenpox and probably of severe her-
pes zoster are increased in non-immune patients
receiving therapeutic doses of systemic cortico-
steroids, and patients should avoid close personal
contact with cither infection. Passive immunisation
is recommended for non-immune patients who do
come into contact with chickenpox. Similar precau-
tions apply to measles. Live vaccines should not be
given to patients receiving high-dose systemic
corticosteroid therapy nor for at least 3 months after-
wards; killed vaccines or toxoids may be given al-
though the response may be attenuated. _ ~.
During prolonged courses of corticosteroid therapy,,
patients should be examined regularly. Sodium in-
take may need to be reduced and calcium and potas-
sium supplements may be necessary. Monitoring of
the fluid intake and output, and daily weight records
may give early warning of fluid retention. Back pain
may signify oSteoporosis. Children are at special
risk from raised intracranial pressure. Patients
should carry cards (and preferably also wear brace-
lets) giving full details of their corticosteroid thera-
py; they and their relatives should be fully
conversant with the implications of their therapy and
the precautions to be taken.
Measures to compensate for the adrenals" inability
to respond to stress (see Withdrawal, above) include
increasing the dose to cover minor intercurrent ill-
nesses or trauma such as surgery (with intramuscu-
lar administration to cover vomiting). For details of
dosages used, see Uses and Administration, below.
Rapid intravenous injection of massive doses of cor-
ticosteroids may sometimes cause cardiovascular
collapse and injections should therefore be given
slowly or by infusion.
Many drugs have been reported to interfere with cer-
tain assay procedures for corticosteroids in body flu-
ids and corticosteroids themselves may interfere
with or alter the results of assays for some endog-
enous substances or drugs.
The risk of systemic absorption should always be
considered when applying corticosteroids topically.
They should not be applied with an occlusive dress-
ing to large areas of the body. Long-term topical use
is best avoided, especially in children. Also they
should not be used for the treatment of ulcerative
conditions, not of rosacea, and should notice used
. indiscriminately for pruritus. Occasionally they may
. be used with the addition of a suitable antimicrobial
substance in the treatment of infected ·skin but there"
is a risk of sensitivity reactions occurring.
Caution is required when corticosteroids are used
locally to treat eye disorders (see under Uses and
Administration,p.l021).
A report of two cases of cushing's syndrome-associated with
inappropriately prolonged use of corticosteroid nasal drops in
children.' Such drops should not be prescribed on a repeat
prescription basis. See also Adrenal Suppression, under Ad-
verse Effects, above. . ,..:
contraception. There are some isolated ciase'repbrts of
contraceptive failure in women using intra-uterine devices
and receiving corticosteroid therapy.
Porphyria. In a review of drug induced porphyrias and
comments on the conflicting evidence concerning corticoster-
oids it was noted that a report suggesting that corticosteroids
may have a role in treating the acute attack together with
many reports attesting to their safety, contrasted with their re-
peated incrimination as the offending agent in producing such
episodes. It was considered that as corticosteroids may be
life-saving, they should be used if really indicated. .
I. Moore MR. Disler PB. Drug-induction of the acute porphyrias.
Adverse Drug React Acute Poisoning Rev 1983: 2: 149-89.
Pregnmey and breast feeding Studies have shown that
corticosteroids administered to pregnant women did not have
adverse effects on the fetusin terms of psychological
development' or growth and general health factors' Howev- .
er, there has been an isolated report3 wherein the topical ad-
ministration of triamcinolone to a pregnant woman for
treatment of eczema was considered to have caused fetal
growth retardation. In another study"* of 11 women with pla-
centa praevia given intramuscular betamethasone 12 mg re-
peated 24 hours later, there were two cases of constriction of
the ductus aiteriosus: neither case was severe.
Early studies in animals have demonstrated an increase in fe*
tal cleft palate following maternal ingestion of high corticos-
teroid doses, and cortisone has been used widely a~ a tool for
the investigation of mechanisms responsible for cteft lip and
palate. With doses used in clinical practice, however, the risk
appears to be low. In an analysis of several hundred cases re-
ported in the literature5 it was concluded that the incidence of
cleft palate in exposed children was slightly higher than in a
random sample, but that in the small selected group studied,
this higher incidence might be fallacious. Although an in-
creased incidence of malformations in the children of asth-
matic mothers given prednisolone 2.5 to 30 mg daily during
pregnancy was noted," others' have suggested that the out-
come might have been worse in untreated asthmatic mothers.
Moreover, no significant increase in the risk of fetal or mater-
nal complications was found in a study of asthmatic mothers
given prednisolone 2.5 to 20 mg daily.8 More recently, no ev-
idence of a teratogenic effect for corticosteroids was. noted in
a comparison of the maternal drug histories of the mothers of
764 infants born with anomalies of the CNS and 764 con-
trols' and in another study to there were no striking differenc-
es in birth-weight and frequency of 'small for dates' infants
born to mothers who received systemic corticosteroids during
pregnancy for pemphigoid gestationis and those who did not.
Fears concerning the administration of corticosteroids during
late pregnancy relate to their direct adverse effects on the fe-
tus. These involve the known side-effects of corticosteroids,
such as increased risk of infection and adrenal insufficiency.
No such adverse effects were noted in the infants of 70 ex-
posed pregnancies' although there have been individual re-
ports. The potential dangers of maternal diabetogenic
effects have been demonstrated in a study of metabolic
changes induced in diabetic women by salbutamol (used in
the prevention of premature labour) which could be exacer-
bated by concomitant administration of dexamethasone (used
to promote maturation of the fetal lung) with consequent dan-
ger to the fetus.
A rtvicw'4 by the Committee on Safety of Medicines in the
.UK concluded that there was no convincing evidence that cor-
ticosteroids caused an increased incidence of corn enital ab-
normality. Prolonged or repeated administration during
pregnancy did increase the risk of intra-uterine
growth retardation but this did not seem to be a problem following
shortterm treattnent. It was noted that the ability of different corti-
costeroids to cross the placenta varied very markedly. It was
also remarked that sufficient prednisolone was distributed
into breast milk that infants of mothers receiving
40 mg or more daily should be monitored for signs of adrenal
suppression: it was not known if this applied to other conicos-
teroids.
Septic shock. Some manufacturers recommend that corri-
cosleroids should not be given to patients with septic shock:
for references to the controversial use of high-dose corticos-
teroids in septic shock see under Septic Shock, in Uses and
Administration, below.
Sickle-cell disease. Sickle-ceir crisis was reported to'have
been precipitated by conicosteroids in 2 patients with sickle
C disease.' The crises in these patients were considered to
have started with ischaemic necrosis of the bone marrow
leading to fat embolism, cerebral hypoxia. and coma.
For mention of the use of conicosteroids in sickle-cell crisis
see under Sickle-cell Disease, in Uses and Administration.
below.
1. Huang JC. el at. Sideling crisis, fat embolism, and coma after
steroids. Lancet F994: 344: 951-2.
Tooth erosion. The increased incidence of tooth erosion
seen in patients with asthma might be related to the pH of
inhaled powder (but not aerosol) formulations.' Beclometha-
sone dipropionate and fluticasone had pHs of 4.76 as powder'
formulations, whereas the aerosols were well above the pH of
5.5 at which tooth substance begins to dissolve. Budesonide
was less acidic in its powder formulation (pH 6.47).
i. O'Sullivan EA. Cur7.on MEJ. Drug treatments for asthma may
cause erosive tooth damage. Br Modi 1998: 317: 820.
Varicella. A number of cases ot fatal or near fatal chicken-
pox have been reported in patients receiving conicoster-
oids.Although mostly associated with systemic use. severe
disseminated varicella and siaphylococcal pericarditis have-
been reported in an intani following a single application of a
potent topical corticosteroid cream.Guidelines issued by the
UK Committee on Safety of Medicines state that all patients
taking systemic corticosteroids for purposes other than re-
placement, and who have not had chickenpox. should be re-
garded as being at risk. irrespective of the dose or duration of
treatment.Passive immunisation with varicella-zoster im-
munoglobulin should be given to non-immune patients who
are receiving corticosteroids. or who have received them
within the last 3 months, if they are exposed to chickenpox.
Passive immunisation should preferably be given within 3
days and not later than 10 days from exposure.
Interactions
Concurrent administration of barbiturates,car
bamazepine, phenytoin, primidone,or rifampicin
may enhance the metabolism and reduce the effects
of corticosteroids. Concurrent administration of cor-
ticosteroids with potassium-depleting diuretics,.
such as thiazides or frusemide.may cause excessive
potassium loss. There may be an increased inci-
dence of gastro-iniestinal bleeding and ulceration
when corticosteroids are given with NSAIDS.Response to
anticoagulants may be altered by corticos-
teroids and requirements of antidiabetic agents and
antihypertensives may be increased. Corticosteroids
may decrease serum concentrations, of salicylates
and may decrease the effect of antimuscarinics in..
myastheniagravis.
Analgesics. For the effect otcoHicosteroids on salicylates
•seeAspirin.
Antibacterials-'Rifampicin reduces the activity-of -
corticosteroids by accelerating their metabolism, and a
similar effect would be expected with other rifamycins. There
is limited evidence that the macrolide antibacterials triacetyl-
oleandomycin and perhaps erythromycin may inhibit
the metabolism of methylprednisolone,but not,of,prednisolo-
ne.Dosage reduction should be carried out as necessary if
triacetyloleandomycin and methylprednisolone are used con-
currently. There is no evidence of a clinically significant in-
teraction between these macrolides and other corticosteroids.
For reference-to corticosteroids lowering plasma concentia-
tions of isoniazid and enhancing its renal clearance, see
Anticoagulants. For the various effects of corticosteroids
on anticoagulants, see under Warfarin Sodium.
Antiepileptics. Reduced efficacy of corticosteroids hag-
been noted in asthmatic, arthritic, renal transplant, and other
patients who also received phenytoin or phenobarbitone.'"
and the clearance Of corticosteroids has also been reported to
be markedly increased by concurrent administration of car-
bamazepine.Induction ofmicrosomal liver enzymes by the-
antiepileptic drug, resulting in enhanced metabolism of the
corticosteroid is believed to be the underlying mechanism.
Different corticosteroids appear to be affected to different de- .
grees, but the disease state, doses, and other determinants
such as diet. sex. and other drugs administered may also be
contributory factors. An increase in the dosage of the corti-
costeroids may be necessary in order to maintain the desired
therapeutic response. '
Antlfungal. Ketoconazole increases serum methyl prednisolone
concentrations and enhances methylprednisolone's .
adrenal suppressive effects.A 50% reduction in intrave-
nous methylprednisolone dose was suggested during con-'
comitant ketoconazole therapy.' A similar effect was not
evident when prednisone was given by mouth' although some
workers' found that ketoconazole reduced the total clearance
of prednisolone given intravenously and of prednisone given
by mouth.
Antineoplastics and immunosuppressants .It has been
suggested that mutual inhibition ot metabolism occurs be-
tween evelosoorin and corticosteroids. and mav increase the
plasma concentrations of either drug.A reviewJ cited stud-
ies supporting this conclusion but also mentioned studies
which showed that cyclosporin did not significantly decrease
clearance of prednisolone and tharcorticosteroids did not -
change or decreased cyclosporin concentrations.Some of
these conflicting results may be due to differences in the
methods used to measure cycl6sporin concentrations.
For reference to single doses of prednisone inhibiting the ac-
tivation of cyclophosphamide (but longer-term treatment in-
-creasing its activation).
Antivirals. As mentioned under lndinavir, it is sug-
gested that corticosteroids such as dexamethasone and pred-
nisolone may reduce plasma concentrations of HIV-protease
inhibitors, and corticosteroid plasma concentrations may in .
turn be increased.
Lipid regulating drugs. Addition ofcolestipol to the thera-
py of a patient with hypopituitarism receiving maintenance
therapy with hydrocortisone resulted in headaches, ataxia.
and lethargy.Mental status returned to normal within hours
of an intravenous dose of hydrocortisone 100 mg. and
colesfipol was subsequently withdrawn uneventfully.
Neuromuscular blockers. For reference to corticoStero'ids
antagonising the neuromuscular blocking effects of pancuro-
nium. see under Atracurium, p. 1306.
Sex hormones. Reviews discussing several reports of an
enhanced effect of corticosteroids in women also receiving
oestrogens or oral contraceptives and commenting that the
dose of corticosteroids in some cases may need to be reduced.
Smoking. There was a report of an appreciable and consist-
ent increase in plasma corticosteroids after cigarette smoking
in man.' However, a review concerning the clinical impor-
tance of smoking and drug interactions' concluded that in the
majorityofexamples.includingcorticosteroids.therewaslit-.
tie evidence of a recognisable hazard from the interaction.
Sympathomimetics. Studies in 21 asthmatic patients sus-
gested that the plasma half-life of dexamethasone was de-
creased when it was administered with ephedrine,' More
significantly, concomitant administration of corticosteroids
with beta2-adrenoceptor stimulants may potentiate any hy-
pokalaemic effects.'
Thalldomide. In a double-blind crossover ftudy of thalido-
mide in the treatment of severe chronic erythema nodosum
leprosum,' the dose of prednisolone necessary to suppress
symptoms was considerably reduced in 9 of 10 patients while
they were receiving thalidomide 300 mg daily and there has
been a comment that prednisolone should not be given with
thalidomide.
XANTHINES : For the effects of corticosteroids on theophylline,
see under theophylline.
Corticosteroids, are, ingeneral, readily absorbed
from the gastroiintestinal tract. They are also ab-
sorbed from sites of local administration. When ad-
ministered by topical application, particularly under
an occlusive dressing or when the skin is broken, or
as a rectal enema, sufficient corticosteroid may be
absorbed to give systemic effects: this is also a pos-
sibility with other local routes of administration
such as inhalation. Water-soluble forms of corticos-
teroids are given by intravenous injection for a rapid
response; more prolonged effects are achieved using
lipid-soluble forms of corticosteroids by intramus-
cular injection.
Corticosteroids are rapidly distributed to all body
tissues. They cross the placenta and may be excreted
in small amounts in breast milk. .
Most corticosteroids in the circulation are extensive-
ly bound to plasma proteins, mainly to globulin and
less so to albumin. The corticosteroid-binding glob-
ulin (transcortin) has high affinity but low binding
capacity, while the albumin has low affinity but large
binding capacity. The synthetic corticosteroids are
less extensively protein bound than hydrocortisone
(cortisol). They also tend to have longer half-lives.
Corticosteroids are metabolised mainly in the liver
but also in other tissues, and are excreted in the
urine. The slower metabolism of the synthetic corti-
costeroids with their lower protein-binding affinity
may account for their increased potency compared
with the natural corticosteroids.