Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 35) doc

Adrenal corticosteroids, antagonists, corticotropin SYNOPSIS • Adrenocortical steroids and their synthetic analogues Mechanisms of action Actions: mineralocorticoid, glucocorticoid Indiv

SYSTEM, METABOLIC CONDITIONS

Adrenal corticosteroids,

antagonists, corticotropin

SYNOPSIS

• Adrenocortical steroids and their synthetic

analogues

Mechanisms of action

Actions: mineralocorticoid, glucocorticoid

Individual adrenal steroids

Pharmacokinetics

Dosage schedules

Choice of adrenal steroid

Adverse effects of systemic

pharmacotherapy

Adrenal steroids and pregnancy

Precautions during chronic therapy:

treatment of intercurrent illness

Dosage and routes of administration

Indications for use

Uses: replacement therapy, pharmacotherapy

Withdrawal of pharmacotherapy

• Inhibition of synthesis of adrenal steroids

• Competitive antagonism

• Adrenocorticotrophic hormone (ACTH)

(corticotropin)

In 1855, Dr Thomas Addison, assisted in his

obser-vations by three colleagues, published his famous

monograph 'On the constitutional effects of disease

on the suprarenal capsules' (Addison's disease) It

was not until the late 1920s that the vital

im-portance of the adrenal cortex was appreciated and

the distinction between the hormones secreted by

the cortex and medulla

By 1936, numerous steroids were being crys-tallised from cortical extracts, but not enough could

be obtained to provide supplies for clinical trial

In 1948 cortisone was made from bile acids in

quantity sufficient for clinical trial, and the dramatic demonstration of its power to induce remission of rheumatoid arthritis was published the following year In 1950 it was realised that cortisone was biologically inert and that the active natural

hormone is hydrocortisone (cortisol) Since then an

embarrassingly large number of synthetic steroids has been made and offered to the clinician They are derived from natural substances (chiefly plant sterols), the constitutions of which approach most nearly to that of the steroids themselves A principal aim in research is to produce steroids with more selective action than hydrocortisone, which induces

a greater variety of effects than desired in any patient who is not suffering from adrenal insufficiency About the same time as cortisone was

intro-duced, corticotropin became available for clinical

use

Adrenal steroids and their synthetic analogues

Hormones normally produced by the adrenal cortex include hydrocortisone (cortisol) and some androgens and oestrogens, the synthesis and release of which is controlled by the

hypothalamic-pituitary system, and aldosterone, whose

bio-synthesis is largely dependent on the

renin-angiotensin system

Numerous analogues have been made in which

the major actions have been separated

When the adrenal cortex fails (Addison's disease)

adrenocortical steroids are available for replacement

therapy, but their chief use in medicine is for their

anti-inflammatory and immunosuppressive effects

(pharmacotherapy) These are obtained only when

the drugs are given in doses far above those needed

for physiological replacement Various metabolic

effects, which are of the greatest importance to the

normal functioning of the body, then become

adverse effects Much successful effort has gone

into separating glucocorticoid from mineralocorticoid

effects1 and some steroids, e.g dexamethasone,

have virtually no mineralocorticoid activity But it

has not yet proved possible to separate the

gluco-corticoid effects from each other, so that if a steroid

is used for its anti-inflammatory action the risks,

e.g of osteoporosis, diabetes, remain

In the account that follows, the effects of

hydro-cortisone will be described and then other steroids

in so far as they differ In the context of this chapter

'adrenal steroid' means a substance with

hydro-cortisone-like activity Androgens are described in

Chapter 37

MECHANISM OF ACTION

Glucocorticoids diffuse into the cell but access to

the receptor may be prevented, for example in

kidney, by the enzyme 11-beta hydroxysteroid

dehydrogenase, which converts active cortisol into

inactive cortisone When activated, the receptors

translocate to the nucleus where they can

upregu-late gene transcription by dimerising on specific

DNA response elements and recruiting co-activator

proteins, but can also oppose other transcription

factor function, for example NFicB and AP-1, by

protein-protein interaction The anti-inflammatory

actions of glucocorticoids are mediated mainly by

this latter mechanism, suggesting that one day

drugs may be found which have the beneficial

1 The mere introduction of a double bond transforms

hydrocortisone to prednisolone, a big biological change: see

Table 34.1 for relative potencies 1.0:1.0 to 4:0.8.

effects of steroids with less of the undesired properties

Glucocorticoids inhibit pathways that normally lead to production of prostaglandins, leukotrienes and platelet activating factor These mediators would normally contribute to increased vascular permeability and subsequent changes including oedema, leucocyte migration, fibrin deposition

ACTIONS OF HYDROCORTISONE

Plainly, there is a distinction between replacement therapy (physiological effects) and the higher doses

of pharmacotherapy

On inorganic metabolism (mineralocorticoid effects): increased retention of sodium by the renal

tubule, and increased potassium excretion in the urine

On organic metabolism (glucocorticoid effects):

• Carbohydrate metabolism: gluconeogenesis is

increased and peripheral glucose utilisation (transport across cell membranes) may be decreased (insulin antagonism) so that hyperglycaemia and sometimes glycosuria result Latent diabetes becomes overt

• Protein metabolism: anabolism (conversion of

amino acids to protein) is decreased but catabolism continues unabated or even faster, so that there is a negative nitrogen balance with muscle wasting Osteoporosis (reduction of bone protein matrix) occurs, growth slows in children, the skin atrophies and this, with increased capillary fragility, causes bruising and striae Healing of peptic ulcers or of wounds is delayed,

as is fibrosis

• Fat deposition: this is increased on shoulders, face

and abdomen

• Inflammatory response is depressed, regardless of

its cause, so that as well as being of great benefit

in 'useless' or excessive inflammation, corticosteroids can be a source of danger in infections by limiting useful protective inflammation Neutrophil and macrophage function are depressed, including the release of chemical mediators and the effects of these on capillaries

• Allergic responses are suppressed The

antigen-antibody interaction is unaffected, but

its injurious inflammatory consequences do not

follow

• Antibody production is reduced by heavy

doses

• Lymphoid tissue is reduced (including leukaemic

lymphocytes)

• Renal excretion of urate is increased.

• Blood eosinophils are reduced in number.

• Euphoria or psychotic states may occur, perhaps

due to CNS electrolyte changes

• Anti-vitamin D action, see calciferol (p 738).

• Reduction of hypercalaemia chiefly where this

is due to excessive absorption of calcium

from the gut (sarcoidosis, vitamin D

intoxication)

• Urinary calcium excretion is increased and renal

stones may form

• Growth reduction where new cells are being

added (growth in children), but not where they

are replacing cells as in adult tissues

• Suppression ofhypothalamic/pituitary/adrenocortical

feedback system (with delayed recovery) occurs

with chronic use, so that abrupt withdrawal

leaves the patient in a state of adrenocortical

insufficiency

Normal daily secretion of hydrocortisone is 10-30 mg The exogenous daily dose that com-pletely suppresses the cortex is hydrocortisone 40-80 mg, or prednisolone 10-20 mg, or its equi-valent of other agents Recovery of function is quick after a few days' use; but when used over months recovery takes months A steroid-suppressed adrenal continues to secrete aldosterone

INDIVIDUAL ADRENAL STEROIDS

The relative potencies2 for glucocorticoid and mineralocorticoid (sodium-retaining) effects which are shown in Table 34.1 are central to the choice of agent in relation to clinical indication

All drugs in Table 34.1 except aldosterone are active when swallowed, being protected from hepatic first-pass metabolism by high binding to

2 Potency (the weight of drug in relation to its effect) rather

than efficacy (strength of response): see page 94 If a large

enough dose of a glucocorticoid, e.g prednisolone, were administered, the Na + -retention would be almost as great as that caused by a mineralocorticoid This is why, in practice, different (more selective, and potent) glucocorticoids, not higher doses of prednisolone, need to be used when maximal stimulation of glucocorticoid receptors is desired (e.g in the treatment of acute transplant rejections).

TABLE 34 1 Relative potencies of adrenal steroids

Compound

(tablet strength, mg)

Cortisone (25)

Hydrocortisone (20)

Prednisolone (5)

Methylprednisolone (4)

Triamcinolone (4)

Dexamethasone (0.5)

Betamethasone (0.5)

Fludrocortisone (0 1 )

Aldosterone none

Approximate relative potency

Anti-inflammatory (glucocorticoid) effect

0.8 1.0 4 5 5 30 30 15 none

Sodium-retaining (mineralocorticoid) effect

1.0 1.0 0.8 minimal none minimal negligible 150

500 3

Equivalent 1 dosage (for anti-inflammatory effect, mg) 2

25 20 5 4 4

0.75 0.75

irrelevant irrelevant

1 Note that these equivalents are in approximate inverse accord with the tablet strengths.

2 The doses in the final column are in the lower range of those that may cause suppression of the hypothalamic/pituitary/adrenocortical axis when given daily continuously Much higher doses, e.g prednisolone 40 mg, can be given on alternate days or daily for up to 5 days without causing clinically significant suppression.

3 Injected.

plasma proteins Some details of preparations and

equivalent doses are given in the table Injectable

and topical forms are available (creams,

supposi-tories, eye drops)

The selectivity of hydrocortisone for the

gluco-corticoid receptor is not due to a different binding

affinity of hydrocortisone to the two receptors but

to the protection of the mineralocorticoid receptor

by locally high concentrations of the enzyme 11

(3-hydroxysteroid dehydrogenase, which converts

cortisol (hydrocortisone) to the inactive cortisone

This enzyme is inhibited by one of the components

of liquorice, and can occasionally harbour a genetic

defect Therefore both acquired (in liquorice addicts)

and inherited syndromes of

'pseudohyperaldo-steronism' can occasionally occur

Hydrocortisone (cortisol) is the principal naturally

occurring steroid; it is taken orally; a soluble salt

can be given i.v for rapid effect in emergency

(whether due to deficiency, allergy or inflammatory

disease) A suspension (Hydrocortisone Acetate

Inj.) can be given intra-articularly

Parenteral preparation for systemic effect: the

soluble Hydrocortisone Sodium Succinate Inj is

used for quick (1-2 h) effect; for continuous effect

about 8-hourly administration is appropriate

Prednisolone Acetate Inj i.m is an alternative, once

or twice a week

Oral tablet strengths, see Table 34.1.

Prednisolone is predominantly anti-inflammatory

(glucorticoid), biologically active, and has little

sodium-retaining activity; it is the standard choice

for anti-inflammatory pharmacotherapy, orally or

i.m

Prednisone is a prodrug, i.e it is biologically inert

and converted into prednisolone in the liver Since

there is 20% less on conversion there seems to be no

point in using it

Methylprednisolone is similar to prednisone;

it is used i.v for megadose pulse therapy (see

below)

Fluorinated corticosteroids: triamcinolone has

virtually no sodium retaining (mineralocorticoid)

effect but has the disadvantage that muscle wasting

may occasionally be severe and anorexia and mental depression may be more common at high dose

Dexamethasone and betamethasone are similar, powerful predominantly anti-inflammatory steroids They are longer-acting than prednisolone and are used for therapeutic adrenocortical suppression Fludrocortisone has a very great sodium-retaining effect in relation to its anti-inflammatory action, and only at high doses need the nonelectrolyte effects

be considered It is used to replace aldosterone where the adrenal cortex is destroyed (Addison's disease) Fludrocortisone is also the drug of choice

in most patients with autonomic neuropathy, in

whom volume expansion is easier to achieve than a sustained increase in vasoconstrictor tone Much higher doses of fludrocortisone (0.5-1.0 mg) are required when the cause of hypotension is a salt-losing syndrome of renal origin, e.g following an episode of interstitial nephritis

Aldosterone (t l / 2 20 min), the principal natural salt-retaining hormone, has been used i.m in acute adrenal insufficiency After oral administration,

it is rapidly inactivated in the first pass through the liver but has no place in routine therapeutics,

as fludrocortisone is as effective and is active orally

Spironolactone (see p 534) is a competitive aldosterone antagonist which also blocks the mineralocorticoid effect of other steroids; it is used

in the treatment of primary hyperaldosteronism and as

a diuretic, principally when severe oedema is due

to secondary hyperaldosteronism, e.g cirrhosis,

con-gestive cardiac failure

Beclomethasone and budesonide are used by inhalation for asthma (see p 561) About 90% of an inhalation dose is swallowed and these steroids are inactivated by hepatic first-pass; the rest, absorbed from the mouth and lungs, gives very low systemic plasma concentration The risk of suppression of the hypothalamic/pituitary/adrenal axis is thus minimal (but it can happen) This property of extensive hepatic first-pass metabolism with low systemic availability is also an advantage in the

topical treatment of inflammatory bowel disease

with minimal risk of systemic adverse effects

PHARMACOKINETICS OF

CORTICOSTEROIDS

Absorption of the synthetic steroids given orally is

rapid The t1// in plasma of most is 1-3 h but the

maximum biological effect occurs after 2-8 h

Administration is usually 2 or 3 times a day They

are metabolised principally in the liver (some

undergoing hepatic first-pass metabolism, see

above) and some are excreted unchanged by the

kidney The i l / 2 is prolonged in hepatic and renal

disease and is shortened by enzyme induction to an

extent that can be clinically important

Topical application (skin, lung, joints) allows

absorption which can be enough to cause systemic

effects

In the blood, adrenal steroids are carried in the

free (biologically active) form (5%) and also bound

(95% in the case of hydrocortisone) to transcortin (a

globulin with high affinity, but low binding

capacity) and, when this is saturated, to albumin

(80% in the case of hydrocortisone) The

concen-tration of transcortin is increased by oestrogens, e.g

pregnancy, hormonal contraception, other oestrogen

therapy; if these substances are taken, the total

plasma hydrocortisone will be found to be raised,

but the amount of free hydrocortisone may be

normal, being controlled by the physiological

feed-back mechanism Patients may be wrongly

sus-pected of having Cushing's syndrome if the fact

that they are taking oestrogen is unrecognised and

only the total is measured (as is usual)

In patients with very low serum albumin, steroid

doses should be lower than usual owing to the

reduced binding capacity In addition, low albumin

concentration may be caused by liver disease,

which also augments the effects of steroids by

delaying metabolism (i l / 2 of prednisolone may be

doubled)

DOSAGE SCHEDULES

Various spaced-out schedules have been used in the

aspiration of reducing hypothalamic/pituitary/

adrenal (HPA) suppression by allowing the plasma

steroid concentration to fall between doses to

pro-vide time for pituitary recovery, e.g prednisolone

40 on alternate days But none has been successful

in both completely avoiding suppression and at the same time controlling symptoms The following are examples:

• Where a single daily dose is practicable it should

be given in the early morning (to coincide with the natural activation of the HPA axis)

• Alternate day schedules are worth using, especially

where immunosuppression is the objective (organ transplants) rather than anti-inflammatory effect (rheumatoid arthritis)

• Short courses (a few days) may be practicable for

some conditions without significant suppression, e.g acute asthma of moderate severity

• Another variant is to give enormous doses (grams,

not mg), orally or i.v., e.g methylprednisolone 1.0 g i.v on 3 successive days, at intervals of weeks

or months (megadose pulses) The technique is used particularly in collagen diseases

• For oral replacement therapy in adrenocortical

insufficiency, hydrocort/sone should be used to supply glucocorticoid and some mineralocorticoid activity In Addison's disease a small dose of a hormone with only

mineralocorticoid effect (fludrocortisone) is normally

needed in addition Prednisolone on its own is not effective replacement therapy.

• For anti-inflammatory and antiallergic

(immunosuppressive) effect, prednisolone,

triamdnolone or dexamethasone It is not possible to

rank these in firm order of merit One or other may suit an individual patient best, especially as regards incidence of adverse effects such as muscle wasting By

inhalation: beclomethasone or budesonide.

• For hypothalamic/pituitary/adrenocortical suppression, e.g in adrenal hyperplasia, prednisolone

or dexamethasone.

ADVERSE EFFECTS OF SYSTEMIC ADRENAL STEROID

PHARMACOTHERAPY

These consist largely of too intense production of the physiological or pharmacological actions listed under actions of hydrocortisone Some occur only with systemic use and for this reason local therapy, e.g inhalation, intra-articular injection, is preferred where practicable

Unwanted effects generally follow prolonged

administration and virtually do not occur with 1 or

2 doses though some occur with a few days' use,

e.g spread of infection The undesired effects

recounted below should never be experienced in

replacement therapy, but are sometimes

unavoid-able when the steroid is used as pharmacotherapy

Obviously, the nature of unwanted effects depends

on the choice of steroid Fludrocortisone

(mineralo-corticoid) in ordinary doses does not cause

osteo-porosis and prednisolone (glucocorticoid) does not

normally cause oedema

In general, serious unwanted effects are unlikely

if the daily dose is below the equivalent of

hydro-cortisone 50 mg or prednisolone 10 mg

The principal adverse effects of chronic

cortico-steroid administration are:

Endocrine To greater or lesser degree features of

Cushing's syndrome result in moon face,

charac-teristic deposition of fat on the body, oedema,

hypertension, striae, bruising, acne, hirsutism

Major skin damage can result from minor injury

of any kind Diabetes mellitus may appear.

Hypothalamic/pituitary'/adrenal (HPA) suppression is

dependent on the corticosteroid used, its dose,

duration and the time of administration A single

morning dose of less than 20 mg of prednisolone

may not be followed by suppression, whereas a

dose of 5 mg given late in the evening is likely to

suppress the essential early morning activation of

the HPA axis (circadian rhythm) Substantial

suppression of the HPA axis can occur within a

week (but see Withdrawal of steroid therapy,

below)

Musculoskeletal Proximal myopathy and tendon

rupture may occur Osteoporosis develops insidiously

leading to fractures of vertebrae, ribs, femora and

feet Pain and restriction of movement may occur

months in advance of radiographic changes A

biphosphonate, with or without vitamin D, is useful

for prevention and treatment Growth in children is

impaired A vascular necrosis of bone (femoral heads)

is a serious complication (at higher doses); it

appears to be due to restriction of blood flow

through bone capillaries

Immune Suppression of the inflammatory response to

infection and immunosuppression causes some

patients to present with atypical symptoms and signs and quickly to deteriorate The incidence of infection is increased with high dose therapy, and any infection can be more severe when it occurs

Candidiasis may appear, particularly in the

alimen-tary tract Previously dormant tuberculosis may

become active insidiously Intra-articular injections

demand the strictest asepsis Live vaccines become dangerous Developing chickenpox may result in a

severe form of the disease and patients who have not

had chickenpox should receive varicella-zoster immune globulin within 3 days of exposure

Similarly, exposure to measles should be avoided.

Gastrointestinal Patients taking continuous steroid, especially in combination with a nonsteroidal anti-inflammatory drug (NSAID), have an excess

inci-dence of peptic ulcer and haemorrhage of about 1-2%.

It is plainly unreasonable to seek to protect all such patients by routine prophylactic antiulcer therapy, i.e to treat 98 patients unnecessarily in order to help two But such therapy (proton pump inhibitor, histamine H2-receptor blocker, sucralfate) is appropriate when ulcer is particularly likely, e.g a patient with rheumatoid arthritis taking an NSAID,

or for patients with a history of peptic ulcer disease

There is increased incidence of pancreatitis.

Central nervous system Depression and psychosis

can occur during the first few days of high dose administration, especially in those with a history of

mental disorder Other effects include euphoria,

insomnia, and aggravation of schizophrenia and epilepsy Long-term treatment may result in raised intracranial pressure with papilloedema, especially in

children

Ophthalmic effects may include posterior

sub-capsular lens cataract (risk if dose exceeds

pred-nisolone 10 mg/day or equivalent for above a year),

glaucoma (with prolonged use of eye drops), and corneal or scleral thinning.

Other effects include menstrual disorders, delayed tissue healing (including myocardial rupture after myocardial infarction), thromboembolism, and paradoxically, hypersensitivity reactions including anaphylaxis

ADRENAL STEROIDS AND

PREGNANCY

Adrenal steroids are teratogenic in animals

Although a relationship between steroid

pharmaco-therapy and cleft palate and other fetal

abnor-malities has been suspected in man, there is no

doubt that many women taking a steroid

through-out have both conceived and borne normal babies

Adrenal insufficiency due to hypothalamic/

pituitary suppression in the newborn occurs only

with high doses to the mother Dosage during

pregnancy should be kept as low as practicable and

fluorinated steroids are best avoided as they are

more teratogenic in animals (dexa- and

beta-methasone, triamcinolone and various topical

steroids, e.g fluocinolone) Hypoadrenal women

who become pregnant may require an increase in

hydrocortisone replacement therapy by about 10

mg per day to compensate for the increased binding

by plasma proteins that occurs in pregnancy

Labour should be managed as described for major

surgery (below)

PRECAUTIONS DURING CHRONIC

ADRENAL STEROID THERAPY

The most important precaution during replacement

and pharmacotherapy is to see the patient regularly

with an awareness of the possibilities of adverse

effects including fluid retention (weight gain),

hypertension, glycosuria, hypokalaemia (potassium

supplement may be necessary) and back pain

(osteoporosis); and of the serious hazard of patient

noncompliance

Mild withdrawal symptoms (iatrogenic cortical

insufficiency) include conjunctivitis, rhinitis, weight

loss, arthralgia and itchy skin nodules

Patients must always

• carry a card giving details of therapy

• be impressed with the importance of compliance

• know what to do if they develop an intercurrent

illness or other severe stress: double their next

dose and to tell their doctor If a patient omits a

dose then it should be made up as soon as

possible so that the total daily intake is

maintained, because every patient should be

taking the minimum dose necessary to control the disease

Treatment of intercurrent illness

The normal adrenal cortex responds to severe stress

by secreting more than 300 mg/day of cortisol Intercurrent illness is stress and treatment is urgent,

particularly of infections; the dose of corticosteroid

should be doubled during the illness and gradually reduced as the patient improves Effective chemo-therapy of bacterial infections is specially important

Viral infections contracted during steroid therapy

can be overwhelming because the immune response

of the body may be largely suppressed This is par-ticularly relevant to immunosuppressed patients exposed to varicella/herpes zoster virus, which may cause fulminant illness; they may need passive protection with varicella/zoster immunoglobulin, VZIG, as soon as practicable Continuous use of prednisolone 20 mg/day (or the equivalent) is immunosuppressive But a corticosteroid may sometimes be useful in therapy after the disease has begun (thyroiditis, encephalitis) and there has been time for the immune response to occur It then acts

by suppressing unwanted effects of immune responses and excessive inflammatory reaction

Vomiting requires parenteral administration.

In the event of surgery being added to that of

adrenal steroid therapy the patient should receive hydrocortisone 100-200 mg i.m or i.v with pre-medication If there is any sign suggestive that the patient may collapse, e.g hypotension, during the operation, i.v hydrocortisone (100 mg) should be infused at once Otherwise, if there are no compli-cations, the dose is repeated 6-hourly for 24-72 h and then reduced by half every 24 h until normal dose level is reached

Minor operations, e.g dental extraction, may be covered by hydrocortisone 20 mg orally 2-4 h before operation and the same dose afterwards

In all these situations an i.v infusion should be available for immediate use in case the above is not enough These precautions should be used in patients who have received substantial treatment with corticosteroid within the past year, because their hypothalamic/pituitary/adrenal system, though sufficient for ordinary life, may fail to respond adequately to severe stress If steroid

therapy has been very prolonged, these precautions

should be taken for as long as 2 years after stopping

it This will mean that some unnecessary treatment

is given, but collapse due to acute adrenal

insufficiency can be fatal and the ill-effects of

short-lived increased dosage of steroid are less grave,

being confined to possible increased incidence and

severity of infection

DOSAGE AND ROUTES OF

ADMINISTRATION

Dosage depends very much on the purpose for

which the steroid is being used and on individual

response There is no single schedule that will suit

every case but examples appear below

Systemic commencing doses

• For a serious disease such as systemic lupus,

dermatomyositis: prednisolone up to 0.75-2.0

mg/kg/d orally in divided doses

• If life-threatening, prednisolone up to 70 mg, or its

equivalent of another steroid The dose is then

increased if necessary until the disease is

controlled or adverse effects occur; as much as

prednisolone 2-3 mg/kg/d can be needed

Cyclophosphamide or azathioprine (see p 292)

are valuable adjuncts; they may enhance the

initial control of the disease and have a sparing

effect on the maintenance dose of prednisolone

required

• More usually now, megadose pulses

(methylprednisolone 1.0 g i.v daily for 3 days)

are used, followed by oral maintenance with

prednisolone and/or a steroid-sparing agent

(above)

• For less dangerous disease, such as rheumatoid

arthritis: prednisolone 7.5-10.0 mg daily,

adjusted later according to the response

• In some special cases, including replacement of

adrenal insufficiency, dosage is given in the

account of the treatment of the disease

• For continuous therapy the minimum amount to

produce the desired effect must be used

Sometimes imperfect control must be accepted

by the patient because full control, e.g of

rheumatoid arthritis, though obtainable,

involves use of doses that must lead to

long-term toxicity, e.g osteoporosis, if

continued for years The decision to embark on such therapy is a serious matter for the patient

Topical applications (creams, intranasal, inhalations,

enemas) are used in attempts, often successful, to obtain local, whilst avoiding systemic, effects; suspensions of solutions are also injected into joints, soft tissues and subconjunctivally All these can, with heavy dose, be sufficiently absorbed to suppress the hypothalamus and cause other unwanted effects Individual preparations are mentioned in the text where appropriate

The relatively high selectivity of inhaled

bec-lomethasone in asthma is due to a combination of

route of administration, high potency and rapid conversion to inactive metabolites by the liver of any drug that is absorbed (see asthma, skin); but yet hypothalamic/pituitary suppression and systemic toxicity occasionally occur

Contraindications to the use of adrenal steroids for

suppressing inflammation are all relative, depend-ing on the advantage to be expected They should

be used only for serious reasons if the patient has: diabetes, a history of mental disorder or peptic ulcer, epilepsy, tuberculosis, hypertension or heart failure The presence of any infection demands that effective chemotherapy be begun before the steroid, but there are exceptions (some viral infections, see above) Topical corticosteroid applied to an inflamed eye (with the very best of

intention) can be disastrous if the inflammation is

due to herpes virus

Steroids containing fluorine (see above) intensify diabetes more than others and so should be avoided in that disease

Long-term use of adrenal steroids in children

presents essentially the same problems as in adults except that growth is retarded approximately in proportion to the dose This is unlikely to be impor-tant unless therapy exceeds 6 months; there is a spurt of growth after withdrawal Intermittent dosage schedules (alternate day) may reduce the risk (rarely, corticotropin may be preferred, see p 675) Some other problems loom larger in children than in adults Common childhood viral infections may be more severe, and if a nonimmune child