Tài liệu CLINICAL PHARMACOLOGY 2003 (PART 35) doc

SECTION ENDOCRINE SYSTEM, METABOLIC CONDITIONS This page intentionally left blank 34 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 observations 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 importance of the adrenal cortex was appreciated and the distinction between the hormones secreted by the cortex and medulla By 1936, numerous steroids were being crystallised 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 introduced, 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 hypothalamic663 34 A D R E N A L C O RT I C O S T E R O I D S , A N TA G O N I S T S , C O RT I C O T R O P I N pituitary system, and aldosterone, whose biosynthesis is largely dependent on the reninangiotensin 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 glucocorticoid 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 hydrocortisone 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 hydrocortisone-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 upregulate 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 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 4:0.8 664 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 ADRENAL STEROIDS AND THEIR SYNTHETIC ANALOGUES • Allergic responses are suppressed The antigen-antibody interaction is unaffected, but its injurious inflammatory consequences 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 TABLE 34 34 Normal daily secretion of hydrocortisone is 10-30 mg The exogenous daily dose that completely suppresses the cortex is hydrocortisone 40-80 mg, or prednisolone 10-20 mg, or its equivalent 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 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) Relative potencies of adrenal steroids Compound (tablet strength, mg) Cortisone Hydrocortisone Prednisolone Methylprednisolone Triamcinolone Dexamethasone Betamethasone Fludrocortisone Aldosterone (25) (20) (5) (4) (4) (0.5) (0.5) (0 ) none Approximate relative potency Anti-inflammatory (glucocorticoid) effect Sodium-retaining (mineralocorticoid) effect Equivalent1 dosage (for anti-inflammatory effect, mg)2 0.8 1.0 5 30 30 15 none 1.0 1.0 0.8 minimal none minimal negligible 150 5003 25 20 4 0.75 0.75 irrelevant irrelevant Note that these equivalents are in approximate inverse accord with the tablet strengths 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 days without causing clinically significant suppression Injected 665 34 A D R E N A L C O RT I C O S T E R O I D S , A N TA G O N I S T S , C O RT I C O T R O P I N plasma proteins Some details of preparations and equivalent doses are given in the table Injectable and topical forms are available (creams, suppositories, eye drops) The selectivity of hydrocortisone for the glucocorticoid 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 (3hydroxysteroid 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 'pseudohyperaldosteronism' 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 666 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 saltlosing syndrome of renal origin, e.g following an episode of interstitial nephritis Aldosterone (tl/2 20 min), the principal natural saltretaining 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, congestive 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 ADRENAL STEROIDS AND THEIR SYNTHETIC ANALOGUES 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 or 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 il/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 concentration 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 feedback mechanism Patients may be wrongly suspected 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 (il/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- 34 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 antiinflammatory 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 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 667 34 A D R E N A L C O RT I C O S T E R O I D S , A N TA G O N I S T S , C O RT I C OT R O P I N Unwanted effects generally follow prolonged administration and virtually not occur with or 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 unavoidable when the steroid is used as pharmacotherapy Obviously, the nature of unwanted effects depends on the choice of steroid Fludrocortisone (mineralocorticoid) in ordinary doses does not cause osteoporosis and prednisolone (glucocorticoid) does not normally cause oedema In general, serious unwanted effects are unlikely if the daily dose is below the equivalent of hydrocortisone 50 mg or prednisolone 10 mg The principal adverse effects of chronic corticosteroid administration are: Endocrine To greater or lesser degree features of Cushing's syndrome result in moon face, characteristic 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 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 668 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 alimentary 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 days of exposure Similarly, exposure to measles should be avoided Gastrointestinal Patients taking continuous steroid, especially in combination with a nonsteroidal antiinflammatory drug (NSAID), have an excess incidence 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 subcapsular lens cataract (risk if dose exceeds prednisolone 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 THEIR SYNTHETIC ANALOGUES ADRENAL STEROIDS AND PREGNANCY Adrenal steroids are teratogenic in animals Although a relationship between steroid pharmacotherapy and cleft palate and other fetal abnormalities has been suspected in man, there is no doubt that many women taking a steroid throughout 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 betamethasone, 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 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 34 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 chemotherapy 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 particularly 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 premedication 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 complications, 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 669 34 A D R E N A L C O R T I C O S T E R O I D S, A N T A G O N I S T S , C O R T I C O T R O P I N therapy has been very prolonged, these precautions should be taken for as long as 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 shortlived 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 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 670 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 beclomethasone 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, depending 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 important unless therapy exceeds 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 ADRENAL STEROIDS AND THEIR SYNTHETIC ANALOGUES 34 taking an adrenal steroid is exposed to one, it is wise to try to prevent the disease with the appropriate specific immunoglobulin (if available) Live virus vaccination is unsafe in immunosuppressed subjects, e.g systemic prednisolone > mg/kg per day for > week in the preceding months, as it may cause the disease, but active immunisation with killed vaccines or toxoids will give normal response unless the dose of steroid is high, when the response may be suppressed Raised intracranial pressure may occur more readily in children than in adults crisis should be sought and treated; it is often an infection When the dose of hydrocortisone falls below 40 mg a day, supplementary mineralocorticoid (fludrocortisone) may be needed (see below) The hyperkalaemia of Addison's disease will respond to the above regimen and must not be treated with insulin because of the risk of severe hypoglycaemia Fixed-dose combinations of adrenal steroids with other drugs in one tablet should never be used as they abrogate the principles for the use of such formulations (p 118) Hydrocortisone orally is used (15^0 mg total daily) in the lowest dose that maintains wellbeing and body weight, with two-thirds of the total dose in the morning and one-third in the evening to mimic the natural diurnal rhythm of secretion.3 Plainly corticotropin is useless Some patients well on hydrocortisone alone, with or without added salt, but most patients require a small amount of mineralocorticoid as well (fludrocortisone, 50-200 micrograms once a day, orally) If the dose of fludrocortisone should exceed 500 micrograms a day, an unlikely event, then its glucocorticoid effect must be taken into account The dosage of the hormones is determined in the individual by following general clinical progress and particularly by observing: weight, blood pressure, appearance of oedema, serum sodium and potassium concentrations and haematocrit The dose of fludrocortisone can be adjusted against the plasma renin activity (routinely assayed in a number of chemical pathology laboratories by the radioimmunoassay of the amount of angiotensin I produced during a timed incubation of a plasma sample) Renin is secreted (by the juxtoglomerular apparatus of the kidney) in response to incomplete reversal of the sodium depletion in patients • • • • Replacement of hormone deficiency Inflammation suppression Immunosuppression Suppression of excess hormone secretion USES OF ADRENOCORTICAL STEROIDS REPLACEMENTTHERAPY Acute adrenocortical insufficiency (Addisonian crisis) This is an emergency and hydrocortisone sodium succinate 100 mg should be given i.v immediately it is suspected, or the patient may die • An i.v infusion of sodium chloride solution (0.9%) is set up immediately and a second 100 mg of hydrocortisone is added to the first litre, which may be given over h (several litres of fluid may be needed in the first 24 h) • The patient should then receive hydrocortisone 50-100 mg i.v or i.m 6-hourly for 24 h; then 12-hourly, initiating oral use when appropriate; then a total of 40-60 mg a day orally in or doses Other treatment to restore electrolyte balance will depend on the circumstances The cause of the Chronic primary adrenocortical insufficiency (Addison's disease) But this can be associated with an unphysiologically low plasma concentration of hydrocortisone in the late afternoon (with loss of wellbeing) Such patients may be best managed on equal doses per day Air travellers on long flights across longitude east to west (> 12 h, i.e longer day): take an extra dose near the end of the flight For west to east flights (> h, i.e shorter day): the normal evening dose may be taken sooner and the usual dose taken on the 'new' morning Night workers may adjust their dosage to their work pattern (Drug and Therapeutics Bulletin 1990 28: 71) 671 34 A D R E N A L C O RT I C O S T E R O I D S , A N TA G O N I S T S , C O RT I C OT R O P I N receiving inadequate replacement therapy If any complicating disease arises, such as infection, a need for surgery or other stress, the hydrocortisone dosage should immediately be doubled, see above If there is vomiting, the replacement hormone must be given parenterally without delay There are no contraindications to replacement therapy The risk lies in withholding rather than in giving it Some patients (particularly those with hypopituitarism), when first treated, cannot tolerate full doses of hydrocortisone because they become euphoric or otherwise mentally upset; 10 mg a day may be all they can take The dose can usually soon be increased if it is done slowly If diabetes is present the full dose is used and the diabetes controlled with insulin Chronic secondary adrenocortical insufficiency This occurs in hypopituitarism In theory the best treatment is corticotropin, but the disadvantages of frequent injection are such that hydrocortisone is preferred Usually less hydrocortisone is needed than in primary insufficiency Special sodiumretaining hormone is seldom required, for the pituitary has little control over aldosterone production which responds principally to plasma potassium concentration and to the reninangiotensin system Thyroxine and sex hormones are given when appropriate The general conduct of therapy does not differ significantly from that in primary adrenal insufficiency latrogenic adrenocortical insufficiency: abrupt withdrawal (See also Withdrawal of corticosteroid pharmacotherapy, below) This occurs in patients who have recently received prolonged pharmacotherapy with a corticosteroid which inhibits hypothalamic production of the corticotropin releasing hormone and so results in secondary adrenal failure It is treated by reinstituting therapy or as for acute insufficiency, as appropriate To avoid an acute crisis on stopping, steroid therapy must be withdrawn gradually to allow the hypothalamus, 672 the pituitary and the adrenal to regain normal function Also, when patients taking corticosteroids have an infection or surgical operation (major stress) they should be treated as for primary insufficiency After the use of large doses of hormone to suppress inflammation or allergy, sudden withdrawal may not only lead to an adrenal insufficiency crisis but to relapse of the disease, which has only been suppressed, not cured Such relapse can be extremely severe, sometimes life-threatening PHARMACOTHERAPY Suppression of adrenocortical function In adrenogenital syndrome and adrenal virilism, an attempt may be made to suppress excess adrenal androgen secretion by inhibiting pituitary corticotropin production by means of prednisolone or dexamethasone Suppression of androgen production is effective if there is adrenal hyperplasia, but not if an adrenal tumour is present Hairiness, which women especially dislike in themselves, is often unaffected even though good suppression is achieved, and menstruation recommences Use in inflammation and for immunosuppression Only a brief survey can be given here Drugs with primarily glucocorticoid effects, e.g prednisolone, are chosen, so that dosage is not limited by the mineralocorticoid effects that are inevitable with hydrocortisone But it remains essential to use only the minimum dose that will achieve the desired effect Sometimes therapeutic effect must be partly sacrificed to avoid adverse effects, for it has not yet proved possible to separate the glucocorticoid effects from each other; indeed it is not known if it is possible to eliminate catabolic effects and at the same time retain anti-inflammatory action In any case, in some conditions, e.g nephrotic syndrome, the clinician cannot specify exactly what action they want the drug developer to provide ADRENAL STEROIDS AND THEIR Further specific uses The decision to give a corticosteroid commonly depends on knowledge of the likelihood and amount of benefit (bearing in mind that very prolonged high dose inevitably brings serious complications such as osteoporosis), on the severity of the disease and on whether the patient has failed to respond usefully to other treatment It often requires expertise that can be imparted only by those with wide experience of the disease concerned The following are examples Adrenal steroids are used in all or nearly all cases of: • Exfoliative dermatitis and pemphigus, if severe • Collagen diseases, if severe, e.g lupus erythematosus (systemic), polyarteritis nodosa, polymyalgia rheumatica and cranial giant cell arteritis (urgent therapy to save sight), dermatomyositis • Acute severe asthma • Acute lymphatic leukaemia (see p 617) • Acquired haemolytic anaemia • Severe allergic reactions of all kinds, e.g serum sickness, angio-oedema, trichiniasis Alone they will not control acute manifestations of anaphylactic shock as they not act quickly enough • Organ transplant rejection • Acute spinal cord injury: early, brief, and high dose (to reduce the oedema/inflammation) • Autoimmune active chronic hepatitis: a corticosteroid improves wellbeing, liver function and histology; prednisolone will benefit some 80% and should be continued in the long term, as most patients relapse if the drug is withdrawn • • • • • Adrenal steroids are used in some cases of: • • • • • • Rheumatic fever Rheumatoid arthritis Ankylosing spondylitis Ulcerative colitis and proctitis Regional enteritis (Crohn's disease) Bronchial asthma and hay-fever (allergic rhinitis): also some bronchitics with marked airways obstruction • Sarcoidosis If there is hypercalcaemia or threat to a major organ, e.g eye, adrenal steroid • SYNTHETIC ANALOGUES 34 administration is urgent Pulmonary fibrosis may be delayed and central nervous system manifestations may improve Acute mountain/altitude sickness, to reduce cerebral oedema Prevention of adverse reaction to radiocontrast media in patients who have had a previous severe reaction Blood diseases due to circulating antibodies, e.g thrombocytopenic purpura (there may also be a decrease in capillary fragility with lessening of purpura even though thrombocytes remain few); agranulocytosis Eye diseases Allergic diseases and nongranulomatous inflammation of the uveal tract But bacterial and virus infections may be made worse and use of steroids to suppress inflammation of infection is generally undesirable, is best left to ophthalmologists and must be accompanied by effective chemotherapy; this is of the greatest importance in herpes virus infection Corneal integrity should be checked before use (by instilling a drop of fluorescein) Prolonged use of corticosteroid eye drops causes glaucoma in in 20 of the population (a genetic trait) Application is generally as hydrocortisone, prednisolone or fluorometholone drops, or subconjunctival injection Nephrotic syndrome Patients with minimal change disease respond well to daily or alternate day therapy With a total of prednisolone 60 mg/d, 90% of those who will lose their proteinuria will have done so within 4-6 weeks, and the dose is tapered off over 3-4 months Longer courses only induce adverse effects Relapses are common (50%) and it is then necessary to find a minimum dose of steroid that will keep the patient well If a steroid is for any reason undesirable, cyclophosphamide or chlorambucil may be substituted Membranous nephropathy may respond to high dose corticosteroid with or without chlorambucil A variety of skin diseases, such as eczema Severe cases may be treated by occlusive dressings if a systemic effect is not wanted, though absorption can be substantial (see Ch 16) 673 34 A D R E N A L C O R T I C O S T E R O I D S, A N T A G O N I S T S , C O R T I C O T R O P I N • Acute gout resistant to other drugs (see p 297) • Hypercalcaemia of sarcoidosis and of vitamin D intoxication responds to prednisolone 30 mg daily (or its equivalent of other steroid) for 10 days Hypercalcaemia of myeloma and some other malignancies responds more variably Hyperparathyroid hypercalcaemia does not respond • Raised intracranial pressure due to cerebral oedema, e.g in cerebral tumour or encephalitis (probably an anti-inflammatory effect which reduces vascular permeability and acts in 12-24 h): give dexamethasone 10 mg i.m or i.v (or equivalent) initially and then mg 6-hourly by the appropriate route, reducing dose after 2-4 days and withdrawing over 5-7 days; but much higher doses may be used in palliation of inoperable cerebral tumour • Preterm labour: (to mother) to enhance fetal lung maturation • Aspiration of gastric acid (Mendelsohn's syndrome) • Myasthenia gravis: see page 439 • Cancer, see Chapter 30 Use in diagnosis: dexamethasone suppression test Dexamethasone acts on the hypothalamus (like hydrocortisone), to reduce output of corticotropin releasing hormone (CRH), but it does not interfere with measurement of corticosteroids in blood or urine Normal suppression of cortisol production after administering dexamethasone indicates that the hypothalamic/pituitary/adrenal axis is intact Failure of suppression implies pathological hypersecretion of ACTH by the pituitary or of cortisol by the adrenal Dexamethasone is used because its action is prolonged (24 h) There are several ways of carrying out the test WITHDRAWAL OF PHARMACOTHERAPY The longer the duration of therapy the slower must be the withdrawal For use of less than week (e.g in severe asthma), although there is some hypothalamic suppression, withdrawal can be safely accomplished in a few steps After use for weeks, 674 if rapid withdrawal is desired, a 50% reduction in dose may be made each day; but if the patient has been treated for a longer period, reduction in dose is accompanied by the dual risk of a flare up of the disease and of iatrogenic hypoadrenalism; then withdrawal should be done very slowly, e.g 2.5-5 mg prednisolone or equivalent at intervals of 3-7 days An alternative scheme is to try halving the dose weekly until 25 mg prednisolone or equivalent is reached, after which it may be reduced by about mg every third to seventh day Paediatric tablets (1 mg) can be useful during withdrawal But these schemes may yet be found too fast (giving rise to the occurrence of fatigue, 'dish-rag' syndrome, or relapse of disease) and the rate may need to be even as slow as prednisolone mg per day (or equivalent) per mouth, particularly as the dose approaches the level of physiological requirement (equivalent of prednisolone 5-7.5 mg daily) The long tetracosactride test (see later) or measurements of plasma corticotropin concentration may be used to assess recovery of adrenal responsiveness, but a positive result should not be taken to indicate full recovery of the patient's ability to respond to stressful situations; the latter is best shown by an adequate response to insulininduced hypoglycaemia (which additionally tests the hypothalamic/pituitary capacity to respond) Corticotropin should not be used to hasten recovery of the atrophied cortex since its effects cause further suppression of the hypothalamicpituitary axis, on the recovery of which the patient's future depends Complete recovery of normal hypothalamic/pituitary/adrenal function sufficient to cope with severe intercurrent illnesses or surgery is generally complete in months but may take as long as years There have been many reports of collapse, even coma, occurring within a few hours of omission of steroid therapy, e.g due to patients' ignorance of the risk to which their physicians are exposing them or failing to have their tablets with them and other trivial causes; but it is not invariable Patients must be instructed on the hazards of omitting therapy and, during intercurrent disease, i.m preparations should be freely used Anaesthesia and surgery in adrenocortical insufficency is discussed on page 676 ADRENOCORTICOTROPHIC Inhibition of synthesis of adrenal and other steroid hormones These agents have use in diagnosis of adrenal disease and in controlling excessive production of corticosteroids, e.g by corticotropin producing tumours of the pituitary (Cushing's syndrome) or by adrenocortical adenoma or carcinoma where the cause cannot be removed They must be used with special care since they can precipitate acute adrenal insufficiency Some members inhibit other steroid synthesis Metyrapone inhibits the enzyme, steroid 11(3hydroxylase, that converts 11-deoxy precursors into hydrocortisone, corticosterone and aldosterone It affects synthesis of aldosterone less than that of glucocorticoids Trilostane blocks the synthetic path earlier (3(3hydroxysteroid dehydrogenase) and thus also inhibits aldosterone synthesis Formestane is a specific inhibitor of the aromatase which converts androgens to oestrogens A depot injection of 250 mg i.m is given twice a month in the treatment of some patients with carcinoma of the breast who relapse on tamoxifen Aminoglutethimide blocks even earlier, preventing the conversion of cholesterol to pregnenolone It therefore blocks synthesis of all steroids, hydrocortisone, aldosterone and sex hormones (including the conversion of androgens to oestrogens); it has a use in breast cancer Ketoconazole is an effective antifungal agent by virtue of its capacity to block sterol/steroid synthesis (ergosterol in the case of fungi) In man it inhibits steroid synthesis in gonads and adrenal cortex and it has been used in Cushing's syndrome and prostatic cancer COMPETITIVE ANTAGONISM OF ADRENAL STEROIDS Spironolactone antagonises the sodium-retaining effect of aldosterone and other mineralocorticoids It is used to treat primary and secondary hyperaldosteronism (p 538) HORMONE (ACTH) (CORTICOTROPIN) 34 Adrenocorticotrophic hormone (ACTH) (corticotropin) Natural corticotropin is a 39-amino-acid polypeptide secreted by the anterior pituitary gland; it is obtained from animal pituitaries The physiological activity resides in the first 24 amino acids (which are common to many species) and most immunological activity resides in the remaining 15 amino acids The pituitary output of corticotropin responds rapidly to physiological requirements by the familiar negative-feedback homeostatic mechanism Since the t1// of corticotropin is 10 and the adrenal cortex responds rapidly (within min) it is plain that adjustments of steroid output can be quickly made Synthetic corticotropins have the advantage that they are shorter amino acid chains (devoid of amino acids 25-39) and so are less likely to cause serious allergy, though this can happen In addition they are not contaminated by animal proteins which are potent allergens Tetracosactride (tetracosactrin) consists of the biologically active first 24 amino acids of natural corticotropin (from man or animals and so it has similar properties, e.g tl/2 10 ACTIONS Corticotropin stimulates the synthesis of corticosteroids (of which the most important is hydrocortisone) and to a lesser extent of androgens, by the cells of the adrenal cortex It has only a minor (transient) effect on aldosterone production, which can proceed independently; in the absence of corticotropin the cells of the inner cortex atrophy The release of natural corticotropin by the pituitary gland is controlled by the hypothalamus via corticotropin releasing hormone (CRH or corticoliberin), production of which is influenced by environmental stresses as well as by the level of circulating hydrocortisone High plasma concentration of any steroid with glucocorticoid effect 675 34 A D R E N A L C O R T I C O S T E R O I D S , A N T A G O N I STS , C O R T I C O T R O P I N prevents release of corticotropin releasing hormone and so of corticotropin, lack of which in turn results in adrenocortical hypofunction This is the reason why catastrophe may follow sudden withdrawal of steroid therapy in the chronically treated patient who has an atrophied cortex • Cortisol and aldosterone produced in the adrenal cortex have a major role in physiology and pharmacology • Physiological concentrations of cortisol are essential for supporting the circulation and glucose production Physiological concentrations of aldosterone are The effects of corticotropin are those of the steroids (hydrocortisone, androgens) liberated by its action on the adrenal cortex Prolonged heavy dosage causes the clinical picture of Cushing's syndrome essential to prevent excessive sodium loss • For systemic pharmacological uses, prednisolone or other synthetic adrenocorticosteriods are used because they are more selective glucocorticoids, i.e have less sodium-retaining activity • For local administration (skin, lung), more potent, fluorinated steroids may be required Uses Corticotropin is used principally in diagnosis and rarely in treatment It is inactive if taken orally and has to be injected like other peptide hormones • Glucocorticoids inhibit the transcriptional activation of many of the inflammatory cytokines, giving them a versatile role in the treatment of many types of inflammation • Diagnostic use: as a test of the capacity of the adrenal cortex to produce cortisol; with the short test, the plasma cortisol (hydrocortisone) concentration is measured before and after an i.m injection of tetracosactride (Synacthen); a normal response is a rise of more than 200 nanomol/1 in the plasma concentration of hydrocortisone Longer variants of the test in cases of difficulty involve use of the depot (sustained-release) formulation i.m For example, mg of the depot is injected daily for days at 9.00 am, with a short tetracosactride test performed on day Therapeutic use is seldom appropriate because the peptide hormone has to be injected; selective glucocorticoid action (without mineralocorticoid effect) cannot be obtained, and clinical results are irregular Corticotropin can not be relied on to restore adrenal cortisol output when a steroid is being withdrawn after prolonged therapy, as it does not restore function in the suppressed hypothalamic/pituitary part of the HPA axis Preparations Tetracosactride Injection is a powder dissolved in water immediately before injection i.v., i.m or s.c Tetracosactride Zinc Injection (Synacthen Depot) in which the hormone is adsorbed on to zinc phosphate from which it is slowly released This is the form used in the long tetracosactride test 676 Fludrocortisone is a valuable treatment for many sodium-losing states, and for most causes of autonomic neuropathy GUIDETO FURTHER READING Boscaro M et al 2001 Cushing's syndrome Lancet 357: 783-791 English J et al 1983 Diurnal variation in prednisolone kinetics Clinical Pharmacology and Therapeutics 33: 381 Freidy J F 1988 Reactions to contrast media and steroid pretreatment British Medical Journal 296: 809 Hench P S et al 1949 The effect of a hormone of the adrenal cortex (17-hydroxy-lldehydrocorticosterone: Compound E) and of pituitary adrenocorticotrophic hormone on rheumatoid arthritis Proceedings of the Staff Meetings of the Mayo Clinic 24:181, 277 (acute rheumatism) The classic studies of the first clinical use of an adrenocortical steroid in inflammatory disease See also page 298 for an account by E C Kendall of the biochemical and pharmaceutical background to the clinical studies Kendall writes of his collaboration with Hench, 'he can now say "17-hydroxy-ll-dehydrocorticosterone" and in turn I can say "the arthritis of lupus erythematosus" In sophisticated circles, however, I prefer to say, "the arthritis of L.E."' A D R E N O C O R T I C O T R O P H IC H O R M O N E Hilditch K 2000 My Addison's disease British Medical Journal 321: 645 (A patient's account of the disease.) Lamberts S W J, Bruining H A, de Jong F H 1997 Corticosteroid therapy in severe illness New England Journal of Medicine 337:1285-1292 Lipworth B J 2000 Therapeutic implications of nongenomic glucocorticoid activity Lancet 356: 87-88 Lavin M J et al 1986 Use of steroid eye drops in general practice British Medical Journal 292:1448 ( A C T H ) ( C O RT I C O T R O P I N ) 34 Marx J 1995 How the glucocorticoids suppress immunity Science 270: 232-233 Mitchell A, O'Keane V 1998 Steroids and depression British Medical Journal 316: 244-245 Newton R W et al 1978 Adrenocortical suppression in workers manufacturing synthetic glucocorticoids British Medical Journal 1: 73 677 ... 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... syndrome Lancet 357: 783-791 English J et al 1983 Diurnal variation in prednisolone kinetics Clinical Pharmacology and Therapeutics 33: 381 Freidy J F 1988 Reactions to contrast media and steroid... the first clinical use of an adrenocortical steroid in inflammatory disease See also page 298 for an account by E C Kendall of the biochemical and pharmaceutical background to the clinical studies