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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) ...

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  3. 34 Adrenal corticosteroids, antagonists, corticotropin SYNOPSIS By 1936, numerous steroids were being crys- tallised from cortical extracts, but not enough could • Adrenocortical steroids and their synthetic be obtained to provide supplies for clinical trial. analogues In 1948 cortisone was made from bile acids in Mechanisms of action quantity sufficient for clinical trial, and the dramatic Actions: mineralocorticoid, glucocorticoid demonstration of its power to induce remission of Individual adrenal steroids rheumatoid arthritis was published the following Pharmacokinetics year. In 1950 it was realised that cortisone was Dosage schedules biologically inert and that the active natural Choice of adrenal steroid hormone is hydrocortisone (cortisol). Since then an Adverse effects of systemic embarrassingly large number of synthetic steroids pharmacotherapy has been made and offered to the clinician. They are Adrenal steroids and pregnancy derived from natural substances (chiefly plant Precautions during chronic therapy: sterols), the constitutions of which approach most treatment of intercurrent illness nearly to that of the steroids themselves. A principal Dosage and routes of administration aim in research is to produce steroids with more Indications for use selective action than hydrocortisone, which induces Uses: replacement therapy, pharmacotherapy a greater variety of effects than desired in any patient Withdrawal of pharmacotherapy who is not suffering from adrenal insufficiency. • Inhibition of synthesis of adrenal steroids About the same time as cortisone was intro- • Competitive antagonism duced, corticotropin became available for clinical • Adrenocorticotrophic hormone (ACTH) use. (corticotropin) In 1855, Dr Thomas Addison, assisted in his obser- vations by three colleagues, published his famous Adrenal steroids and their monograph 'On the constitutional effects of disease synthetic analogues on the suprarenal capsules' (Addison's disease). It was not until the late 1920s that the vital im- Hormones normally produced by the adrenal portance of the adrenal cortex was appreciated and cortex include hydrocortisone (cortisol) and some the distinction between the hormones secreted by androgens and oestrogens, the synthesis and the cortex and medulla. release of which is controlled by the hypothalamic- 663
  4. 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 bio- effects of steroids with less of the undesired synthesis is largely dependent on the renin- properties. angiotensin system. Glucocorticoids inhibit pathways that normally Numerous analogues have been made in which lead to production of prostaglandins, leukotrienes the major actions have been separated. and platelet activating factor. These mediators When the adrenal cortex fails (Addison's disease) would normally contribute to increased vascular adrenocortical steroids are available for replacement permeability and subsequent changes including therapy, but their chief use in medicine is for their oedema, leucocyte migration, fibrin deposition. anti-inflammatory and immunosuppressive effects (pharmacotherapy). These are obtained only when the drugs are given in doses far above those needed ACTIONS OF HYDROCORTISONE for physiological replacement. Various metabolic Plainly, there is a distinction between replacement effects, which are of the greatest importance to the therapy (physiological effects) and the higher doses normal functioning of the body, then become of pharmacotherapy. adverse effects. Much successful effort has gone into separating glucocorticoid from mineralocorticoid On inorganic metabolism (mineralocorticoid effects1 and some steroids, e.g. dexamethasone, effects): increased retention of sodium by the renal have virtually no mineralocorticoid activity. But it tubule, and increased potassium excretion in the has not yet proved possible to separate the gluco- urine. corticoid effects from each other, so that if a steroid is used for its anti-inflammatory action the risks, On organic metabolism (glucocorticoid effects): e.g. of osteoporosis, diabetes, remain. In the account that follows, the effects of hydro- • Carbohydrate metabolism: gluconeogenesis is cortisone will be described and then other steroids increased and peripheral glucose utilisation in so far as they differ. In the context of this chapter (transport across cell membranes) may be 'adrenal steroid' means a substance with hydro- decreased (insulin antagonism) so that cortisone-like activity. Androgens are described in hyperglycaemia and sometimes glycosuria Chapter 37. result. Latent diabetes becomes overt. • Protein metabolism: anabolism (conversion of amino acids to protein) is decreased but MECHANISM OF ACTION catabolism continues unabated or even faster, so Glucocorticoids diffuse into the cell but access to that there is a negative nitrogen balance with the receptor may be prevented, for example in muscle wasting. Osteoporosis (reduction of bone kidney, by the enzyme 11-beta hydroxysteroid protein matrix) occurs, growth slows in children, dehydrogenase, which converts active cortisol into the skin atrophies and this, with increased inactive cortisone. When activated, the receptors capillary fragility, causes bruising and striae. translocate to the nucleus where they can upregu- Healing of peptic ulcers or of wounds is delayed, late gene transcription by dimerising on specific as is fibrosis. DNA response elements and recruiting co-activator • Fat deposition: this is increased on shoulders, face proteins, but can also oppose other transcription and abdomen. factor function, for example NFicB and AP-1, by • Inflammatory response is depressed, regardless of protein-protein interaction. The anti-inflammatory its cause, so that as well as being of great benefit actions of glucocorticoids are mediated mainly by in 'useless' or excessive inflammation, this latter mechanism, suggesting that one day corticosteroids can be a source of danger in drugs may be found which have the beneficial infections by limiting useful protective inflammation. Neutrophil and macrophage 1 The mere introduction of a double bond transforms function are depressed, including the release of hydrocortisone to prednisolone, a big biological change: see chemical mediators and the effects of these on Table 34.1 for relative potencies 1.0:1.0 to 4:0.8. capillaries. 664
  5. ADRENAL STEROIDS AND THEIR SYNTHETIC ANALOGUES 34 • Allergic responses are suppressed. The Normal daily secretion of hydrocortisone is antigen-antibody interaction is unaffected, but 10-30 mg. The exogenous daily dose that com- its injurious inflammatory consequences do not pletely suppresses the cortex is hydrocortisone follow. 40-80 mg, or prednisolone 10-20 mg, or its equi- • Antibody production is reduced by heavy valent of other agents. Recovery of function is quick doses. after a few days' use; but when used over months • Lymphoid tissue is reduced (including leukaemic recovery takes months. A steroid-suppressed adrenal lymphocytes). continues to secrete aldosterone. • Renal excretion of urate is increased. • Blood eosinophils are reduced in number. INDIVIDUAL ADRENAL STEROIDS • Euphoria or psychotic states may occur, perhaps due to CNS electrolyte changes. The relative potencies2 for glucocorticoid and • Anti-vitamin D action, see calciferol (p. 738). mineralocorticoid (sodium-retaining) effects which • Reduction of hypercalaemia chiefly where this are shown in Table 34.1 are central to the choice of is due to excessive absorption of calcium agent in relation to clinical indication. from the gut (sarcoidosis, vitamin D All drugs in Table 34.1 except aldosterone are intoxication). active when swallowed, being protected from • Urinary calcium excretion is increased and renal hepatic first-pass metabolism by high binding to stones may form. • Growth reduction where new cells are being 2 Potency (the weight of drug in relation to its effect) rather added (growth in children), but not where they than efficacy (strength of response): see page 94. If a large are replacing cells as in adult tissues. enough dose of a glucocorticoid, e.g. prednisolone, were • Suppression ofhypothalamic/pituitary/adrenocortical administered, the Na+-retention would be almost as great as feedback system (with delayed recovery) occurs that caused by a mineralocorticoid. This is why, in practice, different (more selective, and potent) glucocorticoids, not with chronic use, so that abrupt withdrawal higher doses of prednisolone, need to be used when maximal leaves the patient in a state of adrenocortical stimulation of glucocorticoid receptors is desired (e.g. in the insufficiency. treatment of acute transplant rejections). TABLE 34. 1 Relative potencies of adrenal steroids Compound Approximate relative potency (tablet strength, mg) Anti-inflammatory Sodium-retaining Equivalent1 dosage (glucocorticoid) effect (mineralocorticoid) effect (for anti-inflammatory effect, mg)2 Cortisone (25) 0.8 1.0 25 Hydrocortisone (20) 1.0 1.0 20 Prednisolone (5) 4 0.8 5 Methylprednisolone (4) 5 minimal 4 Triamcinolone (4) 5 none 4 Dexamethasone (0.5) 30 minimal 0.75 Betamethasone (0.5) 30 negligible 0.75 Fludrocortisone (0. 1 ) 15 150 irrelevant Aldosterone none none 5003 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. 665
  6. 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 may occasionally be severe and anorexia and equivalent doses are given in the table. Injectable mental depression may be more common at high and topical forms are available (creams, supposi- dose. tories, eye drops). The selectivity of hydrocortisone for the gluco- Dexamethasone and betamethasone are similar, corticoid receptor is not due to a different binding powerful predominantly anti-inflammatory steroids. affinity of hydrocortisone to the two receptors but They are longer-acting than prednisolone and are to the protection of the mineralocorticoid receptor used for therapeutic adrenocortical suppression. by locally high concentrations of the enzyme 11 (3- hydroxysteroid dehydrogenase, which converts Fludrocortisone has a very great sodium-retaining cortisol (hydrocortisone) to the inactive cortisone. effect in relation to its anti-inflammatory action, This enzyme is inhibited by one of the components and only at high doses need the nonelectrolyte effects of liquorice, and can occasionally harbour a genetic be considered. It is used to replace aldosterone defect. Therefore both acquired (in liquorice addicts) where the adrenal cortex is destroyed (Addison's and inherited syndromes of 'pseudohyperaldo- disease). Fludrocortisone is also the drug of choice steronism' can occasionally occur. in most patients with autonomic neuropathy, in whom volume expansion is easier to achieve than a Hydrocortisone (cortisol) is the principal naturally sustained increase in vasoconstrictor tone. Much occurring steroid; it is taken orally; a soluble salt higher doses of fludrocortisone (0.5-1.0 mg) are can be given i.v. for rapid effect in emergency required when the cause of hypotension is a salt- (whether due to deficiency, allergy or inflammatory losing syndrome of renal origin, e.g. following an disease). A suspension (Hydrocortisone Acetate episode of interstitial nephritis. Inj.) can be given intra-articularly. Parenteral preparation for systemic effect: the Aldosterone (tl/2 20 min), the principal natural salt- soluble Hydrocortisone Sodium Succinate Inj. is retaining hormone, has been used i.m. in acute used for quick (1-2 h) effect; for continuous effect adrenal insufficiency. After oral administration, about 8-hourly administration is appropriate. it is rapidly inactivated in the first pass through Prednisolone Acetate Inj. i.m. is an alternative, once the liver but has no place in routine therapeutics, or twice a week. as fludrocortisone is as effective and is active Oral tablet strengths, see Table 34.1. orally. Prednisolone is predominantly anti-inflammatory Spironolactone (see p. 534) is a competitive (glucorticoid), biologically active, and has little aldosterone antagonist which also blocks the sodium-retaining activity; it is the standard choice mineralocorticoid effect of other steroids; it is used for anti-inflammatory pharmacotherapy, orally or in the treatment of primary hyperaldosteronism and as i.m. a diuretic, principally when severe oedema is due to secondary hyperaldosteronism, e.g. cirrhosis, con- Prednisone is a prodrug, i.e. it is biologically inert gestive cardiac failure. and converted into prednisolone in the liver. Since there is 20% less on conversion there seems to be no Beclomethasone and budesonide are used by point in using it. inhalation for asthma (see p. 561). About 90% of an inhalation dose is swallowed and these steroids are Methylprednisolone is similar to prednisone; inactivated by hepatic first-pass; the rest, absorbed it is used i.v. for megadose pulse therapy (see from the mouth and lungs, gives very low systemic below). plasma concentration. The risk of suppression of the hypothalamic/pituitary/adrenal axis is thus Fluorinated corticosteroids: triamcinolone has minimal (but it can happen). This property of virtually no sodium retaining (mineralocorticoid) extensive hepatic first-pass metabolism with low effect but has the disadvantage that muscle wasting systemic availability is also an advantage in the 666
  7. ADRENAL STEROIDS AND THEIR SYNTHETIC ANALOGUES 34 topical treatment of inflammatory bowel disease vide time for pituitary recovery, e.g. prednisolone with minimal risk of systemic adverse effects. 40 on alternate days. But none has been successful in both completely avoiding suppression and at the same time controlling symptoms. The following are PHARMACOKINETICS OF examples: CORTICOSTEROIDS • Where a single daily dose is practicable it should Absorption of the synthetic steroids given orally is be given in the early morning (to coincide with rapid. The t1// in plasma of most is 1-3 h but the the natural activation of the HPA axis). maximum biological effect occurs after 2-8 h. • Alternate day schedules are worth using, especially Administration is usually 2 or 3 times a day. They where immunosuppression is the objective are metabolised principally in the liver (some (organ transplants) rather than anti- undergoing hepatic first-pass metabolism, see inflammatory effect (rheumatoid arthritis). above) and some are excreted unchanged by the • Short courses (a few days) may be practicable for kidney. The il/2 is prolonged in hepatic and renal some conditions without significant suppression, disease and is shortened by enzyme induction to an e.g. acute asthma of moderate severity. extent that can be clinically important. • Another variant is to give enormous doses (grams, Topical application (skin, lung, joints) allows not mg), orally or i.v., e.g. methylprednisolone absorption which can be enough to cause systemic 1.0 g i.v. on 3 successive days, at intervals of weeks effects. or months (megadose pulses). The technique is In the blood, adrenal steroids are carried in the used particularly in collagen diseases. 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 • For oral replacement therapy in adrenocortical insufficiency, hydrocort/sone should be used to supply (80% in the case of hydrocortisone). The concen- glucocorticoid and some mineralocorticoid activity. In tration of transcortin is increased by oestrogens, e.g. Addison's disease a small dose of a hormone with only pregnancy, hormonal contraception, other oestrogen mineralocorticoid effect (fludrocortisone) is normally therapy; if these substances are taken, the total needed in addition. Prednisolone on its own is not plasma hydrocortisone will be found to be raised, effective replacement therapy. but the amount of free hydrocortisone may be • For anti-inflammatory and antiallergic normal, being controlled by the physiological feed- (immunosuppressive) effect, prednisolone, triamdnolone or dexamethasone. It is not possible to back mechanism. Patients may be wrongly sus- rank these in firm order of merit. One or other may pected of having Cushing's syndrome if the fact suit an individual patient best, especially as regards that they are taking oestrogen is unrecognised and incidence of adverse effects such as muscle wasting. By only the total is measured (as is usual). inhalation: beclomethasone or budesonide. In patients with very low serum albumin, steroid • For hypothalamic/pituitary/adrenocortical doses should be lower than usual owing to the suppression, e.g. in adrenal hyperplasia, prednisolone reduced binding capacity. In addition, low albumin or dexamethasone. concentration may be caused by liver disease, which also augments the effects of steroids by ADVERSE EFFECTS OF SYSTEMIC delaying metabolism (il/2 of prednisolone may be ADRENAL STEROID doubled). PHARMACOTHERAPY These consist largely of too intense production of DOSAGE SCHEDULES the physiological or pharmacological actions listed Various spaced-out schedules have been used in the under actions of hydrocortisone. Some occur only aspiration of reducing hypothalamic/pituitary/ with systemic use and for this reason local therapy, adrenal (HPA) suppression by allowing the plasma e.g. inhalation, intra-articular injection, is preferred steroid concentration to fall between doses to pro- where practicable. 667
  8. 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 infection and immunosuppression causes some administration and virtually do not occur with 1 or patients to present with atypical symptoms and 2 doses though some occur with a few days' use, signs and quickly to deteriorate. The incidence of e.g. spread of infection. The undesired effects infection is increased with high dose therapy, and recounted below should never be experienced in any infection can be more severe when it occurs. replacement therapy, but are sometimes unavoid- Candidiasis may appear, particularly in the alimen- able when the steroid is used as pharmacotherapy. tary tract. Previously dormant tuberculosis may Obviously, the nature of unwanted effects depends become active insidiously. Intra-articular injections on the choice of steroid. Fludrocortisone (mineralo- demand the strictest asepsis. Live vaccines become corticoid) in ordinary doses does not cause osteo- dangerous. Developing chickenpox may result in a porosis and prednisolone (glucocorticoid) does not severe form of the disease and patients who have not normally cause oedema. had chickenpox should receive varicella-zoster In general, serious unwanted effects are unlikely immune globulin within 3 days of exposure. if the daily dose is below the equivalent of hydro- Similarly, exposure to measles should be avoided. cortisone 50 mg or prednisolone 10 mg. The principal adverse effects of chronic cortico- Gastrointestinal. Patients taking continuous steroid, steroid administration are: especially in combination with a nonsteroidal anti- inflammatory drug (NSAID), have an excess inci- Endocrine. To greater or lesser degree features of dence of peptic ulcer and haemorrhage of about 1-2%. Cushing's syndrome result in moon face, charac- It is plainly unreasonable to seek to protect all such teristic deposition of fat on the body, oedema, patients by routine prophylactic antiulcer therapy, hypertension, striae, bruising, acne, hirsutism. i.e. to treat 98 patients unnecessarily in order to Major skin damage can result from minor injury help two. But such therapy (proton pump inhibitor, of any kind. Diabetes mellitus may appear. histamine H2-receptor blocker, sucralfate) is Hypothalamic/pituitary'/adrenal (HPA) suppression is appropriate when ulcer is particularly likely, e.g. a dependent on the corticosteroid used, its dose, patient with rheumatoid arthritis taking an NSAID, duration and the time of administration. A single or for patients with a history of peptic ulcer disease. morning dose of less than 20 mg of prednisolone There is increased incidence of pancreatitis. may not be followed by suppression, whereas a dose of 5 mg given late in the evening is likely to Central nervous system. Depression and psychosis suppress the essential early morning activation of can occur during the first few days of high dose the HPA axis (circadian rhythm). Substantial administration, especially in those with a history of suppression of the HPA axis can occur within a mental disorder. Other effects include euphoria, week (but see Withdrawal of steroid therapy, insomnia, and aggravation of schizophrenia and below). epilepsy. Long-term treatment may result in raised intracranial pressure with papilloedema, especially in Musculoskeletal. Proximal myopathy and tendon children. rupture may occur. Osteoporosis develops insidiously leading to fractures of vertebrae, ribs, femora and Ophthalmic effects may include posterior sub- feet. Pain and restriction of movement may occur capsular lens cataract (risk if dose exceeds pred- months in advance of radiographic changes. A nisolone 10 mg/day or equivalent for above a year), biphosphonate, with or without vitamin D, is useful glaucoma (with prolonged use of eye drops), and for prevention and treatment. Growth in children is corneal or scleral thinning. impaired. A vascular necrosis of bone (femoral heads) is a serious complication (at higher doses); it Other effects include menstrual disorders, delayed appears to be due to restriction of blood flow tissue healing (including myocardial rupture after through bone capillaries. myocardial infarction), thromboembolism, and paradoxically, hypersensitivity reactions including Immune. Suppression of the inflammatory response to anaphylaxis. 668
  9. ADRENAL STEROIDS AND THEIR SYNTHETIC ANALOGUES 34 ADRENAL STEROIDS AND taking the minimum dose necessary to control PREGNANCY the disease. Adrenal steroids are teratogenic in animals. Although a relationship between steroid pharmaco- Treatment of intercurrent illness therapy and cleft palate and other fetal abnor- The normal adrenal cortex responds to severe stress malities has been suspected in man, there is no by secreting more than 300 mg/day of cortisol. doubt that many women taking a steroid through- Intercurrent illness is stress and treatment is urgent, out have both conceived and borne normal babies. particularly of infections; the dose of corticosteroid Adrenal insufficiency due to hypothalamic/ should be doubled during the illness and gradually pituitary suppression in the newborn occurs only reduced as the patient improves. Effective chemo- with high doses to the mother. Dosage during therapy of bacterial infections is specially important. pregnancy should be kept as low as practicable and Viral infections contracted during steroid therapy fluorinated steroids are best avoided as they are can be overwhelming because the immune response more teratogenic in animals (dexa- and beta- of the body may be largely suppressed. This is par- methasone, triamcinolone and various topical ticularly relevant to immunosuppressed patients steroids, e.g. fluocinolone). Hypoadrenal women exposed to varicella/herpes zoster virus, which who become pregnant may require an increase in may cause fulminant illness; they may need passive hydrocortisone replacement therapy by about 10 protection with varicella/zoster immunoglobulin, mg per day to compensate for the increased binding VZIG, as soon as practicable. Continuous use of by plasma proteins that occurs in pregnancy. prednisolone 20 mg/day (or the equivalent) is Labour should be managed as described for major immunosuppressive. But a corticosteroid may surgery (below). sometimes be useful in therapy after the disease has begun (thyroiditis, encephalitis) and there has been PRECAUTIONS DURING CHRONIC time for the immune response to occur. It then acts ADRENAL STEROID THERAPY by suppressing unwanted effects of immune responses and excessive inflammatory reaction. The most important precaution during replacement Vomiting requires parenteral administration. and pharmacotherapy is to see the patient regularly In the event of surgery being added to that of with an awareness of the possibilities of adverse adrenal steroid therapy the patient should receive effects including fluid retention (weight gain), hydrocortisone 100-200 mg i.m. or i.v. with pre- hypertension, glycosuria, hypokalaemia (potassium medication. If there is any sign suggestive that the supplement may be necessary) and back pain patient may collapse, e.g. hypotension, during the (osteoporosis); and of the serious hazard of patient operation, i.v. hydrocortisone (100 mg) should be noncompliance. infused at once. Otherwise, if there are no compli- cations, the dose is repeated 6-hourly for 24-72 h Mild withdrawal symptoms (iatrogenic cortical and then reduced by half every 24 h until normal insufficiency) include conjunctivitis, rhinitis, weight dose level is reached. loss, arthralgia and itchy skin nodules. Minor operations, e.g. dental extraction, may be covered by hydrocortisone 20 mg orally 2-4 h Patients must always before operation and the same dose afterwards. • carry a card giving details of therapy In all these situations an i.v. infusion should be • be impressed with the importance of compliance available for immediate use in case the above is not • know what to do if they develop an intercurrent enough. These precautions should be used in illness or other severe stress: double their next patients who have received substantial treatment dose and to tell their doctor. If a patient omits a with corticosteroid within the past year, because dose then it should be made up as soon as their hypothalamic/pituitary/adrenal system, possible so that the total daily intake is though sufficient for ordinary life, may fail to maintained, because every patient should be respond adequately to severe stress. If steroid 669
  10. 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 continued for years. The decision to should be taken for as long as 2 years after stopping embark on such therapy is a serious matter for it. This will mean that some unnecessary treatment the patient. is given, but collapse due to acute adrenal insufficiency can be fatal and the ill-effects of short- Topical applications (creams, intranasal, inhalations, lived increased dosage of steroid are less grave, enemas) are used in attempts, often successful, to being confined to possible increased incidence and obtain local, whilst avoiding systemic, effects; severity of infection. suspensions of solutions are also injected into joints, soft tissues and subconjunctivally. All these can, with heavy dose, be sufficiently absorbed to DOSAGE AND ROUTES OF suppress the hypothalamus and cause other ADMINISTRATION unwanted effects. Individual preparations are Dosage depends very much on the purpose for mentioned in the text where appropriate. which the steroid is being used and on individual The relatively high selectivity of inhaled bec- response. There is no single schedule that will suit lomethasone in asthma is due to a combination of every case but examples appear below. route of administration, high potency and rapid conversion to inactive metabolites by the liver of Systemic commencing doses any drug that is absorbed (see asthma, skin); but yet • For a serious disease such as systemic lupus, hypothalamic/pituitary suppression and systemic dermatomyositis: prednisolone up to 0.75-2.0 toxicity occasionally occur. mg/kg/d orally in divided doses. • If life-threatening, prednisolone up to 70 mg, or its Contraindications to the use of adrenal steroids for equivalent of another steroid. The dose is then suppressing inflammation are all relative, depend- increased if necessary until the disease is ing on the advantage to be expected. They should controlled or adverse effects occur; as much as be used only for serious reasons if the patient has: prednisolone 2-3 mg/kg/d can be needed. diabetes, a history of mental disorder or peptic Cyclophosphamide or azathioprine (see p. 292) ulcer, epilepsy, tuberculosis, hypertension or heart are valuable adjuncts; they may enhance the failure. The presence of any infection demands that initial control of the disease and have a sparing effective chemotherapy be begun before the effect on the maintenance dose of prednisolone steroid, but there are exceptions (some viral required. infections, see above). Topical corticosteroid • More usually now, megadose pulses applied to an inflamed eye (with the very best of (methylprednisolone 1.0 g i.v. daily for 3 days) intention) can be disastrous if the inflammation is are used, followed by oral maintenance with due to herpes virus. prednisolone and/or a steroid-sparing agent Steroids containing fluorine (see above) intensify (above). diabetes more than others and so should be • For less dangerous disease, such as rheumatoid avoided in that disease. arthritis: prednisolone 7.5-10.0 mg daily, adjusted later according to the response. Long-term use of adrenal steroids in children • In some special cases, including replacement of presents essentially the same problems as in adults adrenal insufficiency, dosage is given in the except that growth is retarded approximately in account of the treatment of the disease. proportion to the dose. This is unlikely to be impor- • For continuous therapy the minimum amount to tant unless therapy exceeds 6 months; there is a produce the desired effect must be used. spurt of growth after withdrawal. Intermittent dosage Sometimes imperfect control must be accepted schedules (alternate day) may reduce the risk by the patient because full control, e.g. of (rarely, corticotropin may be preferred, see p. 675). rheumatoid arthritis, though obtainable, Some other problems loom larger in children involves use of doses that must lead to than in adults. Common childhood viral infections long-term toxicity, e.g. osteoporosis, if may be more severe, and if a nonimmune child 670
  11. ADRENAL STEROIDS AND THEIR SYNTHETIC ANALOGUES 34 taking an adrenal steroid is exposed to one, it is crisis should be sought and treated; it is often an wise to try to prevent the disease with the appro- infection. When the dose of hydrocortisone falls priate specific immunoglobulin (if available). below 40 mg a day, supplementary mineralo- Live virus vaccination is unsafe in immuno- corticoid (fludrocortisone) may be needed (see suppressed subjects, e.g. systemic prednisolone below). > 2 mg/kg per day for > 1 week in the preceding The hyperkalaemia of Addison's disease will 3 months, as it may cause the disease, but active respond to the above regimen and must not be immunisation with killed vaccines or toxoids will treated with insulin because of the risk of severe give normal response unless the dose of steroid is hypoglycaemia. high, when the response may be suppressed. Raised intracranial pressure may occur more Chronic primary adrenocortical readily in children than in adults. insufficiency (Addison's disease) Fixed-dose combinations of adrenal steroids with Hydrocortisone orally is used (15^0 mg total daily) other drugs in one tablet should never be used as in the lowest dose that maintains wellbeing and they abrogate the principles for the use of such body weight, with two-thirds of the total dose in formulations (p. 118). the morning and one-third in the evening to mimic the natural diurnal rhythm of secretion.3 Plainly corticotropin is useless. Some patients do well on hydrocortisone alone, • Replacement of hormone deficiency with or without added salt, but most patients • Inflammation suppression • Immunosuppression require a small amount of mineralocorticoid as well • Suppression of excess hormone secretion (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. USES OF ADRENOCORTICAL The dosage of the hormones is determined in the STEROIDS individual by following general clinical progress and particularly by observing: weight, blood REPLACEMENTTHERAPY pressure, appearance of oedema, serum sodium and potassium concentrations and haematocrit. The Acute adrenocortical insufficiency dose of fludrocortisone can be adjusted against the (Addisonian crisis) plasma renin activity (routinely assayed in a This is an emergency and hydrocortisone sodium number of chemical pathology laboratories by the succinate 100 mg should be given i.v. immediately radioimmunoassay of the amount of angiotensin I it is suspected, or the patient may die. produced during a timed incubation of a plasma sample). Renin is secreted (by the juxtoglomerular • An i.v. infusion of sodium chloride solution apparatus of the kidney) in response to incomplete (0.9%) is set up immediately and a second reversal of the sodium depletion in patients 100 mg of hydrocortisone is added to the first litre, which may be given over 2 h (several litres 3 of fluid may be needed in the first 24 h). But this can be associated with an unphysiologically low • The patient should then receive hydrocortisone plasma concentration of hydrocortisone in the late afternoon (with loss of wellbeing). Such patients may be best managed 50-100 mg i.v. or i.m. 6-hourly for 24 h; then on 3 equal doses per day. Air travellers on long flights across 12-hourly, initiating oral use when appropriate; longitude east to west (> 12 h, i.e. longer day): take an extra then a total of 40-60 mg a day orally in 2 or dose near the end of the flight. For west to east flights (> 8 h, 3 doses. i.e. shorter day): the normal evening dose may be taken sooner and the usual dose taken on the 'new' morning. Night Other treatment to restore electrolyte balance workers may adjust their dosage to their work pattern (Drug will depend on the circumstances. The cause of the and Therapeutics Bulletin 1990 28: 71). 671
  12. 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 the pituitary and the adrenal to regain normal complicating disease arises, such as infection, a function. Also, when patients taking corticosteroids need for surgery or other stress, the hydrocortisone have an infection or surgical operation (major dosage should immediately be doubled, see above. stress) they should be treated as for primary If there is vomiting, the replacement hormone insufficiency. must be given parenterally without delay. After the use of large doses of hormone to There are no contraindications to replacement suppress inflammation or allergy, sudden with- therapy. The risk lies in withholding rather than in drawal may not only lead to an adrenal insufficiency giving it. crisis but to relapse of the disease, which has only Some patients (particularly those with hypo- been suppressed, not cured. Such relapse can be pituitarism), when first treated, cannot tolerate full extremely severe, sometimes life-threatening. 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 PHARMACOTHERAPY be increased if it is done slowly. If diabetes is present the full dose is used and the diabetes Suppression of adrenocortical function controlled with insulin. In adrenogenital syndrome and adrenal virilism, an attempt may be made to suppress excess adrenal Chronic secondary adrenocortical androgen secretion by inhibiting pituitary insufficiency corticotropin production by means of prednisolone or dexamethasone. Suppression of androgen This occurs in hypopituitarism. In theory the best production is effective if there is adrenal treatment is corticotropin, but the disadvantages of hyperplasia, but not if an adrenal tumour is present. frequent injection are such that hydrocortisone is Hairiness, which women especially dislike in preferred. Usually less hydrocortisone is needed themselves, is often unaffected even though good than in primary insufficiency. Special sodium- suppression is achieved, and menstruation retaining hormone is seldom required, for the recommences. pituitary has little control over aldosterone pro- duction which responds principally to plasma potassium concentration and to the renin- Use in inflammation and for angiotensin system. Thyroxine and sex hormones immunosuppression are given when appropriate. The general conduct of therapy does not differ significantly from that in Only a brief survey can be given here. primary adrenal insufficiency. Drugs with primarily glucocorticoid effects, e.g. prednisolone, are chosen, so that dosage is not limited by the mineralocorticoid effects that are latrogenic adrenocortical insufficiency: inevitable with hydrocortisone. But it remains abrupt withdrawal essential to use only the minimum dose that will (See also Withdrawal of corticosteroid pharmaco- achieve the desired effect. Sometimes therapeutic therapy, below) This occurs in patients who have effect must be partly sacrificed to avoid adverse recently received prolonged pharmacotherapy with effects, for it has not yet proved possible to separate a corticosteroid which inhibits hypothalamic the glucocorticoid effects from each other; indeed it production of the corticotropin releasing hormone is not known if it is possible to eliminate catabolic and so results in secondary adrenal failure. It is effects and at the same time retain anti-inflam- treated by reinstituting therapy or as for acute matory action. In any case, in some conditions, e.g. insufficiency, as appropriate. To avoid an acute nephrotic syndrome, the clinician cannot specify crisis on stopping, steroid therapy must be exactly what action they want the drug developer withdrawn gradually to allow the hypothalamus, to provide. 672
  13. ADRENAL STEROIDS AND THEIR SYNTHETIC ANALOGUES 34 Further specific uses administration is urgent. Pulmonary fibrosis may be delayed and central nervous system The decision to give a corticosteroid commonly manifestations may improve. depends on knowledge of the likelihood and • Acute mountain/altitude sickness, to reduce amount of benefit (bearing in mind that very cerebral oedema. prolonged high dose inevitably brings serious • Prevention of adverse reaction to radiocontrast complications such as osteoporosis), on the severity media in patients who have had a previous severe of the disease and on whether the patient has failed reaction. to respond usefully to other treatment. It often • Blood diseases due to circulating antibodies, e.g. requires expertise that can be imparted only by thrombocytopenic purpura (there may also be a those with wide experience of the disease con- decrease in capillary fragility with lessening of cerned. The following are examples. purpura even though thrombocytes remain few); Adrenal steroids are used in all or nearly all cases of: agranulocytosis. • Exfoliative dermatitis and pemphigus, if severe • Eye diseases. Allergic diseases and • Collagen diseases, if severe, e.g. lupus nongranulomatous inflammation of the uveal erythematosus (systemic), polyarteritis nodosa, tract. But bacterial and virus infections may be polymyalgia rheumatica and cranial giant cell made worse and use of steroids to suppress arteritis (urgent therapy to save sight), inflammation of infection is generally dermatomyositis undesirable, is best left to ophthalmologists and • Acute severe asthma must be accompanied by effective • Acute lymphatic leukaemia (see p. 617) chemotherapy; this is of the greatest importance • Acquired haemolytic anaemia in herpes virus infection. Corneal integrity • Severe allergic reactions of all kinds, e.g. serum should be checked before use (by instilling a sickness, angio-oedema, trichiniasis. Alone they drop of fluorescein). Prolonged use of will not control acute manifestations of corticosteroid eye drops causes glaucoma in 1 in anaphylactic shock as they do not act quickly 20 of the population (a genetic trait). Application enough is generally as hydrocortisone, prednisolone or • Organ transplant rejection fluorometholone drops, or subconjunctival • Acute spinal cord injury: early, brief, and high injection. dose (to reduce the oedema/inflammation) • Nephrotic syndrome. Patients with minimal • Autoimmune active chronic hepatitis: a change disease respond well to daily or alternate corticosteroid improves wellbeing, liver day therapy. With a total of prednisolone 60 function and histology; prednisolone will benefit mg/d, 90% of those who will lose their some 80% and should be continued in the long proteinuria will have done so within 4-6 term, as most patients relapse if the drug is weeks, and the dose is tapered off over 3-4 withdrawn. months. Longer courses only induce adverse effects. Relapses are common (50%) and it is Adrenal steroids are used in some cases of: then necessary to find a minimum dose of • Rheumatic fever steroid that will keep the patient well. If a • Rheumatoid arthritis steroid is for any reason undesirable, • Ankylosing spondylitis cyclophosphamide or chlorambucil may be • Ulcerative colitis and proctitis substituted. Membranous nephropathy may • Regional enteritis (Crohn's disease) respond to high dose corticosteroid with or • Bronchial asthma and hay-fever (allergic rhinitis): without chlorambucil. also some bronchitics with marked airways • A variety of skin diseases, such as eczema. Severe obstruction. cases may be treated by occlusive dressings if a • Sarcoidosis. If there is hypercalcaemia or threat to systemic effect is not wanted, though absorption a major organ, e.g. eye, adrenal steroid can be substantial (see Ch. 16). 673
  14. 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). if rapid withdrawal is desired, a 50% reduction in • Hypercalcaemia of sarcoidosis and of vitamin D dose may be made each day; but if the patient has intoxication responds to prednisolone 30 mg been treated for a longer period, reduction in dose daily (or its equivalent of other steroid) for is accompanied by the dual risk of a flare up of the 10 days. Hypercalcaemia of myeloma and some disease and of iatrogenic hypoadrenalism; then other malignancies responds more variably. withdrawal should be done very slowly, e.g. 2.5-5 mg Hyperparathyroid hypercalcaemia does not prednisolone or equivalent at intervals of 3-7 days. respond. An alternative scheme is to try halving the dose • Raised intracranial pressure due to cerebral oedema, weekly until 25 mg prednisolone or equivalent is e.g. in cerebral tumour or encephalitis reached, after which it may be reduced by about (probably an anti-inflammatory effect which 1 mg every third to seventh day. Paediatric tablets reduces vascular permeability and acts in (1 mg) can be useful during withdrawal. 12-24 h): give dexamethasone 10 mg i.m. or i.v. But these schemes may yet be found too fast (or equivalent) initially and then 4 mg 6-hourly (giving rise to the occurrence of fatigue, 'dish-rag' by the appropriate route, reducing dose after syndrome, or relapse of disease) and the rate may 2-4 days and withdrawing over 5-7 days; but need to be even as slow as prednisolone 1 mg per much higher doses may be used in palliation day (or equivalent) per mouth, particularly as the of inoperable cerebral tumour. dose approaches the level of physiological require- • Preterm labour: (to mother) to enhance fetal lung ment (equivalent of prednisolone 5-7.5 mg daily). maturation. The long tetracosactride test (see later) or • Aspiration of gastric acid (Mendelsohn's measurements of plasma corticotropin concen- syndrome). tration may be used to assess recovery of adrenal • Myasthenia gravis: see page 439. responsiveness, but a positive result should not be • Cancer, see Chapter 30. 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 insulin- Use in diagnosis: dexamethasone suppression test. induced hypoglycaemia (which additionally tests Dexamethasone acts on the hypothalamus (like the hypothalamic/pituitary capacity to respond). hydrocortisone), to reduce output of corticotropin Corticotropin should not be used to hasten releasing hormone (CRH), but it does not interfere recovery of the atrophied cortex since its effects with measurement of corticosteroids in blood or cause further suppression of the hypothalamic- urine. Normal suppression of cortisol production pituitary axis, on the recovery of which the patient's after administering dexamethasone indicates that future depends. Complete recovery of normal the hypothalamic/pituitary/adrenal axis is intact. hypothalamic/pituitary/adrenal function sufficient Failure of suppression implies pathological hyper- to cope with severe intercurrent illnesses or surgery secretion of ACTH by the pituitary or of cortisol by is generally complete in 2 months but may take as the adrenal. Dexamethasone is used because its long as 2 years. action is prolonged (24 h). There are several ways of There have been many reports of collapse, even carrying out the test. 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 WITHDRAWAL OF them or failing to have their tablets with them and PHARMACOTHERAPY other trivial causes; but it is not invariable. Patients The longer the duration of therapy the slower must must be instructed on the hazards of omitting be the withdrawal. For use of less than 1 week (e.g. therapy and, during intercurrent disease, i.m. in severe asthma), although there is some hypo- preparations should be freely used. Anaesthesia thalamic suppression, withdrawal can be safely and surgery in adrenocortical insufficency is dis- accomplished in a few steps. After use for 2 weeks, cussed on page 676. 674
  15. ADRENOCORTICOTROPHIC HORMONE (ACTH) (CORTICOTROPIN) 34 Inhibition of synthesis of Adrenocorticotrophic adrenal and other steroid hormone (ACTH) hormones (corticotropin) These agents have use in diagnosis of adrenal Natural corticotropin is a 39-amino-acid poly- disease and in controlling excessive production of peptide secreted by the anterior pituitary gland; it is corticosteroids, e.g. by corticotropin producing obtained from animal pituitaries. tumours of the pituitary (Cushing's syndrome) or The physiological activity resides in the first 24 by adrenocortical adenoma or carcinoma where the amino acids (which are common to many species) cause cannot be removed. They must be used with and most immunological activity resides in the special care since they can precipitate acute adrenal remaining 15 amino acids. insufficiency. Some members inhibit other steroid The pituitary output of corticotropin responds synthesis. rapidly to physiological requirements by the Metyrapone inhibits the enzyme, steroid 11(3- familiar negative-feedback homeostatic mechanism. hydroxylase, that converts 11-deoxy precursors into Since the t1// of corticotropin is 10 min and the hydrocortisone, corticosterone and aldosterone. It adrenal cortex responds rapidly (within 2 min) it is affects synthesis of aldosterone less than that of plain that adjustments of steroid output can be glucocorticoids. quickly made. Trilostane blocks the synthetic path earlier (3(3- hydroxysteroid dehydrogenase) and thus also Synthetic corticotropins have the advantage that inhibits aldosterone synthesis. they are shorter amino acid chains (devoid of amino Formestane is a specific inhibitor of the aromatase acids 25-39) and so are less likely to cause serious which converts androgens to oestrogens. A depot allergy, though this can happen. In addition they injection of 250 mg i.m. is given twice a month in are not contaminated by animal proteins which are the treatment of some patients with carcinoma of potent allergens. the breast who relapse on tamoxifen. Tetracosactride (tetracosactrin) consists of the Aminoglutethimide blocks even earlier, prevent- biologically active first 24 amino acids of natural ing the conversion of cholesterol to pregnenolone. It corticotropin (from man or animals and so it has therefore blocks synthesis of all steroids, hydro- similar properties, e.g. tl/2 10 min. cortisone, aldosterone and sex hormones (including the conversion of androgens to oestrogens); it has a ACTIONS use in breast cancer. Ketoconazole is an effective antifungal agent by Corticotropin stimulates the synthesis of cortico- virtue of its capacity to block sterol/steroid steroids (of which the most important is hydro- synthesis (ergosterol in the case of fungi). In man it cortisone) and to a lesser extent of androgens, by inhibits steroid synthesis in gonads and adrenal the cells of the adrenal cortex. It has only a minor cortex and it has been used in Cushing's syndrome (transient) effect on aldosterone production, which and prostatic cancer. can proceed independently; in the absence of corticotropin the cells of the inner cortex atrophy. The release of natural corticotropin by the COMPETITIVE ANTAGONISM OF pituitary gland is controlled by the hypothalamus ADRENAL STEROIDS via corticotropin releasing hormone (CRH or cortico- Spironolactone antagonises the sodium-retaining liberin), production of which is influenced by effect of aldosterone and other mineralocorticoids. environmental stresses as well as by the level of It is used to treat primary and secondary hyper- circulating hydrocortisone. High plasma concen- aldosteronism (p. 538). tration of any steroid with glucocorticoid effect 675
  16. 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 • Cortisol and aldosterone produced in the adrenal in adrenocortical hypofunction. This is the reason cortex have a major role in physiology and why catastrophe may follow sudden withdrawal of pharmacology. steroid therapy in the chronically treated patient • Physiological concentrations of cortisol are essential who has an atrophied cortex. for supporting the circulation and glucose production. Physiological concentrations of aldosterone are essential to prevent excessive sodium loss. The effects of corticotropin are those of the steroids • For systemic pharmacological uses, prednisolone or (hydrocortisone, androgens) liberated by its action other synthetic adrenocorticosteriods are used on the adrenal cortex. Prolonged heavy dosage because they are more selective glucocorticoids, i.e. causes the clinical picture of Cushing's syndrome. have less sodium-retaining activity. • For local administration (skin, lung), more potent, fluorinated steroids may be required. Uses. Corticotropin is used principally in diagnosis • Glucocorticoids inhibit the transcriptional activation and rarely in treatment. It is inactive if taken orally of many of the inflammatory cytokines, giving them a and has to be injected like other peptide hormones. versatile role in the treatment of many types of inflammation. • Fludrocortisone is a valuable treatment for many Diagnostic use: as a test of the capacity of the sodium-losing states, and for most causes of adrenal cortex to produce cortisol; with the short autonomic neuropathy. test, the plasma cortisol (hydrocortisone) concen- tration is measured before and after an i.m. injection of tetracosactride (Synacthen); a normal GUIDETO FURTHER READING response is a rise of more than 200 nanomol/1 in the plasma concentration of hydrocortisone. Longer Boscaro M et al 2001 Cushing's syndrome. Lancet 357: variants of the test in cases of difficulty involve use 783-791 of the depot (sustained-release) formulation i.m. English J et al 1983 Diurnal variation in prednisolone For example, 1 mg of the depot is injected daily for kinetics. Clinical Pharmacology and Therapeutics 3 days at 9.00 am, with a short tetracosactride test 33: 381 performed on day 3. Freidy J F 1988 Reactions to contrast media and Therapeutic use is seldom appropriate because steroid pretreatment. British Medical Journal 296: the peptide hormone has to be injected; selective 809 glucocorticoid action (without mineralocorticoid Hench P S et al 1949 The effect of a hormone of the effect) cannot be obtained, and clinical results are adrenal cortex (17-hydroxy-ll- irregular. Corticotropin can not be relied on to dehydrocorticosterone: Compound E) and of restore adrenal cortisol output when a steroid is pituitary adrenocorticotrophic hormone on being withdrawn after prolonged therapy, as it rheumatoid arthritis. Proceedings of the Staff does not restore function in the suppressed Meetings of the Mayo Clinic 24:181, 277 (acute hypothalamic/pituitary part of the HPA axis. 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 Preparations Kendall of the biochemical and pharmaceutical Tetracosactride Injection is a powder dissolved in background to the clinical studies. Kendall writes water immediately before injection i.v., i.m. or s.c. of his collaboration with Hench, 'he can now say Tetracosactride Zinc Injection (Synacthen Depot) in "17-hydroxy-ll-dehydrocorticosterone" and in which the hormone is adsorbed on to zinc phos- turn I can say "the arthritis of lupus phate from which it is slowly released. This is the erythematosus". In sophisticated circles, however, I form used in the long tetracosactride test. prefer to say, "the arthritis of L.E."'. 676
  17. 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 ( A C T H ) ( C O RT I C O T R O P I N ) 34 Hilditch K 2000 My Addison's disease. British Medical Marx J 1995 How the glucocorticoids suppress Journal 321: 645 (A patient's account of the immunity. Science 270: 232-233 disease.) Mitchell A, O'Keane V 1998 Steroids and depression. Lamberts S W J, Bruining H A, de Jong F H 1997 British Medical Journal 316: 244-245 Corticosteroid therapy in severe illness. New Newton R W et al 1978 Adrenocortical suppression in England Journal of Medicine 337:1285-1292 workers manufacturing synthetic glucocorticoids. Lipworth B J 2000 Therapeutic implications of non- British Medical Journal 1: 73 genomic 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 677
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