Adrenal corticosteroids, antagonists, corticotropin

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Chapter 35 Adrenal corticosteroids, antagonists, corticotropin

Diana C. Brown

Synopsis

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 made between the hormones secreted by the cortex and medulla.

By 1936, numerous steroids were being crystallised from cortical extracts, but the quantities were insufficient 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 cortisol. The pharmaceutical term for cortisol is hydrocortisone. The two terms are often used interchangeably. In this chapter, cortisol is used when describing endogenous hormone secretion, and hydrocortisone when describing exogenous drug administration. Since then many steroids have been synthesised, covering the wide range of efficacy and potency required by the many indications for systemic and local use. Steroids derive from natural substances, chiefly plant sterols. The ideal steroid drug, providing all the desirable and none of the undesirable effects of cortisol, remains elusive. Research showing the multiple molecular actions of steroids within the target cell has explained the difficulty of achieving the ideal, but may help to bring this closer.

About the same time as cortisone was introduced, adrenocorticotrophin (ACTH) became available for clinical use. Its use is now largely for diagnostic tests of the pituitary–adrenal axis.

Adrenal steroids and their synthetic analogues

The adrenal is a composite endocrine gland, and each zone of the cortex synthesises a different predominant steroid; a mnemonic is offered in Figure 35.1, in which the first letter of each word is the first letter of each zone and its corresponding steroid product. The principal synthetic pathways are illustrated in Figure 35.2.

Fig. 35.1 The zones of the adrenal gland and the hormones they secrete.

Fig. 35.2 Adrenal corticosteroid biosynthesis.

The principal hormone is the glucocorticoid cortisol secreted from the largest zone, the fasciculata; the mineralocorticoid aldosterone is secreted by the glomerulosa, and a number of androgens and oestrogens are secreted by the zona reticularis. The hypothalamic–pituitary system, through corticotropin releasing factor (CRF) and ACTH, controls cortisol and, to a lesser extent, aldosterone secretion; synthesis and secretion of aldosterone is regulated mainly by the renin–angiotensin system, and by variation in plasma K⁺ levels.

Adrenal corticosteroids are available for physiological replacement therapy, in primary (Addison’s disease), secondary adrenal insufficiency and congenital adrenal hyperplasia, but their chief use in medicine is for their anti-inflammatory and immunosuppressive effects (pharmacotherapy). Supraphysiological doses are generally required to achieve these pharmacological effects. Chronic use of supraphysiological doses has many adverse effects. Much successful effort has gone into separating glucocorticoid from mineralocorticoid effects.

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 38.

Mechanism of action

Glucocorticoids stimulate the cell through both a classical cytosolic receptor that, on binding with agonist, translocates to the nucleus, and an unidentified membrane-bound receptor (Fig. 35.3). The classical receptor is responsible for so-called genomic effects through either activation or repression of DNA transcription. Up-regulation of gene transcription occurs when the receptor dimerises on specific DNA glucocorticoid response elements (GREs) with consequent recruitment of coactivator proteins. Many of the undesired effects of glucocorticoid occur through this pathway.

Fig. 35.3 Three general mechanisms of action of glucocorticoids and the glucocorticoid receptor in the inhibition of inflammation: non-genomic activation, DNA-dependent regulation, and protein interference mechanisms (e.g. NF-κBΒ elements). Red arrows denote activation, the red line inhibition, the blue arrow repression, and the red X lack of product (i.e. no mRNA). HSP, heat-shock protein; mRNA, messenger RNA; NF, nuclear factor; P, phosphate; TNF, tumour necrosis factor.

(Adapted from Rhen T, Cidlowski J A 2005 Antiinflammatory action of glucocorticoids – new mechanisms for old drugs. New England Journal of Medicine 353(16):1711–1723.)

Repression of DNA transcription occurs at slightly lower cortisol concentrations than required for transactivation. Through protein–protein interaction, the glucocorticoid–receptor complex inactivates pro-inflammatory transcription factors such as nuclear factor (NF)-κB and activator protein 1 (AP-1), preventing their stimulation of inflammatory mediators: prostaglandins, leukotrienes, cytokines and platelet-activating factor. These mediators would normally contribute to increased vascular permeability and subsequent changes including oedema, leucocyte migration and fibrin deposition.¹

There is a distinction between replacement therapy (physiological effects) and the higher doses of pharmacotherapy. However, the distinction is not absolute because cortisol is a stress hormone, and some of its physiological actions are triggered by the increased secretion of cortisol during acute or chronic stress. In the list that follows, the main physiological effects are those concerned with elimination of a water load, and mobilisation of glucose. The suppression of inflammatory mediators may also be seen as part of physiological homeostasis.

On inorganic metabolism

Cortisol is required for excretion of a water load. This action is due to maintenance of glomerular filtration, activation of atrial natriuretic factor, and inhibition of vasopressin secretion. These physiological effects are unrelated to the mineralocorticoid (Na⁺-retaining) action of cortisol that occurs at supraphysiological concentrations.

On organic metabolism

• Carbohydrate metabolism. Glycogenolysis and gluconeogenesis are increased and peripheral glucose utilisation is decreased (due to insulin antagonism).

• Protein metabolism. Anabolism (conversion of amino acids to protein) decreases but catabolism continues, so that there is a negative nitrogen balance with muscle wasting. 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.

• Bone metabolism. Cortisol inhibits the number and function of osteoblasts, and the synthesis of collagen. Osteoporosis (reduction of bone protein matrix) is the main consequence of chronic glucocorticoid administration. Growth slows in children.

• Fat metabolism. Lipolysis is increased, and the secretion of leptin (the appetite suppressant) is inhibited. These actions lead to increased appetite and deposition of adipose tissue, particularly on shoulders, face and abdomen.

• Inflammatory response is depressed. Neutrophil and macrophage function are depressed, including the release of chemical mediators and the effects of these on capillaries.

• Allergic responses are suppressed. The antigen–antibody interaction is unaffected, but its injurious inflammatory consequences do not follow.

• Antibody production is lessened by heavy doses.

• Lymphoid tissue is reduced (including leukaemic lymphocytes).

• Renal excretion of urate is increased.

• Blood eosinophils reduce in number and neutrophils increase.

• Euphoria or psychotic states may occur, perhaps due to central nervous system (CNS) electrolyte changes.

• Anti-vitamin D action, see calciferol (p. 635).

• Reduction of hypercalcaemia, 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 reduces where new cells are being added (growth in children), but not where they are replacing cells as in adult tissues.

• Suppression of hypothalamic–pituitary–adrenocortical feedback system (with delayed recovery) occurs with chronic use, so that abrupt withdrawal leaves the patient in a state of adrenocortical insufficiency.

The average daily secretion of cortisol is normally 10 mg (5.7 mg/m²). 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 gland continues to secrete aldosterone.

Individual adrenal steroids

The relative potencies ¹ for glucocorticoid and mineralocorticoid (sodium-retaining) effects (Table 35.1) are central to the choice of agent in relation to clinical indication.

Table 35.1 Relative potencies of adrenal steroids

All drugs in Table 35.1 except aldosterone are active when swallowed, being protected from hepatic first-pass metabolism by high binding to plasma proteins. Some details of preparations and equivalent doses appear in the table. Injectable and topical forms are available (creams, suppositories, eye drops).

The selectivity of hydrocortisone for the glucocorticoid receptor is due not 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 β-hydroxysteroid dehydrogenase, which converts cortisol to the inactive cortisone. This enzyme saturates at concentrations of cortisol (and some synthetic glucocorticoids) just above the physiological range, which explains the onset of mineralocorticoid action with pathological secretion of cortisol, and pharmacological use of glucocorticoids.

Hydrocortisone

(cortisol) is the principal naturally occurring steroid; it is taken orally; a soluble salt can be given intravenously for rapid effect in emergency whether due to deficiency, allergy or inflammatory disease. A suspension (Hydrocortisone Acetate Inj.) is available for intra-articular injection.

Parenteral preparation for systemic effect: the soluble Hydrocortisone Sodium Succinate Inj. gives quick (1–2 h) effect; for continuous effect, about 6-hourly administration is appropriate. Prednisolone Acetate Inj. i.m. is an alternative, once or twice a week.

Tablet strengths, see Table 35.1.

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 intramuscularly.

Methylprednisolone

Fluorinated corticosteroids (triamcinolone, fludrocortisone)

Triamcinolone

has virtually no sodium-retaining (mineralocorticoid) effect. Muscle wasting may occasionally be severe, and chronic administration is therefore contraindicated. Anorexia and mental depression can occur at high dose.

Fludrocortisone

is a synthetic mineralocorticoid, which stimulates sodium retention. It can replace aldosterone when the adrenal cortex is destroyed (Addison’s disease). Fludrocortisone is also the drug of choice in most patients with autonomic neuropathy, in whom volume expansion is easier to achieve than a sustained increase in vasoconstrictor tone. Much higher doses of fludrocortisone (0.5–1.0 mg) are required when the cause of hypotension is a salt-losing syndrome of renal origin, e.g. after an episode of interstitial nephritis.

Dexamethasone and betamethasone

Aldosterone

(t_½ 20 min), is the principal natural salt-retaining hormone. After oral administration, it is rapidly inactivated in the first pass through the liver and is not available for therapeutic use.

Spironolactone

(see p. 550) is a competitive mineralocorticoid (aldosterone) antagonist. It is used in the treatment of primary hyperaldosteronism, as a diuretic in resistant hypertension, and when severe oedema is due to secondary hyperaldosteronism, e.g. cirrhosis, congestive cardiac failure. Long-term treatment increases survival in cardiac failure, possibly through blocking the fibrotic effect of aldosterone upon the heart. The dose of spironolactone is limited by its anti-androgen activity. Eplerenone has greater selectivity than spironolactone for the mineralocorticoid than androgen receptor, but has lower efficacy in blocking aldosterone and may need to be used together with amiloride.

Beclometasone, budesonide, fluticasone, mometasone and ciclesonide

are potent soluble steroids suitable for use by inhalation for asthma (see p. 474) and intranasally for hay fever. Patients swallow about 90% of an inhalation dose, which is then largely inactivated by hepatic first-pass. The drugs are listed in order of development; some newer agents possess properties (first-pass metabolism, high protein binding and lipophilicity) that may increase pulmonary residence time and reduce systemic effects. The main protection against these effects is simply that absorption through mouth, lungs and gut is low relative to the amounts used in systemic administration. The risk of suppression of the hypothalamic–pituitary–adrenal (HPA) axis is infrequent and dose dependent. The greatest risk of suppression appears to occur with high-dose fluticasone usage in children, who may present with hypoglycaemia and acute adrenal insufficiency.

Pharmacokinetics of corticosteroids

Absorption of the synthetic steroids given orally is rapid. The plasma t_½ of most is 1–3 h but the maximum biological effect occurs after 2–8 h. Administration is usually two or three times a day. They are metabolised principally in the liver (some undergoing hepatic first-pass metabolism, see above) and some pass unchanged into the urine. Hepatic and renal disease prolongs, and enzyme induction shortens, t_½ 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 circulate in both free and bound forms. Only the free form is biologically active. In the case of hydrocortisone, 95% is bound to cortisol-binding globulin (CBG). This has high affinity, but low capacity; when CBG is saturated, hydrocortisone is 80% bound to albumin.

Because CBG is saturated at peak diurnal levels of cortisol, the free cortisol concentration ranges from approximately 1 nanomol/L at the diurnal trough to approximately 100 nanomol/L at the diurnal peak. CBG concentrations increase in the presence of oestrogens, e.g. pregnancy, oral contraceptives.

In patients with very low serum albumin, the steroid dose should be lowered to allow for reduced binding capacity. In liver disease, low albumin concentration may be accompanied by slow metabolism (t_½ of prednisolone may be doubled).

Dosage schedules

Various dosing schedules have attempted to limit HPA suppression by allowing the plasma steroid concentration to fall between doses in order to provide time for pituitary recovery. These have not been successful. Daily administration, preferably as a single morning dose, is required for the shortest time necessary. For some indications, e.g. use of methylprednisolone in collagen diseases, pulsed administration of high doses is employed at intervals of weeks or months.

Choice of adrenal steroid: summary

• For oral replacement therapy in adrenocortical insufficiency, use hydrocortisone as the glucocorticoid. In primary adrenal failure (Addison’s disease and congenital adrenal hyperplasia), use fludrocortisone as the mineralocorticoid to replace aldosterone.

• For anti-inflammatory and antiallergic (immunosuppressive) effect, use prednisolone or dexamethasone. For inhalation, more potent adrenal steroids are required, e.g. beclometasone or budesonide.

• In diagnostic testing use dexamethasone. In adults with congenital adrenal hyperplasia use hydrocortisone, prednisolone or dexamethasone and hydrocortisone in children.

Adverse effects of systemic adrenal steroid pharmacotherapy

These arise from an excess of the physiological or pharmacological actions of hydrocortisone. Adverse effects are dependent on the corticosteroid used, and on dose and duration. Some occur only with systemic use and for this reason local therapy, e.g. inhalation, intra-articular injection, is preferred where practicable.

The principal adverse effects of chronic corticosteroid administration are:

Precautions during chronic adrenal steroid therapy

The most important precaution during replacement and pharmacotherapy is regular review for adverse effects including fluid retention (weight gain), hypertension, glycosuria, hypokalaemia (potassium supplements may be necessary) and back pain (osteoporosis). The main hazard is patient non-compliance.

Patients must always:

• carry a steroid card giving details of therapy

• be impressed with the importance of compliance

• know what to do if they develop an intercurrent illness or other severe stress, i.e. double their next dose and consult their doctor. If a patient omits a dose, a replacement dose should be taken as soon as possible to maintain the same total daily intake, because every patient should be taking the minimum dose necessary to control the disease

• have access to parenteral hydrocortisone (their own supply for i.m. injection, if urgent medical referral is not always possible).

Membership of one of the self-help patient groups can be helpful.

Treatment of intercurrent illness

The normal adrenal cortex responds to severe stress by secreting more than 300 mg hydrocortisone daily. During intercurrent illness, or any other form of severe stress, escalation of steroid dose, and treatment of the underlying problem, is urgent. Effective chemotherapy of bacterial infections is especially important.

Viral infections contracted during steroid therapy (prednisolone 20 mg/day, or the equivalent) can be overwhelming. Immunosuppressed patients exposed to varicella/herpes zoster virus may need passive protection with varicella zoster immunoglobulin (VZIG) as soon as practicable. However, corticosteroid may sometimes be useful therapy for some viral diseases (e.g. thyroiditis, encephalitis) once there has been time for the immune response to occur. Corticosteroid then acts by suppressing unwanted effects of immune responses and excessive inflammatory reaction.

Vomiting warrants parenteral steroid.

Surgery requires that patients receive hydrocortisone 100 mg i.m. or i.v. (or hydrocortisone 20 mg orally) with premedication. If there are any signs of cardiovascular collapse during the operation, infuse hydrocortisone (100 mg) i.v. at once. If surgery is uncomplicated, hydrocortisone 50–100 mg i.v. or i.m. every 6 h for 24–72 h is adequate for most patients on replacement therapy. Then reduce the dose by half every 24 h until the normal dose 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 of these situations, an intravenous infusion should be available for immediate use in case the recommendations above are insufficient. These precautions are particularly relevant for patients who have received substantial corticosteroid treatment within the previous year, because their HPA system may fail to respond adequately to severe stress. If steroid therapy has been very prolonged, and in patients undergoing adrenalectomy for Cushing’s syndrome for adrenal adenoma (because the remaining adrenal gland is atrophic), the precautions apply for as long as 2 years afterwards, or until there is evidence of recovery of normal adrenal function.

Dosage and routes of administration

No single schedule suits every case, but examples appear below.

Systemic commencing doses:

• For a serious disease such as systemic lupus, dermatomyositis: prednisolone up to 0.5–1.5 mg/kg daily, orally in divided doses. There is no evidence of increased benefit above 60–80 mg/day.

• If the condition is life-threatening, give prednisolone up to 60 mg, or its equivalent of another steroid. Cyclophosphamide or azathioprine (see p. 250) are valuable adjuncts which may enhance the initial control of the disease and have a sparing effect on the maintenance dose of prednisolone.

• Alternatively, high dose pulses (methylprednisolone 1.0 g i.v. daily for 3 days) may be used, followed by oral maintenance with prednisolone and/or a steroid-sparing agent (above).

• For less dangerous disease, e.g. rheumatoid arthritis, give prednisolone 7.5–10.0 mg daily, adjusted later according to the response.

• In particular cases, including replacement of adrenal insufficiency, the dosage appears in the account of the disease.

• For continuous therapy, give the minimum amount to produce the desired effect. Imperfect control may have to be accepted by the patient if full control, e.g. of rheumatoid arthritis, though obtainable, involves doses that will lead to toxicity, e.g. osteoporosis, if continued for years.

Topical applications

(creams, intranasal, inhalations, enemas) are used in order to obtain local effect, while avoiding systemic effects; suspensions of solutions are also injected into joints, soft tissues and subconjunctivally. All can, in heavy dose, be absorbed sufficiently to suppress the hypothalamus and cause other unwanted effects. Individual preparations appear in the text where appropriate.

Contraindications

to adrenal steroids for suppressing inflammation are all relative. Where the patient has diabetes, a history of mental disorder or peptic ulcer, epilepsy, tuberculosis, hypertension or heart failure, the reasons for use must be compelling. The presence of any infection demands that effective chemotherapy be begun before the corticosteroid, but there are exceptions (some viral infections, see above). Topical corticosteroid applied to an inflamed eye can be disastrous if the inflammation is due to herpes virus.

Adrenal steroids containing fluorine (see above) intensify diabetes more than do others and are to be avoided in that disease.

Long-term use of adrenal steroids in children

presents essentially the same problems as in adults with the addition of growth retardation. This is unlikely to be important unless therapy exceeds 6 months; there is a growth spurt after withdrawal. The dose should be reduced to the minimum required to maintain immunosuppression and be given daily or alternate days.

Common childhood viral infections may be more severe, and if a non-immune child taking steroids is exposed to virus infection it is wise to try to prevent the disease with the appropriate specific immunoglobulin.

Live virus vaccination is unsafe in immunosuppressed subjects, e.g. systemic prednisolone, more than 2 mg/kg/day for more than 1 week in the preceding 3 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.

Indications for use of adrenal steroids

• Replacement of hormone deficiency.

• Inflammation suppression.

• Immunosuppression.

• Suppression of excess hormone secretion.

Uses of adrenocortical steroids

Replacement therapy

Acute adrenocortical insufficiency (Addisonian crisis)

This is an emergency; hydrocortisone sodium succinate 100 mg is given i.v. immediately it is suspected.

• An intravenous infusion of sodium chloride solution (0.9%) is set up immediately and a second 100 mg hydrocortisone is added to the first litre, which should be given as quickly as the cardiovascular status permits (2–3 L of sodium chloride may be infused in the first 1–2 h and 5–6 L may be needed in the first 24 h).

• The patient should then receive hydrocortisone 50 mg i.v. or i.m. 6-hourly for 24–72 h; thereafter a total of 30–40 mg/day orally in two or three divided doses usually suffices.

Treatment to restore electrolyte balance will depend on the circumstances. Seek and treat the cause of the crisis; it is often an infection. When the dose of hydrocortisone falls below 40 mg/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.

Chronic primary adrenocortical insufficiency (Addison’s disease)

Hydrocortisone is given orally (15–25 mg total daily) in two to three divided doses, according to the algorithm in Figure 35.4. Some patients working under increased physical activity or mental stress may require higher doses up to 40 mg daily. The aim is to mimic the natural diurnal rhythm of secretion. All patients also require mineralocorticoid replacement, and fludrocortisone; 50–200 micrograms orally once a day is the usual dose.

Fig. 35.4 Algorithm for treatment of the glucocorticoid-deficient patient. Patients should be reassessed at 6–8-week intervals while their treatment is optimised.

(Adapted from Crown A, Lightman S 2005 Why is the management of glucocorticoid deficiency still controversial: a review of the literature? Clinical Endocrinology 63:483–492.)

The dose 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. In addition, measurement of cortisol levels at critical points in the day as a day curve can be done and the information used to adjust the hydrocortisone dose. Where available, plasma renin assay is useful for titration of fludrocortisone dose. If any complicating disease arises, e.g. infection, a need for surgery or other stress, the hydrocortisone dose is immediately doubled.

If there is vomiting, the parenteral replacement hormone must be given without delay.

Chronic secondary adrenocortical insufficiency

This occurs in hypopituitarism. The need for hydrocortisone may be less than in primary insufficiency, especially when ACTH deficiency is partial. Some patients with borderline adrenocortical insufficiency may require steroid supplementation only during periods of stress, such as infection or surgery. Mineralocorticoid replacement is seldom required, for the pituitary has little control over aldosterone production. Other pituitary replacement is given as appropriate (see p. 596).

Iatrogenic adrenocortical insufficiency: abrupt withdrawal

Sudden withdrawal of large doses of steroid hormone used to suppress inflammation or allergy may lead not only to an adrenal insufficiency crisis but also to relapse of the disease that is suppressed, not cured. Such relapse can be extremely severe, and sometimes life-threatening. Secondary adrenal insufficiency can occur after high-dose inhaled potent glucocorticoids in the treatment of asthma (see above).

It remains essential to use only the minimum dose that will achieve the desired effect. Sometimes therapeutic effects are partly sacrificed to avoid adverse effects, as it has not so far proved possible to separate all the glucocorticoid effects from one another; for example, it is not known whether it is possible to eliminate catabolic effects and yet retain anti-inflammatory action. In some conditions, e.g. nephrotic syndrome, the clinician cannot specify exactly what action they want the drug developer to provide.

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), on the severity of the disease and on whether the patient has failed to respond usefully to other treatment.

Adrenal steroids are used in nearly all cases of the following:

• Exfoliative dermatitis and pemphigus, if severe.

• Connective tissue diseases, if severe, e.g. lupus erythematosus (systemic), polyarteritis nodosa, polymyalgia rheumatica and cranial giant cell arteritis (urgent therapy to save sight), dermatomyositis.

• Severe asthma (see p. 477).

• Acute lymphatic leukaemia (see Ch. 31).

• Acquired haemolytic anaemia.

• Severe allergic reactions of all kinds, e.g. serum sickness, angioedema, trichiniasis. Alone, they will not control acute manifestations of anaphylactic shock as they do 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 well-being, liver function and histological findings; 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 the following:

• Rheumatic fever.

• Rheumatoid arthritis.

• Ankylosing spondylitis.

• Ulcerative colitis and proctitis.

• Regional enteritis (Crohn’s disease).

• 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 administration is urgent. Pulmonary fibrosis may be delayed and CNS 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 non-granulomatous inflammation of the uveal tract. Bacterial and viral infections may be made worse and use of corticosteroids 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 1 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 prednisolone, 2 mg/kg, for 6 weeks followed by 1.5 mg/kg on alternate days. Relapses are treated with the higher dose until proteinuria is trace level only, and then the lower dose for a month. Multiple relapses then require a tapering dose over several months rather than complete withdrawal. In such patients, steroid sparing agents, ciclosporin, tacrolimus, and mycophenolate, may be used to reduce long-term dosing.

• A variety of skin diseases, such as eczema. Severe cases may involve occlusive dressings if a systemic effect is undesirable, though absorption can be substantial (see Ch. 17).

• Aphthous ulcers. Hydrocortisone 2.5 mg oromucosal tablets are allowed to dissolve next to the ulcer; beclometasone dipropionate inhaler 50-100 micrograms may be sprayed on the oral mucosal, or betamethasone soluble talet 500 miligrams dissolved in water may be used, without swallowing, as a mouth wash. Triamcinolone acetonide in Orabase, or fluocinonide gel covered by Orabase may be used where available. Early initiation of treatment may accelerate healing.

• Acute gout resistant to other drugs (see p. 255).

• Hypercalcaemia of sarcoidosis and of vitamin D intoxication responds to prednisolone 30 mg daily (or its equivalent of other adrenal steroid) for 10 days. Hypercalcaemia of myeloma and some other malignancies responds more variably. Hyperparathyroid hypercalcaemia does not respond (see p. 638).

• Raised intracranial pressure due to cerebral oedema, e.g. in cerebral tumour or encephalitis. This is 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 4 mg 6-hourly by the appropriate route, reducing the dose after 2–4 days and withdrawing over 5–7 days. 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 377.

• Cancer, see Chapter 31.

Use in diagnosis

Dexamethasone suppression test. Dexamethasone acts on the hypothalamus to reduce output of corticotropin releasing hormone (CRH), but it does not interfere with measurement of cortisol in blood or urine. Normal suppression of cortisol production after administering low dexamethasone (0.5 mg 6-hourly) indicates that the HPA axis is intact. Failure of suppression implies pathological hypersecretion of ACTH by the pituitary, ectopic ACTH or autonomous secretion 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.

If use is less than 1 week, e.g. for acute asthma, although some hypothalamic suppression will have occurred, withdrawal can be safely accomplished in a few steps.

After use for 2 weeks, for rapid withdrawal, a 50% reduction in dose each day is reasonable.

If the duration of treatment is longer, dose reduction is accompanied by the dual risk of resurgence of the disease and iatrogenic hypoadrenalism; withdrawal should then proceed very slowly, e.g. 2.5–5 mg prednisolone or equivalent at intervals of 3–7 days.

An alternative scheme is to halve the dose weekly until it is 25 mg/day of prednisolone or equivalent, then to make reductions of about 1 mg/day every third to seventh day. Paediatric tablets (1 mg) can be useful during withdrawal.

These schemes may yet be too rapid (with the occurrence of fatigue, ‘dish-rag’ syndrome or relapse of disease). The rate of reduction may then need to be as slow as prednisolone 1 mg/day (or equivalent) per month, particularly as the dose approaches the level of physiological requirement (equivalent of prednisolone 5–7.5 mg daily).

The long tetracosactide test (see below) or plasma corticotropin concentration is useful to assess recovery of adrenal responsiveness. A positive result does not necessarily indicate full recovery of the patient’s ability to respond to stressful situations; the latter is best shown by an adequate response to insulin-induced hypoglycaemia (which additionally tests hypothalamic–pituitary capacity to respond).

Corticotropin should not be used to hasten recovery of the atrophied cortex because its effects further suppress the hypothalamic–pituitary axis, on recovery of which the patient’s future depends. Complete recovery of normal HPA function sufficient to cope with severe intercurrent illnesses or surgery is generally complete in 2 months but may take as long as 2 years.

There are many reports of collapse, even coma, occurring within a few hours of omission of adrenal steroid therapy, e.g. due to patients’ ignorance of the risk to which their physicians are exposing them, or failure to carry their tablets with them. Patients must be instructed on the hazards of omitting therapy and, during intercurrent disease, intramuscular preparations should be freely used. For anaesthesia and surgery in adrenocortical insufficiency, see page 566.

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. Use of these drugs calls for special care as they can precipitate acute adrenal insufficiency. Hydrocortisone replacement in a block and replace regimen may be given. Some members inhibit other steroid synthesis.

Metyrapone inhibits the enzyme, steroid 11β-hydroxylase, which 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 (3β-hydroxysteroid dehydrogenase) and thus inhibits aldosterone synthesis as well.

Formestane is a specific inhibitor of the aromatase that converts androgens to oestrogens. A depot injection of 250 mg i.m. is given twice a month to treat some patients with carcinoma of the breast who have relapsed on tamoxifen.

Aminoglutethimide blocks at an even earlier stage, preventing the conversion of cholesterol to pregnenolone. It therefore stops synthesis of all steroids, hydrocortisone, aldosterone and sex hormones (including the conversion of androgens to oestrogens); it has a use in breast cancer.

Ketoconazole inhibits several cytochrome P450 enzymes, including those involved in steroid synthesis. It is an effective antifungal agent by virtue of its capacity to block ergosterol synthesis. In humans it inhibits steroid synthesis in gonads and adrenal cortex. Its principal P450 target in the adrenal is the enzyme CYP 11B1 (11β-hydroxylase), which catalyses the final step in cortisol synthesis. CYP 11B1 inhibition by ketoconazole renders it a useful treatment for Cushing’s syndrome, while testosterone synthesis inhibitors may be useful in advanced prostatic cancer.

Anastrozole is an adrenal aromatase inhibitor that finds use as adjuvant treatment of oestrogen receptor-positive early breast cancer in postmenopausal women. It is used as sole therapy, following 2–3 years of tamoxifen, in advanced breast cancer in postmenopausal women that is oestrogen receptor positive or responsive to tamoxifen. Letrozole and exemestane are similar.

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 (see p. 563).

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 lies in the remaining 15 amino acids.

The pituitary output of corticotropin responds rapidly to physiological requirements by the familiar negative-feedback homeostatic mechanism. As the t_½ of corticotropin is 10 min and the adrenal cortex responds within 2 min, corticosteroid output can adjust rapidly.

Synthetic corticotropins

have the advantage of shorter amino acid chains (they lack amino acids 25–39) which are less likely to cause serious allergy, although this does occur. Additionally, they are devoid of animal proteins, which are potent allergens.

Tetracosactide (tetracosactrin) consists of the biologically active first 24 amino acids of natural corticotropin (from humans or animals) and so it has similar properties, e.g. t_½ 10 min.

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Corticotropin stimulates the synthesis of corticosteroids (of which the most important is cortisol) 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 proceeds 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 through corticotropin releasing hormone (CRH, or corticoliberin), production of which is influenced by environmental stresses as well as by the level of circulating cortisol. High plasma concentration of any adrenal steroid with glucocorticoid effect prevents release of CRH and so of corticotropin, lack of which in turn results in adrenocortical hypofunction. This is why catastrophe may accompany abrupt withdrawal of long-term adrenal steroid therapy with adrenal atrophy.

is to test the capacity of the adrenal cortex to produce cortisol. With the short synacthen test, the plasma cortisol concentration is measured before and 30 min and 60 min after an intramuscular injection of 250 micrograms of tetracosactide (Synacthen); a normal response is a rise in plasma cortisol concentration of more than 200 nmol/L or a peak of greater than 500 nmol/L at 30 or 60 min. In cases of uncertainty, the longer variants of the test require intramuscular injection of a depot (sustained-release) formulation, e.g. 1 mg daily for 3 days at 09:00 hours, with a short tetracosactide test performed on day 3.

Therapeutic use

is seldom appropriate, as the peptide hormone must be injected. Selective glucocorticoid (without mineralocorticoid) action is not possible, and clinical results are irregular. Corticotropin cannot 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

• Tetracosactide Injection is supplied as an ampoule for injection i.v., i.m. or s.c.

• Tetracosactide Zinc Injection (Synacthen Depot) i.m. in which the hormone is adsorbed on to zinc phosphate from which it is slowly released. This is the form used in the long tetracosactide test.

Summary

• Physiological concentrations of cortisol are essential for supporting the circulation and glucose production. Physiological concentrations of aldosterone are essential to prevent excessive sodium loss.

• For systemic pharmacological uses, prednisolone or other synthetic adrenocorticosteroids 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.

• Glucocorticoids inhibit the transcriptional activation of many of the inflammatory cytokines, giving them a versatile role in the treatment of many types of inflammation.

• Fludrocortisone is a valuable treatment for many sodium-losing states, and for most causes of autonomic neuropathy.

• Corticotropin is used to test the capacity of the adrenal gland to produce cortisol.

Guide to further reading

Arlt W. Junior doctors’ working hours and the circadian rhythm of hormones. Clin. Med. (Northfield Il). 2006;6:127–129.

Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J. Clin. Endocrinol. Metab.. 2009;94:1059–1067.

Barnes P.J., Adcock I.M. Glucocorticoid resistance in inflammatory diseases. Lancet. 2009;373:1905–1917.

Buttgereit F., Burmester G.R., Lipworth B.J. Optimised glucocorticoid therapy: the sharpening of an old spear. Lancet. 2005;365:801–803.

Cooper M.S., Stewart P.M. Corticosteroid insufficiency in acutely ill patients. N. Engl. J. Med.. 2003;348:727–734.

Hench P.S., et al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone: Compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proceedings of the Staff Meetings of the Mayo Clinic. 1949;24:181–277. (acute rheumatism)

The classic studies of the first clinical use of an adrenocortical steroid in inflammatory disease. See also page 301 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-11-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”.’

Hochhaus G. New developments in corticosteroids. Proc. Am. Thorac. Soc.. 2004;1:269–274.

Lipworth B.J. Therapeutic implications of non-genomic glucocorticoid activity. Lancet. 2000;356:87–88.

Løvås K., Husebye E. Addison’s disease. Lancet. 2005;365:2058–2061.

Newell-Price J., Bertagna X., Grossman A.B., Nieman L.K. Cushing’s syndrome. Lancet. 2006;367:1605–1617.

¹ Potency (the weight of drug in relation to its effect) rather than efficacy (strength of response); see page 83. 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.

Clinical Pharmacology 11e

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