Corticosteroids and Corticosteroid Replacement Therapy

Hydrocortisone (cortisol) is secreted by the adrenal cortex and has both glucocorticoid and mineralocorticoid effects. The term “glucocorticoid” derives from the early discovery that these hormones were important in glucose metabolism. Since the 1940's synthetic glucocorticoids have been developed for their anti-inflammatory and immunomodulatory effects. Attempts have been made to increase the beneficial effects and reduce the adverse effects by modifying the steroid nucleus and side groups.

Even an outline of complex steroid biosynthesis and physiology is helpful when considering the therapeutic benefits and adverse effects of the glucocorticoids.

• The adrenal cortex has 3 distinct anatomical zones. Glucocorticoids originate from the zona fasiculata (mineralocorticoids from the zona glomerulosa, and androgens from the zona reticularis).
• Regulation of glucocorticoid synthesis and release is complex. Glucocorticoids are not stored and must be synthesized when required. The mechanism involves:
  • The hypothalamo-pituitary axis. Feedback mechanism inhibits production
  • Feedback via catecholamines from the adrenal medulla
  • The autonomic nervous system
• Glucocorticoids have anti-inflammatory and immunosuppressive effects important in natural immune responses. They are involved in the mobilisation of substrates for gluconeogenesis (amino acids, fatty acids etc) and maintenance of normal blood glucose by:
  • Stimulating gluconeogensis in the liver
  • Mobilising amino acids from extrahepatic tissues
  • Reducing glucose usage by inhibiting uptake in muscle and fat
  • Stimulating fat breakdown.
• These effects are mediated through the glucocorticoid receptor (GR), an intracellular protein acting as a nuclear transcription factor regulating the expression of a diverse range of genes. This process involving mediation of the main metabolic and cardiovascular effects is called ”transactivation“ and the inhibitory effect is called ”transrepression“.
• The basal daily rate of cortisol secretion is 6-8 mg per square metre, and this increases ten fold in acute stress. Physiological replacement requires 10-15 mg per square metre because of reduced bioavailability. The different natural and synthetic glucocorticoids have different potencies and pharmacodynamic properties according to:
  • Relative and absolute affinity for the GR and mineralocorticoid receptor (MR)
  • Affinity for the associated enzyme
  • Ability to modulate the glucocorticoid responsive genes.
• The different glucocorticoids also have differing pharmacokinetic properties affecting:
  • Bioavailability
  • Plasma half life
  • Clearance rates
  • Water solubility etc.

• Corticosteroids can be life saving and have dramatic benefits. However their therapeutic use has to be balanced against the risks of serious adverse effects.
• Dose, route of administration, duration of treatment and choice of corticosteroid must be considered to maximize therapeutic benefit and minimise adverse effects.
• The list of conditions below clearly illustrates the diverse range of benefits that are possible.

• Benefits should be weighed against risks
• Every patient should be given a steroid card (see below) as recommended by the CSM following concern about severe chickenpox associated with systemic steroids.¹ Patients should also be given the manufacturers patient information leaflet with their prescription.
• Commonly used at high initial dose and then reduced to maintain remission
• Choice of steroid made according to properties required:
  • Hydrocortisone and cortisone have glucocorticoid effects but relatively high mineralocorticoid activity. They are therefore unsuitable for long term use, but useful intravenously in emergency situations. Hydrocortisone can be used topically with less risk of side effects as it is less potent.
  • Prednisolone has high glucocorticoid activity with less mineralocorticoid effect and is used for longer term treatment.
  • Betamethasone and dexamethasone have even higher glucocorticoid activity and insignificant mineralocorticoid effect. They can thus be used when high dosages are required without effects such as fluid retention. (For example cerebral oedema from malignancy). They cross the placenta readily and should be avoided in pregnancy.¹
  • Long duration of action with betamethasone and dexamethasone makes them useful in conditions like congenital adrenal hyperplasia when suppression of corticotrophin must be maintained.
• Local treatments should be used when possible in preference to systemic
• Adrenal suppression can be reduced by:
  • Morning dosage
  • Alternate day dosing
  • Intermittent courses of treatment
  • Addition of small doses of immunosuppressive drug.

Adverse effects are dose related and often predictable according to the glucocorticoid actions (e.g. diabetes, osteoporosis, muscle wasting, neuropsychiatric effects) and mineralocorticoid actions (e.g. hypertension, electrolyte and fluid balance).
There are a wide range of adverse effects (see table below):

• Cardiovascular - Hypertension. Congestive cardiac failure
• Central nervous system: Mood disturbance (including mania), psychosis, sleep disturbance
• Endocrine/Metabolic: Adrenal suppression, growth failure in children, insulin resistance, diabetes, disturbance of thyroid function, hypokalaemia, metabolic alkalosis
• Gastrointestinal: Gastric effects (peptic ulceration etc), fatty liver
• Haematopoietic:Leucocytosis and other effects (e.g. reduced eosinophils and monocytes)
• Immune System:
  • Suppression type IV hypersensitivity (interferes with Mantoux)
  • Inhibitory effects (leucocytes, macrophages, cytokines)
  • Suppression of primary antigen response (important with vaccines).
• Musculoskeletal System:
  • Myopathy (especially proximal muscles)
  • Osteoporosis
  • Avascular necrosis of bone
• Ophthalmic:Cataracts (more common in children), elevation of intraocular pressure, glaucoma
• Skin and other systems: Moon face, truncal obesity, dorsolumbar hump, acne, thin skin, skin striae (violaceous), impotence, irregular periods.

In addition to the disadvantages of longer term treatment there a number of clinical scenarios worthy of special mention:

Corticosteroids and surgery

Adrenal suppression caused by steroid therapy may result in an inadequate adrenocortical response to surgery (acute adrenocortical insufficiency can precipitate hypotension and death). Therefore:

• Anaesthetists must be informed when patients have taken corticosteroids within 3 months of surgery (10 mg or more) so that:
• For minor surgery under general anaesthesia either the usual corticosteroid dose can be given orally, or 25-50 mg of hydrocortisone is given intravenously at induction.
• For moderate/major surgery the usual oral dose is taken on the day of surgery with hydrocortisone as above at induction and the same intravenous dose three times daily for between 24 and 72 hours after surgery depending on the extent of surgery. This is then followed by the usual oral dose.
• Patients on prolonged treatment with potent inhaled or nasal corticosteroids and the same precautions should be taken as above before surgery.¹

Corticosteroids and live vaccines

Live vaccines should not be given within 3 months of:

• An adult receiving 40 mg/day of prednisolone or equivalent for more than a week
• A child receiving either 2 mg/kg/day for 1 week or 1 mg/kg/day for 1 month

Corticosteroids in pregnancy and breast feeding

The CSM's 1997 review looked at safety in pregnancy and lactation.¹ This stressed again the importance of weighing risk and benefit and concluded:

• Corticosteroids vary in their ability to cross the placenta. Prednisolone is mostly (88%) inactivated as it crosses the placenta, whereas betamethasone and dexamethasone cross readily.
• Although corticosteroids can cause abnormalities in foetal development in animals, this has not been shown in humans (for example cleft lip and palate).
• Prolonged or repeated corticosteroid administration in pregnancy increases the risk of intra-uterine growth retardation (IUGR). Short term treatment carries no such risk.
• The theoretical risk of adrenal suppression in neonates after prenatal exposure to corticosteroids is not clinically important and resolves spontaneously after birth.
• Prednisolone is excreted in small amounts in breast milk and is unlikely to cause systemic effects in the infant unless doses exceed 40 mg daily. Above this dose infants should be monitored for adrenal suppression. No data is available on other corticosteroids.

Corticosteroids and infection

Corticosteroids affect the severity and clinical presentation of infections as well as susceptibility to infections.
For example:

• Ocular infections may be exacerbated (fungal and viral)
• Diagnosis of serious infection may be delayed (septicaemia, tuberculosis)
• Corticosteroids may activate or exacerbate infections (tuberculosis, amoebiasis, strongyloides)
• Corticosteroids predispose to fungal infections in chronic lung disease (pulmonary aspergillosis)^2,3
• Topical corticosteroids probably predispose to eczema herpeticum although the association may not be as strong as is often suggested⁴
• Patients on corticosteroids should avoid measles exposure and seek medical advice if exposed. Prophylaxis with human normal immunoglobulin may be given.⁵

Corticosteroids and chickenpox

Patients on corticosteroids (systemic but not topical, rectal or inhaled) or who have used them within 3 months and are non-immune to varicella infection are at risk of severe chicken pox. Infection can be severe (fulminant pneumonia, hepatitis and disseminated intravascular coagulation often without prominent rash). Therefore:

• Exposed non-immune patients on or within 3 months of taking corticosteroids should be given passive immunisation with varicella-zoster immunoglobulin (within 3 and no later than 10 days after exposure).
• Confirmed chickenpox in such patients warrants urgent referral and urgent treatment.⁵

Corticosteroids and osteoporosis

Corticosteroid therapy is a major risk factor for osteoporosis, such that:⁶

• Any patient over 65 or with a relevant fracture should be started on prophylaxis/treatment if taking steroids at any dose for 3 months or longer.
• Any patient over 65 or with relevant fracture and taking intermittent corticosteroids should have a bone mineral density measured.⁶

Steroids and the skin

Systemic and local side effects can occur particularly with moderate strength steroids. The emphasis should be on appropriate use to produce benefit and minimise side effects.
Once daily applications are recommended by NICE.⁷ Information on steroids and the skin-link suggests:

• Appropriate strength steroids
• Use of emollients with steroids
• Clear patient instructions
• Regular follow up

Inhaled and nasal corticosteroids

The CSM has advised that:¹

• Systemic effects can occur with prolonged high dose therapy
• Susceptibility to side effects varies between individuals
• Intranasal steroids are less likely than inhaled steroids to cause systemic side effects

5 main areas of concern are identified:

• Adrenal suppression
• Osteoporosis and reduced BMD
• Growth retardation in children
• Cataracts
• Glaucoma

Advice to reduce risk includes:

• Give lowest dose to control asthma and rhinitis.
• Dose and duration of treatment as well as strength of steroid should be monitored.
• Height of children on moderate strength steroids should be monitored (reduce treatment and/or refer if growth affected).
• Precautions for surgery as above when patients on prolonged high dose steroids.

Important interactions include:

• Antagonism of antihypertensives
• Exacerbation of GI side effects (e.g. NSAIDS and peptic ulcer)
• Enhanced anticoagulant effects
• Antagonism of diabetic drugs
• Exacerbation of hypokalaemia with digoxin, diuretics, theophyllines and beta 2 agonists
• Impaired immune response of vaccines.

Monitoring may include the following (as well as monitoring of the disease being treated):
The CSM has suggested that, in patients whose disease is unlikely to relapse, steroids should be reduced gradually when they have:

• Received repeated courses (especially courses lasting >3 weeks)¹
• Taken a short course within 1 year of long term corticosteroid therapy
• Other possible causes of adrenal suppression
• Received more than 40 mg daily of prednisolone or equivalent
• Received more than 3 weeks of corticosteroid treatment

The dose may be reduced rapidly to physiological doses of about 7.5 mg of prednisolone and then more slowly at the same time ensuring that disease relapse does not occur.
Patients not in the groups above (e.g. who have received less than 3 weeks of corticosteroids) may have corticosteroids stopped abruptly.

• Ensure steroid cards are available and given out appropriately.
• Ensure patients at risk of osteoporosis are identified and treated.
• Ensure good instructions are given for topical steroid use.
• Identify patients on regular high dose inhaled steroids at risk of systemic side effects and in need of steroids before surgery.
• Ensure patients receiving live vaccines are asked about corticosteroid usage.