Classify corticosteroids. Describe their mechanism, pharmacological actions, uses and adverse effects.

Classification of Corticosteroids

Mechanism of Action

The steroid is lipid-soluble and crosses the cell membrane freely → Binds the cytoplasmic glucocorticoid receptor, displacing heat shock proteins → The complex translocates to the nucleus → Binds glucocorticoid response elements on DNA → transactivation of anti-inflammatory genes (lipocortin/annexin-1, IL-10) and transrepression of inflammatory genes (via NF-kappaB and AP-1) → annexin-1 inhibits phospholipase A2, so both prostaglandins and leukotrienes are suppressed → Because the effect requires gene transcription, the onset takes hours — steroids are not an emergency drug in anaphylaxis or acute asthma

Pharmacological Actions

• Anti-inflammatory — reduced capillary permeability, reduced leucocyte migration, suppressed phagocytosis, reduced cytokines and eicosanoids, and reduced fibroblast proliferation, which impairs healing
• Immunosuppressive — lymphopenia (redistribution and apoptosis), reduced T-cell function, reduced antibody production at high dose. Neutrophil count rises through demargination, which can be mistaken for infection
• Metabolic — increased gluconeogenesis and insulin resistance (hyperglycaemia); protein catabolism (muscle wasting, thin skin, poor healing, negative nitrogen balance); lipolysis with redistribution to the face, neck and trunk
• Mineralocorticoid — sodium and water retention, potassium and hydrogen loss; hypertension, oedema, hypokalaemic alkalosis
• Calcium — reduced intestinal absorption and increased renal excretion, with direct inhibition of osteoblasts — hence osteoporosis
• Permissive effects — catecholamines cannot act normally on vessels and bronchi without a background of cortisol, which is why patients in adrenal crisis do not respond to vasopressors until steroid is given
• CNS — euphoria, insomnia, and at high dose psychosis or depression

Therapeutic Uses

• Replacement — Addison disease and hypopituitarism (hydrocortisone with fludrocortisone), and congenital adrenal hyperplasia
• Inflammatory and allergic disease — asthma and COPD, allergic rhinitis, eczema, severe drug reactions
• Autoimmune and connective tissue disease — rheumatoid arthritis, SLE, vasculitis, inflammatory bowel disease, autoimmune hepatitis, glomerulonephritis
• Malignancy — lymphomas and leukaemias (lymphocytolytic), and as an antiemetic and appetite stimulant in palliative care
• Transplant rejection
• Cerebral oedema from a tumour or abscess — dexamethasone, which has no mineralocorticoid effect
• Specific infections as an adjunct — tuberculous meningitis and pericarditis, bacterial meningitis, severe Pneumocystis pneumonia, and severe COVID-19
• Antenatal betamethasone or dexamethasone for fetal lung maturation in threatened preterm delivery — one of the most effective single interventions in obstetrics
• Diagnostically — the dexamethasone suppression test

Adverse Effects of Long-term Therapy

Comparison with Nsaids and Choice of Preparation

• Choosing the preparation — prednisolone for most oral anti-inflammatory use; hydrocortisone for replacement and parenteral emergency use (it has the mineralocorticoid activity replacement requires); dexamethasone where fluid retention must be avoided, as in cerebral oedema, or where a long action is wanted
• Because steroids act through transcription, they are not emergency drugs — in anaphylaxis and acute severe asthma they are given for the later phase, while adrenaline and a bronchodilator act immediately

Withdrawal and Applied Aspects

• The hypothalamo-pituitary-adrenal axis is suppressed by more than about 2 to 3 weeks of supraphysiological steroid, and recovery takes months to a year
• Abrupt withdrawal causes acute adrenal insufficiency — weakness, vomiting, hypotension, hypoglycaemia, hyponatraemia and shock; it can be fatal
• Always taper after prolonged use, and increase the dose during illness, injury or surgery ("sick day rules"), since the patient cannot mount their own stress response
• Every patient on long-term steroids needs a steroid card or alert bracelet
• Measures to limit harm — the lowest effective dose for the shortest time; alternate-day dosing where possible; single morning dose to mimic the diurnal rhythm and reduce suppression; topical, inhaled or intra-articular routes in preference to systemic; and steroid-sparing agents
• Bone protection from the outset — calcium, vitamin D and a bisphosphonate for anyone expected to take steroids for more than 3 months
• Screen for tuberculosis and Strongyloides before prolonged steroids in India, where both are common and reactivation can be fatal