Hydrocortisone

Hydrocortisone is the synthetic form of cortisol, used as replacement therapy in adrenal insufficiency and for emergency glucocorticoid and mineralocorticoid action. It is the preferred replacement because its short half-life allows physiological timing, and it has mineralocorticoid activity at higher doses. It is also given intravenously in adrenal crisis, anaphylaxis, severe asthma and septic shock, and used topically and rectally.

Classification. Glucocorticoid with mineralocorticoid activity. Tablets 5 mg, 10 mg and 20 mg; intravenous or intramuscular injection 100 mg (sodium succinate); oral granules for children; modified-release capsules; topical and rectal forms.

Mechanism. Binds the intracellular glucocorticoid receptor (and the mineralocorticoid receptor), altering gene transcription: anti-inflammatory and immunosuppressive effects, gluconeogenesis, protein breakdown, lipolysis, and sodium and water retention with potassium loss.

Pharmacodynamics. Relative potency (equivalent anti-inflammatory doses): hydrocortisone 20 mg, prednisolone 5 mg, methylprednisolone 4 mg, dexamethasone 0.75 mg. Biological effect lasts 8 to 12 hours; mineralocorticoid effect is about equal to fludrocortisone 0.1 mg for each 20 mg of hydrocortisone.

Pharmacokinetics. Oral bioavailability about 90%, peak 1 to 2 hours; 90% bound to cortisol-binding globulin and albumin; plasma half-life 1.5 to 2 hours. Metabolised by the liver; excreted in urine.

Primary or secondary adrenal insufficiency, adults (chronic replacement).

• Total 15 to 25 mg daily orally in 2 or 3 divided doses; for example 10 mg on waking, 5 mg at lunch and 5 mg in the mid-afternoon, with the largest dose on waking. Adjust to symptoms, aiming for the lowest dose that gives wellbeing.
• Primary insufficiency also needs fludrocortisone 50 to 200 micrograms daily; secondary insufficiency does not.

Congenital adrenal hyperplasia and adrenal insufficiency in children.

• 8 to 10 mg/m2/day in 3 divided doses; neonates and infants may need higher doses. Directed by a paediatric endocrinologist.

Stress dosing.

• Illness with fever or needing antibiotics: double the oral dose for 2 to 3 days; with fever over 39 degrees Celsius triple it. Vomiting or diarrhoea, or unable to take tablets: injection.
• Minor surgery: usual dose plus 25 to 50 mg intravenously at induction. Major surgery or severe illness: 100 mg intravenously at induction then 200 mg over 24 hours by infusion (or 50 mg every 6 hours), halving daily as recovery allows until back to the usual dose.

Adrenal crisis (emergency).

• Hydrocortisone 100 mg intravenously or intramuscularly immediately, without waiting for tests. Then 200 mg over 24 hours by continuous infusion (or 50 mg every 6 hours) in 0.9% sodium chloride with dextrose, with fluid resuscitation of 1 litre of 0.9% sodium chloride in the first hour. Children 2 mg/kg (maximum 100 mg) immediately, then 50 to 100 mg/m2/day.

Adjunct in anaphylaxis and severe asthma.

• Hydrocortisone 100 to 200 mg intravenously after adrenaline in anaphylaxis (does not replace adrenaline). Acute asthma: 100 mg intravenously every 6 to 8 hours until oral prednisolone is possible.

Myxoedema coma. 100 mg intravenously every 8 hours before or with levothyroxine until adrenal insufficiency is excluded.

Septic shock (refractory to fluids and vasopressors). 200 mg daily by continuous infusion or 50 mg every 6 hours.

Pregnancy. Safe and used as replacement; stress dosing for labour (100 mg intravenously at onset, then 200 mg over 24 hours or 50 mg every 6 hours).

Adjustments.

• Kidney: no change.
• Liver: lower dose in cirrhosis; monitor.
• Older adults: keep to 15 mg daily where possible.
• Weight: body surface area dosing in children.

Contraindications. Systemic fungal infection (for immunosuppressive doses); hypersensitivity. In adrenal crisis there is no contraindication to a single dose.

Serious adverse effects.

• Over-replacement: weight gain, central obesity, hypertension, diabetes, osteoporosis, mood change, insomnia.
• Under-replacement: tiredness, nausea, hyperpigmentation, hypotension, hypoglycaemia, adrenal crisis.
• Fluid retention and hypokalaemia at high doses.
• Infection risk at immunosuppressive doses.
• Withdrawal: abrupt cessation after long use precipitates adrenal crisis.

Major interactions.

• Reduced effect: rifampicin, phenytoin, carbamazepine, phenobarbital (increase the dose by 50 to 100%).
• Increased effect or toxicity: ketoconazole, itraconazole, clarithromycin, ritonavir.
• Hypokalaemia: loop and thiazide diuretics, amphotericin; digoxin toxicity follows.
• Oestrogen-containing contraceptives raise cortisol-binding globulin; the dose may need to rise.
• NSAIDs: gastrointestinal bleeding risk.
• Antidiabetic drugs: glucose rises; adjust treatment.
• Vaccines: live vaccines are avoided at immunosuppressive doses.

Special groups.

• Pregnancy: safe; the placenta inactivates most hydrocortisone. Raise the dose in the third trimester if needed and give stress dosing for labour.
• Breastfeeding: compatible; avoid feeding within 4 hours of high doses.
• Children: surface area dosing; growth suppression with excess.
• Older adults: lower doses; bone and glucose monitoring.
• Kidney impairment: no change; liver impairment: lower dose.
• East Africa: adrenal insufficiency is often missed, especially after prolonged herbal or skin lightening steroid use, HIV and TB (adrenal destruction), and abrupt withdrawal of steroids bought without prescription. Patients need a written steroid card, an emergency injection kit where possible and a plan for illness. Hydrocortisone tablets are widely available; prednisolone is a common substitute when they are not.

Formulation and administration. Take tablets with food or milk, the first dose on waking. Intravenous doses: dilute in 0.9% sodium chloride; give a bolus over 1 to 2 minutes (100 mg) or 10 minutes for children's doses; infuse the rest. Intramuscular injection into a large muscle is an alternative when no intravenous access. Do not store diluted infusions beyond 24 hours.

Baseline. Morning cortisol, ACTH, electrolytes, glucose, renin and aldosterone in suspected primary insufficiency; do not delay treatment in crisis.

Monitoring.

• Symptoms, weight, blood pressure (lying and standing), electrolytes and glucose at each visit.
• In primary insufficiency: plasma renin and potassium to adjust fludrocortisone.
• Bone density with long-term doses over 25 mg.
• Children: height, weight and bone age.

Dose reduction and stopping. Reduce to the lowest dose giving wellbeing. Never stop replacement abruptly. After courses of high-dose therapy, reduce by 5 to 10 mg every 1 to 2 weeks to 10 mg, then by 1 mg every 2 to 4 weeks.

Referral and escalation. Admit adrenal crisis. Refer new adrenal insufficiency, suspected congenital adrenal hyperplasia, pregnancy, unexplained hypotension or collapse on steroids, and dose requirements over 30 mg daily.