Management of glucocorticoid therapy, including pharmacology and physiology

Normal physiology being replaced or overridden

Cortisol secretion ~5-10 mg/m2/day (~15-25 mg hydrocortisone equivalent)
Diurnal: peak 6-8 am, nadir around midnight
>90% protein bound (CBG, albumin) - inflammation and oestrogen raise CBG and hence total cortisol
11beta-HSD2 in kidney inactivates cortisol -> protects the mineralocorticoid receptor
- Overwhelmed in high-dose therapy and in liquorice ingestion -> apparent mineralocorticoid excess

Equivalence, potency and half-life

Drug	Equivalent dose	GC potency	MC potency	Biological t1/2
Hydrocortisone	20 mg	1	1	8-12 h
Cortisone acetate	25 mg	0.8	0.8	8-12 h
Prednisolone	5 mg	4	0.8	18-36 h
Methylprednisolone	4 mg	5	0.5	12-36 h
Dexamethasone	0.75 mg	25-50	0	36-54 h
Fludrocortisone	-	10	125-200	18-36 h

Dexamethasone: no mineralocorticoid effect (used where fluid retention matters, and in the dexamethasone suppression test because it does not cross-react in the cortisol assay)
Prednisolone, not prednisone, in liver disease - prednisone needs hepatic 11beta-HSD1 activation

Epidemiology

1-3% of the population is on systemic glucocorticoids at any time; higher over age 70
Adrenal suppression after >4 weeks of supraphysiological dosing is the rule, not the exception
Prevalence of glucocorticoid-induced adrenal insufficiency by route: oral > intra-articular > inhaled/topical, but all can suppress

Mechanism of action

Lipophilic -> cytoplasmic glucocorticoid receptor -> nuclear translocation
- Transactivation (GRE binding) -> anti-inflammatory proteins (annexin-1, IkB) and most metabolic adverse effects
- Transrepression (tethering NF-kB, AP-1) -> most anti-inflammatory benefit
Genomic effects take hours; non-genomic membrane effects within minutes at very high dose

Anti-inflammatory / immune effects

Inhibit phospholipase A2 -> dec arachidonic acid -> dec prostaglandin and leukotriene precursors
dec COX-2, dec cytokines (IL-1, IL-2, IL-6, TNF)
Neutrophilia - demargination and delayed apoptosis, plus prevent PMNs leaving the circulation (dec adhesion molecule expression)
- A high WCC on steroids is usually demargination, not infection - but steroids also mask infection
Lymphopenia, monocytopenia, eosinopenia
Impair cell-mediated immunity -> TB reactivation, PJP, fungal and Strongyloides hyperinfection

Metabolic effects

Carbohydrate - inc hepatic gluconeogenesis and glycogen deposition, oppose insulin action -> steroid hyperglycaemia, worst post-lunch and afternoon on morning prednisolone
Lipid - inc peripheral lipolysis with central/truncal and dorsocervical fat deposition
Protein - catabolic; proximal myopathy
- Cardiac and diaphragmatic muscle relatively spared
Bone - dec osteoblast function, inc osteocyte apoptosis, dec intestinal Ca absorption, inc urinary Ca
Stress response - inc cardiac contractility and output, mobilise energy stores, permissive for catecholamine action

Developmental effects

Developmental

Fetus/neonate: accelerate maturation of lung (surfactant), gut and liver - the basis of antenatal betamethasone
Excess in childhood inhibits linear growth and skeletal maturation

Who has adrenal suppression?

*Assume it in anyone on >=5 mg prednisolone equivalent daily for >=3-4 weeks, and in anyone with Cushingoid features on any dose or route*
Higher risk: evening/night dosing, long-acting agent (dexamethasone), repeated intra-articular injection, concurrent CYP3A4 inhibitors (ritonavir, itraconazole, clarithromycin) with inhaled/intranasal steroid

Testing - only once at physiological dose

Morning (8-9 am) cortisol, taken >=24 h after the last hydrocortisone dose (or while on dexamethasone, which does not cross-react)

Morning cortisol	Interpretation
>300-350 nmol/L	Axis recovered - stop
150-300 nmol/L	Indeterminate -> short Synacthen test, continue cover for stress
<150 nmol/L	Adrenal insufficiency - continue replacement, retest in months

ACTH is low or normal in glucocorticoid-induced (secondary) AI, and aldosterone/renin are normal - fludrocortisone is not needed
Do not test during acute illness or on prednisolone (immunoassay cross-reactivity is negligible for prednisolone but the axis is not at steady state)

Glucocorticoid withdrawal syndrome

Lethargy, arthralgia, myalgia, nausea, mood disturbance, postural symptoms with a normal cortisol
Occurs on tapering from supraphysiological doses; tissue glucocorticoid withdrawal, not adrenal insufficiency
Manage by slowing the taper, not by abandoning it

Prescribing decisions before starting

A. Prescribing decisions before starting

Lowest effective dose, shortest duration, single morning dose where possible
Steroid-sparing agent planned from the outset for any expected course >3 months
Document indication, target duration and exit plan

Prophylaxis to start with the steroid

B. Prophylaxis to start with the steroid

Risk	Action
Bone	Calcium + vitamin D; bisphosphonate/denosumab if >=7.5 mg prednisolone for >=3 months, or prior fracture, or older age
PJP	Trimethoprim-sulfamethoxazole if >=20 mg prednisolone for >=4 weeks, especially with a second immunosuppressant
Gastric	PPI only if concurrent NSAID, anticoagulant, or prior ulcer - steroids alone are a weak risk
Strongyloides	Serology +/- empiric ivermectin if from an endemic area (northern Australia, PNG, SE Asia) - hyperinfection is fatal
Glycaemia	Baseline HbA1c; afternoon/post-lunch capillary glucose is the sensitive time
Latent TB, hepatitis B	Screen before prolonged high-dose therapy
Vaccination	Bring forward; *live vaccines contraindicated at >=20 mg prednisolone for >=2 weeks*

Tapering

C. Tapering

*Only taper once the underlying disease is controlled and steroid is no longer needed for it*
<3-4 weeks of therapy at any dose -> stop outright, no taper, no testing
Longer courses:
- Taper rapidly while supraphysiological (e.g. reduce by ~2.5-5 mg prednisolone every 1-2 weeks above 10 mg)
- Taper slowly below the physiological range (~4-6 mg prednisolone equivalent) - this is where the axis has to restart
- Then test morning cortisol, or simply continue a slow taper to zero with stress cover
Recovery takes weeks to >12 months; retest 3-6 monthly
A flare of the underlying disease and glucocorticoid withdrawal syndrome and adrenal insufficiency all look similar - the cortisol distinguishes the third

Sick day rules and stress dosing

D. Sick day rules and stress dosing - for everyone at risk, tested or not

Sick Day 1: fever/intercurrent illness -> double the usual glucocorticoid dose for the duration
Sick Day 2: vomiting, diarrhoea, unable to take oral -> IM hydrocortisone 100 mg and seek care
Surgery/procedures:
- Minor / local anaesthetic - usual dose or hydrocortisone 25-50 mg
- Moderate - hydrocortisone 50-100 mg at induction
- Major - hydrocortisone 100 mg then 200 mg/24 h infusion, taper over 48-72 h
Medical alert bracelet + steroid emergency card + a home ampoule with training to self-inject
Adrenal crisis in this group is a systems failure - it happens when nobody told the patient

Adverse effects

Iatrogenic Cushing syndrome - the commonest cause of Cushing overall
Glucocorticoid-induced osteoporosis and osteonecrosis of the femoral head
Steroid-induced diabetes; weight gain; hypertension
Cataract (posterior subcapsular) and glaucoma
Proximal myopathy; skin atrophy, purpura, striae, poor wound healing
Psychiatric - insomnia, mania, psychosis, depression (dose-related, early)
Immunosuppression: PJP, TB reactivation, herpes zoster, invasive fungal, Strongyloides hyperinfection
Growth suppression in children
Adrenal suppression from inhaled, intranasal, topical and intra-articular routes

HPA axis recovery

HPA recovery order: CRH/ACTH first, then adrenal cortisol response - hence a normal ACTH with a low cortisol during recovery
Full recovery in most within 6-12 months of stopping; a minority never recover
Adrenal crisis mortality is entirely preventable and still occurs - precipitants are gastroenteritis, surgery, and stopping steroids abruptly on discharge
Bone loss is fastest in the first 3-6 months of therapy and partly reversible after cessation
The dose-response for harm is continuous - there is no completely safe long-term dose above physiological replacement

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