| | Corticosteroids
Mechanism of action
- enter cells where they combine with steroid receptors in cytoplasm
- combination enters nucleus where it controls synthesis of protein, including
enzymes that regulate vital cell activities over a wide range of metabolic
functions including all aspects of inflammation
- formation of a protein that inhibits the enzyme phospholipase A2
which is needed to allow the supply of arachidonic acid. Latter is essential
for the formation of inflammatory mediators
- also act on cell membranes to alter ion permeability
- also modify the production of neurohormones
Actions
Important to distinguish between physiological effects (replacement therapy)
and pharmacological effects (occur at higher doses)
Mineralocorticoid
- Na retention by renal tubule
- increased K excretion in urine
Glucocorticoid
- CHO metabolism: increased gluconeogenesis, ±
peripheral glucose uptake may be decreased with resultant hyperglycaemia ±
glycosuria
- protein metabolism: anabolism is decreased but catabolism continues unabated
or is increased resulting in negative N balance and muscle wasting.
Osteoporosis occurs, growth slows in children, skin atrophies (together with
increased capillary fragility leads to bruising and striae), healing and
fibrosis delayed
- fat deposition: increased on shoulders, face and abdomen
- inflammatory response depressed
- allergic response depressed
- antibody production reduced by large doses
- lymphoid tissue reduced (including leukaemic lymphocytes)
- decreased eosinophils
- renal urate excretion increased
- euphoria or psychotic states may occur. ? due to CNS electrolyte changes
- anti-vitamin D action
- reduction of hypercalcaemia (chiefly where this is due to increased
absorption from gut: vit D intoxication, sarcoidosis)
- increased urinary Ca excretion. Renal stones may form
- growth reduction where new cells are being added (eg in children) but not
where they are replacing cells as in adult tissues
- suppression of HPA axis. NB steroid suppressed adrenal continues to secrete
aldosterone
Normal daily secretion of hydrocortisone is 10-30 mg. Exogenous daily dose that
completely suppresses cortex is 40-80 mg (or prednisolone 10-20 mg).
Individual steroids
Relative potencies |
Glucocorticoid |
Mineralocorticoid |
Hydrocortisone |
1 |
1 |
Cortisol |
1.25 |
1 |
Prednisolone |
4 |
0.8 |
Methylprednisolone |
5 |
minimal |
Dexamethasone |
30 |
minimal |
Fludrocortisone |
15 |
150 |
- prednisolone is standard choice for anti-inflammatory therapy. Can be
given orally or IM
- methylprednisolone used for IV pulsed therapy
- dexamethasone longer acting.
- fludrocortisone used to replace aldosterone where the adrenal cortex has
been destroyed
- beclomethasone and budesonide used by inhalation for asthma. About 90% of
inhalation dose is swallowed and inactivated by first-pass hepatic
metabolism (steroids listed above are protected from this by protein
binding). The rest, which is absorbed from the mouth and lungs gives very
low systemic plasma concentrations. Although risk of HPA axis suppression is
very low it can happen.
Pharmacokinetics
Administration: PO/IM/IV/intra-articular/topical/inhaled. Absorption
after oral administration is rapid. Maximum biological effect seen after 2-8 h
Distribution: high plasma protein binding (95% in case of hydrocortisone)
to transcortin and when this is saturated to albumin (80% in the case of
hydrocortisone). Concentration of transcortin is increased by oestrogens (eg
pregnancy, oral contraceptives). In patients with very low serum albumin doses
should be reduced due to reduced binding capacity
Elimination: hepatic and renal.t1/2 of most steroids 1-3 h.
Prolonged in renal and hepatic disease and shortened by hepatic enzyme induction
to an extent that may be clinically important
Adverse effects
In general serious unwanted effects are unlikely if daily dose is < 50 mg
hydrocortisone or 10mg of prednisolone or equivalent
- iatrogenic Cushings
- avascular necrosis of bone
- depression and psychosis
- peptic ulceration
- others include cataract (chronic use), glaucoma (prolonged use of eye
drops), raised ICP and convulsions, blood hypercoagulability, menstrual
disorders, fever
- immunosuppression
- HPA axis suppression: dependent on steroid used, dose, duration of
administration and time of administration. Single morning dose of <20mg
prednisolone does not usually cause suppression while 5mg in evening
suppresses early morning activation of HPA axis
Use in pregnancy
- teratogenic in animals
- ? relationship between high dose steroids and cleft palate and other fetal
abnormalities
- adrenal insufficiency due to HPA axis suppression in newborn only occurs
with high maternal doses
- keep doses as low as possible in pregnancy
- avoid fluorinated steroids (eg dexamethasone) as they are more teratogenic
in animals
Treatment of intercurrent illness
- maximum stress-induced output of cortisol is 200-300 mg/day
- production following surgery tends to be much less. Based on normal cortisol
production rates the recommended daily doses of hydrocortisone equivalent for
different categories of surgery are:
|
Daily dose |
Duration |
Minor (eg hernia repair) |
25 mg |
1 day |
Intermediate (eg cholecystectomy, colectomy, joint replacement) |
50-75 mg |
2 days |
Major (eg oesophagectomy, cardiac surgery requiring CPB) |
100-150 mg |
2-3 days |
If the patients maintenance dose exceeds recommended dose to cover surgical
stress there is no evidence that any dose alteration is necessary and patient
should continue to receive maintenance dose over the perioperative period.
In the case of perioperative complications continued glucocorticoid
administration consistent with the postoperative stress response is appropriate
Further reading
Laurence DR, Bennett PN. Clinical Pharmacology, 7th ed, 1992
Chin R, Eagerton DC, Salem M. Corticosteroids. In Chernow B (ed). The
pharmacological approach to the critically ill patient, 3rd ed, 1994
© Charles Gomersall December 1999 |