For the first time glucocorticoids (GCS) were used in medicine over 60 years ago in the treatment of rheumatoid arthritis and Addison’s disease which was then called a „cortisone miracle”. Due to their anti--inflammatory and immunomodulative action GCS are widely used in the treatment of many diseases. Despite unquestionable beneficial effects of this group of compounds, these medications are characterized by a large number of adverse events. The disorders caused by GCS, dependent on dose, the duration of treatment and route of administration, range from iatrogenic Cushing’s syndrome through hypothalamic-pituitary-adrenal axis suppression to neurological and psychiatrical diseases. Even inhaled glucocorticoids (ICS), intraarticularly injected or topically used are not free from systemic side effects. Due to the fact that GCS are one of the most used group of medicines, the important task facing modern medicine is to prevent the numerous adverse effects that they cause. The problem of serious side effects caused by glucocorticoids is the subject of studies for many years, however apart from the prevention of osteoporosis and gastrointestinal bleeding (with simultaneous use of nonsteroidal anti-inflamatory drugs), there are no Evidence Based Medicine recommendations concerning prevention of adverse events during treatment.

Obtaining glucocorticosteroids with stronger anti--inflammatory activity can be achieved by modification of cortisol structure. These changes include the formation of a double bond between the 1^st and 2^nd position, which increases anti-inflammatory effect with reduction of binding with mineralocorticoid receptor (prednisolone). Other modifications include the introduction of fluoro group in 9^th position (Dexamethasone, Triamcinolone, Fludrocortisone), methyl group in 6^th position (Methylprednisolone) and 16^th (Dexamethasone), which effected in further intensification of anti-inflammatory activity, reduction of mineralocorticoid effect and simultaneously prolongation of action. Exception in the mentioned group is fludrocortisone, which to a great extent is characterized by the mineralocorticoid effect and it is not used for anti-inflammatory activity. Modification in chemical structure and activity of glucocorticoids, comparing to cortisol, are presented in table 1 and figure 1.

The presence of hydroxyl group in 11^th position is responsible for glucocorticoid and anti-inflammatory activity while substances with ketone group in the mentioned position (cortisone, prednisone) are biologically inactive and first have to be hydroxylated by 11β-hydroxysteroid dehydrogenase type 1. This enzyme is present in almost every tissue susceptible to glucocorticoids. The 11β-hydroxysteroid dehydrogenase type 2 is responsible for the reverse reaction of inactivation (oxidation). The medicines having in its structure a fluoro or methyl group are insensitive to the action of this enzyme. Cortisol, to a small extent, is also metabolized by 6β-hydroxylase (to biologically inactive 6β-hydrocortisone). This reaction is catalyzed by cytochrome P450 3A4. Therefore, interactions can occur between glucocorticosteroids (including ICS and intranasally admitted) and drugs inducing or inhibiting CYP3A4. The strong inhibitors of CYP 3A4 may slow the metabolism of GCS and in consequence cause its’ increased concentration and toxicity. The strong inducers of CYP 3A4 may cause the reverse reaction. The most important drugs that can influence the metabolism of glucocorticosteroids are listed in table 2.

Regardless of the effect on cytochrome P450, glucocorticoids may increase the potency of other drugs for instance warfarin by not well known multiple mechanism, diuretics by enhancing their kaluretic action or NSAIDs by increasing the risk of peptic ulcer (4).

Endogenous glucocorticoids in blood are bound mainly (in 75%) to CBG protein (Corticosteroid Binding Globulin), in 15% are transported by albumins (in this form it is biologically inactive fraction) while 10% is a free fraction. CBG (transcortin) concentration increases under influence of medicaments such as mitotane, high estrogen levels (pregnancy, hormone replacement therapy, oral contraception) or in pathological conditions (diabetes, hyperthyroidism) (5). Increased CBG concentration may give falsely high values of serum total cortisol concentration. In such cases free cortisol in the blood or saliva should be measured.

Synthetic GCS (except prednisolone) are bound in 2/3 with albumins while the remaining 1/3 is present in serum in a free state (6). Protein binding also affects biological half-life, which for cortisol and cortisone is much shorter than that of the synthetic glucocorticoids. The results presented by Kozowera et al. shows that predisolone clearance in patients with side effects during corticotherapy was decreased comparing to those without adverse events (7). In the other study, elderly people had decreased corticoid clearance (8): for that reason it is necessary to lower GCS doses in this group of patients.

Comorbidities also affects the metabolism of GCS. The most important include:

Hyperthyroidism – the increased metabolism of prednisone and prednisolone, as well as the reduction of the biological effect, was reported (9). It may be necessary to use higher doses of GCS.

Inflammatory bowel disease – the investigation showed reduced protein binding with prednisolone in patients with active disease, probably caused by lower albumin concentration, which can accelerate the elimination of the drug from the body (10). Chronic kidney disease increases the half-life of GCS and thus it is necessary to reduce the dose. On the contrary, the patients on hemodialysis may need the increased dose of GCS.

Obesity – when determining the doses of glucocorticosteroids the ideal body weight should be taken into consideration instead the actual body weight.

Cirrhosis – together with deteriorating liver function, the concentration of 6β-hydroxylase may decrease, which leads to increased exposure to the biologically active form of corticosteroids (11). Hypoalbuminemia, increasing the free fraction of GCS is an additional factor causing that in this disease dose should be reduced.

Before initiation of therapy with GCS the indications should be carefully considered. The determination whether the patient can receive other treatment for the given disease and if it has already been implemented, whether the dose is optimal. Therapeutic targets, assumed duration of therapy, the dose (the smallest dose for the shortest time period) and the preparation of GCS need to be identified. The most important is to define the criteria of effectiveness and ineffectiveness of treatment, when the treatment should be absolutely stopped. The next step is to identify the comorbidities whose course may deteriorate during treatment and may affect the metabolism of GCS (along with chronically taken medications) what in consequence may intensify action of GCS and lead to occurrence of side effects. Even very small dose of GCS (< 5 mg of prednisone equivalent) may cause adverse events thus it is important to follow the given recommendation at every case of chronic treatment with GCS. The typical doses of glucocorticoids are presented in table 3.

Considering the number of patients treated with GCS annually, the fact that the main cause of Cushing’s syndrome is iatrogenic does not seem to be a surprise. The phenotype includes inter alia: weight gain, visceral obesity, plethora, dorsocervical fat pads („buffalo hump”), proximal myopathy, leg edema, ecchymoses, skin thinning and atrophy, red striae, hirsutism and acne (11). Not all of these symptoms must be present. The frequency of Cushingoid appearance is a „linear” dependent on dose and duration of treatment. It develops even while using less than 5 mg of prednisone/day and its occurrence is estimated from 4.3% after such doses to 24.6% when dosage increased over 7.5 mg prednisone/day during at least 6 months of glucocorticoid intake (12).