Pharmacological Glucocorticoid Treatment

Essentials

• The fact that glucocorticoids suppress inflammation and the immune response is utilized in the treatment of inflammatory, immunological and allergic diseases.
• Doses exceeding normal endogenous cortisol production have adverse effects, of which adrenocortical insufficiency, osteoporosis, diabetes, infections and mood effects are the most significant.
• Adverse effects can be minimized by correct administration and dosage.
• When starting the treatment, it should be clear what the disease or symptoms are that are to be treated with the glucocorticoid and how disease activity and the efficacy of the treatment will be monitored. Extended or ineffective treatment should be replaced by other medication suppressing inflammation or the immune response.
• The ability to withstand stress may be decreased after cessation of glucocorticoid treatment given by any administration route, and adrenocortical suppression may continue for several months after long-term glucocorticoid treatment. Adrenocortical suppression should be entered in the risk data for the patient.

Indications

• Polymyalgia rheumatica and temporal arteritis
• Severe rheumatoid arthritis and other collagen diseases
• Severe asthma, where the symptoms are not controlled by inhaled corticosteroids or other asthma medication
• Subacute thyroiditis
• Facial nerve paresis, acute optic neuritis
• Graves' ophthalmopathy
• Severe dermatological diseases, such as pemphigus and pemphigoid
• Adjuvant therapy in certain haematological diseases and cancers
• Immunosuppression after organ transplantation
• Adrenocortical insufficiency and congenital adrenal hyperplasia
• Increased intracranial pressure)

Choice of glucocorticoid product

• Intermediate acting prednisolone and methylprednisolone are the best choices for long-term treatment because of their negligible mineralocorticoid action.
• Dexamethasone is the first-line corticoid in the treatment of increased intracranial pressure. In addition, dexamethasone is used for diagnosing Cushing's disease because it inhibits ACTH production by the pituitary gland.
• Because of its minor anti-inflammatory potency, hydrocortisone is used for physiological replacement therapy, only, or when the patient is recovering from adrenocortical suppression.
• Systemic glucocorticoid treatment can be given by the intravenous or oral route.
• Glucocorticoids can also be given locally, e.g. intra-articularly, transcutaneously or by the respiratory or rectal route. Locally administered glucocorticoids undergo some systemic absorption and may cause the same adverse effects as systemically administered glucocorticoids.

Implementation of drug therapy

• Start the treatment witha sufficiently high dose
• Use the lowest possible dose for maintenance therapy and if more long-term glucocorticoid therapy proves to be necessary, consider use of other anti-inflammatory drugs..
• Consider the possibility of ocal treatment.
• Tell the patient about the aims of the therapy, and give detailed instructions for its implementation, as well as for situations involving stress.
• Enter the use of glucocorticoid therapy in the risk data in the patient record.
• Glucocorticoids are usually given as single doses in the morning.
  • The daily dose is divided into two doses if ACTH suppression is desired (in adrenal hyperplasia) and often in diabetic patients, because only by dividing the daily dose can a constant level of blood glucose be achieved.

Equivalent doses

Adverse effects of glucocorticoid treatment

• In addition to the intended effects, pharmacological glucocorticoid treatment causes adverse effects, such as weight gain, development of diabetes and osteoporosis.
• The aims in monitoring glucocorticoid treatment should be to predict and prevent its adverse effects. When ending glucocorticoid treatment, individual suppression and recovery of endogenous cortisol production should be considered.

Adrenocortical suppression

• Is due to the inhibition of ACTH secretion, adrenocortical atrophy and reduced cortisol secretion.
• The probability of adrenocortical suppression depends on the dose, dosage form and duration of treatment with glucocorticoids. There is individual variation in this depending on how rapidly glucocorticoids are metabolized.
• Not only systemic treatment, but also glucocorticoids administered by inhalation, intra-articularly, intramuscularly, transcutaneously or rectally may cause adrenocortical suppression.
• Decreased endogenous cortisol production is not clinically significant as long as a glucocorticoid is administered regularly. Adrenocortical suppression becomes a risk if the patient is subjected to stress from an infection or surgical procedure while endogenous cortisol production cannot increase, or if glucocorticoid treatment is stopped abruptly.
• The risk of adrenocortical suppression is
  • low if systemic glucocorticoid treatment has continued for less than 10 days or local treatment for less than 3 weeks
  • high if prednisolone has been given in doses exceeding 20 mg/day for more than 3 weeks or if the patient has developed features of Cushing's syndrome (rounded face, upper body obesity, fatty hump between the shoulders, muscular atrophy).
• If, based on clinical assessment, adrenocortical suppression is probable, an ACTH test is not required to verify it. Only when the probability of adrenocortical suppresion is low while a major procedure is planned, a short ACTH test may be performed to assess the patient's tolerance of stress.
• In unclear cases, serum cortisol assay can be performed before taking the morning medication.
  • In practice, serum cortisol levels exceeding 250 nmol/l exclude the possibility of adrenocortical suppression.
  • If the serum cortisol level is below 150 nmol/l, start giving hydrocortisone at doses of 10 + 5 mg and reassess serum cortisol before morning medication in 3 months. Hydrocortisone replacement therapy can be ended when the serum cortisol level before morning medication exceeds 250 nmol/l.
  • As exogenous glucocorticoid affects the serum cortisol assay, the patient should not use oral or local glucocorticoids for 24-48 hours before the assay. Oestrogen replacement will also affect serum cortisol assay.
  • Serum cortisol assays are performed using immunological methods developed by different equipment manufacturers. There is great individual variation in the results obtained with these methods even though the methods were calibrated according to the same standard. Therefore, target ranges are only suggestions. A single aberrant value should therefore usually be controlled before deciding on treatment.

Tapering off of glucocorticoid treatment

• To avoid recurrence of the disease being treated, as well as symptoms and risks associated with adrenocortical suppression, long-term glucocorticoid treatment should be tapered off gradually.
• If the daily dose of prednisolone or an equivalent dose of other corticosteroid is
  • higher than 40 mg, the dose of prednisolone should be reduced by 5-10 mg at intervals of 2 weeks
  • 20-40 mg, the dose of prednisolone should be reduced by 5 mg at intervals of 2 weeks (i.e. if the daily dose is 40 mg, then 35 mg - 30 mg - 25 mg - 20 mg, changes being made at intervals of 2 weeks)
  • 10-20 mg, the dose of prednisolone should be reduced by 2.5 mg at intervals of 2-4 weeks (i.e. if the daily dose is 20 mg, then 17.5 mg - 15 mg - 12.5 mg - 10 mg, with changes being made at intervals of 2-4 weeks)
  • 10 mg, the dose of prednisolone should be reduced by 2.5 mg every other day at intervals of 2-4 weeks (i.e. 7.5 mg and 10 mg given on alternate days for 2-4 weeks, followed by 7.5 mg once, then 5 and 7.5 mg on alternate days for 2-4 weeks, 5 mg once and, finally, 5 mg every other day for 2-4 weeks).

Substitution therapy during stress

• Substitution therapy is needed during stress if the patient is on glucocorticoid therapy or has stopped using such therapy but adrenocortical suppression is evident or probable. If this is uncertain, in an acute case proceed as if adrenocortical suppression were probable.
• Instruct the patient to carry an SOS card or bracelet.
• Add to the risk data in the patient record the text: ”Adrenocortical suppression. In case of severe disease, vomiting and diarrhoea, give 100 mg hydrocortisone (Solu-Cortef^® ) intravenously".
• Patients taking less than 10 mg/day prednisolone should be instructed to double the dose in association with febrile diseases. If the patient is on continuous high-dose glucocorticoid therapy, no additional treatment is needed.
• Recommendations for substitution therapy are given in table T1.

Prevention of osteoporosis

• Glucocorticoids reduce bone mineral density most during the first 6-12 months of treatment, after which the reduction in bone density levels off. All patients on glucocorticoids are at risk of osteoporosis.
• Calcium (1 000 mg/day) and vitamin D (20 µg/day) should be prescribed for nearly all patients.
• Bone mineral density should be tested before treatment if the treatment is going to take more than 6 months.
• A bisphosphonate is recommended if prednisone is administered at a dose of ≥ 7.5 mg for more than 3 months and if bone density measurement shows a T-score < -1.5 SD or if the risk of fracture within the next 10 years is more than 10% as assessed by FRAX. In patients with a history of osteoporotic fracture, bisphosphonate treatment should be started at an even lower dose and shorter duration of treatment.
• Bisphosphonates are given orally: 70 mg alendronate once a week, 150 mg ibandronate once a month or 35 mg risedronate once a week.
  • Five milligrammes zoledronic acid administered as an intravenous infusion is a good option for patients receiving long-term glucocorticoid treatment. A single dose is sufficient for one year.
• Teriparatide is recommended for patients with vertebral compression fractures. Specialized care (an endocrinologist) should be consulted about starting such treatment.

Treatment of hyperglycaemia

• Glucocorticoids reduce insulin sensitivity and often cause hyperglycaemia.
• If the glucocorticoid is administered as a single dose in the morning, hyperglycaemia is most marked in the afternoon. Insulin treatment may be necessary, and its effect is most needed in the afternoon.
• Hyperglycaemia can be treated, as necessary, with NPH insulin (e.g. Protaphane^® ) at a dose of 10 IU or more once daily, in the morning, and/or with prandial insulin injected before lunch (and dinner).
• Adrenocortical insufficiency caused by glucocorticoid treatment predisposes to nocturnal hypoglycemias. Consequently, the dosage of insulin taken in the evening must be considered with care, and in diabetics with insulin deficiency it may be necessary to take the daily dose of prednisolone in two divided doses.

Electrolyte imbalance

• The mineralocorticoid action of glucocorticoids causes water and salt retention. This appears as oedema, hypertension and hypokalaemia.
• Blood pressure should be measured and plasma electrolytes tested at each visit.
• If high doses of glucocorticoids are used, potassium chloride tablets may be needed and sometimes spironolactone in doses of 50-100 mg daily.

Mood

• In high doses, glucocorticoids affect the central nervous system, which may appear as difficulty falling asleep, impaired memory, extreme mood swings, euphoria, depression or even psychosis.
• Mental problems can be elicited by asking appropriate questions; medication such as 7.5-15 mg/day of oxazepam can be prescribed.