Discuss the pharmacology of the glucocorticoids.

Outline:

·        Natural glucocorticoids in the body and their physiologic roles.

·        Mechanisms of action.

·        Pharmacokinetics.

·        Adverse effects.

·        Dosing schedules and withdrawal of therapy.

Suggested Answer:

The naturally occurring adrenocortical hormones are 21-C steroid molecules synthesized from cholesterol by the adrenal cortex. The inner region, zona fasciculata and zona reticularis, produces glucocorticoids and weak androgens. The outer zone, zone glomerulosa, produces mineralocorticoids.

Glucocorticoids principally affect carbohydrate and protein metabolism. The major naturally-occurring glucocorticoids are cortisol and its derivatives. Mineralocorticoids principally affect sodium balance. The major natural occurring minerolocorticoid is aldosterone.

Under physiological conditions, corticosteroids are mainly bound to corticosteroid-binding globulin (CBG, transcortin) in the plasma. Albumin binds most of the remaining glucocorticoid (about 10%) not complexed with CBG, leaving only a small portion of the steroid unbound and free to exert its physiologic and pharmacological actions.

The existence of glucocorticoid activity depends on the presence of a hydroxyl group at carbon 11 of the steroid molecule.

Being lipid soluble, glucocorticoids enter inside their target cells and combine with the glucocorticoid receptor in the cytoplasm. The unoccupied receptor is normally bound to a heat shock protein HSP90. After occupation by a glucocorticoid molecule, the HSP90 is induced to change conformation and dissociate from the occupied glucocorticoid receptor. This translocates to the nucleus where it binds to glucocorticoid response elements (GRE) in the promoter region of several genes; some of these are switched off by binding of the receptor to their GRE whereas others are activated and this accounts for the multiple actions of glucocorticoids and their long onset of action.

The transcription factor NF-kB is stimulated by a variety of inflammatory mediators to turn on production of cytokines. Glucocorticoids induce transcription of a protein, IkB, which traps activated NF-kB in inactive cytoplasmic complexes. The lipocortins are another family of proteins which are activated by glucocorticoids. They inhibit phospholipase A which releases arachidonic acid from the phospholipid membrane. Hence, the pathway leading to the production of prostaglandins, leukotrienes, platelet activators and other inflammatory mediators is inhibited by glucocorticoids which accounts for its anti-inflammatory effects.

Glucocorticoids increase glycogen deposition in the liver, gluconeogenesis, glucose output from the liver and protein catabolism with mobilization of amino acids from peripheral tissues. They also decrease glucose utilization by peripheral tissues. Fat deposition is increased on shoulders, face and abdomen. Inflammatory and allergic responses are depressed, regardless of the cause.

Absorption of synthetic glucocorticoids given orally is rapid. The half-life of most in plasma is 1 – 3h but the maximum biological effect occurs after 2 – 8h. They are usually given 2 or 3 times a day. They are metabolized principally in the liver and some are excreted unchanged by the kidney. The half-life is prolonged in hepatic and renal disease.

Glucocorticoids are used as replacement therapy in acute adrenal insufficiency (Addisonian crisis) and chronic adrenal insufficiency (Addison’s disease). Addisonian crisis is an emergency and hydrocortisone sodium succinate 100 mg should be given i.v. immediately. In Addison’s disease, hydrocortisone orally is used in the lowest dose that maintains well-being and body weight, with two-thirds of the total dose in the morning and one-third in the evening to mimic the natural diurnal rhythm of secretion. There are no contraindications in replacement therapy. The risk lies in withholding rather than in giving it.

Glucocorticoids are used in much higher doses in suppressive therapy for anti-inflammatory effects and immuno-suppressive action in all or nearly all cases of:

·        Exfoliative dermatitis and pemphigus, if severe.

·        Collagen diseases, if severe, e.g. SLE, polyarteritis nodosa, giant cell arteritis.

·        Status asthmaticus.

·        Acute lymphatic leukaemia.

·        Severe allergic reactions of all kinds, e.g. serum sickness, angioneurotic edema.

·        Organ transplant rejection.

·        Acute spinal cord injury.

·        Active chronic hepatitis.

They are used in some cases of:

·        Rheumatic fever.

·        Rheumatoid arthritis.

·        Ankylosing spondylitis.

·        Ulcerative colitis and proctitis.

·        Regional iteitis.

·        Bronchial asthma and hay fever.

·        Sarcoidosis.

·        Acute mountain / altitude sickness, to reduce cerebral edema.

·        Blood diseases due to circulating antibodies, e.g. thrombocytopenic purpura.

·        Eye diseases: allergic diseases and nongranulomatous inflammation of the uveal tract.

·        Nephrotic syndrome: patients with minimal change diseases respond well to daily or alternate day therapy.

·        A variety of skin diseases, such as eczema.

·        Acute gout resistant to other drugs.

·        Hypercalcaemia of sarcoidosis and of vitamin D intoxication.

·        Raised intracranial pressure due to cerebral edema.

·        Preterm labor: (to mother) to enhance fetal lung maturation.

Dexamethasone is used in the diagnosis of Cushing’s disease. Failure of suppression implies pathological hypersecretion of ACTH by the pituitary or of cortisol by the adrenal.

The decision to give a glucocorticoid depends on the knowledge of the likelihood and amount of benefit, on the severity of the disease and on whether the patient has failed to respond to other treatment. Glucocorticoids should be used only as a last resort when all else fail as prolonged high dose inevitably brings serious complications such as osteoporosis. They should only be used for serious reasons in patients with diabetes, a history of mental disorder or peptic ulcer, epilepsy, tuberculosis, hypertension or heart failure. Topical glucocorticoid applied to an inflamed eye can be disastrous if the inflammation is due to herpes virus.

Glucocorticoids cause mobilization and redistribution of body fat, which together with loss of protein from peripheral tissues lead to a characteristic appearance: ‘moon-face’, ‘buffalo hump’, truncal obesity with relatively thin limbs. In addition to wasting due to catabolism of protein from skeletal muscle, patients also develop muscular weakness in the thighs and upper arms (proximal myopathy). Disturbed carbohydrate metabolism leads to hyperglycaemia and glycosuria and, rarely, may proceed to overt diabetes mellitus.

Osteoporosis and collapse of vertebrae occur due to reduced bone formation, increased calcium loss and bone protein mobilization. Avascular necrosis of femoral head may occur. Retardation of growth may be seen after long-term use in children due to inhibition of DNA synthesis and cell division.

Sodium and water retention due to the inherent mineralocorticoid activity leads to increased body weight, hypertension and edema. This may proceed to cardiac failure. Hypokalaemic alkalosis may be associated.

Suppression of all components of the inflammatory and immune responses lead to increased susceptibility to bacterial, viral and fungal infection. Latent tuberculosis foci may be reactivated. Psychotic reactions of all types may occur – euphoria, mania or depression.

Glucocorticoids cause increased intraocular pressure in the eye which may lead to glaucoma and posterior subcapsular cataract, a rare complication, usually in children, reflecting prolonged high-dosage therapy.

Prolonged glucocorticoid therapy leads to increased incidence of dyspepsia, peptic ulceration and upper GIT bleeding. Hirsutism and menstrual disturbances are disturbing effects commonly seen in women on long-term steroids.

The complications associated with topical application are worsening of local infections, local thinning of skin and formation of irreversible atrophic striae. The use of high doses of beclomethasone by aerosol inhalation can result in hoarseness or oral candidiasis.

The administration of exogenous corticosteroids results in negative feedback to the anterior pituitary hypothalamic-axis with inhibition of ACTH release and the consequent withdrawal of trophic stimulation to the adrenal cortex. Adrenal suppression leads to impairment of the patient’s response to stress as well as to symptoms and signs of adrenal insufficiency if the steroid is abruptly withdrawn. Hence, apart from short-term therapy, withdrawal must be undertaken cautiously and gradually.

Various spaced-out dosage schedules have been used in the hope of reducing hypothalamic / pituitary / adrenal suppression by allowing the plasma steroid concentration to fall enough between doses to provide time for pituitary recovery.

The recommended dosing schedule is:

·        Where a single daily dose is practicable, it should be given in the early morning.

·        Alternate day schedules are worth trying, especially where immunosuppression is the objective.

·        Short courses (a few days) may be practicable for some without significant suppression.

·        Another variant is to give enormous doses orally or i.v. on 3 successive days, at intervals of weeks or months.

The longer the duration of therapy, the slower must be the withdrawal:

·        For use of less than 1 week, withdrawal can be safely accomplished in a few steps.

·        After use for 2 weeks, if rapid withdrawal is desired, a 50% reduction in dose may be made each day.

·        An alternate scheme is to try halving the dose weekly until 25 mg prednisolone or equivalent is reached, after which it may be reduced by about 1 mg every third to seventh day.

Complete recovery of normal hypothalamic / pituitary / adrenal function sufficient to cope with severe intercurrent illnesses or surgery is generally complete in 2 months but may take as long as 2 years. Patients must be instructed on the side effects of glucocorticoid use and on the hazards of omitting therapy and, during intercurrent disease.