CORTICOSTEROIDS. Layers of Adrenal Cortex Zona Glomerulosa Zona Fasciculata Zona Reticularis

Transcription

1 CORTICOSTEROIDS Adrenal gland has cortex and medulla. Adrenal cortex secretes steroidal hormones; adrenal medulla secretes adrenaline and noradrenaline. Hormones of adrenal cortex are given in Table Adrenal cortical hormones are more important than medullary hormones. Among cortical hormones, mineralocorticoids are more essential than glucocorticoids. Table 10.2 Anatomical and Functional Divisions of Adrenal Cortex Layers of Adrenal Cortex Zona Glomerulosa Zona Fasciculata Zona Reticularis Hormones secreted Mineralocorticoids: Aldosterone : Hydrocortisone (cortisol) Androgens Desoxycorticosterone Main actions Regulate water and electrolyte balance Metabolic (carbohydrate, protein and fat), antiin ammatory, immunosuppressant and antiallergic actions Hypersecretion Primary hyperaldosteronism (Conn s syndrome) Cushing s syndrome Adrenogenital syndrome (precocious puberty) De ciency of adrenal cortical hormones (chronic) Addison s disease Synthesis and release of glucocorticoids is controlled by pituitary adrenocorticotropic hormone (ACTH), which in turn is stimulated by corticotrophin-releasing factor (CRF) produced by hypothalamus. have negative feedback control on ACTH and CRF secretion (Fig. 10.4). Hypothalamus CRF Anterior pituitary ACTH Adrenal cortex Mineralocorticoids Fig Regulation of synthesis and secretion of corticosteroids. CRF, corticotropin-releasing factor; ACTH, adrenocorticotropic hormone;, stimulation,, inhibition. 1

2 SRC R DNA H H mrna Regulates protein synthesis Response Fig Mechanism of action of steroid hormones. H, hormone; R, receptor; SRC, steroid receptor complex. Mineralocorticoid (e.g. aldosterone) release is controlled by the renin angiotensin system. There is a diurnal variation in the rate of release of ACTH and cortisol (circadian rhythm). The plasma cortisol levels are highest in the early hours of morning and the lowest in the late evening. The long-term use of corticosteroids in large doses will decrease ACTH secretion and gradually cause adrenal cortical atrophy. Hence, sudden stoppage of corticosteroids after prolonged treatment is dangerous and can precipitate acute adrenal insufficiency. Mechanism of action of steroid hormones The mechanism of action of steroid hormones is depicted in Figure Steroid hormone enters the cells of target organ Binds to specific receptors in the cytoplasm Steroid receptor complex becomes activated 2 Enters the nucleus Binds to specific site on the DNA Regulates protein synthesis Response Classification and important features of corticosteroids: See Table 10.3.

3 Table 10.3 Comparison of Corticosteroids Using Hydrocortisone as a Standard Agent Activity Equivalent dose (mg) Antiin ammatory Salt (Antiin ammatory) retaining 1. (a) Short acting (8 12 hours) (i) Hydrocortisone (cortisol) Uses and route of administration It has a rapid onset but short duration of action. It is the drug of choice for replacement therapy in acute adrenal insuf ciency. Other uses are status asthmaticus and anaphylactic shock (emergency uses) Routes: Oral, i.m., i.v., intra-articular and topical (ii) Cortisone It is cheap; prodrug, converted to hydrocortisone after metabolism in liver; rarely used at present (b) Intermediate acting (12 36 hours) (i) Prednisolone It is the most commonly used preparation for allergic, in ammatory, autoimmune disorders and in malignancies. It causes less HPA axis suppression if given once daily in the morning Routes: Oral, i.m., intra-articular and topical (ii) Prednisone It is a prodrug, gets converted to prednisolone in liver; less ef cacious, hence rarely used (iii) Methylprednisolone It is used for its antiin ammatory and immunosuppressant effects; as high-dose pulse therapy in renal transplant, pemphigus vulgaris, etc. Routes: i.m., i.v., retention enema in ulcerative colitis (iv) Triamcinolone* More potent and relatively more toxic than prednisolone. It has no mineralocorticoid activity Routes: Oral, i.m., intra-articular and topical (Contd ) 3

4 4 Table 10.3 Comparison of Corticosteroids Using Hydrocortisone as a Standard (Contd ) Agent Activity Equivalent dose (mg) Antiin ammatory Salt (Antiin ammatory) retaining (c) Long acting (36 72 hours) (i) Betamethasone* (ii) Dexamethasone* Local acting glucocorticoids (i) Beclomethasone Uses and route of administration Long acting; have highly potent antiin ammatory and immunosuppressant effects. Have no mineralocorticoid activity They cause severe HPA axis suppression. Used in allergic and in ammatory conditions; cerebral oedema due to neoplasm, where water retention is undesirable and to promote lung maturation in fetus when premature delivery is anticipated Routes: Oral, i.v., i.m. and topical They have local action It is used by inhalation in bronchial asthma, as nasal spray for allergic rhinitis; as ointment for skin and mucous membrane lesions. HPA-axis suppression is minimal (ii) Budesonide Same as beclomethasone, but is more potent than beclomethasone (iii) Fluticasone It is used by inhalation for asthma and chronic obstructive pulmonary disease (COPD); orally for in ammatory bowel disease; as ointment for skin and mucous membrane lesions 2. Mineralocorticoids (i) Desoxycorticosterone acetate (DOCA) It has selective mineralocorticoid activity and is used in Addison s disease as replacement therapy (ii) Fludrocortisone Has potent mineralocorticoid activity. It is used with hydrocortisone for replacement therapy in Addison s disease (iii) Aldosterone Not used * am containing drugs have no mineralocorticoid activity. +, Activity present;, Activity absent.

5 Pharmacological actions Corticosteroid with predominant sodium and water retaining property, e.g. aldosterone and desoxycorticosterone, are mineralocorticoids. Corticosteroid with predominant liver glycogen deposition and gluconeogenic effects, e.g. hydrocortisone (cortisol) and cortisone, are glucocorticoids (Table 10.3). The two actions (mineralocorticoid and glucocorticoid) are not completely separated in naturally occurring steroids, whereas synthetic preparations are available with selective action. Carbohydrate metabolism Stimulate glycogen deposition in liver and gluconeogenesis (formation of glucose from amino acids) Decrease peripheral utilization of glucose The net result is: (i) hyperglycaemia, (ii) decreased tissue sensitivity to insulin and (iii) diabetes may be precipitated or exacerbated. Therefore, glucocorticoids are (relatively) contraindicated in diabetics. Lipid metabolism Prolonged use of glucocorticoids causes redistribution of body fat that is deposited over the neck, face, shoulder, etc. resulting in moon face, buffalo hump and fish mouth with thin limbs. Protein metabolism (catabolic) Protein breakdown and mobilization of amino acids from lymphoid tissue, muscle, skin, bone, etc. Muscle wasting, lympholysis, thinning of skin, loss of bone matrix (osteoporosis) and growth retardation; wound healing and fibrosis are also inhibited. Electrolyte and water metabolism have weak mineralocorticoid action, cause sodium and water retention and promote potassium excretion. Thus, prolonged use of these drugs may cause oedema and hypertension. The synthetic glucocorticoids (dexamethasone, betamethasone, and triamcinolone) have no sodium and water retaining property. Calcium metabolism (anti-vitamin D action) Prolonged use of these drugs may lead to osteoporosis and pathological fracture of vertebral bodies. Inhibit calcium absorption from the gut Blood Ca 2 level Increase renal excretion of calcium 5

6 Bone Osteoblasts (bone forming cells) Osteoclasts (bone resorption cells) Cardiovascular system have sodium and water retaining property and have permissive effect on pressor action of adrenaline and angiotensin. On chronic administration, these drugs may cause hypertension and worsening of congestive cardiac failure (CCF). Skeletal muscles Corticosteroids are required for the normal function of skeletal muscles. Weakness occurs in both hypocorticism and hypercorticism. in Hypocorticism: due to inadequate circulation Muscle weakness and fatigue in Hypercorticism: due to hypokalaemia Prolonged use of glucocorticoids may cause muscle wasting and weakness (steroid myopathy). Central nervous system Corticosteroids have a number of indirect effects on the CNS through maintenance of (i) blood pressure, (ii) blood glucose concentration and (iii) electrolyte levels. They also have direct effects on the CNS and influence mood and behaviour. Patients with Addison s disease show mental depression, irritability and even psychosis. On the other hand, glucocorticoid therapy can cause euphoria, insomnia, restlessness and psychosis. Gastrointestinal tract 6 Inhibit PGs Gastric acid and pepsin secretion; may aggravate peptic ulcer Local immune response against H. pylori Blood and lymphoid tissue Glucocorticoid therapy leads to a decrease in the number of circulating lymphocytes, eosinophils, basophils and monocytes. This is due to redistribution of cells. They have a marked lympholytic action; therefore they are used in lymphomas and leukaemias. Antiinflammatory effect They have powerful antiinflammatory and immunosuppressant effects. They prevent or suppress the clinical features of inflammation such as redness, heat, pain and swelling. At tissue level, they suppress the early phenomena (capillary permeability, oedema, cellular infiltration and phagocytosis) and late responses like capillary proliferation, collagen deposition, fibroblast activity and scar formation.

7 Membrane phospholipids Phospholipase A 2 Lipocortin Arachidonic acid Cyclooxygenase Lipoxygenase PGs LTs 1. induce a protein called lipocortin, which inhibits phospholipase A 2, so prostaglandins (PGs), leukotrienes (LTs) and PAF are not formed. 2. Tumour necrosis factor-alpha (TNF- is inhibited by glucocorticoids, which is necessary for initiating inflammatory process. 3. stabilize the lysosomal membrane and prevent the release of inflammatory mediators. Immunosuppressant effect Bone marrow stem cells T-lymphocytes Lymphokines Cell-mediated immunity B-lymphocytes Immunoglobulins Humoral immunity have immunosuppressant effect. They inhibit both B-cell and T-cell lymphocyte functions, and this results in impairment of humoral and cell-mediated immunity. Cell-mediated responses may be inhibited indirectly by inhibiting the production of cytokines, including TNF- and interleukins. They also suppress all types of hypersensitivity or allergic reactions. Adverse reactions A single dose of glucocorticoids is practically harmless; rather they are life-saving drugs in conditions like anaphylactic shock, acute adrenal insufficiency, etc. The use of glucocorticoids in supraphysiological doses for more than 2 3 weeks causes a number of undesirable effects. Most of the adverse effects are extension of pharmacological actions. 1. Metabolic effects: Hyperglycaemia, precipitation of diabetes mellitus (DM) or aggravation of preexisting diabetes. 2. Cushing s habitus: Abnormal fat distribution causes peculiar features with moon face, buffalo hump and thin limbs. 7

8 8 3. Gastrointestinal tract: Peptic ulceration sometimes with haemorrhage or perforation. 4. Salt and water retention: Mineralocorticoid effect may cause oedema, hypertension and even precipitation of CCF, particularly in patients with primary hyperaldosteronism. This can be minimized by using synthetic steroids like dexamethasone, betamethasone, etc. 5. Muscle: Steroid treatment can cause hypokalaemia leading to muscle weakness and fatiguability. Long-term steroid therapy leads to steroid myopathy. 6. Bone: Osteoporosis with pathological fractures of vertebral bodies is common. Ischaemic necrosis of the femoral head can also occur. 7. Growth retardation in children is more common with dexamethasone and betamethasone. 8. Eye: Glaucoma and cataract may occur on prolonged therapy. 9. Central nervous system: Behavioural disturbances like nervousness, insomnia, mood changes can occur; psychosis may be precipitated. 10. Long-term therapy with steroids leads to immunosuppression, which makes the patient more vulnerable to various infections like fungal (candidiasis, cryptococcosis), viral (herpes, viral hepatitis), bacterial (reactivation of latent tuberculosis), etc. Inhalational steroids can cause local irritation and fungal infection of upper respiratory tract, which can be prevented by the use of spacer and by rinsing the mouth after inhalation. 11. Hypothalamic pituitary adrenal (HPA) axis suppression: The most dangerous side effect of longterm steroid therapy is HPA-axis suppression. Therefore, the important precautions to be taken during long-term steroid therapy to minimise HPA-axis suppression are: a. Whenever possible, topical use of steroids is preferred. b. Short- or intermediate-acting steroids (e.g. hydrocortisone, prednisolone) should be preferred. c. Give steroids as a single morning dose at 8 a.m.; if the daily dose is high, two-third of the dose in the morning and one-third in the evening, which will mimic the endogenous hormone levels and minimize the chances of HPA axis suppression. d. Try alternate-day steroid therapy in chronic conditions like bronchial asthma, nephrotic syndrome, systemic lupus erythematosus (SLE), etc. e. Withdrawal of steroids after long-term ( 2 weeks) treatment should be very slow to allow recovery of normal adrenocortical function. The doses of steroid should be tapered gradually. Abrupt stoppage of glucocorticoid therapy following prolonged use leads to: flaring up of the underlying disease being treated. withdrawal symptoms like fever, myalgia, arthralgia, malaise, etc. acute adrenal insufficiency on exposure to stress, which manifests as anorexia, nausea, vomiting, abdominal pain, hypotension, dehydration, hyponatraemia, hyperkalaemia, etc. Therapeutic uses of glucocorticoids Endocrinal uses 1. Acute adrenal insufficiency: It is a medical emergency. It is treated with i.v. hydrocortisone and i.v. normal saline with 5% glucose to correct fluid and electrolyte imbalance. Precipitating causes such as trauma, infection or haemorrhage should be treated. 2. Chronic adrenal insufficiency: Treated with oral hydrocortisone (two-third of the daily dose is given in the morning and one-third in the evening) along with adequate salt and water. Nonendocrinal uses Corticosteroids are one of the most important groups of drugs used clinically in a variety of diseases. Because of their dramatic symptomatic relief, they are often misused. Nonendocrinal diseases require

9 supraphysiological doses of steroid, which inevitably carries risk. The beneficial effects of glucocorticoids are mainly due to their antiinflammatory and immunosuppressant effects. 1. In dentistry: Topical or systemic glucocorticoids are used in: a. Recurrent aphthous stomatitis b. Chronic ulcerative stomatitis c. Oral pemphigoid d. Erythema multiforme e. Temporomandibular joint pain: Intra-articular triamcinolone is used. 2. Rheumatoid arthritis: They produce an immediate and dramatic symptomatic relief in rheumatoid arthritis; but they do not halt the progression of the disease. Intra-articular injection is preferred only if one or two joints are involved. Steroid could be given as an adjunct to nonsteroidal antiinflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). 3. Osteoarthritis: They are rarely used in osteoarthritis. Intra-articular injection is recommended for acute episodes. 4. Rheumatic fever: They produce more rapid symptomatic relief than aspirin and are indicated in cases with carditis and CCF. Prednisolone is given along with aspirin and should be continued until the erythrocyte sedimentation rate (ESR) comes to normal and then the steroid is tapered off gradually. 5. Allergic diseases: The manifestations of allergic diseases, such as hay fever, reactions to drugs, urticaria, contact dermatitis, angioneurotic oedema and anaphylaxis, can be suppressed by glucocorticoids; but they have a slow onset of action. Hence, severe reactions such as anaphylaxis and angioneurotic oedema require immediate therapy with adrenaline. In hay fever, serum sickness and mild allergic reactions, antihistamines are the preferred drugs. 6. Bronchial asthma: They have antiinflammatory and antiallergic effects; hence they reduce mucosal oedema and bronchial hyperirritability. In acute severe asthma, i.v. hydrocortisone is given along with nebulized 2 -agonist and ipratropium bromide. If a chronic asthmatic needs steroid, it is better to give inhalational preparations like beclomethasone, budesonide or fluticasone because they cause minimal systemic adverse effects. 7. Collagen diseases: Collagen diseases such as polymyositis, polyarteritis nodosa, etc. can be controlled with large doses of glucocorticoids. Steroids with negligible salt and water retaining property is preferred. 8. Renal disease: are the first-line drugs in nephrotic syndrome. 9. Ocular diseases: They are frequently used to suppress inflammation in the eye; thus they prevent damage to vision. Agents may be administered topically, subconjunctivally, systemically or by retrobulbar injection, depending upon the condition. Steroids are contraindicated in herpes simplex keratitis and ocular injuries. 10. Skin diseases: They dramatically relieve itching, pain, and inflammation in allergic and other dermatoses. To minimize systemic effects, topical steroids are preferred. Systemic steroid therapy is needed in severe conditions like exfoliative dermatitis, dermatomyositis, pemphigus, etc. Psoriasis, keloids and hypertrophic scar are sometimes treated by intralesional injection of steroids. 11. Haematological disorders: Autoimmune haemolytic anaemias usually respond to glucocorticoids. Because of their lympholytic action, glucocorticoids are used to treat certain malignancies, leukaemia, lymphomas, Hodgkin s disease, multiple myeloma, etc., usually in combination with antineoplastic drugs. 9

10 12. Cerebral oedema: The effectiveness of glucocorticoids in cerebral oedema depends upon the underlying cause. They are very effective when the oedema is caused by brain tumours, metastatic lesions and tubercular meningitis. A steroid without salt and water retaining activity (e.g. dexamethasone) is preferred. 13. Intestinal diseases: They are used in ulcerative colitis when the patient is not responding to other forms of treatment. Methylprednisolone can be administered as retention enema during acute episodes. 14. Shock: Prompt intensive treatment with i.v. glucocorticoids may be life saving in septic shock. 15. Organ transplantation: are used to prevent as well as treat graft rejections. 16. Hypercalcaemia of malignant diseases, and vitamin D intoxication responds to prednisolone. 17. Other uses include Bell s palsy and acute polyneuritis. Relative contraindications for the use of corticosteroids 1. Hypertension 7. Epilepsy 2. Diabetes mellitus 8. Psychosis 3. Peptic ulcer 9. Congestive cardiac failure 4. Tuberculosis 10. Renal failure 5. Herpes simplex keratitis 11. Glaucoma 6. Osteoporosis Key Points for Dentists Prophylactic antibiotics are required before dental procedures for patients on long-term glucocorticoid therapy, as they are more prone for infection. In patients on glucocorticoid therapy, the preferred analgesic is paracetamol. Wound healing is impaired in patients on long-term glucocorticoid therapy. Abrupt stoppage of glucocorticoid therapy is dangerous after a prolonged course, as it may precipitate acute adrenal insuf ciency on exposure to stress. 10